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

Abstract

4530 Background: RAD001 an oral serine-threonine kinase inhibitor of mTOR, blocks progression from the GI to the S phase of the cell cycle by a mechanism of action that is unique for an anticancer drug. Mechanistically, it is thought that RAD001 may play a role in VEGF inhibition. Main endpoints were to evaluate: time to progression (TTP), response rate, toxicity and to assess changes in metabolic imaging utilizing CT-PET. Methods: Eligibility included: 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 3 cycles (12 weeks). RECIST criteria is utilized to determine response rate. TTP is determined from entry into the study. Results: 25 pts have been enrolled as of this review. 19 male/6 female, range 43–80 (median 60) years. All pts had predominant clear cell elements with progressive MRCC. 17 pts received prior immunotherapy, targeted agents, or chemotherapy. 22 pts had a ZPS of 0, 2/1 and 1/2. Sites of disease included: lung, nodal, bone, adrenal, kidney and liver. 7 pts had 1 metastatic site, 10 pts/2 metastatic sites and 8 pts/3 or more metastatic sites. 22 pts continue to receive RAD001 therapy. 7 pts had partial responses, 11 pts were stable for 3+ months, (5 pts/6+ months). 4 pts too early. Median duration of therapy is 7+ months (range 1+ to 9+). Treatment related adverse events to date include: mucositis, skin rash, pneumonitis, hypophosphatemia, hyperglycemia, thrombocytopenia, anemia and elevated LFTs. Conclusion: RAD001 has promising anti-tumor activity in pts with MRCC as demonstrated by a 33% partial response rate. Anti-tumor activity was further suggested by prolonged TTP ≥ 3 months for 86% of pts. The tumor effect was also demonstrated as a second line therapy. Independent radiology review is planned. Anti-tumor activity, toxicity and metabolic imaging correlation will be presented. [Table: see text]

The Biology Behind mTOR Inhibition in Sarcoma

“…RAD001 has also been tested in a phase II study in 25 patients with advanced and metastatic RCC. Response was observed in 33% of RAD001-treated patients [69].…”

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].…”

Use of proliferation signal inhibitors in the management of post-transplant malignancies--clinical guidance

“…Conversion from CNIs to PSIs has been shown to cause regression of Kaposi's sarcoma [27][28][29] and registry and clinical study data show that PSI treatment has been associated with a lower incidence of skin cancer [21] and non-skin solid malignancy [19]. Furthermore, data from clinical oncology studies indicate that PSIs show promise in the treatment of advanced or metastatic renal cell carcinoma [30,31].…”

“…Oncology clinical trial data [30,31] Partial response of renal cell carcinoma to PSI treatment PTLD Case studies [40] PTLD successfully treated with rituximab and conversion to PSIs Solid organ tumours Registry data [19] Reduced incidence of non-skin cancers associated with PSIs and CNI elimination Case studies from liver transplantation [43,44] Treatment of hepatocellular carcinoma and metastases…”

“…The first of these is the use of PSIs with therapeutic intent directly used to treat a cancer. Ongoing phase I and Phase II clinical trials in oncology are currently using high doses of PSIs, with everolimus doses of 5 mg/day or 10 mg/ day currently under investigation [30,45], Phase III trials are ongoing. These doses are much higher than those recommended in renal transplantation, where doses of 1.5 mg/day or 3.0 mg/day are routinely used to obtain everolimus trough blood levels of 3-8 ng/ml [23,46].…”