A phase I study of pazopanib in combination with escalating doses of 131I in patients with well-differentiated thyroid carcinoma borderline refractory to radioiodine

Objective This trial was conducted to evaluate the ability of pazopanib to overcome therapeutic 131I resistance. Materials, methods and patients This phase 1 trial assesses the combination of pazopanib and escalating doses of radioiodine (131I) in patients with recurrent or metastatic thyroid cancer that are borderline or relatively iodine refractory. Radioiodine uptake scans were assessed post therapy and compared to historical pre-treatment scans. Patients underwent FDG PET/CT before and after the initial pazopanib treatment to identify the impact of pazopanib on the cancer prior to 131I therapy. Results A dose limiting toxicity (cardiac arrhythmia and grade 3 fatigue) in the first patient in the first cohort prompted expansion to a total of 6 patients. Additional grade 3–4 hematologic toxicity and low accrual in the expanded cohort led to the decision not to pursue further study of the regimen. In patients with measurable disease 4/5 (80%) achieved stable disease. Median progression free survival was 6.7 months. At 3 years of follow up, one patient died due to progressive disease, two are being treated with systemic therapy and 3 continue without requiring subsequent therapy at 15, 27 and 35 months from the last dose of pazopanib. There was no convincing impact of pazopanib on iodine uptake in scans performed pre- and post-therapy compared to scans from historical 131I treatments without pazopanib. Conclusion Despite a suggestion of therapeutic efficacy, combined pazopanib and 131I resulted in increased toxicity. There was no convincing evidence that the administration of pazopanib improved iodine uptake or retention. Trial registration ClinicalTrials.gov NCT01413113


BACKGROUND
Although thyroid cancer only comprises 1-2% of all cancers, it is the most common endocrine malignancy. 1,2 Its incidence has doubled in the last decade and continues to rapidly rise, causing substantial morbidity and mortality: 44,670 estimated new cases and 1690 deaths due to thyroid cancer were recorded in the United States in 2010. 3,4 The major epidemiologic factors for thyroid cancer are radiation exposure and iodine deficiency. Localized well-differentiated thyroid carcinoma is treated well with surgical excision (near total/total thyroidectomy, or unilateral lobectomy with isthmusectomy) followed by radioiodine 131 ablation of the remnant. 5 Although many patients will be cured with the above approach, 10-15% of WDTC patients will develop recurrent and/or distant metastatic disease. 6 At least 5% of patients with advanced thyroid cancer develop life-threatening progressive disease with a dismal 10 year overall survival for WDTC of less than 40%. 2 WDTC is compromised of predominantly (> 90%) papillary and follicular subtypes which are generally radioactive iodine-avid. 7 When patients with advanced WDTC become iodine-refractory; however, there are no standard of care options and systemic chemotherapy is of little benefit.
Radioiodine 131 I therapy has been a highly effective mainstay of therapy since the 1940's with undisputable clinical benefits in recurrent or metastatic WDTC patients with high RAI-avidity and uptake. 8 Most RAI-avid WDTC patients respond well to 131 I therapy, except patients with bulkier tumors and predominant bone disease. 9,10 WDTC patients are considered refractory to RAI when their cancers no longer have any 131 I uptake, or when they fail to respond to 131 I RAI despite evidence of uptake. 11,12 Furthermore, patients with WDTC tumors with elevated glycolysis, demonstrated by 18 Ffluorodeoxyglucose (FDG) PET, are often resistant to RAI, even when their tumors are RAI-avid. 13 When patients become RAI-refractory and WDTC tissue fails to take up RAI, treatment options are limited and survival is greatly decreased: radiation therapy and traditional cytotoxic chemotherapy have failed to substantially impact survival. 7,8 The unmet need in this patient population has driven the search for more effective therapies. Due to the highly vascular nature of this tumor, many of the multitargeted anti-angiogenic tyrosine inhibitors (TKIs), including sorafenib, axitinib, pazopanib, and particularly sunitinib in our own institutional phase II clinical study, have demonstrated significant promise and efficacy. [14][15][16][17][18][19][20][21][22][23][24] Although these agents had demonstrated substantial promise with tumor responses, stability, and improved time to progression (TTP) in the phase II setting in RAI-refractory patients, toxicities can limit chronic administration and responses may not be sustained. [14][15][16][17][18][19][20][21][22][23][24] Phase III clinical trials are ongoing to confirm the effectiveness and benefit of these agents in the advanced and metastatic setting.
Angiogenesis plays a prominent role in thyroid cancer: WDTC are highly vascular and microvessel density appears to correlate with disease-free survival. 25 The major angiogenic factor, the vascular endothelial growth factor (VEGF), is often overexpressed and VEGF receptor tyrosine kinases (RTKs) are frequently activated in WDTC and in the surrounding stoma. WDTCs with high VEGF expression may be associated with increased tumor size, local and distant metastastic spread. 26 Pazopanib, (GW786034, GSK, GlaxoSmithKline) is an oral, mutli-targeted tyrosine kinase inhibitor that has potent nanomolar in vitro activity against the vascular endothelial growth factor receptor (VEGFR), plateletderived growth factor receptor (PDGFR), fibroblast Growth Factor Receptor (FGFR), c-Kit, c-fms and other key proteins involved in angiogenesis, cancer cell progression, growth and survival. 27 Potent antiangiogenic and anti-tumor effects were observed with pazopanib in a number of in vivo xengraft models. 27 Pazopanib was well-tolerated in the phase I clinical trial setting with early clinical activity observed in renal cell carcinomas and pancreatic islet cell carcinoma. Importantly, evidence of pazopanib's anti-angiogenic effects were demonstrated with greater than 50% decreases in tumor blood flow on dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in 10 out of 12 patients. 28 Pazopanib administered at a dose of 800 mg once daily in 4 week cycles in a phase II study of 37 patients with metastatic, rapidly progressive radioiodine-refractory differentiated thyroid cancer, demonstrated exceptionally promising anti-tumor activity. 14 These patients had up to two prior previous therapies and had demonstrated radiographic progression in the 6 month period prior to enrollment. Treatment was well-tolerated and patients received a median of 12 cycles of therapy with confirmed partial responses in 18 patients (response rate of 49%, 95% CI 35-68) and a 66% likelihood of response lasting longer than a year. 14 The maximum concentration of pazopanib in plasma during cycle one appeared to correlate with radiographic response. The initial dose of 800 mg once daily continuous dosing appeared to be well tolerated; however, 43% of patients required dose reductions for fatigue, skin and hair hypopigmentation, diarrhea, and nausea. 14 Astonishingly, this study with pazopanib reported the highest partial response rate yet reported in patients with differentiated thyroid cancers and appeared to modify the disease course dramatically in responders. 14 The clinical activity of pazopanib seems to be better than any other VEGF receptor kinase inhibitor agent to date. 14 Due to this promising activity, pazopanib is being assessed further assessed in confirmatory phase III trials in well-differentiated (papillary and follicular), medullary and anaplastic thyroid carcinomas.
Although radioiodine 131 I therapy is highly effective, treatment can be limited by its side effects. Acute nausea, vomiting and dehydration are common but preventable and treatable; whereas, radiation thyroiditis, painless neck edema, sialadenitis and tumor hemorrhage or edema occur less commonly in 10-20% of patients -but are seen predominantly at higher doses. 29, 30 Chronically, there is the risk of secondary malignancies such as bladder, salivary, gastrointestinal tract cancers and possibly breast cancer and acute myeloid leukemia. 29, 30 Moreover, gonadal dysfunction, particularly ovarian failure in woman can occur and obstruction of the nasolacrimal duct causing excessive tearing. Many of the chronic risks increase with higher cumulative doses. 29, 30 Although RAI therapy is indisputably effective, very few studies have attempted to increase the activity and effectiveness of RAI by combinational techniques; therefore, the toxicities of RAI therapy in combination are not well elucidated and should be approached very cautiously. This will be the first phase I dose-finding study of pazopanib at standard doses in combination with escalating doses of 131 I radioiodine.

Hypothesis of 131 I and Pazopanib in WDTC:
The combined actions of the multi-targeted anti-angiogenic tyrosine kinase inhibitor (TKI), pazopanib, and concurrent 131 I radioiodine may additively or synergistically overcome therapeutic 131 I resistance in recurrent or metastatic well-differentiated thyroid carcinoma (WDTC) patients with radioactive iodine (RAI)-avidity but progressive disease after high-dose RAI, or in RAI-refractory patients who still maintain some RAI uptake in one or more sites of known disease, by (1) improving delivery of 131 I in bulky tumors by vascular normalization, by (2) increasing sensitivity to the radiation effects, and/or by (3) independent, combined anti-tumor effects.

Rationale of 131 I and Pazopanib in Combination in WDTC
The effectiveness of 131 I is dependent on its uptake, accumulation, and retention, and radiation delivery to WDTC cells in RAI-avid disease. Anti-angiogenic agents are ideally combined with 131 I in WDTC as 1) they have independent anti-tumor effects, 22, 24 2) anti-angiogenic agents in combination with chemotherapy transiently normalize tumor vasculature, increase permeability, reduce interstitial pressure, facilitate drug diffusion and reduce intratumoral hypoxia to enhance drug delivery to the tumor mass, 31-33 and 3) anti-angiogenic agents combined with radiation therapy enhance radiation-induced apoptosis with improved anti-tumor effects by antagonizing radiation-induced increased hypoxia, normalizing tumor vasculature and increasing oxygenation. 34,35 Our protocol addresses patients that have failed to respond to 131 I RAI despite evidence of uptake, and also patients that are RAI refractory, but still maintain minor 131 I uptake in at least one site of known disease. There is no clear consensus as to the best course of action for these patients and discrepancy as to when to start anti-angiogenic TKI therapy, as the rate of clinical progression can vary and change from slow indolent growth to rapid progressive disease. If 131 I therapy in RAI-refractory patients could be optimized in combination with anti-angiogenic TKIs such as pazopanib, the morbidity and mortality of patients with recurrent and metastatic WDTC could be greatly reduced. Furthermore, this combination would also potentially expand the current use of anti-angiogenic TKIs from largely RAI-negative patients to patients with RAIavid metastatic disease -a substantially larger group of patients.
Our study differs from prior studies that have used agents to try to enhance the efficacy of RAI in iodine-negative patients: six weeks of bexarotene pre-treatment prior to RAI did increase RAI uptake in non-iodine-avid WDTC patients in all eight of the patients, but the study numbers were too small to determine much clinical benefit to subsequent radioiodine therapy. 36 Similarly, lithium increased 131 I retention, prolongation, and increased the 131 I dose to the thyroid remnant and metastatic sites in 6 out of 7 patients in one study, and 7 out of 12 patients in another study; but study numbers were too small to determine a significant clinical benefit. 37-39 A single arm phase II study of sorafenib given for 26 weeks to 32 patients with metastatic or locally advanced RAI-refractory WDTC prior to RAI imaging did not restore or re-induce RAI-uptake in non-RAI-avid WDTC; however, combined therapy was not attempted. 40 There is no data in regards to the concurrent treatment of radioiodine with a multi-targeted anti-angiogenic TKI agent in patients that are RAI-refractory who still maintain some level of RAIuptake.
In this trial, we will test the hypothesis that the combined actions of pazopanib and 131 I will overcome therapeutic resistance in patients with RAI-avidity but progressive disease after high-dose RAI by (1) improving delivery of 131 I in bulky tumors by vascular normalization, by (2) increasing sensitivity to the radiation effects, and/or by (3) independent, combined anti-tumor effects. Additive or synergistic antitumor effects may potentially be seen in the population who still retain some minor 131 I uptake. We propose that concurrent administration of pazopanib and 131 I may improve 131 I anti-tumor efficacy in refractory disease, prolong the TTP, and improve the quality of life by deferring the need to initiate lifelong systemic anti-angiogenic therapy and its associated toxicities. There is no published data regarding this combination as anti-angiogenic TKIs have never previously been combined with radioiodine. Therefore, the safety and dose of 131 I in this situation are not known, and combined toxicities may be additive. We propose a phase I dose-finding, safety and feasibility study of combined pazopanib and escalating doses of 131 I therapy, in patients with relatively RAI-refractory disease with still minor RAI uptake. The optimal treatment of RAI-refractory recurrent or metastatic WDTC patients which still maintain minor RAI uptake is a common unresolved therapeutic dilemma. This combination would be a novel approach with high scientific merit which would lend valuable knowledge to an area previously unexplored. Importantly, correlative imaging with dynamic FDG-PET will also look at tumor perfusion, flow dynamics, and PET response with pazopanib alone in WDTC, and its effect on RAIuptake, tumor response and TTP.

Hypothesis and Rationale for Correlative Dynamic FDG-PET Imaging
Position emission tomography (PET) can be used to monitor blood flow, blood volume, and vascular permeability, and to assess tumor perfusion and drug effects in animals and patient studies. A variety of radiotracers can monitor blood flow within tumors such as radioactive forms of water labeled with 15 O. 41 Although not a direct measure of biological activity, 18 F-deoxyglucose (FDG)-PET is a validated marker to monitor cellular metabolisms and determine metabolic changes to therapy in most solid tumors. 42 Phase I and II clinical trials have increasingly used FDG-PET as an early indicator of an antitumor effect. PET scans demonstrate changes in vascular permeability, volume fraction or metabolism after therapy, and may potentially predict the clinical efficacy of anti-angiogenic agents. 42 Preliminary institutional data has been published demonstrating the use of early FDG PET to indicate the response to sunitinib in RAI-refractory thyroid cancer patients, 16 and in using dynamic PET to asses both perfusion changes and metabolism change of breast cancer in response to chemotherapy. 41 In our prior study of sunitinib in iodine-refractory thyroid cancer, patients underwent FDG PET pre-and one-week post-starting sunitinib, and a 20% decline in uptake was taken as evidence of a tumor response based upon prior published data for repeatability in PET 43,44 and our clinical experience. A decline of 20% in FDG early in treatment was somewhat predictive of clinic benefit to treatment (response or stable disease), and that patients with an increase in FDG uptake were likely to have progression. Dynamic FDG-PET can also be used to provide a more sensitive measure of response as well as an indicator of perfusion. 45 Doot RK et al. showed that dynamic PET provided up to 35% greater sensitivity for measuring declines in FDG uptake compared to static measures such as SUV. 45 Tseng J et al. showed measures of FDG delivery (typically called K 1 ) provided an indirect measure of tumor perfusion that correlated with validated measures of tumor blood flow. 41 Moreover, Tseng and Dunnwald showed that changes in FDG K1 were highly predictive of tumor response and outcome. 41,46 Frequently, dynamic FDG PET studies of cancer response are used at our institution and currently this method is being used in a number of projects, including an assessment of perfusion and metabolism for locally advanced breast cancer treated with combined sunitinib/chemotherapy. The additional dynamic FDG-PET studies and data will certainly add additional information regarding the activity and response of pazopanib in advanced WDTC patients.

Drug Information and Formulation
Please refer to the GlaxoSmithKline Pazopanib (GW786034) Investigator Brochure which gives additional information. 47

Pazopanib (GW786034B) Tablets
GW786034B Tablets are supplied as 50 mg, 100 mg, 200 mg, 400 mg and 500 mg (as free base) tablets for oral administration to support oncology indications. 47 The 50 mg and 100 mg tablets are round, the 200 mg and 400 mg tablets are oval shaped or capsule-shaped, and the 500 mg tablets are capsule shaped. The 50 mg, 100 mg, and 500 mg tablets are white to slightly colored, while the ovalshaped 200 mg and 400 mg tablets are white. Additionally, the capsule-shaped 200 mg tablets can be gray or pink and may be debossed, and the capsule-shaped 400 mg tablets can be white or yellow and may be debossed. Tablets are packaged in white high density polyethylene (HDPE) bottles with white plastic, induction seal, child-resistant caps. 47

Effects on cell proliferation
The ability of pazopanib to inhibit proliferation of various cell types was evaluated in an in vitro assay for 3 days. Pazopanib selectively inhibited the proliferation of human umbilical vein endothelial cells (HUVEC) stimulated with VEGF (IC50 = 21 nM) compared to basic fibroblast growth factor (bFGF) stimulated proliferation (IC50 =721 nM). Pazopanib was further evaluated in a cell proliferation assay using a panel of 282 human cell lines. Only 7 tumor cell lines showed an IC50 value of <1000 nM, suggesting that pazopanib is a weak or inactive inhibitor of proliferation in the majority of human cell lines tested in vitro. Since pazopanib inhibits c-Kit and Flt-3 receptors, which are expressed on hematopoietic progenitor cells and have a pleiotropic role during progenitor cell proliferation and differentiation of various hematopoietic lineages, the effects of pazopanib on bone marrow progenitor growth were investigated in multiple growth factor formats in standard colony forming assays in vitro. Pazopanib had weak activity in the colony forming unit assay induced by granulocyte-macrophage colony stimulating factor (GMCSF) and Flt-3 ligand alone. However, addition of stem cell factor (ligand for c-Kit) enhanced the ability of pazopanib to inhibit colony formation, consistent with its activity against c-Kit kinase. One of the circulating metabolites of pazopanib, GSK1268997, inhibited VEGF-induced endothelial cell proliferation with similar potency to that of pazopanib. The other 3 circulating metabolites, GSK1268992, GSK1071306 and GW700201, showed at least 10 to 20-fold less activity than pazopanib.
In summary, pazopanib potently inhibits VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-α, PDGFR-β and c-Kit kinases. Consistent with its kinase activity, pazopanib selectively inhibited proliferation of endothelial cells stimulated with VEGF compared to bFGF stimulated proliferation and it had no direct antiproliferative effect against the majority of the large number of tumor cell lines evaluated.

Inhibition of VEGFR2 phosphorylation
In vivo effects of pazopanib on VEGFR-2 phosphorylation, angiogenesis and tumor growth have been investigated in a variety of animal models. Inhibition of VEGFR-2 phosphorylation was studied in naïve mice given an intravenous bolus administration of VEGF. The lungs of mice that received VEGF showed increased phosphorylation of VEGFR-2 compared to untreated control mice. Pre-treatment of mice with a single oral dose of pazopanib inhibited VEGF-induced VEGFR-2 phosphorylation in lungs in a dose-and time-dependent manner. The results from the time course and dose-response experiments together suggest that plasma concentrations of ~40 μM or higher are required for the optimal inhibition of VEGFR-2 phosphorylation in mice.

Inhibition of angiogenesis
Pazopanib given orally at ≥ 30 mg/kg inhibited bFGF-and VEGF-induced angiogenesis in a variety of animal models including the Matrigel plug and corneal micropocket models of angiogenesis in Swiss nu/nu or C57B1/6 mice. Pazopanib also showed generally dose-dependent inhibition of aberrant ocular angiogenesis in laser-induced choroidal neovascularization in C57B1/6J mice (≥ 8 mg/kg PO) and Brown Norway rats (2.25 mg/kg, eye drops) as well as corneal neovascularization in a suture-induced model in New Zealand white rabbits (≥ 0.3 mg/kg, eye drops). These results are consistent with the role of VEGFR and PDGFR signaling in angiogenesis and demonstrate the effectiveness of pazopanib in blocking angiogenesis induced by various approaches.

Anti-tumor activity in human tumor xenografts in mice
Pazopanib showed significant growth inhibition of a variety of human tumor xenografts in mice, and also inhibited basic fibroblast growth factor (bFGF) and VEGF-induced angiogenesis in several different models of angiogenesis (e.g., the Matrigel plug assay, and the cornea micropocket and laser-induced choroidal neovascularization models). 47-49 The anti-tumor activity of oral pazopanib has been investigated as a single agent and in combination with various antineoplastic agents in various human tumor xenograft models in mice. Pazopanib was administered orally in these studies on a once or twice daily schedule and was well tolerated. Pazopanib inhibited the growth of different tumor xenografts to varying degrees. Pazopanib had no effect on the growth of prostate tumors in the transgenic prostate cancer mouse model, CR2-T-Ag. These data demonstrate that different tumors have varying dependence on angiogenesis and VEGFR/PDGFR signaling. Since treatment with pazopanib alone does not eradicate tumors in mouse models, the effect of combining pazopanib with various antineoplastic agents was evaluated, including various signal transduction inhibitors using human tumor xenograft models in mice. In general, the combination of pazopanib with all agents was well tolerated in mice in these studies, with no significant increase in body weight loss or any overt clinical effects.

Pazopanib Clinical Safety Summary
Approximately 5390 subjects with cancer have been enrolled in clinical studies of pazopanib (including studies conducted by the National Cancer Institute [NCI], part of the United States National Institutes of Health) as of 09 September 2010. Data collected to date show that oral pazopanib is absorbed after administration and that pazopanib administration at 800 mg daily is associated with a reasonable safety profile and encouraging efficacy in various oncology settings.
In a renal cell carcinoma (RCC) study where pazopanib was compared to placebo, the median time on treatment was approximately twice that on placebo (7.4 months versus 3.8 months). The overall frequency of adverse events (AEs) reported during the study was higher in the pazopanib arm (92%) compared with placebo (74%). 47,50,51 Most common AEs reported in >20% subjects in the pazopanib arm (as of 23 May 2008) were diarrhea (52%), hypertension (40%), hair color change (depigmentation; 38%), nausea (26%), anorexia (22%), and vomiting (21%). These AEs were all reported at a higher incidence in the pazopanib arm than in the placebo arm. Most of these events were Grade 1 or 2 using the National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE) Version 3.0. More Grade 3 AEs were reported in the pazopanib arm (33%) compared with the placebo arm (14%). The frequency of Grade 4 AE and Grade 5 events was similar between the pazopanib and placebo arms: Grade 4 in 7% and 6%, respectively; Grade 5 in 4% and 3%, respectively. At the time of the final analysis, a subsequent review of safety data did not reveal any changes to the previously observed safety profile; no new safety signals were detected.
Based on the analysis of the safety data integrated across three RCC studies, as of 09 January 2009 (N=593, the most common AEs and serious adverse events (SAEs) were similar to those observed in the pazopanib arm. 47,50,51 Rare but serious AEs previously described for VEGFR inhibitors, such as cardiac/cerebral ischemia, hemorrhage, and bowel perforation, were observed with pazopanib treatment. A review of SAEs across oncology studies revealed that the most frequently reported SAEs (≥ 50 events), regardless of causality and treatment regimen, as of 09 September 2010 in decreasing order of frequency were alanine aminotransferase (ALT) increased, vomiting, dyspnea, abdominal pain, diarrhea, dehydration, pyrexia, fatigue, pneumonia, anaemia, aspartate aminotransferase (AST) increased, nausea, pleural effusion, hypertension, and pulmonary embolism. The most common chemistry abnormalities, occurring almost twice as frequently on pazopanib compared with placebo included ALT (53% versus 22%), AST (52% versus 19%) and bilirubin elevations (36% versus 10%), hypophosphatemia (34% versus 11%), hypomagnesemia (26% versus 14%), hypoglycemia (17% versus 3%) and hypokalemia (9% versus 2%). Most of these abnormalities were Grade 1/2. The most common Grade 3/4 abnormalities were ALT and AST elevations. Although leukopenia, neutropenia, and thrombocytopenia were more common on pazopanib than placebo, Grade 3/4 cytopenias were uncommon. For pazopanib, the major laboratory abnormality appears to be elevation of hepatic enzymes, which typically occurred during the first 18 weeks of treatment. As of 09 January 2009, the transaminase elevations were reversible in 96 (91%) of 106 subjects with elevated ALT ≥ 3x upper limit of normal (ULN); 7 of the remaining 10 subjects had limited or no follow-up to determine recovery and 3 died of cancer progression with no follow-up ALT data. It was noted early in development that some of the subjects with elevated hepatic enzymes remained on study drug despite these elevations and had normalization of their transaminases while remaining on pazopanib ("adaptation"). Most subjects with transaminase elevations in whom dosing was interrupted could be successfully re-challenged. 47 (2), hepatic failure (2), hepatic function abnormal (2), peritonitis (2), sepsis (2), thrombocytopenia (2), and vomiting (2). 47 Many of these events are expected with pazopanib therapy, including pulmonary haemorrhage, gastrointestinal haemorrhage, hepatic failure and abnormal hepatic function, thrombocytopenia, and vomiting. Others are not unexpected given combination chemotherapy or background disease in the cancer populations under study. 47 As of 09 September 2010, there have been 22 deaths reported from the marketed use of pazopanib. In the majority of cases (most reported by a consumer and not medically verified by a healthcare professional), there was insufficient information available to make a clinical assessment regarding the cause of death. For the remainder, the death was likely associated with advanced clinical condition and disease progression. For the majority of reports, no autopsy information was provided. 47 There have been no reports of pregnancy exposures from pazopanib oncology clinical trials or marketed use as of 09 September 2010. 47

Pazopanib Pharmacokinetics and Pharmacology
The oral bioavailability of pazopanib reflects absorption that is limited by solubility above doses of 800 mg once daily; therefore, increases in doses above 800 mg, up to the highest dose evaluated (2000 mg), in the fasted state will not result in increased systemic exposure. Geometric mean pazopanib t½ values ranged from 18.1 to 52.3 hours. The mean t½ was 30.9 hours in the 800 mg once daily dose group, the monotherapy dose selected for administration in Phase II and Phase III clinical trials. The tmax was 3 to 4 hours. The oral bioavailability of pazopanib may also be affected by its substrate affinity for gut efflux transporters. Oral absorption is significantly enhanced when pazopanib is dosed with food; therefore, it is recommended to administer pazopanib on an empty stomach, at least 1 hour before or 2 hours after a meal. The absolute bioavailability of pazopanib (median 21%) suggests that the majority (67%) of the oral dose recovered unchanged in feces represents unabsorbed drug. 47 Pazopanib is not extensively metabolized and first-pass metabolism is minor, consistent with its low plasma clearance and small volume of distribution. Pazopanib is metabolized primarily by CYP3A4 and systemic exposure to pazopanib is altered by inhibitors and inducers of this enzyme. The concomitant use of strong CYP3A4 inhibitors should be avoided. If co-administration of a strong CYP3A4 inhibitor is warranted, a dose reduction to 400 mg of pazopanib is recommended. Grapefruit, which has also been shown to inhibit CYP3A4, may also increase plasma concentrations of pazopanib and should be avoided. CYP3A4 inducers such as rifampin may decrease plasma pazopanib concentrations. Selection of an alternate concomitant medication with no or minimal enzyme induction potential is recommended. The metabolites of pazopanib are produced in low abundance and are therefore unlikely to contribute to its pharmacological activity. 47 Age, race, and gender had no effect on pazopanib pharmacokinetics (PK). Renal impairment is not expected to influence pazopanib exposure, and dose adjustment is not necessary. Based on baseline hepatic function, 800 mg pazopanib is recommended for patients with mild impairment, and 200 mg for patients with moderate impairment. 47 There were no clinically meaningful changes in QTc interval following pazopanib in a dedicated QT Holter study. 47 Pharmacodynamic data indicate that pazopanib, at a monotherapy dose of 800 mg once daily, results in effects consistent with inhibition of the VEGF receptors and angiogenic factors it was designed to target (i.e., increases in VEGF and decreases in soluble VEGFR2). Concentration-effect relationships were observed between trough plasma pazopanib concentrations and the development of hypertension in the First Time in Human study as well as in the percent change from baseline in Human study, as well as in the percent change from baseline in soluble VEGFR2 nadir in the Phase II study in renal cell carcinoma. The trough plasma pazopanib concentrations associated with one-half the maximal effect (EC50) in both concentration-effect relationships were similar (15.3 μg/mL for hypertension and 21.3 μg/mL for sVEGFR2), which demonstrates that there is a consistent inhibition of VEGF receptor(s) in subjects with cancer when plasma pazopanib concentrations are maintained above 15 μg/mL. 47 Pazopanib is currently under development by GSK for the treatment of a variety of human cancers in adults. Currently, pazopanib is administered orally at 800 mg daily in Phase II and Phase III monotherapy studies. In combination therapy, doses ranged from 200 to 800 mg daily in a Phase I combination dose-ranging study in which pazopanib was administered in combination with the GSK compound lapatinib (GW572016). Pazopanib 200 to 800 mg daily is being investigated in combination with multiple cytotoxic chemotherapy regimens. 47

Radioiodine 131 I
Radioiodine 131 I (RAI) has been used in the management of well-differentiated papillary and follicular thyroid cancer subtypes for decades. 52 It is taken up and concentrated in thyroid cells through a sodium-iodide membrane transporter and likely retained as organified iodine through the action of thyroid peroxidase. As there is lower expression of this transporter in thyroid cancer cells, there is less iodine retention in thyroid cancer tissue than in normal thyroid tissue. 12,53,54 Radioiodine is often used adjuvantly post surgery or used to treat residual, recurrent or metastatic thyroid cancer. Patients with thyroid cancer that are able to concentrate 131 I generally have a better prognosis than those patients that lose the ability to concentrate or take up radioiodine. 53 In fact, the 5 year survival in patients with WDTC pulmonary metastases is much higher (60%) in patients who are sensitive and take up 131 I than those who are refractory (30%). 55,56 Skeletal metastases are less sensitive to 131 I, possibly due to poor concentration of RAI. Some studies have suggested that metastatic lesions positive on FDG PET scans are refractory to RAI therapy even if iodine-avid. 13 Generally, the cumulative doses of RAI range from 100 to 600 mCi in patients with metastatic disease. 52 Patients with lymph node and mediastinal disease are generally treated with 150 mCi, patients with pulmonary metastases are generally treated with 150 to 200 mCi and patients with skeletal disease and other distant metastatic disease are usually treated with 200 mCi of RAI, or higher if guided by radiation dosimetry. 52. However, RAI is not without side effects. Acutely, nausea, vomiting and dehydration are common but preventable and treatable with antinauseants and hydration; whereas, radiation thyroiditis, painless neck edema, sialadenitis and tumor hemorrhage or edema occur less commonly in 10-20% of patients, and are seen predominantly at higher doses. 29, 30 Chronically, there is a very small risk of future secondary malignancies such as bladder, salivary, gastrointestinal tract cancers and possibly breast cancer and acute myeloid leukemia. 29,30 Moreover, gonadal dysfunction, particularly ovarian failure in woman can occur, as well as obstruction of the nasolacrimal duct causing excessive tearing. Many of the chronic risks increase with higher cumulative doses. 29,30 Furthermore, the risks of exposure to family members should be minimized by avoidance of close contact with family members for two days post treatment. 52

Selection of Subjects: Inclusion Criteria
Deviations from inclusion criteria are not allowed because deviations can potentially jeopardize the scientific integrity of the study, regulatory acceptability, or subject safety. Therefore, adherence to the criteria as specified in the protocol is essential.
1) Subjects must provide written informed consent prior to performance of study-specific procedures or assessments, and must be willing to comply with treatment and follow-up. Procedures conducted as part of the subject's routine clinical management (e.g., blood count, imaging study) and obtained prior to signing of informed consent may be utilized for screening or baseline purposes provided these procedures are conducted as specified in the protocol.
2) Age ≥ 18 years or legal age of consent if greater than 18 years 3) Histologically confirmed diagnosis of WDTC, including papillary and follicular subtypes, and documented recurrent and/or metastatic disease. Patients must have unresectable disease: patients must not be amenable to surgery but prior thyroidectomy is allowed.
4) Patient must have demonstrated evidence of disease progression by RECIST criteria (Appendix D) using site assessment of CT/MRI scans within 12 months (+1 month to allow for variances in patient scanning intervals) prior to study entry or by >50% increase in suppressed thyroglobulin levels during this time period.

5)
Patients with WDTC must be relatively 131 I refractory/resistant as defined by at least one of the following: a) One or more measurable lesions with low or absent 131 I uptake on the most recent pre-study radioiodine scans, based on a visual review of scans or RAI scan reports.
b) One or more measurable lesions with disease progression by RECIST within 12 months (+ 1 month to allow for variances in patient scanning intervals) of 131 I therapy despite 131 I uptake on RAI scan, based on site assessment of CT/MRI scans or by >50% increase in suppressed thyroglobulin levels during this time period.
c) Evidence of at least one site of known disease with preserved 131 I uptake above background levels on a diagnostic post-therapy 131 I scan prior to study entry. d) Patients with WDTC must be receiving thyroxine suppression therapy and TSH should not be elevated (TSH should be ≤ 5.50 mcu/mL). 6) Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. (Appendix C) 7) Adequate organ system function as defined in Table 1 below. If UPC 1, then a 24-hour urine protein must be assessed. Subjects must have a 24-hour urine protein value <1 g to be eligible. Use of urine dipstick for renal function assessment is not acceptable. b) Childbearing potential, including any female who has had a negative serum pregnancy test within 2 weeks prior to the first dose of study treatment, preferably as close to the first dose as possible, and agrees to use adequate contraception for at least 2 weeks following the last dose of the investigational product. GSK acceptable contraceptive methods, when used consistently and in accordance with both the product label and the instructions of the physician, are as follow:  Complete abstinence from sexual intercourse for 14 days before exposure to investigational product, through the dosing period, and for at least 21 days after the last dose of investigational product  Oral contraceptive, either combined or progestogen alone  Injectable progestogen  Implants of levonorgestrel  Estrogenic vaginal ring  Percutaneous contraceptive patches  Intrauterine device (IUD) or intrauterine system (IUS) with a documented failure rate of less than 1% per year  Male partner sterilization (vasectomy with documentation of azoospermia) prior to the female subject's entry into the study, and this male is the sole partner for that subject  Double barrier method: condom and an occlusive cap (diaphragm or cervical/vault caps) with a vaginal spermicidal agent (foam/gel/film/cream/suppository) 9) Female subjects who are lactating should discontinue nursing prior to the first dose of study drug and should refrain from nursing throughout the treatment period and for 14 days following the last dose of study drug.

Selection of Subjects: Exclusion Criteria
Deviations from exclusion criteria are not allowed because they can potentially jeopardize the scientific integrity of the study, regulatory acceptability or subject safety. Therefore, adherence to the criteria as specified in the protocol is essential.
1) Patients with medullary thyroid cancer, thyroid lymphoma or anaplastic thyroid cancer are excluded.
2) Resolution of all acute toxic effects of prior systemic therapy (including iodine therapy or systemic therapy), radiotherapy or surgical procedure to NCI CTCAE version 4.0 (Appendix E) grade ≤ 1. ..  Note: Initiation or adjustment of antihypertensive medication(s) is permitted prior to study entry.

3) Patients with cumulative
12) History of cerebrovascular accident including transient ischemic attack (TIA), pulmonary embolism or untreated deep venous thrombosis (DVT) within the past 6 months. Subjects with recent DVT who have been treated with therapeutic anti-coagulating agents for at least 6 weeks are eligible 13) Prior major surgery or trauma within 28 days prior to first dose of study drug and/or presence of any non-healing wound, fracture, or ulcer (procedures such as catheter placement not considered to be major).
14) Evidence of active bleeding or bleeding diathesis.
15) Known endobronchial lesions and/or lesions infiltrating major pulmonary vessels that increase the risk of pulmonary hemorrhage. Note: Lesions infiltrating major pulmonary vessels (contiguous tumor and vessels) are excluded; however, the presence of a tumor that is touching, but not infiltrating (abutting) the vessels is acceptable (CT with contrast is strongly recommended to evaluate such lesions).

16) Recent
Hemoptysis in excess of 15 ml of bright red blood in the 8 weeks prior to study entry. 17) Any serious and/or unstable pre-existing medical, psychiatric, or other condition that could interfere with subject's safety, provision of informed consent, or compliance to study procedures.
18) Unable or unwilling to discontinue use of prohibited medications listed in §5.8 for at least 14 days or five half-lives of a drug (whichever is longer) prior to the first dose of study drug and for the duration of the study. 19) Treatment with any of the following anti-cancer therapies:  radiation therapy, surgery or tumor embolization within 14 days prior to the first dose of pazopanib OR  chemotherapy, immunotherapy, biologic therapy, investigational therapy or hormonal therapy within 14 days or five half-lives of a drug (whichever is longer) prior to the first dose of pazopanib

Trial Design
This is a phase I open-label, dose-finding, safety study of pazopanib in combination with escalating doses of radioiodine 131 I in patients with advanced or recurrent WDTC who still maintain some uptake on RAI scans. This will be a single center study, un-controlled, non-comparative and non-randomized trial with no stratification.

ENDPOINTS:
 The primary end point of this phase I study is to assess the toxicity and the occurrence of dose limiting toxicity (DLT) when pazopanib is given in conjunction with radioiodine to establish the MTD and RP2D in combination.
 Secondary endpoints include tumor response (RECIST criteria) and TTP. Tumor response and TTP will be compared to responses and duration of TTP after last prior historical RAI treatment.
 Tertiary endpoints involve assessing increased radioiodine uptake, retention (through comparison of radioiodine scans in prior historical studies) and correlative effects of pazopanib on tumor blood flow and response in WDTC (assessed by dynamic FDG-PET).

Treatment Regimen Pazopanib Monotherapy
Pazopanib 800 mg once daily is the recommended monotherapy dose based on clinical and preclinical results. Once daily doses of 50 mg to 2000 mg pazopanib were investigated in the "First Time in Human", Phase I Study VEG10003. Increases in the pazopanib dose above 800 mg once daily when administered in the fasted state did not result in a consistent increase in systemic exposure at steady-state. Therefore, no further benefit is expected at pazopanib doses above 800 mg once daily. 47 Pharmacodynamic data indicate that pazopanib, at a monotherapy dose of 800 mg once daily, results in effects consistent with inhibition of the VEGF receptors it was designed to target. Concentrationeffect relationships were observed between trough plasma pazopanib concentrations and the development of hypertension in Study VEG10003 and the percent change from baseline in sVEGFR2 nadir in Study VEG102616. The trough plasma pazopanib concentrations associated with one-half the maximal effect (EC 50 ) in both concentration-effect relationships were similar (21.3 g/mL and 15.3 g/mL) and demonstrate that there is a consistent inhibition of VEGF receptor(s) in subjects with cancer when plasma pazopanib concentrations are maintained above 15 g/mL. The plasma pazopanib EC 50 values for biologic effects observed in the clinical studies are similar to the plasma concentration of 40 M (17.5 g/mL) required for optimal inhibition of VEGFR-2 phosphorylation in mice. 47 Progression Free Survival (PFS) in subjects with renal cell cancer in Study VEG102616 was compared between subjects whose trough plasma pazopanib concentrations (Cmin) at Week 4 were above or below selected threshold values. The deciles of the observed Cmin values were selected as threshold values so that approximately equal numbers of subjects were included in each Cmin interval. Subjects with a Cmin at Week 4 above the threshold values had significantly better PFS, compared to the remaining subjects, when the threshold concentrations were 12.6 g/mL, 17.4 g/mL, and 20.6 g/mL. Use of thresholds higher than 21 g/mL did not result in a significant improvement in PFS between patients with Cmin values above and below the threshold. Patients with Cmin concentrations above 20.6 g/mL also had a significantly better response rate and tumor shrinkage than the remaining patients. 47 Pazopanib C24 at steady-state was greater than 15 g/mL in 93% of subjects who received 800 mg once daily in Study VEG10003. Individual subjects receiving pazopanib doses below 800 mg once daily can achieve plasma concentrations over 15 g/mL, albeit at a lower frequency compared with what is observed at 800 mg once daily. Therefore, the pharmacokinetic and pharmacodynamic results across clinical studies demonstrate that pazopanib 800 mg once daily results in plasma concentrations that provide optimal biologic effects associated with VEGFR inhibition in the greatest proportion of subjects. 47 Additional support for an 800 mg once daily pazopanib dose comes in results from Study VEG105192, a 435-subject Phase III study of pazopanib (800 mg once daily) versus placebo in treatment-naïve and cytokine-pretreated subjects with renal cell carcinoma (RCC). In this study, the median progressionfree survival (PFS) in the pazopanib arm was 9.2 months (95% CI, 7.4, 12.9) compared to 4.2 months (95% CI, 2.8, 4.2) in the placebo arm. This finding represented a statistically significant improvement in PFS in response to pazopanib monotherapy (HR 0.46, 95% CI 0.34 to 0.62, p<0.0000001). In addition, the response rate (defined as the percentage of subjects achieving either a confirmed complete or partial response according to RECIST) in the pazopanib arm was 30% versus 3% in the placebo arm, and the median duration of response in pazopanib-treated subjects was 58.7 weeks. Results from Study VEG105192 therefore indicate that an 800 mg once daily dose of pazopanib is highly effective in treating subjects with advanced RCC. 47

Treatment Regimen Radioiodine 131 I
The radioiodine dosing will be based upon estimated radiation exposure to the blood as an indicator of the marrow radiation dose using the maximal dose dosimetry method. 53,54, 57 We have been routinely using this method for WDTC patients with distant metastases over 15 years and over 500 patients. For this method, in the absence of concurrent therapy, the maximum tolerated dose with severe marrow toxicity has been show to be 200 rads. 53,54,57 As additive hematologic toxicity may occur in combination with pazopanib, the starting dose of 131 I will be at 50 rads to the blood as estimated by dosimetry based upon radioiodine whole-body and blood clearance measures and escalation will proceed up the clinically established single agent dose of 150 rads. The combined effect of pazopanib on hematologic and non-hematologic toxicity, particularly marrow and pulmonary toxicity, on 131 I will be assessed in this study.

Treatment Plan
The clinically efficacious and tolerable phase II dose of pazopanib will be fixed at 800 mg po once daily and initiated for 4 weeks before adding in combined escalating doses of 131 I radioiodine in a 3+3 phase I design according to Table 2 below, starting at Dose Level 1. Pazopanib continued to be will be administered once daily for 8 weeks post radioiodine therapy, for a total of 12 weeks of therapy. During the 4 week run-in period, if grade ≥ 3 pazopanib-related persistent toxicities occur despite supportive measures, patients may continue on study at the Investigator's discretion with a reduced dose of to 600 mg po once daily concurrent with escalating doses of 131 I, which will be continued post RAI. The radioiodine dosing will be based upon estimated radiation exposure to the blood as an indicator of the marrow radiation dose using the maximal dose dosimetry method. 53,54, 57 We have been routinely using this method for WDTC patients with distant metastases over 15 years and over 500 patients. For this method, in the absence of concurrent therapy, the maximum tolerated dose with severe marrow toxicity has been show to be 200 rads. 53,54,57 As additive hematologic toxicity may occur in combination with pazopanib, the starting dose of 131 I will be at 50 rads and escalation will proceed up the clinically established single agent dose of 150 rads, slightly below the accepted marrow toxicity limit of up to 200 rads to the blood for patients not receiving concurrent systemic therapy. The combined effect of pazopanib on hematologic and non-hematologic toxicity, particularly marrow and pulmonary toxicity, on 131 I will be assessed in this study.

Drug Regimen:
Pazopanib at a fixed dose will be administered for 4 weeks before adding in combined escalating doses of 131 I radioiodine in a 3+3 phase I design according to Table 2 below, starting at Dose Level 1. Pazopanib will continue for 8 weeks post radioiodine therapy, for a total of 14 weeks of therapy. The radioiodine dosing will be based upon estimated radiation exposure to the blood as an indicator of the marrow radiation dose using the maximal dose dosimetry method. 53,54,57 Severe marrow toxicity has been observed at 200 rads using this method. 53,54,57 As additive hematologic toxicity may occur in combination with pazopanib, the starting dose of 131 I will be at 50 rads and escalation will proceed up our center's typical clinical dose of 150 rads for 131 I alone.

Administration of Pazopanib
Pazopanib will be provided by GSK.
Pazopanib should be taken orally without food at least one hour before or two hours after a meal. The tablets should be swallowed whole and must not be crushed or broken.  4 Pazopanib 800 mg po once daily continuous dosing Radioiodine 131 I 150 rad dose of therapy is due in less than 12 hours, the subject should skip the missed dose and take the next dose as scheduled.
If vomiting occurs after taking pazopanib, the subject should not take a replacement dose on that day. The subject should resume taking pazopanib at the next scheduled dose on the following day. If vomiting persists, the subject should be instructed to notify the Investigator.

Handling and Storage of Study Treatment
Pazopanib should be stored at room temperature up to 25 o C. When stored at these temperatures and in unopened bottles, pazopanib tablets will remain stable until the expiration date indicated on the bottle label.

4.4.3
Administration of Radioiodine 131 I The radioiodine dosing will be based upon estimated radiation exposure to the blood as an indicator of the marrow radiation dose using the maximal dose dosimetry method. 53,54,57 This is a standard RAI administration method used throughout North America.

Treatment Schedule
Study treatment will proceed as per the schema outlined in Appendix A. A lead-in period of 4 weeks starting with pazopanib at 800 mg po once daily alone will be conducted to assess for severe toxicities prior to initiating RAI therapy. If severe (≥ Grade 3) toxicities which cannot be controlled by medical management and supportive care measures, or major uncorrectable laboratory abnormalities -occur with pazopanib alone, patients may need to stop drug and once toxicities resolve to ≤ Grade 1, patients may continue pazopanib therapy at a reduced dose of 600 mg po once daily prior to receiving RAI therapy. Patients who require pazopanib treatment to be held for greater than 14 days prior to RAI therapy, will be taken off study. Patients should have received at least 14 consecutive days of pazopanib prior to starting RAI. In the event of Grade 2 toxicities which are deemed intolerable by the patient at the 800 mg po daily dose, patients may also continue pazopanib at a reduced dose of 600 mg po once daily prior to receiving RAI therapy at the discretion of the Investigator. Patients who cannot tolerate the 600 mg po once daily dosing prior to receiving RAI therapy, will be considered unevaluable and be replaced. Patients who do not receive any RAI therapy will be unevaluable and replaced. Patients whose pazopanib dose has been reduced, should continue at the reduced dose for the remainder of the study and no intra-patient re-dose escalation will be allowed.
Pazopanib therapy will be administered continuously throughout the RAI therapy and for a total of 8 weeks post RAI treatment for a total of approximately 14 weeks of therapy. Pazopanib toxicities will be observed throughout the treatment period and the 8 weeks of pazopanib therapy post RAI treatment will serve as the dose-limiting toxicity (DLT) assessment period.
Dose modifications, dose delays and other toxicities will be assessed throughout all courses of treatment when determining the optimal dose for phase II studies (RP2D).

Pre-Study Preparation:
Relevant baseline CT/MRI imaging will be performed within 4 weeks of study initiation. Baseline dynamic FDG-PET, suppressed thyroglobulin levels and laboratory assessments and will be performed within 1 week prior to study initiation.
Week 1 Initiate pazopanib: Pazopanib will be administered starting on Day 1, as per the dose levels above, as a continuous once daily oral dose. Continuous dosing of pazopanib will continue through the preparation and administration of radioactive iodine until 8 weeks post radioactive iodine -for a total of approximately 14 weeks of therapy.

Week 3 to 4 Initiation of low iodine diet:
A low iodine diet should be initiated at least two weeks prior to starting diagnostic scan for RAI therapy.
Guidelines for a low iodine diet: Consume less than 50 mcg iodine per day. Avoid foods high in iodine (over 20 mcg per serving) Limit the quantity of food moderate in iodine (5 to 20 mcg per serving) Eat any foods low in iodine (up to 5 mcg per serving)

Weeks 4 to 5:
After completing 3 -3.5 weeks of continuous pazopanib therapy, repeat dynamic FDG-PET imaging will be performed to assess the PET uptake, tumor perfusion (from FDG delivery rates) and response in WDTC.

Weeks 5 to 7: RAI therapy with continued daily dosing of pazopanib
A diagnostic scan to determine uptake of radioiodine by thyroid tissue will be performed with whole body imaging and dosimetric calculations using a low dose of 2 to 5 mCi 131 I. Dosimetric calculations are performed by measuring whole body (WB) and blood 131 I clearance. 53,54,57 Localization of uptake is determined with WB scans taken pre-and post-therapy and compared to each patient's prior historical control obtained in the absence of pazopanib. Dosemetric scans will be compared to the baseline historical evaluations to determine the effects on increased iodine uptake, radiosensitization and possible response. In addition, WB and blood clearance 131 I will be compared to look for effects of pazopanib on iodine kinetics.

RAI preparation:
For RAI therapy, our center will only use the rhTSH-stimulated (Thyrogen-stimulated) preparation methods in this study for maximal dose dosimetry treatments to avoid possible issues of tolerability inherent with total hormone withdrawal while on pazopanib. Preparation for the RAI therapy for this study will use recombinant rhTSH-stimulated (Thyrogen-stimulated) preparation methods and compare this to the patient's most recent prior iodine therapy to allow for determination of radioiodine uptake changes in the presence of pazopanib.
The recombinant rhTSH method requires the administration of rhTSH several days prior to RAI therapy at a dose of 0.9 mg IM once daily for two days prior to the diagnostic radioiodine dose (typically, this should fall on a Saturday or Sunday). The diagnostic dose is then given, followed by 5 days (Monday to Friday) of dosimetry/scanning. Generally, the same timing is used for the diagnostic dose given for scanning/dosimetry measurement and again for the therapeutic dose. Specifically, the next week, patients will receive rhTSH 0.9 mg IM once daily for two days prior to the treatment therapeutic dose (typically a Monday or Tuesday), then patients will be given a therapeutic dose and this will be given an inpatient as patients are admitted for isolation to avoid radiation exposure. Patients remain on thyroxine suppression throughout the process and no thyroid hormone withdrawal is needed. We expect most patients to be admitted for radiation isolation after therapeutic radioiodine. Patients will not be hospitalized for radiation isolation if they are treated with less than 200 mCi and are able to comply with regulations that limit the exposure to others including the use of their own bathroom for 3-4 days.
Patients unable to comply with these regulations, including patients who live with pregnant women or children that cannot avoid being close to the patient will be admitted. Hospital admission occurs from dosing until the exposure rate is safe for release (less than 7mrem/hr at one meter), typically 1-2 days, almost never > 3 days.

Radioiodine Dose:
The administered radio-iodine activity (mCi) dose will be determined from the estimated blood radiation dose from clearance measurements, in escalating doses from 50 to 150 rads (see Table 2.) will be administered in the presence of chronic pazopanib therapy. In patients with diffuse lung disease, calculations will also assure that patients are under the anticipated dose for pulmonary toxicity, 80 mCi retained at 2 days, 54 (by the same proportion as the marrow dose compared to 200 rads), for any given dose escalation level. If needed, the dose will be reduced to avoid a potentially lung-toxic dose.

Weeks 7 to 8: Post-treatment scanning:
Tumor uptake of the treatment dose of 131 -I will be confirmed with a whole body scan appropriately 1 week (7 -10 days) post treatment dose of RAI therapy. Post-treatment scans will be compared to pretreatment scans and also historical post-treatment scans in the absence of pazopanib therapy.

Weeks 7 to 15:
The acute toxicities and hematologic toxicities of RAI are prominent for 6 to 8 weeks post RAI administration. Pazopanib will continue as a daily therapy for a total of an additional 8 weeks post RAI before being discontinued. Regular bi-monthly or monthly assessment of blood counts will be performed during this period. Toxicity assessments and the DLT evaluation period will occur up to 8 weeks post RAI therapy.

Week 15 + :
Pazopanib therapy is discontinued and post-treatment follow-up is initiated. Tumor imaging and suppressed thyroglobulin levels will be performed within a week of discontinuing pazopanib therapy to establish a post-treatment follow-up baseline. Radiologic and suppressed thyroglobulin monitoring will occur regularly at 3 to 6 months intervals or per institutional standard of care intervals or as deemed necessary and relevant by the Investigator. Post therapy tumor response and TTP will be determined with respect to censored post pazopanib therapy baseline imaging and thyroglobulin levels. Progression will be determined by clinical radiologic progression by RECIST criteria compared to radiologic imaging post completion of pazopanib and/or increase in suppressed serum thyroglobulin levels >50% with comparison to post-pazopanib levels. Week -1 Week 1 Week 2

Baseline CT/MRI imaging and laboratory assessments Suppressed thyroglobulin levels
Week 3 Week 4 Week 5

Continue assessing for toxicities and DLT for 8 weeks post RAI
Week 9 Week 10 Week 11

Pazopanib once daily continuous oral dosing Stop pazopanib continuous daily dosing at 8 weeks post RAI treatment
Week 12 Week 13 Week 14

Continue assessing for toxicities and DLT for 8 weeks post RAI
Week 15

STUDY CONDUCT AND TRIAL PROCEDURES
Prior to undergoing any study-specific procedure, patients must read and sign the current Institutional Review Board (IRB)-approved informed consent form. Procedures conducted as part of the subject's routine clinical management (e.g., blood count, imaging study) and obtained prior to signing of informed consent may be utilized for screening or baseline purposes provided these procedures are conducted as specified in the protocol. All on-study procedures are permitted within the window frame indicated in Schedule of Protocol Activities (Appendix A).

Screening
The following screening procedures should be performed within 7 days prior to initiation of treatment on-study unless otherwise specified:  Patient signature on current IRB-approved informed consent form. May be obtained up to 30 days prior to treatment.
 Demographics specifically including date of birth, race and gender.

 Medical history including and specifying:
o Tumor-specific history including: date of diagnosis, primary tumor type with histology/cytology determination, current stage of cancer, prior treatment(s) for WDTC (systemic, surgical and/or radiotherapy), ongoing toxicity related to prior treatment(s); and history of other malignancies.
o Current medical conditions.  ECOG performance status.
 Height (only recorded at baseline) body weight, and vital signs (temperature, blood pressure, heart rate, respiratory rate).
o Note: If a subject presents with poorly controlled hypertension, defined as SBP 140 mmHg or DBP  90 mmHg, antihypertensive medication(s) should be initiated or adjusted with a goal to control the blood pressure to <140/90 mmHg.
 Physical examination, including examination of major body systems.
 Hematology and Chemistry as described in Appendix B.
 Baseline thyroglobulin levels, TSH, free T4 and free T3 levels.
 Serum pregnancy test for women of childbearing potential (if applicable). May be performed up to 14 days prior to treatment. o May be done up to 28 days prior to treatment.
o Note that the same imaging modality must be used for each patient throughout the study.
 Brain CT or MRI scan for known (treated) or suspected brain metastases. May be done up to 28 days prior to treatment. Imaging of the brain is not needed in the absence of clinical symptoms or clinical suspicion of brain metastases or CNS involvement.
 Bone scan for patients with known or suspected bone metastases. May be done up to 28 days prior to treatment. Bone scan not needed in the absence of clinical symptoms or lack of clinical suspicion for bone metastases.
 The results of all screening assessments should be reviewed by the Investigator to ensure the patient meets all eligibility requirements as outlined in §3.0. Thereafter, qualified subjects can begin the initial pazopanib treatment.

Prior to Initiating Pazopanib Therapy on Day 1
 Review of the inclusion/exclusion criteria.
 Physical examination: to identify any changes in the subject's mental and medical conditions since baseline assessment that would make him/her ineligible for the study.
 Blood pressure measurement: o It is particularly important to check the blood pressure of any subject for whom anti-hypertensive medication has been initiated and/or dosing has been adjusted during the Baseline Period. At least 24 hours must have elapsed between anti-hypertensive medication initiation or adjustment and BP measurement. If, after treatment with antihypertensive medication, a subject's blood pressure is not <140/90mmHg, then further modifications of these medication(s) may be made while the subject is still in the Baseline Period. After further anti-hypertensive treatment, the subject's blood pressure must then be rechecked to determine eligibility for the trial.
 ECOG PS. Subjects having deterioration of ECOG PS to 2 will be excluded from the study.
 Review results of all the other baseline assessments to determine the subject's eligibility for the study. All laboratory results must be within the values outlined in the Inclusion Criteria (Section 3.1), otherwise the subject is not eligible to participate in the study.

Pazopanib Monotherapy Treatment Weeks 1 to 4
Please refer to Appendix A for a comprehensive list of required assessments and procedures.
 Pazopanib will be administered as a standard dose at 800 mg po once daily. Assessment of toxicities due to pazopanib alone will be determined and recorded. If dose reductions are necessary due to toxicity as previously specified, patients may decrease down to 600 mg po once daily continuous dosing.
 Weekly laboratory work may be performed as per local clinical practice. Urine protein creatinine ratio, hematology and chemistry as per Appendix B are suggested.

Reassessment Prior to Initiation of RAI Week 4 to 5
 Low iodine diet must be started 2 weeks prior to initiating diagnostic scans for RAI therapy.
 Reassessment of all toxicities, and all drug-related adverse events.
 ECOG performance status, body weight, and vital signs.
 Physical examination including major body systems.
 Hematology and Blood Chemistry (see Appendix B) if not performed within the previous 7 days.
 Following 4 weeks of pazopanib therapy and prior to initiation of RAI in combination with pazopanib, the following criteria must be met:  Patients must have received at least 14 days or more of pazopanib therapy.  Patients who cannot meet the minimal criteria above prior to starting combined RAI therapy, will be replaced.

Combined Therapy with Pazopanib and RAI Weeks 5 to 7
Refer to Appendix A for a comprehensive list of required assessments and procedures.
Refer to §4.4 for details on cohort enrollment, assignment of RAI dose level, and assessment of doselimiting toxicities.
 Assessment of adverse events and tumor-related signs and symptoms at each study visit.
 Hematology and blood Chemistry (see Appendix B) according to the schedule in Appendix A.

Weeks 5 to 7: RAI therapy with continued daily dosing of pazopanib
 Assessment of adverse events and tumor-related signs and symptoms at each study visit. A diagnostic scan to determine uptake of radioiodine by thyroid tissue will be performed with whole body imaging and dosimetric calculations using a low dose of 2 to 5 mCi 131 I. Dosimetric calculations are performed by measuring whole body (WB) and blood 131 I clearance. 53,54,57 Localization of uptake is determined with WB scans taken pre-and post-therapy and compared to each patient's prior historical control obtained in the absence of pazopanib. Dosemetric scans will be compared to the baseline historical evaluations to determine the effects on increased iodine uptake, radiosensitization and possible response. In addition, WB and blood clearance 131 I will be compared to look for effects of pazopanib on iodine kinetics.

RAI preparation:
For RAI therapy, our center will only use the rhTSH-stimulated (Thyrogen-stimulated) preparation methods in this study for maximal dose dosimetry treatments to avoid possible issues of tolerability inherent with total hormone withdrawal while on pazopanib. Preparation for the RAI therapy for this study will use recombinant rhTSH-stimulated (Thyrogen-stimulated) preparation methods and compare this to the patient's most recent prior iodine therapy to allow for determination of radioiodine uptake changes in the presence of pazopanib. Patients undergo a two-week low-iodine diet as per clinical routine.
The recombinant rhTSH method requires the administration of rhTSH on the two days prior to RAI therapy at a dose of 0.9 mg IM. Patients remain on thyroxine suppression throughout the process and no thyroid hormone withdrawal is needed.

Radioiodine Dose:
The administered radio-iodine activity (mCi) dose will be determined from the estimated blood radiation dose from clearance measurements, in escalating doses from 50 to 150 rads (see Table 2.) will be administered in the presence of chronic pazopanib therapy. In patients with diffuse lung disease, calculations will also assure that patients are under the anticipated dose for pulmonary toxicity, 80 mCi retained at 2 days, 54 (by the same proportion as the marrow dose compared to 200 rads), for any given dose escalation level. If needed, the dose will be reduced to avoid a potentially lung-toxic dose.

Weeks 7 to 8: Post-treatment scanning:
Tumor uptake of the treatment dose of 131 -I will be confirmed with a whole body scan appropriately 1 week (7 -10 days) post therapy. Post-treatment scans will be compared to pretreatment scans and also historical post-treatment scans in the absence of pazopanib therapy.

Post RAI Therapy with Continued Pazopanib Weeks 7 to 15
 Assessment of adverse events and tumor-related signs and symptoms at each study visit.  The acute toxicities and hematologic toxicities of RAI are prominent for 6 to 8 weeks post RAI administration.  Pazopanib will continue as a daily therapy for a total of an additional 8 weeks post RAI before being discontinued.  Regular bi-monthly or monthly assessment of blood counts will be performed during this period. Toxicity assessments and the DLT evaluation period will occur up to 8 weeks post RAI therapy.

Completion of Pazopanib Therapy at 8 weeks post RAI (Week 15)
Pazopanib therapy is discontinued and post-treatment follow-up is initiated.


Tumor imaging and suppressed thyroglobulin levels will be performed within a week of discontinuing pazopanib therapy to establish a post-treatment follow-up baseline.
 Laboratory assessments of hematology and blood chemistry (including TSH, free T3 and free F4), study visits, clinical disease assessments, assessments of toxicity, physical examination and vitals will occur regularly at 3 to 6 months intervals or per institutional standard of care intervals or as deemed necessary and relevant by the Investigator.
o Assessment of adverse events and tumor-related signs and symptoms at each study visit.
o ECOG performance status, body weight, and vital signs at each study visit.
o Physical examination, including major body systems, at each study visit. A problem-oriented PE can be conducted at the Investigator's discretion at any time.
 Radiologic and suppressed thyroglobulin monitoring will occur regularly at 3 to 6 months intervals or per institutional standard of care intervals or as deemed necessary and relevant by the Investigator.
o Tumor imaging, including CT or MRI scans of the chest and other applicable sites of disease (must be the same imaging modality(ies) and anatomical sites as screening assessments.
 Post therapy tumor response and TTP will be determined with respect to censored post pazopanib therapy baseline imaging and thyroglobulin levels.
IRB Approved Document Release Date: 10/22/2015  Progression will be determined by clinical radiologic progression by RECIST criteria and/or increase in suppressed serum thyroglobulin levels >50% with comparison to post-pazopanib levels.

Concomitant Medications and Supportive Care
If future changes are made to the list of permitted/prohibited medications, formal documentation will be provided by GSK and stored in the study file. Any such changes will be communicated to the investigative sites in the form of a letter.

Permitted Medications
All subjects will be asked to provide a complete list of prescription and over-the-counter medications that have been taken within the 4 weeks prior to Screening. The Investigator must be informed as soon as possible about any new medication(s) taken from the time of Screening until the completion of the post-treatment follow-up visit.
Subjects should be provided with full supportive care measures as clinically indicated, and in accordance with institutional standards, including transfusion of blood and blood products, and treatment with antibiotics, analgesics, erythropoietin, or bisphosphonates, when appropriate. Antiemetics (such as prochlorperazine, lorazepam, ondansetron or other 5-HT antagonists) may be administered prophylactically in the event of nausea. Anti-diarrheals, such as loperamide, may be administered as needed in the event of diarrhea. Although acetaminophen at doses of 2 g/day is permitted, it should be used with caution in subjects with impaired liver function.
Localized radiotherapy is permitted for palliation of painful lesions at the Principal Investigator's discretion provided it is not within 2 weeks (before or after) of RAI administration

Specific recommendations regarding anticoagulants:
Results from drug-drug interaction studies conducted in subjects with cancer suggest that pazopanib has no effect on the metabolism of S-warfarin. Hemorrhagic events, however, have been reported in clinical studies with pazopanib; therefore, pazopanib should be used with caution in subjects with increased risk of severe bleeding or who are receiving concomitant anticoagulant therapy (e.g., warfarin or its derivatives, low molecular weight heparin, unfractionated heparin). Subjects taking concomitant anticoagulant therapy should be monitored regularly for changes in relevant coagulation parameters as clinically indicated, as well as for any clinical bleeding episodes.

Specific recommendations regarding hypoglycemic therapy including insulin:
Results from drug-drug interaction studies conducted in subjects with cancer suggest that there will be no clinically relevant pharmacokinetic interaction between pazopanib and hypoglycemic agents. Transient decreases in serum glucose (mainly Grade 1 and 2, rarely Grade 3) have been observed in clinical studies with pazopanib. In addition, decreases in blood sugar have been recently reported in subjects treated with another small molecule tyrosine kinase inhibitor, sunitinib. 58 Such changes may require an adjustment in the dose of hypoglycemic and/or insulin therapy. Subjects should be advised to report symptoms of hypoglycemia (e.g., confusion, visual disturbances, palpitations, sweating). Serum glucose should be tested during treatment with pazopanib as outlined in the protocol and as clinically indicated.

The Effects of Pazopanib on Other Drugs
In vitro data indicate that pazopanib is a potential inhibitor for CYP3A4, CYP2C8, CYP2D6, CYP1A2, CYP2C9, CYP2C19, CYP2A6, CYP2B6, and CYP2E1. 47 Pregnane X receptor transient transfection assay suggested some potential for human CYP3A4 induction at high concentrations. Results from drug-drug interaction studies conducted in subjects with cancer suggest that pazopanib is a weak inhibitor of CYP3A4, CYP2C8, and CYP2D6 in vivo, but had no clinically relevant effect on CYP1A2, CYP2C9 or CYP2C19 metabolism. Therefore, concomitant use of pazopanib with certain medications (substrates of CYP3A4, CYP2C8, and CYP2D6) with a narrow therapeutic window should be undertaken with CAUTION due to the potential for alterations in the pharmacologic effects of these medications or an increased risk for serious or life threatening adverse events associated with such medications (see below) secondary to the inhibition of specific CYP enzymes by pazopanib. In addition, the potential for drug interaction with such medications, although diminished, may persist after the last dose of pazopanib due to its long half-life (i.e., mean 30.9 hours); therefore, continue to exercise CAUTION for at least 7 days and up to 15 days after the last dose of pazopanib when administering these medications. These medications include (but are not limited to): • Ergot derivatives: dihydroergotamine, ergonovine, ergotamine, methylergonovine (potential increased risk for developing ergot toxicity that includes severe vasospasm leading to peripheral as well as cerebral ischemia). • Neuroleptics: pimozide (potential increased risk for QT interval prolongation, ventricular arrhythmia, and sudden death) • Antiarrhythmics: bepridil, flecainide, lidocaine, mexiletine, amiodarone, quinidine, propafenone (potential increased risk for QT interval prolongation and Torsade de Pointes) • Immune modulators: cyclosporine, tacrolimus, sirolimus (potential increased risk for nephrotoxicity and neurotoxicity) • Miscellaneous: quetiapine, risperidone, clozapine, atomoxetine.

The Effects of Other Drugs on Pazopanib
Results from in vitro studies suggest that the oxidative metabolism of pazopanib in human liver microsomes is mediated primarily by CYP3A4, with minor contributions from CYP1A2 and CYP2C8. Furthermore, in vitro data suggest that pazopanib is a substrate for p-glycoprotein. 47 Substances that induce or inhibit CYP3A4 may alter the pharmacologic effects of pazopanib and should be used with CAUTION.
Medications that inhibit CYP3A4 may result in increased plasma pazopanib concentrations. Coadministration of strong CYP3A4 inhibitors is prohibited (see Section on Prohibited Medications); therefore selection of an alternate concomitant medication with no or minimal potential to inhibit CYP3A4 is recommended.

Prohibited Medications
The following medications and interventions are prohibited from the time of study screening until the End of Study visit:  Subjects should not receive other anti-cancer therapy [cytotoxic, biologic, radiation, or hormonal (other than leuprolide or other GnRH agonists)] while on treatment in this study.
 Any investigational device or drug other than pazopanib  Medications that inhibit CYP3A4 may result in increased plasma pazopanib concentrations; therefore, co-administration of strong CYP3A4 inhibitors is PROHIBITED beginning 14 days prior to the first dose of study drug until discontinuation from the study.

End of Study Treatment / Withdrawal Procedures
Patients will have completed their participation in the study in the case of:  Disease progression, except as described below  Unacceptable toxicity  Need for treatment rest > 14 days; refer to §5.14.1  Need to reduce dose of pazopanib to lower than 400 mg po daily; refer to §5.14  Need for anticancer therapy not specified in the protocol  Patient noncompliance  Patient lost to follow-up  Patient choice to withdraw from treatment (follow-up permitted by patient; see below)  Withdrawal of patient consent (cessation of follow-up; see below)  Study closure by Sponsor-Investigator Subjects may withdraw from the trial at any time at their own request, or they may be withdrawn at any time at the discretion of the Investigator or Sponsor for safety, behavioral, or administrative reasons.
If the subject withdraws from the trial and also withdraws consent for disclosure of future information, no further evaluations should be performed and no additional data should be collected. The Sponsor may retain and continue to use any data collected before such withdrawal of consent.
At the end of the study or at withdrawal, the following procedures should be performed if they were not performed during the last week on study:  ECOG performance status, body weight, and vital signs  Assessment of adverse events and tumor-related signs and symptoms IRB Approved Document Release Date: 10/22/2015  Physical examination including major body systems  Hematology and Blood Chemistry as described in Appendix B  ECG, if clinically indicated  Relevant tumor imaging including bone scans, CT or MRI or PET/CT scans of known sites of disease (utilizing the same imaging modalities and anatomical areas as Screening)

Follow-up Visit Procedures
Patients should continue to be evaluated for 28 calendar days after the last dose of study treatment. At the post-treatment follow-up visit, the following procedures should be performed:  Assessment of adverse events and tumor-related signs and symptoms.  Physical examination, ECOG performance status, body weight, vital signs, laboratory assessments, or other tests necessary to follow unresolved adverse events. During this period, the outcome of adverse events with a date of onset during the study period should be reevaluated. Adverse events will be followed until they are resolved or until a new anti-cancer treatment is initiated. All serious adverse events, and those non-serious adverse events assessed by the Investigator as possibly related to study drug, should continue to be followed even after patient withdrawal from study. These adverse events should be followed until they resolve or until the Investigator assesses them to be "chronic" or "stable."

Cohort Enrollment, Expansion & Replacement of Patients
This study will evaluate pazopanib in combination with RAI in a dose-escalation scheme, whereby cohorts of n=3 patients will be enrolled and administered increasing doses of RAI until the MTD/RP2D is determined.
For each cohort, 3 patients will be enrolled and administered pazopanib and RAI at the assigned dose level. Safety data through week 14 for all 3 patients must be reviewed before enrollment of the next cohort can be considered.
If none of the 3 patients experiences a DLT (see §5.12) after week 14, dose escalation may proceed and 3 new patients may be enrolled in the next cohort (cohort 2) and administered pazopanib plus RAI at the next dose level. Cohort 3 will be enrolled and advanced in this same manner. If 1 of 3 patients in a cohort experiences a DLT during Cycle 1, the cohort will be expanded and up to 3 additional patients must be treated at that dose level before RAI dose escalation can proceed. If a total of 1 of 6 patients experiences a DLT during Cycle 1, dose escalation may continue. If 2 or more patients in a cohort experience a DLT in Cycle 1, no additional patients will be treated at that dose of RAI, and that dose level will be considered unacceptable. Once the MTD/RP2D (defined as the highest dose level at which 0 of 3 or 1 of 6 patients experiences a DLT in Cycle 1) has been identified, up to 3 additional patients should be enrolled at that dose level of RAI to ensure a total of 6 patients are treated at the RP2D.
Patients will be initiated at Dose Level 1. In the case of ≥ 2 patients with DLT, a de-escalation will occur to enroll patients onto Dose Level -1.

Dose-Limiting Toxicities (DLT)
Toxicity will be evaluated using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE v 4.03).
Dose Limiting Toxicity (DLT) is defined as any study-drug related adverse event, occurring during and the RAI therapy through to the end of pazopanib therapy at 8 weeks post RAI, which meets the following criteria:  Any Grade ≥ 3 hematologic toxicity lasting ≥ 5 days, or febrile neutropenia  Any Grade 4 hematologic toxicity.
 Any ≥ Grade 3 non-hematologic toxicity, except diarrhea, nausea or vomiting will only be considered dose limiting toxicity when ≥ Grade 3 toxicity occurs despite adequate anti-emetics or anti-diarrhea medications.
 Treatment delay due to toxicity lasting greater than 14 days since the last dose of pazopanib.
"Study-drug related" refers to events that are possibly or probably related to the administration of pazopanib or the combined treatment regimen of pazopanib and RAI, and not clearly attributed to other causes (Toxicities during the administration of pazopanib alone during weeks 1 to 4 prior to RAI therapy will not be considered a DLT for dose escalation purposes as RAI will not have been administered in combination with pazopanib). Patients will be replaced if:  they are unable to complete at least 14 days of continuous dosing of pazopanib alone prior to combined RAI therapy (patients can continue if drug is held or dose reductions are required down to 600 mg po once daily prior to RAI therapy). OR  they must discontinue the study prematurely due to disease-related complications (e.g., disease progression) or for any other reason(s). AND  they have not experienced a DLT Note: DLTs are adverse events that occur during the administration of and meet the specific criteria outlined above. The presence or absence of DLTs dictates whether cohorts must be expanded and whether or not dose escalation (enrollment of the next cohort) can occur. However, individual subjects who experience DLTs may nevertheless receive additional doses of pazopanib, following careful medical evaluation and appropriate treatment and/or a dose delay at the discretion of the Investigator.

Maximum Tolerated Dose
The maximum tolerated dose (MTD) will be the highest dose at which no more than one of six patients experience a DLT. The MTD level in this study will be expanded to enroll up to 6 evaluable patients. The MTD and general tolerability will be used in the determination of the RP2D.

Dose Modifications
In order to maintain dose-intensity and cumulative dose-delivery on this study, reasonable efforts will be made to minimize dose reduction and treatment delays as specified. Any patient whose treatment is delayed must be evaluated on a weekly basis until adequate hematologic and non-hematologic parameters have been met. No intra-patient dose escalation is planned for this study. Patients should be monitored for study-drug related toxicity according to the procedures outlined in Appendix A.
The investigator should carefully assess all treatment-associated toxicities and, whenever possible, determine if they can reasonably be attributed to pazopanib alone, RAI, or the combination regimen. If appropriate, dose delays and/or adjustments should be restricted to the suspected causative agent. As previously noted, toxicity grades are defined using the NCI CTCAE version 4.03.
 In general, no more than two dose reduction is allowed for hematological or non-hematological toxicities of pazopanib (i.e. any patient who has had 2 dose reductions and who experiences a toxicity that would cause a third dose reduction should be discontinued from the study).  Any patient who requires a dose reduction of pazopanib will continue to receive the reduced dose for the remainder of the study.  No dose escalations are allowed in this study.

Pazopanib Dose Modifications
Refer to the Pazopanib label for current recommendations regarding dose delays and reductions.
As a general rule, if dose reduction of pazopanib is necessary, the dose should be reduced stepwise by 200 mg at each step, and the subject should be monitored for approximately 10 to 14 days at each dose level. If toxicity does not abate during this monitoring time, the IP may need to be interrupted and/or the dose further decreased with continued monitoring for an additional 10-14 days at each dose level, and so on.
If a subject's treatment has been interrupted for more than 14 days, the Investigator must contact the NCCN to review the subject's condition in order to resume the treatment. Patients that require dose reductions after 400 mg po once daily dosing of pazopanib should be taken off study.

Dose Interruptions/Modifications for Specific, Non-liver Related, Toxicities
Recommendations for investigational product dose interruptions/modifications in case of specific treatment-emergent AEs are provided in Table below. Management of Diarrhea and Nausea and Vomiting will be described in Appendix H Table 3 Dose Modification Algorithms for Potential Treatment-Related Adverse Events

AE Terms & Descriptions Dose Modification Algorithms
Hypertension (A). Asymptomatic and persistent SBP of 140 and <170 mmHg, or DBP  90 and < 110 mmHg, or a clinically significant increase in DBP of 20 mmHg (but still below 110 mmHg).
Step 1. Continue pazopanib at the current dose.
Step 2. Adjust current or initiate new antihypertensive medication(s).
Step 3. Titrate antihypertensive medication(s) during next 2 weeks as indicated to achieve well-controlled a blood pressure (BP). If BP is not well-controlled within 2 weeks, consider referral to a specialist and go to scenario (B).
Step 1.Consider reducing or interrupting IP, as clinically indicated.
Step 2. Adjust current or initiate new antihypertensive medication(s).
Step 3. Titrate antihypertensive medication(s) during next 2 weeks as indicated to

AE Terms & Descriptions Dose Modification Algorithms
achieve well-controlled BP.
Step 4. Once BP is well-controlled, restart pazopanib dose-reduced by 200 mg if IP was interrupted.
Step 3. Titrate antihypertensive medication(s) during next 2 weeks as indicated to achieve well-controlled BP. Referral to a specialist for further evaluation and follow-up is also recommended.
(D). Refractory hypertension unresponsive to above interventions. Discontinue pazopanib and continue follow-up per protocol.

Prolongation of QTc Interval:
If the QTc is prolonged, the ECG should be manually read to ensure accuracy of the reading. The values below refer to manually-read ECGs. REFER READER TO ECG SECTION IN PROTOCOL QTc  480 < 500 msec Continue pazopanib; monitor as clinically indicated.
QTc 500 msec Discontinue pazopanib and continue follow-up per protocol.
Step 2. Weekly UPC or 24-hr urine protein monitoring until UPC is < 3 or 24-hr urine protein is < 3 grams. Then restart pazopanib dose-reduced by 200 mg.
Step 4. If UPC ≥ 3 or 24-hr urine protein ≥ 3 recurs and the pazopanib dose can no longer be reduced, discontinue pazopanib and continue follow-up per protocol.

Hemorrhage /Bleeding: Investigate and document underlying etiology of the bleeding
Grade 1 For hemoptysis, interrupt pazopanib and contact NCCN to discuss whether further treatment with pazopanib is appropriate.
For other Grade I hemorrhage/bleeding events, continue pazopanib at the current dose; monitor as clinically indicated.

Grade 2
Step 1. If pulmonary or GI bleed (other than hemorrhoidal bleeding), discontinue IP and continue follow-up per protocol. Otherwise, interrupt IP until the AE resolved to  Grade 1.
Step 2. Restart pazopanib; consider reducing dose and monitor as clinically indicated.

Grade 3 or 4, or
Recurrent  Grade 2 event after dose interruption/reduction.
Discontinue pazopanib and continue with follow-up per protocol. Step 1. Interrupt pazopanib.
Step 2. Initiate and monitor anticoagulation as clinically indicated.
Step 3. Resume pazopanib same dose, only if all of the following criteria are met:  The subject must have been treated with anticoagulant at the desired level of anticoagulation for at least one week. Subject should be monitored as clinically indicated during anticoagulation treatment and after resuming study treatment. When treating with warfarin, international normalized ratio (INR) should be monitored within three to five days after any change in pazopanib dosing (eg, re-initiating, escalating/de-escalating, or discontinuing pazopanib), and then at least weekly until the INR is stable. The dose of warfarin (or its derivatives) may need to be adjusted to maintain the desired level of anticoagulation Grade 4 and/or PE Discontinue pazopanib and continue follow-up per protocol.

Arterial Thrombosis/Ischemia
Any Grade Discontinue pazopanib and continue follow-up per protocol.

Thrombocytopenia: Investigate and document underlying cause
Grade 1 or 2 Continue pazopanib with current dose; monitor as clinically indicated.
Step 2. Restart pazopanib, dose-reduced by 200 mg and monitor as clinically indicated.
If no recovery to ≤ Grade 2 or recurrent Grade 3 or 4 thrombocytopenia, discontinue pazopanib and follow-up per protocol.

Dose Interruptions/Modifications for Hepatotoxicity
Recommendations for pazopanib dose interruptions/modifications in case of liver-related treatmentemergent AEs are provided in Table 4. As a general rule, since many subjects are taking multiple concurrent medications, it is critical to (a) do a thorough evaluation of the subject's concurrent medications, and (b) identify and discontinue those with known hepatotoxicity and replace with a nonhepatotoxic equivalent for the same indication if necessary. Liver dysfunction must be fully evaluated even if clinical signs and symptoms indicate progression of liver tumor lesions. Imaging studies may be obtained to document potential progression of malignancy. x ULN without bilirubin elevation (defined as total bilirubin b < 2.0 x ULN or direct bilirubin ≤ 35%) and without hypersensitivity symptoms (e.g., fever, rash)

Liver Event Monitoring Criteria:
(1) Continue pazopanib at current dose levels.
(2) Monitor subject closely for clinical signs and symptoms; perform full panel LFTs weekly or more frequently if clinically indicated until ALT/AST is reduced to Grade 1.
(C). ALT > 8.0 x ULN without bilirubin elevation (defined as total bilirubin < 2.0 x ULN or direct bilirubin ≤ 35%) and without hypersensitivity symptoms (e.g., fever, rash) 1 st occurrence -Liver Event Interruption CriteriaError! Reference source not found.: (1) Interrupt pazopanib until toxicity resolves to Grade 1 or baseline. Report the event to GSK as an SAE within 24 hours of learning of its occurrence . Make every reasonable attempt to have subjects return to the clinic within 24 to 72 hours for repeat liver chemistries and liver event follow up assessments. (2) Liver imaging and other laboratory investigations should be considered as clinically appropriate.
(3) Monitor subject closely for clinical signs and symptoms; perform full panel LFTs weekly or more frequently if clinically indicated until ALT/AST is reduced to Grade 1. (4) If the subject is benefiting from the study treatment, contact NCCN for possible re-challenge. Retreatment may be considered if ALL following criteria are met: -ALT/AST reduced to Grade 1 -Total bilirubin <1.5 x ULN or direct bilirubin 35% -No hypersensitivity signs or symptoms -Subject is benefiting from therapy.

Recurrence -Liver Event Stopping Criteria:
Discontinue pazopanib permanently and monitor subject closely for clinical signs and symptoms; perform full panel LFTs weekly or more frequently if clinically indicated until ALT/AST is reduced to Grade 1. (D). ALT >3.0 x ULN with concomitant elevation in bilirubin b (defined as total bilirubin  2.0 x ULN; with direct bilirubin > 35%) or with hypersensitivity symptoms (e.g., fever, rash).

Liver Event Stopping CriteriaError! Reference source not found.:
(1) Discontinue pazopanib immediately, report the event to GSK as an SAE within 24 hours of learning of its occurrence. Make every reasonable attempt to have subjects return to the clinic within 24 hours for repeat liver chemistries and liver event follow up assessments. (2) Consult a gastroenterologist / hepatologist, and perform the following assessments to identify potential co-factors: -Eosinophil count -Viral serology for hepatitis A, B, C and E, cytomegalovirus, Epstein-Barr virus (IgM antibody, heterophile antibody, or monospot testing) -Anti-nuclear antibody, anti-smooth muscle antibody, Type 1 anti-liver kidney microsomal antibodies. -Serum creatinine phosphokinase for possible muscle injury caused LFT elevation -Liver imaging -Consider toxicological blood screen for possible contributing chemical/medical entities (3) Monitor subject closely for clinical signs and symptoms; record the appearance or worsening of clinical symptoms of hepatitis, or hypersensitivity, such as fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever rash or eosinophilia as relevant on the AE report form. Perform full panel LFTs weekly or more frequently if clinically indicated until LFTs are reduced to Grade 1. For isolated total bilirubin b elevation without concurrent ALT increases (defined as ALT <3 X ULN).
(1) Isolated hyperbilirubinemia (i.e., in the absence of elevated ALT or other signs/symptoms of liver injury) does not require dose modification. Pazopanib inhibits UGT1A1 and OATP1B1, which can cause elevation of indirect (unconjugated) bilirubin in the absence of liver injury.. (2) If bilirubin is >1.5 x ULN in the absence of ALT elevation, fractionation of bilirubin elevation should be performed. If bilirubin is >35% direct (conjugated), further evaluation for underlying cause of cholestasis should be performed.
Abbreviations: ALT alanine aminotransferase; AST aspartate aminotransferase; IP investigational product; LFT liver function tests; SAE serious adverse event; ULN upper limit of normal

TREATMENT OF INVESTIGATIONAL PRODUCT OVERDOSE
No maximum tolerated dose (MTD) was reached in the dose escalation study of pazopanib administered as a single agent at repeated doses of up to 2000 mg/day (Study VEG10003). Systemic exposure to pazopanib at steady-state appeared to plateau at doses greater than 800 mg once daily. Increases in the daily pazopanib dose above 800 mg in the fasted state resulted in a small or no increase in mean systemic exposure to pazopanib.
In the event of pazopanib overdose (defined as administration of more than the protocol-specified dose), the investigator should contact GSK. Decisions regarding pazopanib dose modifications or interruptions will be made by the investigator in consultation with GSK based on the clinical evaluation of the subject. Following an overdose, additional monitoring of the subject for AEs/SAEs and laboratory abnormalities should be considered.

DATA ANALYSIS/STATISTICAL METHODS
Sample Size Determination: The number of patients to be enrolled in the study will depend upon the observed safety profile, which will determine the number of patients per dose level and the number of dose escalations. It is anticipated that a total of approximately 12 to 15 patients (maximum of 18 patients) will be enrolled in this study with an estimated annual accrual of 12. The study will take place at a single center.
The operating characteristics of this study design are shown in Table 5, which provides the probability of escalation to the next higher dose for each underlying true DLT rate. For example, for a toxicity that occurs in 5% of subjects, there is a greater than 95% probability of escalating. Conversely, for a common toxicity that occurs with a rate of 70%, the probability of escalating is <5%.  Table 6 shows the probability of failing to observe toxicity in a sample size of 3 or 6 patients given various true underlying toxicity rates. For example, with 6 patients, the probability of failing to observe toxicity occurring at least 40% of the time is less than 5%.

Data Analysis
The study population for toxicity analyses will include all patients enrolled in the study who receive at least one dose of study medication pazopanib. Efficacy will be determined based on patients who receive the combination of pazopanib and RAI. Due to the exploratory nature of this study, no confirmatory inferential analyses are planned, and no imputation for missing data will be done. Descriptive statistics (such as means, medians, standard deviations and ranges for continuous data and percentages for categorical data) will be used to summarize patient characteristics, treatment administration/compliance, efficacy, safety, and correlative study data. Data will also be displayed graphically, where appropriate.

Analysis of Primary Endpoint
The primary end point of this phase I study is to assess the toxicity and the occurrence of dose limiting toxicity (DLT) when pazopanib is given in conjunction with radioiodine to establish the MTD and RP2D in combination. Toxicities will be classified by NCI common toxicity criteria. For each cohort DLT's will be summarized by category (hematologic and non-hematologic) and by MedDRA preferred term.
The period for determination of dose-limiting toxicity (DLT) for the purposes of dose escalation and the MTD will be determined from the first 8 weeks post radioactive iodine administration; whereas DLT, dose modifications, and other toxicities will be assessed over all courses when determining the optimal dose for phase II evaluation. Descriptive statistics will be calculated for all variables and responses; continuous data will be expressed as their mean ± standard deviation, median and range, and categorical data will be listed by frequency of occurrence and proportion of total (with 95% confidence intervals) for all enrolled patients and by dose cohort.

Analysis of Secondary Endpoints
Secondary endpoints include post-pazopanib treatment tumor response (RECIST criteria), and TTP with respect to censored baseline imaging and suppressed thyroglobulins at week 14+. Tumor response and TTP will be compared to responses and duration of TTP after last prior historical RAI treatment.
Objective Response: For each cohort and tumor type, the best response (CR, PR, SD or PD according to RECIST criteria) for each patient with measurable disease who received pazopanib in combination with RAI will be listed. Progression-free survival will be determined in days or week and waterfall plots and graphical data will be provided where suitable.

Analysis of Other Endpoints
Analysis of Clinical Labs: Listing tables will be prepared for each laboratory measure, and will be structured to permit review of the data by patient as they progress on treatment. The tables will list the schedule, day and cycle of treatment, pazopanib dose, RAI dose and associated NCI CTCAE toxicity grade.
Summary tables and graphic displays, as appropriate, will be prepared to examine the distribution of these toxicities per cycle. Graphic displays and shift tables may be provided to illustrate the results over time on study. Assessment of cumulative toxicities may be made.

Analysis of Other Endpoints
Tertiary endpoints involve assessing increased radioiodine uptake, retention (through comparison of radioiodine scans in prior historical studies) and correlative effects of pazopanib on tumor blood flow and response in WDTC (assessed by dynamic FDG-PET). will be predominantly descriptive with graphical information where available.

ASSESSMENTS
Safety Assessment and Determination of Dose Level for Subsequent Patient Cohorts. Subjects will be required to have the following assessments, as specified in the Schedule of Events (Appendix A). These assessments may be performed more frequently than specified if clinically indicated.

Laboratory Safety Assessments
Comprehensive blood work: Hematology and blood chemistry will be drawn at the time points described in the Schedule of Events (Appendix A) and analyzed at local laboratories. Investigators may have additional blood tests performed for the purpose of planning treatment administration, dose modification, or following adverse events.
Pregnancy test: Serum or urine pregnancy test for women of childbearing potential will be performed by a local laboratory. A screening serum -HCG pregnancy test is mandatory for all women of childbearing potential and should be done within 2 weeks prior to the first dose of study medication. Thereafter, the serum pregnancy test only needs to be repeated if clinically indicated or as required by local regulation.

Other Safety Assessments
Physical examination: At screening, a complete medical history and physical examination-including height (baseline only), body weight, vital signs, and examination of relevant body organ systems, concomitant treatments, performance status will be performed and repeated at subsequent visits, according to Appendix A. Any new or worsening medical condition from the baseline level (pre-dose on Day 1) should be recorded in the AE or SAE eCRF.

Specific Additional Safety Assessments
Vital Signs and Blood Pressure Monitoring Hypertension is a common drug-related AE with pazopanib; therefore, frequent blood pressure monitoring is mandatory.
ECOG PS If subjects discontinue study treatment without disease progression (e.g., withdrawal of study treatment due to unacceptable toxicity), continue the assessments of ECOG PS in accordance with the disease assessments until subjects experience disease progression.

12-Lead Electrocardiogram
In clinical studies with pazopanib, events of QT prolongation have occurred. A 12-lead ECG will be obtained according to Appendix A.
Screening/Baseline QTc o If QTc interval is > 480 msecs, then 2 additional ECGs should be obtained over a brief period of time (e.g., within 15-20 minutes) to confirm the abnormality. o The average QTc interval will be determined from the 3 ECG tracings by manual evaluation and will be used to determine if the subject will be excluded from the study. o If the average QTc interval is >480 msec, then the subject is not eligible to participate in the study.
During Treatment QTc o If the average QTc is less ≤ 500 msec, the subject may continue therapy.
o If a QTc >500 msec is noted on a scheduled or unscheduled ECG, then 2 additional ECGs should be obtained over a brief period of time (e.g., within 15-20 minutes) to confirm the abnormality.  Each ECG tracing should be evaluated manually to obtain RR and QT intervals for QTc calculation.  The average QTc will be determined from the 3 ECG tracings by manual evaluation and will be used to determine appropriate next steps. A cardiologist should be consulted, if necessary, to determine the diagnosis of QT prolongation.
o If the average QTc is >500 msec, the following steps should be taken:  Study treatment should be interrupted immediately.  Electrolytes, particularly potassium and magnesium, should be checked and corrected if abnormal.  Concomitant medications with a potential for QTc interval prolongation should be discontinued if clinically appropriate.
 A cardiologist should be consulted to assist with the management of the subject if clinically appropriate.  The subject should be treated appropriately for QTc prolongation and monitored until resolution is documented by a repeat ECG with QTc interval returning to ≤ 480 msec.
o If the QTc prolongation > 500 msec is clearly and causally associated with an underlying situation that is clearly reversible (e.g., a subject with severe diarrhea and hypokalemia with QTc prolongation that resolves once the diarrhea improves and potassium is corrected), then the subject may restart study drug once the underlying situation has been corrected (e.g., electrolytes supplemented) and the QTc interval prolongation has resolved.
o If the QTc prolongation > 500 msec is not clearly and causally associated with an underlying situation that is clearly reversible, then the subject should have study drug permanently discontinued and be withdrawn from the study.

Safety Assessments upon Discontinuation of Study Treatment
Subjects should have the following safety assessments performed upon discontinuation of study treatment: physical examination and vital signs, ECOG PS, clinical chemistry, hematology, and UPC. Laboratory tests do not need to be repeated if less than 4 weeks have elapsed since most recent assessments. Coagulation tests and ECG should be performed if clinically indicated. The date and reason for discontinuation of study treatment must be recorded clearly in the Study Treatment Discontinuation eCRF.

7.3.
Adverse Events Assessment of adverse events will include type, incidence, severity (graded by the National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE], Version 4.03), timing, seriousness, and relatedness; and laboratory abnormalities. Patients who receive 1 or more doses of pazopanib will be evaluable for toxicity.

Adverse Event Reporting
In the event of an adverse event the first concern will be for the safety of the subject. The adverse event recording period will start on the first day of study treatment and end 28 days (+/-3 days) of termination pazopanib dosing. All adverse events will be reported for the 14 weeks of pazopanib therapy. Thereafter, only AEs which can reasonably be attributed to pazopanib and/or RAI will be reported.

Adverse Event Causality
The Investigator will use the following definitions to assess the relationship of the adverse event to the use of study drug: Related -An adverse event has a strong temporal relationship to study drug, recurs on rechallenge or is known to be an effect of the study drug. Another reasonable etiology either doesn't exist or is unlikely. Possibly Related -An adverse event has a strong temporal relationship to the study drug and an alternative etiology is either equally or less likely when compared to the potential relationship to study drug. The SAE report should comprise a full written summary, detailing relevant aspects of the adverse events in question. Where applicable, information from relevant hospital case records and autopsy reports should be included. Follow-up information should be forwarded to GSK within 24 hours.
SAEs brought to the attention of the Investigator at any time after cessation of pazopanib and considered by the investigator to be related or possibly related to pazopanib must be reported to GSK if and when they occur. Additionally, in order to fulfill international reporting obligations, SAEs that are related to study participation (e.g., procedures, invasive tests, change from existing therapy) or are related to a concurrent medication will be collected and recorded from the time the subject consents to participate in the study until he/she is discharged In addition, the Investigator will adhere to the safety reporting requirements and timelines described in the Clinical Trial Agreement with National Comprehensive Cancer Network (NCCN).

Evaluation of Disease Progression
During the course of the study, the Investigator will assess a subject's disease status based on the radiological assessment and clinical assessment, and will make clinical decisions on the subject's care based on medical judgment..
Disease response criteria will be determined as per RECIST criteria version1.1 (Appendix D)

REGULATORY, QUALITY AND ADMINISTRATIVE REQUIREMENTS 8.1 Source Data Verification
Monitoring of source documents will occur during the active treatment phase of the trial. Monitoring visits will be arranged by the Monitoring Program Coordinator at the Fred Hutchinson Cancer Research Center. The monitors are independent contractors and are external to the Cancer Consortium (University of Washington and Fred Hutchinson Cancer Research Center). Study monitors will perform ongoing source data verification to confirm that critical protocol data transcribed on the CRFs by authorized site personnel are accurate, complete, and verifiable from source documents. To facilitate source documentation verification, the investigator(s) and institution(s) must provide the Monitor direct access to applicable source documents and reports for trial-related monitoring, audits, and IRB/EC review.
The investigational site must also allow inspection by applicable regulatory authorities.

Compliance with Laws and Regulations
The proposed study will be conducted according to

Informed Consent
The informed consent documents must be signed and dated by the patient, or the patient's legally authorized representative, before his or her participation in the study. The case history for each patient shall document that informed consent was obtained prior to participation in the study. A copy of the informed consent documents must be provided to the patient or the patient's legally authorized representative.

Institutional Review Board
This protocol, the informed consent document, and relevant supporting information must be submitted to the IRB for review and must be approved before the study is initiated. In addition, any advertising materials must be approved by the IRB. The study will be conducted in accordance with applicable national and local health authority and IRB requirements.
The Principal Investigator is responsible for keeping the IRB apprised of the progress of the study and of any changes made to the protocol as deemed appropriate, but in any case the IRB must be updated at least once a year. In addition, the Principal Investigator is required to promptly notify the IRB of all adverse drug reactions that are both serious and unexpected. This generally refers to serious adverse events that are not already identified in the Investigator Brochure and that are considered possibly or probably related to the study drug by the Investigator.

Retention of Records
U.S. FDA regulations (21 CFR §312.62[c]) require that records and documents pertaining to the conduct of this study and the distribution of investigational drug-including CRFs, consent forms, laboratory test results, and medication inventory records-must be retained by the Principal Investigator for 5 years after marketing approval is received for pazopanib or for 5 years after all clinical and product development of pazopanib is discontinued and the applicable national and local health authorities are notified. The Principal Investigator must notify GSK/NCCN prior to the destruction of any records relating to this study.

Drug Accountability
GSK Pharmaceuticals will provide the Principal Investigator with adequate supplies of pazopanib for the study population and protocol requirements. Damaged supplies will be replaced. Drug supplies must be kept in an appropriate, secure area (e.g., locked pharmacy) and stored in accordance with the conditions specified in this protocol and on the investigational drug labels.
Drug supplies are to be used only in accordance with this protocol. Investigational drug may be administered only to eligible subjects who are enrolled in the study, and the Sponsor-Investigator is accountable for all used and unused investigational drug. Used and partially used study drug will be destroyed according to the standard practice of the Investigational Pharmacy at the University of Washington / Seattle Cancer Care Alliance. Upon written notification, the Principal Investigator will ship unused investigational drug according to instructions provided by GSK Pharmaceuticals, Inc. All material containing pazopanib will be treated and disposed of as hazardous waste in accordance with governing regulations.
Study drug accountability records should be maintained by the site in accordance with the regulations. A master drug log must be maintained of all pazopanib vials received, dispensed (including the lot number of the vials, the subject's ID number, the subject's initials, and the dates each vial is dispensed), and returned or destroyed. In addition, a subject-specific record of each vial administered, including the date and lot number of each vial, will be maintained with the case file for each subject. Any discrepancy in the drug distribution logs (master log and subject logs) must be explained in detail.

Premature Closure of the Study
This study may be prematurely terminated, if in the opinion of the Principal-Investigator, NCCN or GSK Pharmaceuticals Inc, there is sufficient reasonable cause. Written notification documenting the reason for study termination will be provided to the Principal Investigator, NCCN or GSK Pharmaceuticals Inc by the terminating party.
Circumstances that may warrant termination include, but are not limited to:  Determination of unexpected, significant, or unacceptable risk to patients.  Failure to enter patients at an acceptable rate.  Insufficient adherence to protocol requirements.  Insufficient complete and/or evaluable data.  Plans to modify suspend or discontinue the development of the drug. 12 Page 55 of 67

CLINICAL LABORATORY ASSESSMENTS
Laboratory assessments should be performed as indicated in the Schedule of Protocol Assessments and Events (Appendix A) Table. These assessments may be carried out within 3 days before the actual visit to allow flexibility in scheduling. Assessments may be performed more frequently if clinically indicated. Correction of electrolytes (most importantly, potassium, magnesium and calcium) to within normal ranges should take place prior to study entry and during study conduct as clinically indicated.
All laboratory tests with values that become abnormal and clinically significant while the subject is participating in the study or within 28 days after the last dose of study drug should be repeated until the values return to normal or baseline.
The a) Estimated creatinine clearance should be calculated using the Cockroft and Gault method (Appendix G). Alternatively, creatinine clearance can be measured directly by 24-hour urine collection. b) A direct bilirubin level should be obtained if the total bilirubin level is greater than 1.5 X upper limit of normal (ULN). See Section 5.14 and 5.14.1 for stopping criteria and dose modification guidelines for treatment-emergent liver function abnormality. c) Coagulation tests may also be performed in response to an AE/SAE of bleeding and as clinically indicated. d) UPC should be evaluated as described in Appendix F or by 24