Conceived and designed the experiments: SD JM FF JG. Performed the experiments: DF SA AS FD DM DC DK RU RR SC JP NL CW ET. Analyzed the data: SD NL JM. Contributed reagents/materials/analysis tools: FF. Wrote the paper: SD.
Wyeth/Pfizer supplied study drug at no charge per an investigator originated proposal written by SD. SD has been a consultant to Novartis. There are no patents, products in development or marketed products to declare. This does not alter the authors' adherence to all the PLoS ONE policies on sharing data and materials.
Tuberous sclerosis (TSC) related tumors are characterized by constitutively activated mTOR signaling due to mutations in
We completed a phase 2 multicenter trial to evaluate the efficacy and tolerability of the mTOR inhibitor, sirolimus, for the treatment of kidney angiomyolipomas.
36 adults with TSC or TSC/LAM were enrolled and started on daily sirolimus. The overall response rate was 44.4% (95% confidence intervals [CI] 28 to 61); 16/36 had a partial response. The remainder had stable disease (47.2%, 17/36), or were unevaluable (8.3%, 3/36). The mean decrease in kidney tumor size (sum of the longest diameters [sum LD]) was 29.9% (95% CI, 22 to 37; n = 28 at week 52). Drug related grade 1–2 toxicities that occurred with a frequency of >20% included: stomatitis, hypertriglyceridemia, hypercholesterolemia, bone marrow suppression (anemia, mild neutropenia, leucopenia), proteinuria, and joint pain. There were three drug related grade 3 events: lymphopenia, headache, weight gain. Kidney angiomyolipomas regrew when sirolimus was discontinued but responses tended to persist if treatment was continued after week 52. We observed regression of brain tumors (SEGAs) in 7/11 cases (26% mean decrease in diameter), regression of liver angiomyolipomas in 4/5 cases (32.1% mean decrease in longest diameter), subjective improvement in facial angiofibromas in 57%, and stable lung function in women with TSC/LAM (n = 15). A correlative biomarker study showed that serum VEGF-D levels are elevated at baseline, decrease with sirolimus treatment, and correlate with kidney angiomyolipoma size (Spearman correlation coefficient 0.54, p = 0.001, at baseline).
Sirolimus treatment for 52 weeks induced regression of kidney angiomyolipomas, SEGAs, and liver angiomyolipomas. Serum VEGF-D may be a useful biomarker for monitoring kidney angiomyolipoma size. Future studies are needed to determine benefits and risks of longer duration treatment in adults and children with TSC.
Clinicaltrials.gov
Tuberous sclerosis (TSC) is a tumor suppressor gene disorder characterized by the development of benign tumors (hamartomas) in multiple organs
Hamartin and tuberin, the
Kidney angiomyolipomas are a common and problematic major clinical feature of TSC. These tumors consist of blood vessels, smooth muscle, and fat cells. They occur in approximately 75% of TSC patients over the age of 6–8 years
We implemented this multicenter sirolimus trial to provide efficacy and safety data regarding the treatment of TSC associated angiomyolipomas with sirolimus. In addition to the primary endpoints evaluating safety and kidney angiomyolipoma response, we investigated the utility of mTOR inhibitor treatment for many common clinical features of TSC by collecting secondary endpoint data on liver angiomyolipomas, subependymal giant cell astrocytomas (SEGAs), tubers, subependymal nodules (SENs), seizures, skin lesions (facial angiofibromas, hypomelanotic macules, shagreen patches, forehead plaques), renal cysts, kidney function, and lung function in those individuals with LAM. We also collected data on TSC gene mutations and explored the utility of serum vascular endothelial growth factor D (VEGF-D) as a biomarker for TSC associated kidney angiomyolipomas.
Participants were recruited at 6 clinical sites in the U.S. Five of the clinical sites were comprehensive TSC clinics (Boston, Cincinnati, Loma Linda, Hartford, New York) and one was a Urology clinic (Dallas). The protocol was approved by the appropriate institutional review boards (IRBs) which included: 1) Dana-Farber Cancer Institute IRB; 2) UT Southwestern Medical Center IRB; 3) Connecticut Children's Medical Center IRB; 4) Cincinnati Children's Medical Center IRB; 5) NYU School of Medicine IRB; 6) Loma Linda University IRB. The study was registered with clinicaltrials.gov (ID NCT00126672) and conducted according to institutional and national guidelines. This was an open label, single arm, multicenter study with a Simon two-stage design
Eligible patients were 18–65 years old with at least one kidney angiomyolipoma ≥2 cm in diameter and a diagnosis of TSC or LAM. Additional inclusion criteria included adequate renal, liver, and bone marrow function (Cr<4.1, SGOT, SGPT, TBili, Alk Phos all<2× normal, hematocrit >30, normal WBC, and platelets >100,000). Patients were excluded if they had unstable seizures (recent changes in seizure pattern or use of anti-epileptic agents), clinically significant bleeding from kidney angiomyolipoma(s), severe LAM (dependent on continuous supplemental oxygen or limited performance status), evidence for accelerating renal dysfunction or acute renal failure, renal cell carcinoma (suspected or known), active infection, recent use of other investigational agent in the 30 days prior to study entry, or prior history of coronary artery disease. Pregnant or nursing women were also excluded.
The primary objectives were the evaluation of kidney angiomyolipoma response and tolerability of sirolimus. The overall response rate was determined using magnetic resonance imaging (MRI) before and after treatment according to the Response Evaluation Criteria in Solid Tumors (RECIST)
Sirolimus treatment was initiated with a loading dose of 6 mg by mouth on day 1 followed by 2 mg by mouth daily. Sirolimus is FDA approved for use after kidney transplantation and this is the standard dose used in the kidney transplant population. The dose was then adjusted to maintain a target blood level of 3–9 ng/ml for the first 16 weeks. After week 16, the dose of sirolimus was increased to a target level of 9–15 ng/ml unless there was evidence for a partial response or complete response by kidney MRI. There was no change in dose for those with a partial response or complete response at week 16. Trough sirolimus levels were checked every 8–12 weeks (at 24 weeks, 32 weeks, 40 weeks, and 52 weeks) in all patients until the 12-month (week 52) study visit. If the sirolimus dose was below target, the dose was increased by 1–2 mg until the target trough level was achieved. Sirolimus levels were checked every 2–3 weeks while the dose was adjusted.
There was a wide range of sirolimus doses required to maintain target trough levels. At the end of year 1 (week 52), the mean daily dose was 6.7 mg per day. The lowest dose was 1 mg every other day and the highest dose was 24 mg per day. Sirolimus is metabolized by CYP3A4 and at the dose extremes, subjects were taking concomitant drugs that likely had a significant impact on drug metabolism. The participant on the lowest dose was also on verapamil, a CYP3A4 inhibitor, which should reduce the clearance of sirolimus. The participant on the highest dose was on primidone, a CYP3A4 inducer, which should increase the clearance of sirolimus. During our study there were 5 participants that exceeded the upper limit of our target levels (15 ng/ml) at any time. Almost all participants (28/33, 85%) required a one time dose increase per protocol at week 16 because they did not have a partial response.
We had a low threshold to hold sirolimus doses during minor infections or to allow symptomatic mouth ulcers to heal, so many participants had drug held at some point during the course of the study. Per our protocol, if there were more than 10 consecutive missed doses, these were made up at the end of year 1 on study so that 28 participants received ∼52 weeks of sirolimus treatment (range 49–56 weeks). We monitored sirolimus levels every 8–12 weeks in order to avoid toxicity by holding or reducing doses if the target drug level was exceeded. There is substantial evidence indicating a single steady state trough sirolimus level corresponds well to drug exposure because it has been well documented that the 24 hour trough sirolimus level correlates well with the AUC (area under concentration time curve)
Serum was collected using standard clinical red top serum collection vacutainer tubes with no additive. After clot formation, the tube was spun at low speed, the serum was collected, aliquoted, frozen, and shipped overnight on dry ice to the Dabora Lab at Brigham and Women's Hospital, Boston, MA. VEGF-D levels were measured using ELISA (Quantikine Human VEGF-D Immunoassay kit from R&D Systems, catalog number DVED00). The VEGF-D ELISA was done according the manufacturer's protocol (Quantikine Human VEGF-D Immunoassay kit from R&D Systems) with the following modifications: 1) known concentrations of 125, 250, 500, 1000, 2000, 4000, and 40,000 pg/ml were used to generate the standard curve; 2) we used a correction wavelength of 550 nm instead of 540 nm because 540 nm was not an option on our plate reader (THERMOmax microplate reader, Molecular Devices Corp.); 3) sample concentrations were extrapolated from the standard curve using GraphPad Prism software (version 4.01) using the one-site competition option in order to optimize the fit of the standard curve
Since this trial was designed in 2003 (before there was any published clinical data available on the efficacy of mTOR inhibitors for TSC related tumors), a two-stage adaptive design was employed because it would allow early stopping if there was no evidence for response in a small cohort of subjects, but continuation if there was some early evidence of efficacy
GraphPad Prism software (version 4.01) was used for all data analysis, with a p-value≤0.05 indicating statistical significance. A paired
There were a total of 64 protocol deviations/violations that were reported to the Dana-Farber IRB between March 2007 and August 2009. Deviations/violations occurred in these categories: baseline testing issue-2, baseline testing timing issue-2, consent issue-6, documentation-1, eligibility issue-7, eligibility issue and baseline testing timing-2, enrollment target issue-2, lab test missing-2, lab test timing-7, missing data-1, study conduct issue-3, study drug dispensing issue-1, study drug issue-1, treatment issue-10, visit date issue-13, visit date and leaving study early-3, visit date and missing data-1. These deviations/violations were judged to have minimal impact on risks to the subjects and did not affect overall data quality. Many of the violations/deviations prompted amendments to allow clinically and scientifically acceptable changes that would reduce the number of future deviations/violations. All deviations/violations were submitted to the IRB for review, and our corrective action plan was approved in all cases. We have included the complete list of deviations/violations with the description as reported to the Dana-Farber IRB (
During the course of this study we submitted a total of 3 amendments that modified the study design (Amendments 15, 17, and 20). Amendment 15 was submitted in August 2007 and approved in February 2008. It included the following changes in eligibility requirements: the platelet count requirement was changed to >100,000 (from normal), the white blood count (WBC) requirement was changed to absolute neutrophil count (ANC) >1500 (from WBC normal), eligible age was changed to 3–65 years (from 16–65 years), exclusion of those with kidney bleed was changed to exclusion of those with clinically significant kidney bleed; baseline renal function required was changed to eGFR of at least 30 (from creatinine less than 4.1 ). There were also minor changes made in timing of tests or timing of visits including these: baseline kidney MRI should be done within 4 weeks (instead of 2 weeks); sirolimus levels should be done within 2 weeks of target date. A change was also made to allow CT scanning instead of MRI for patients unable to undergo MRI testing. A number of other minor changes were made to improve or clarify study details. Amendment 17 was submitted in February 2008 and approved in March 2008. The change requested was to increase target enrollment from 36 to 76 participants. However, we were unable to obtain adequate funding to increase the enrollment so unable to implement this change in enrollment. Amendment 20 was submitted in January 2009 and approved in June 2009. This change was requested to allow additional sirolimus treatment during months 12–24 if the treating site investigator judged that this was in the best interest of the study participant. Additional details regarding this amendment can be found in the results section. The final protocol version and CONSORT checklist are included in the supporting information (
We enrolled 36 adults between December 2005 and April 2008. All participants met diagnostic criteria for TSC
Characteristic | Number (range) | % | Characteristic | Number (range) | % |
Ave. age at study enrollment, years | 34 (19–60) |
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Ave. age when TSC diagnosed, years | 13 (0–60) | Subependymal nodules (SENs) |
30 | 83% | |
Diagnosis | Subependymal nodules (average number) | 3.4 (0–8) | |||
TSC | 13 | 36% | Cortical Tubers |
30 | 83% |
TSC & LAM |
23 | 64% | None | 4 | 11% |
Sex | Minimal (0–2) | 3 | 8% | ||
Male | 10 | 28% | Mild (3–5) | 3 | 8% |
Female | 26 | 72% | Moderate (6–10) | 11 | 31% |
Race | Severe (11+) | 13 | 36% | ||
White | 34 | 94% | Unknown | 2 | 6% |
Black | 1 | 3% | Subependymal Giant Cell Astrocytoma |
13 | 36% |
Other | 1 | 3% | Seizures | ||
ECOG performance status 0 | 32 | 89% | chronic | 7 | 19% |
ECOG performance status 1 | 4 | 11% | prior history | 20 | 56% |
never | 8 | 22% | |||
|
unknown | 1 | 3% | ||
Kidney angiomyolipomas |
Cognitive impairment | 15 | 42% | ||
Average sum of the longest diameters (sum LD), cm | 21.2 (2.0–51.8) | None | 21 | 58% | |
Average number of measurable kidney tumors per person | 3.8 (1–10) | Mild | 10 | 28% | |
Angiomyolipoma diameter >4 cm | 25 | 69% | Moderate | 4 | 11% |
Angiomyolipoma diameter >10 cm | 7 | 19% | Severe | 1 | 3% |
Prior invasive kidney procedures | 18 | 50% | Psychological/Behavioral Issues | 18 | 50% |
Nephrectomy | 7 | 19% | ADHD | 1 | 3% |
Biopsy | 3 | 8% | Anxiety | 5 | 14% |
Vascular emobolization | 6 | 17% | Autism | 1 | 3% |
More than one | 2 | 6% | Depression | 2 | 6% |
Kidney Cysts |
22 | 61% | More than one | 9 | 25% |
None | 14 | 39% | None | 18 | 50% |
0–2 Small Cysts (<2 cm) | 5 | 14% | |||
>2 Small Cysts (<2 cm) | 6 | 17% |
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>2 Cysts with at least one >2 cm | 9 | 25% | History of cardiac rhabdomyoma |
4 | 11% |
Classic Polycystic Disease | 2 | 6% | Liver angiomyolipoma | 15 | 42% |
Chronic renal insufficiency (Cr≥1.5 mg/dl) | 6 | 17% | Retinal hamartoma |
10 | 28% |
Proteinuria | 4 | 11% | Genetics | ||
Hematuria | 4 | 11% | 14 | 39% | |
0 | 0% | ||||
|
No mutation identified | 4 | 11% | ||
Facial angiofibromas |
35 | 97% | Mutation unknown (not tested or test inconclusive) | 18 | 50% |
None | 1 | 3% | |||
Macular lesions only on cheek | 3 | 8% | |||
Papular lesions, <3 mm diameter | 22 | 61% | |||
Papular lesions, >3 mm diameter | 10 | 28% | |||
Hypomelanotic macules |
24 | 67% | |||
Shagreen patch |
22 | 61% | |||
Ungual/subungual fibromas |
20 | 56% | |||
Forehead plaque |
14 | 39% |
*TSC major feature.
**TSC minor feature.
After baseline testing was completed, participants were started on oral sirolimus at a dose of 6 mg on day 1, then 2 mg per day. The sirolimus trough level was measured 1–3 weeks later and the dose was adjusted to an initial target range of 3–9 ng/ml. Kidney angiomyolipoma size was evaluated by MRI at baseline and weeks 16, 32, and 52 during year 1 (CT was used for 1 subject who was unable to undergo MRI). In those patients with a partial response at week 16, drug treatment continued at the same dose. The sirolimus dose was increased for all other patients to achieve a trough target range of 9–15 ng/ml. Sirolimus treatment continued for 52 weeks. Tolerability and drug levels were monitored every 8–12 weeks.
There were 36 adults enrolled and 28 were evaluable at 12 and 24 months (see
According to RECIST criteria
Panel A) percent change in kidney tumor size (sum LD) for individual cases (black bars-best response during year one on study; adjacent white bars-week 52 response for same subject). All subjects were treated with sirolimus from weeks 0 to 52. Panels B and C) percent change in kidney tumor size compared with baseline for kidney tumors at each time point. After week 52, a subset (Panel B) was observed off treatment (black, OFF SIROLIMUS AFTER WK 52 group, n = 15). Another subset (Panel C) received additional study drug treatment after week 52 (red, ON SIROLIMUS AFTER WK 52 group, n = 13). Panel D) percent change in kidney tumor size at 24 months (104 weeks) for indicated groups. Panel E) kidney tumor size at week 0 and week 104 (month 24) for the OFF SIROLIMUS AFTER WK 52 group. Panel F) kidney tumor size at week 0 and week 104 (month 24) for ON SIROLIMUS AFTER WK 52 group.
Assessing kidney tumor size during months 12–24 was another objective. In the original version of our protocol, this was a secondary objective and the plan was to stop sirolimus at week 52 and evaluate kidney tumor size at 18 and 24 months in all subjects. However, tumor regrowth after stopping sirolimus treatment was observed in a similar single institution study
Of those in the OFF SIROLIMUS AFTER WK 52 group (n = 15) who received no additional study drug during months 12–24, there was 1 participant with a partial response, 13 with stable disease, and 1 with progressive disease at 24 months. In contrast, of those in the ON SIROLIMUS AFTER WK 52 group (n = 13) who received additional treatment during months 12–24, there were 6 with a partial response, 7 with stable disease, and 0 with progressive disease at 24 months. The difference in the proportion of subjects with a partial response (versus stable disease plus progressive disease) was significant between these two treatment groups (p = 0.029, two-sided Fisher's exact test). The duration of sirolimus treatment in the ON SIROLIMUS AFTER WK 52 group varied because of logistic issues (delays in IRB approval for amendment, time needed to obtain additional study drug supply, and scheduling issues). In all cases, there was a period of time off of sirolimus (mean time off was 24 weeks, range 4–44 weeks) prior to restarting study drug. The average total duration of treatment (including the first 52 weeks) was 78 weeks (range 60–100). In 2 cases, the month 24 visit was delayed (to 26 and 28 months respectively). The target sirolimus trough level for those on drug treatment during months 12–24 was 3–15 ng/ml. The dose and frequency of drug level monitoring was at the discretion of the treating study physician. See additional details in
Overall, sirolimus was reasonably well tolerated and unexpected toxicities were not observed. Common drug related grade 1–2 events with a frequency of >20% included: stomatitis, hypertriglyceridemia, hypercholesterolemia, bone marrow suppression (anemia, mild neutropenia, leucopenia), proteinuria, and joint pain. Drug related grade 3 events were rare and included:1-lymphopenia, 1-headache, 1-weight gain. These events did not require intervention (headache, weight gain) or were clinically insignificant (lymphopenia). See
ALL EVENTS INCLUDING UNRELATED TOXICITIES | TREATMENT RELATED EVENTS | |||||||||
All Events (36 patients) | Grade 1 | Grade 2 | Grade 3 | All Grades (1–3) | Grade 1 | Grade 2 | Grade 3 | All Grades (1–3) | Percent |
|
Alkaline phosphatase | 7 | 1 | 0 | 8 | 4 | 0 | 0 | 4 | 11.1% | |
ALT, SGPT | 4 | 1 | 0 | 5 | 3 | 1 | 0 | 4 | 11.1% | |
Diarrhea w/o prior colostomy | 10 | 1 | 0 | 11 | 3 | 1 | 0 | 4 | 11.1% | |
Head/headache | 7 | 1 | 1 | 9 | 3 | 1 | 1 | 5 | 13.9% |
|
Hematologic-other | 11 | 0 | 0 | 11 | 4 | 0 | 0 | 4 | 11.1% | |
Hemoglobin | 6 | 2 | 0 | 8 | 6 | 2 | 0 | 8 | 22.2% | |
Hypercholesterolemia | 13 | 3 | 0 | 16 | 11 | 3 | 0 | 14 | 38.9% | |
Hypertriglyceridemia | 12 | 8 | 0 | 20 | 10 | 8 | 0 | 18 | 50.0% | |
Infection Gr0-2 neut, urinary tract | 6 | 2 | 0 | 8 | 4 | 2 | 0 | 6 | 16.7% | |
Infection w/unk ANC sinus | 3 | 2 | 0 | 5 | 3 | 2 | 0 | 5 | 13.9% | |
Infection w/unk ANC upper airway NOS | 2 | 2 | 0 | 4 | 2 | 2 | 0 | 4 | 11.1% | |
Irregular menses | 5 | 1 | 0 | 6 | 5 | 0 | 0 | 5 | 13.9% | |
Joint, pain | 10 | 0 | 1 | 11 | 8 | 0 | 0 | 8 | 22.2% | |
Leukocytes | 15 | 3 | 0 | 18 | 11 | 3 | 0 | 14 | 38.9% | |
Lymphopenia | 4 | 0 | 1 | 5 | 2 | 0 | 1 | 3 | 8.3% |
|
Metabolic/Laboratory-other | 8 | 0 | 0 | 8 | 4 | 0 | 0 | 4 | 11.1% | |
Necrosis, oral | 15 | 6 | 0 | 21 | 15 | 6 | 0 | 21 | 58.3% | |
Neutrophils | 10 | 3 | 0 | 13 | 6 | 2 | 0 | 8 | 22.2% | |
Nose, hemorrhage | 6 | 0 | 0 | 6 | 5 | 0 | 0 | 5 | 13.9% | |
Proteinuria | 12 | 3 | 0 | 15 | 7 | 3 | 0 | 10 | 27.8% | |
Rash: acne/acneiform | 3 | 2 | 0 | 5 | 2 | 2 | 0 | 4 | 11.1% | |
Skin-other | 5 | 0 | 0 | 5 | 4 | 0 | 0 | 4 | 11.1% | |
Weight gain | 1 | 0 | 1 | 2 | 0 | 0 | 1 | 1 | 2.8% |
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treatment related grade 3 event-headache, lymphopenia, weight gain.
percent of treatment related adverse events occuring in >10% of those enrolled and/or those with a grade 3 treatment related event.
Most subjects missed some doses of sirolimus during the study for a variety of reasons. In the 28 subjects who completed 52 weeks of treatment, study drug was held per protocol for >10 days in seven subjects for medical reasons including: pneumonia-2, bronchitis-1, surgery-3, edema and herpes zoster-1. Study drug was held for >10 days for issues not specified in the protocol in another three subjects (inadequate birth control-1, symptomatic mouth ulcers-2). Study drug was restarted in most cases and the week 52 visit was adjusted per protocol so missed doses were made up at the end of year 1. Most others (∼15 subjects) missed between 1 and 9 doses of study drug for minor infections or to let mouth ulcers heal.
There were 13 participants with a measurable SEGA (brain tumor) at baseline ranging in size from 0.9–3.0 cm. SEGA measurement data were available after 52 weeks of sirolimus treatment in 11 individuals (
Panel A shows the diameter (cm) of brain tumors (SEGAs) at baseline and week 52 in 11 participants. T1 post gadolinium MR images (courtesy of Dr. Nathaniel D. Wycliffe, Department of Radiology, Loma Linda University School of Medicine) in panels B–E show a SEGA near the right foramen of Monroe that measured 1.8 cm maximal diameter at baseline (B,D) with near complete resolution of the lesion after sirolimus treatment (C,E).. Panel F is a graph of liver angiomyolipoma size for all cases (longest diameter in cm) at baseline and at best response. Panel G shows changes in TSC skin lesions with sirolimus treatment. Panels H–J show pulmonary function data (FVC, FEV1, DLCO) at week 0 and week 52 for female participants with TSC/LAM (n = 15). See
Liver angiomyolipomas were present at baseline in 15 subjects (42%) but only 5 cases had measurable disease with a longest diameter of at least 2 cm. Best responses for percent change from baseline diameter were −14.3%, 0.0%, −8.6%, −72.9%, and −64.8% (mean of −32.1%), see
We collected baseline and week 52 data on facial angiofibromas, shagreen patch, ungual fibromas, and hypomelanotic macules. At 52 weeks, clinical site investigators reported their clinical impression on response using the following four subjective choices: improvement, no change, worse, unable to evaluate. After one year of sirolimus treatment, we observed subjective improvement in facial angiofibromas, shagreen patches, ungual fibromas, and hypomelanotic macules (
The evaluation of pulmonary function before and after sirolimus treatment was another important objective of this study because LAM is an important cause of early mortality for women with TSC, 10–20% of women with TSC are at risk for developing clinically significant LAM
Brain manifestations were common in study participants. Exploratory data was collected on tubers, subependymal nodules (SENs), and seizures before and after 52 weeks of sirolimus treatment. We did not observe significant changes in tubers, SENs or seizures (see
Vascular endothelial growth factor (VEGF) signaling is an important signal transduction mechanism that regulates angiogenesis and lymphangiogenesis. There are several VEGF isoforms (A–E) that bind dimers of VEGF receptors 1–3, which all have intracellular tyrosine kinase domains and play a role in regulating these important processes
Panel A shows baseline serum VEGF-D levels for all subjects and indicated subgroups (women, men, TSC/LAM and TSC). According to other studies
The major objectives of this single arm, multicenter, phase 2 study were to evaluate kidney angiomyolipoma response to and tolerability of sirolimus treatment. Overall, we found that sirolimus is relatively safe and may be a useful systemic option for treating patients with problematic multifocal kidney angiomyolipomas and other TSC related tumors. We observed that responses persisted at 24 months in a subset treated with additional sirolimus during year 2 of the study. We also observed regression of liver angiomyolipomas and SEGAs. Furthermore, serum VEGF-D levels were elevated at baseline, decreased with sirolimus treatment, and correlated with kidney angiomyolipoma size (for a comparison of our VEGF-D results to several sporadic LAM studies, see
There are two other published kidney angiomyolipoma clinical trial studies so we compared the kidney angiomyolipoma response rate and toxicity data from our study (36 enrolled, 28 completed 1 year of sirolimus treatment) with the two related studies
Progressive LAM is a devastating disorder with a known defect in the mTOR pathway
To our knowledge, this is the first clinical trial to report VEGF-D results in a TSC population with kidney angiomyolipomas before and after mTOR inhibitor treatment. The correlation between VEGF-D and kidney tumor size suggests that serum VEGF-D levels may be useful for monitoring kidney angiomyolipoma size over time. Our observations that VEGF-D levels are elevated at baseline and decrease with sirolimus treatment in a population with kidney angiomyolipomas associated with kidney disease are consistent with the VEGF-D results reported in the phase 3 sirolimus trial for women with LAM reported recently
The numerous clinical features of TSC are well known
There are recent preclinical studies using mouse models of TSC related tumors that indicate other approved drugs (such as angiogenesis inhibitors, interferon-gamma, asparaginase) may have potential therapeutic utility as single agents or in combination with mTOR inhibitors
This multicenter study should provide useful efficacy and safety data to clinicians who are considering the option of recommending sirolimus treatment for individuals with TSC and problematic kidney angiomyolipomas or other TSC associated tumors. Although there are alternative treatment options for problematic kidney angiomyolipomas (vascular embolization, nephrectomy, partial nephrectomy), these are all local, invasive procedures with associated risks. Furthermore, the available local interventions are often not suitable for the bilateral, multifocal kidney tumors that are frequently observed associated with TSC
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We would like to thank all participants and their families. We also thank the following individuals: Michael Messina, Alison Nobil, Paul Sudentas, David Kwiatkowski (Brigham and Women's Hospital); Lila Dalton, Regina Parham, Nathaniel D. Wycliffe (Loma Linda University); Karen Agricola, Gail Chuck, Prajakta Mangeshkar (Cincinnati Children's Medical Center); Robert Sims, Beth Petty, Alison Beaver (University of Texas, Southwestern); Mary Miceli (New York University); Vicky Whittemore, Jo Anne Nakagawa (Tuberous Sclerosis Alliance); Caroline Harvey, Jessica Allen (Dana-Farber Cancer Institute); Daniele Gelone, Neal Wasserman, Sandi See Tai (Wyeth/Pfizer).