A phase II trial of RAD001 in patients (Pts) with metastatic renal cell carcinoma (MRCC)

Abstract

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.

Renal Cell Carcinoma: New Developments in Molecular Biology and Potential for Targeted Therapies

“…An additional 19 patients had stable disease for Ͼ3 months. The toxicity profile seen in that trial was similar to what has been seen with other mTOR inhibitors [81].…”

Everolimus: A Proliferation Signal Inhibitor with Clinical Applications in Organ Transplantation, Oncology, and Cardiology

“…Two phase II studies evaluated the use of everolimus compared with placebo in patients with metastatic renal cell carcinoma. 36,37 Both of these trials demonstrated superior efficacy in the progression of disease and set the stage for a large-scale randomized trial.…”

Optimal management of metastatic renal cell carcinoma: an algorithm for treatment

“…Pazopanib has completed phase I evaluation [60] and is being investigated in a phase II randomized discontinuation trial [61] and a phase III study. Everolimus has shown antitumour activity in pre‐treated patients with mRCC in phase II studies [46,62]. In a phase III trial in patients with mRCC who had progressed after treatment with RTK inhibitors, those treated with everolimus had a median PFS of 4.9 months (independent central review) compared with 1.87 months for placebo (HR 0.33, 95% CI 0.25–0.43) [63].…”

“…We present an overview of a treatment algorithm for mRCC, based predominantly on patient stratification according to previous treatment and prognostic risk groups (Fig. 1) [10,12–14,16,18,26,33,46]; other factors for consideration are discussed. The algorithm relies primarily on efficacy data due to the patient‐specific nature of tolerability, although this is a key factor in treatment choice [25].…”