5113 Background: Everolimus, an oral mTOR inhibitor, affects tumor growth by blocking growth factor stimulation, arresting cell cycle progression, and inhibiting angiogenesis. mTOR inhibitors and agents with primarily antiangiogenic activity have shown efficacy in renal cell cancer (RCC). Reported at ASCO 2007, everolimus has promising anti-tumor activity in patients with MRCC demonstrated by 32% partial response (PR) and stable disease (SD) for >6 months in 38% of patients. This phase II study assessed the efficacy of daily oral dosing with everolimus in MRCC patients who have failed no more than 2 prior therapies one of which was a tyrosine kinase inhibitor (sorafenib or sunitinib). Methods: Patients had confirmed predominantly clear cell RCC, progressive measurable metastatic disease, adequate organ/marrow function, good performance status and no active CNS involvement. Everolimus was given (10 mg daily, p.o.) without an interruption (28-day cycle), with dose modifications for toxicity per NCI-CTC, version 3.0. Patients were evaluated every 2 cycles (8 weeks) using RECIST. Results: Among the first 22 enrolled patients, 22 were treated and evaluable for safety, 19 for response after withdrawal of 2 patients following the first 4 weeks of therapy, and 1 too early. Patients were mostly male (68%) with a median age 57 years, 100% Zubrod Performance Status 0–1. PR were seen in 3(16%) and SD for ≥ 3 months in 14 (74%). Median PFS was 5.5+ months (1–12+ months), median OS was 8+ months (1–14+). The most common treatment related adverse events were Grade 1/2: hypertriglyceridemia (73%), hyperglycemia (59%). hypercholesterolemia (64%), stomatitis (45%), rash (32%), nausea (27%), and diarrhea (18%); Grade 3/4 adverse events included pneumonitis (27%). Conclusions: Everolimus shows encouraging anti-tumor activity against MRCC patients who have had prior exposure to sorafenib or sunitinib as indicated by the tumor responses and progression free survival. Anti-tumor activity and toxicity will be presented in addition an update of the ASCO 2007 data. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Novartis
14603 Background: Emergence of targeted therapy for MRCC has been a turning point in improving outcomes. Evaluation of a tyrosine kinase inhibitor (TKI) plus an mTOR inhibitor to increase the magnitude and duration of anti-angiogenic effect, and potentially to overcome the development of resistance is being evaluated. Phase I study to determine the maximum tolerated dose, data on response rate, progression free survival (PFS) and overall survival (OS) was assessed. Methods: Predominantly clear cell RCC, progressive measurable metastatic disease, adequate organ/marrow function, no more than 3 prior therapies, and no active CNS involvement. Everolimus and sorafenib are administered orally, daily without interruption. A treatment cycle is 28 days. Dose modifications were performed per the National Cancer Institute, toxicity criteria version 3.0. Dose levels are: shown in the Table. Patients are evaluated every 4 weeks and after every 2 cycles (8 weeks) using RECIST. CT PET imaging is performed at baseline and first restaging to determine changes in the metabolic activity compared to the traditional response criteria. Results: 13 Patients were enrolled to date, 7 pts were enrolled on dose level 0 (1 pt was replaced due to only receiving Everolimus for 2 days). Adverse events included; Grades 1/2: hand-foot syndrome (69%), rash (62%), diarrhea (54%), and stomatitis (38%). Grade 3/4 adverse events included: hand-foot syndrome (17%), pneumonitis (8%), pleural effusion (8%), and thrombocytopenia (8%). Partial responses were seen in 7 (58%), stable disease ≥ 3 months, 4 (30%), progressive disease, 1 (8%). PFS and OS are too early. Conclusions: Everolimus combined with sorafenib is well tolerated with reversible toxicities. We are actively enrolling for dose level +2. The combination demonstrates encouraging anti- tumor activity as indicated by tumor responses. Safety data and anti-tumor activity will be presented in addition to correlation with radiographic studies and metabolic imaging. Dose Levels Everolimus mg Sorafenib mg 0 2.5 400 +1 5 400 +2 10 400 Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Novartis
Everolimus, an oral mammalian target of rapamycin (mTOR) inhibitor, affects tumor growth by blocking growth factor stimulation, arresting cell cycle progression, and inhibiting angiogenesis. mTOR inhibitors and agents with primarily antiangiogenic activity have been shown to have efficacy in renal cell cancer (RCC). This phase 2 study assessed the efficacy of daily oral dosing with everolimus in patients with RCC.Patients had confirmed predominantly clear cell RCC; had received or=3 months was reported in 27 (73%) patients, and stable disease lasting >or=6 months was reported in 21 (57%) patients. Nausea (38% of patients), anorexia (38% of patients), diarrhea (31% of patients), stomatitis (31% of patients), pneumonitis (31% of patients), and rash (26% of patients) were common. Grade 3 of 4 adverse events included pneumonitis (18% of patients); transaminase elevations (10% of patients); thrombocytopenia, hyperglycemia, and alkaline phosphatase elevations (8% each of patients); and hyperlipidemia (5% of patients).In the current study, everolimus demonstrated encouraging antitumor activity against metastatic RCC as indicated by a PFS >or= 6 months for approximately 70% of patients.
5107 Background: RAD001 is an oral mammalian target of Rapamycin (mTOR) inhibitor. Three mechanisms of anti-tumor activity; shuts down tumor response to nutrients and growth factors; cell cycle arrest at late G1 and anti-angiogenesis via VEGF. Molecular alterations in the mTOR modular pathway increase sensitivity in PTEN deficient tumors such as RCC. Endpoints: time-to-progression (TTP), response rate (RR), overall survival (OS), toxicity, and to assess changes in metabolic imaging utilizing CT-PET. Methods: Eligibility included; predominant clear cell, progressive measurable MRCC, adequate organ/marrow function, zubrod performance status (ZPS) = 2, no more than 1 prior therapy, and no active CNS involvement. RAD001 is given orally at a dose of 10mg daily without an interruption (28-day cycle), with dose modifications for toxicity. Re-evaluation was assessed every 2 cycles (8 weeks). RECIST criteria is utilized. TTP and OS are determined from entry into the study. Results: 41 pts have been enrolled. 37 pts are evaluable for response/toxicity. 2 pts toxicity only. 2 pts screened failures. 31 were male/8 female, median age 60 (38–80) years. 31 pts received prior therapy. 23 pts had a ZPS of 0, 13 /1 and 3/2. Sites of disease included; lung, nodal, liver, bone, adrenal, and kidney. 9 pts had 1 metastatic site, 17 pts/2 and 13 pts/3 or more. 15 pts continue to receive RAD001. 12 pts had partial responses, 19 pts were stable for 3+ months. Median duration of therapy is 8+ (range 01–20+) months. Treatment related adverse events; mucositis, skin rash, pneumonitis, hypophosphatemia, hyperglycemia, hypertriglyceridemia, hypercholesterolemia, thrombocytopenia, anemia and elevated LFTs. PET scans have demonstrated decreased metabolic activity in responding or stable pts. Median overall survival is 11.5+ months (range 01–20+). Conclusion: RAD001 has promising anti-tumor activity in pts with MRCC demonstrated by partial response rate. Anti-tumor activity is further suggested by prolonged TTP =3 months. Anti-tumor activity, toxicity and metabolic imaging correlation will be presented. An additional 40 pts who failed prior sunitinib or sorafenib therapy are being enrolled. No significant financial relationships to disclose.
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