Abstract
Abstract 2884
Poster Board II-860
Introduction.
Multiple myeloma is an incurable plasma cell neoplasm for which most treatments involve a therapeutic agent combined with dexamethasone. Because steroids have been linked to early deaths and many patients are steroid intolerant, there is a need for novel steroid-free therapeutic combinations. CCI-779 (an ester of sirolimus) inhibits the mammalian target of rapamycin (mTOR), a Ser/Thr kinase involved in the initiation of mRNA translation. mTOR, a member of the phosphatidylinositide 3'-kinase (PI3K)-related family, acts downstream of the PI3K/Akt pathway and is phosphorylated in response to mitogenic signals. CCI-779 reacts with intracellular FK506-binding protein 12 (FKBP12) to suppress mTOR and thereby suppress downstream signaling effectors, p70S6k and the eukaryotic initiation factor 4 binding protein 1 (4E-BP1). The combination of lenalidomide and rapamycin displayed synergy in inhibiting proliferation and inducing apoptosis in a number of drug-resistant myeloma cell lines and fresh MM cells at concentrations significantly lower than those achievable clinically with these agents (5-fold lower concentration of CC-5013 (lenalidomide); 15-fold lower concentration of rapamycin) (Raje et al., 2004).
Methods.
A phase I clinical trial was initiated with both agents supplied by CTEP. Patients were required to have relapsed myeloma after at least one prior therapy (which could have contained CCI-779 or lenalidomide, but not both) and patients were required to have an ANC > 1500 and creatinine < 2 mg/dL. This was a standard 3×3 dose escalation starting at 20 mg lenalidomide days 1-21 of a 28 day cycle and CCI-779 given IV starting at 15 mg on days 1,8,15, and 21; dose levels escalated both agents to 25 mg. VTE prophylaxis was required in all patients – 325 mg aspirin for patients without a history of DVT/PE and full dose Coumadin or LMWH for patients with thrombophilia. Pk for both agents as well as PBMCS for phospho-p70S6k were obtained on all patients.
Results.
21 patients have been treated and one patient continues on therapy. The median number of prior therapies was 3 (range 1-6) and 8 patients had previously undergone autologous transplant. Eight patients had received prior thalidomide and three patients had received lenalidomide and dexamethasone. MTD was determined to be 25 mg lenalidomide and 15 mg CCI-779. Toxicities included one grade 4 each of neutropenia, hypophosphatemia, and hypertriglyceridemia. In order of frequency, the most common grade 3 toxicities included hypophosphatemia (7 patients), hypokalemia (6 patients), neutropenia (4 patients), pneumonia (3 patients), anorexia (1), hypertriglyceridemia (1), diarrhea (1), and fatigue (1). All patients experienced grade 2 fatigue. Of evaluable patients, responses by IMWG criteria included one complete response (unconfirmed), one partial response, and three marginal responses. One patient that had previously progressed on lenalidomide and dexamethasone had a marginal response with the combination. Three patients at the time of progression were salvaged with lenalidomide and weekly dexamethasone.
Conclusion.
With a combination that led to two partial responses or better in this heavily pre-treated population, the MTD was 25 mg lenalidomide with 15 mg CCI-779. There were no Pk effects on either agent with the combination; pharmacodynamic studies are ongoing. Fatigue, neutropenia, and electrolyte wasting were problematic and patients benefitted from aggressive routine electrolyte supplementation (K, PO4). Given its toxicities, this combination should be pursued if a biomarker indicating CCI-779 sensitivity is developed.
Disclosures:
No relevant conflicts of interest to declare.
Mechanisms involved in the nutritional regulation of mRNA translation: features of the avian model