Phase I trial of temsirolimus and lenalidomide in pts with rel/ref lymphomas.
8075 Background: The PI3K/Akt/mTOR axis is deregulated in lymphomas and is an emerging therapeutic target. We previously reported activity of temsirolimus (TEM) in DLBCL and FL (JCO 2010 28(31); however, the response duration was short. Lenalidomide (LEN) is an immunomodulatory agent with multiple anti-tumoral and microenvironmental effects, with activity across lymphoma subtypes. We are thus conducting a phase I/II study of TEM plus escalating doses of LEN. The phase I portion is completed. Methods: Patients (pts) had rel/ref lymphoma after >1 cytotoxic regimen. Other criteria: ANC > 1000/mL, platelets > 75,000/mL, nl renal and hepatic function, no VTE within 3 months, non-pregnant. A standard “3 + 3” design was used with dose levels (DL) listed (Table). TEM was given IV weekly and LEN was dosed orally on D1-D21, q28 days. Dose-limiting toxicity (DLT) was defined as cycle 1 grade 3 or 4 non-hematologic toxicity not responsive to standard supportive care, grade 4 thrombocytopenia > 7 days (or associated with bleeding or requiring more than 1 platelet transfusion), ANC < 500/mL > 7 days despite growth factors, or any thromboembolic event. Results: 18 pts (13M, 5F), med age 64 y (range, 42-80 y) were enrolled. 3 pts are ineval for DLT evaluation: one withdrew consent before starting treatment, 1 withdrew consent after a single dose, and 1 died of rapid disease progression after 1 dose. There was 1 DLT at DL1 and 2 DLTs at DL3 (Table). Adverse effects that did not meet DLT criteria: hypokalemia, hypertriglyceridemia, vomiting, urinary tract infection, skin infection, nausea, hypoxia, hyponatremia, diarrhea, and hyperglycemia (each occurring in one pt). There are 5 partial responses, 4 stable disease, 3 progressive disease, 2 not adequately assessed, and 4 still on active treatment. Conclusions: The combination of weekly intravenous TEM plus oral LEN is well-tolerated in a heavily pretreated group of pts with rel/ref lymphomas. The recommended phase II doses are TEM 25mg weekly plus LEN 20mg (D1-D21, q28d). [Table: see text]