A phase I study of the mTOR inhibitor sirolimus (rapamycin) in combination with nanoparticle albumin-bound paclitaxel (ABI-007, abraxane) in advanced solid cancers

C151 Background: Preclinical data suggest that mTOR inhibitors potentiate the efficacy of cytotoxic agents including taxanes. Rapamycin (R) is an mTOR inhibitor currently FDA approved for the treatment of renal allograft rejection, and has been found to have antiproliferative and antiangiogenic actions in a diverse range of tumors. Abraxane (A) is a nanoparticle, albumin-bound paclitaxel that has shown greater efficacy and less toxicity than Cremophor-based paclitaxel in several xenograft models and in clinical trials. The primary aims of this study are to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of R administered in combination with A. The secondary aims are to describe the pharmacokinetic (PK) and pharmacodynamic (PD) interactions of the combination in patients with advanced malignancies. Methods: Cohorts of 3-6 patients (pts) were enrolled and treated. Escalating oral dose of R (5-40 mg) was administered on days -7, 2, 9 and 16 in combination with intravenous fixed dose of A (100 mg/m2 )on days -14, 1, 8, and 15 of a 28 day cycle. Tumor tissue samples have been collected from consenting patients for PD measurement of pre and post therapy p70S6K (S6K1) by Automated Quantitative Analysis (AQUA) 1, and transcription profile analysis2. PET imaging was also performed prior to and at the end of cycle one. Results: To date 14 pts (8 lung, 2 sarcoma, 1 ovarian, 1 breast, 1 endometrial and 1 melanoma) with a median age 62 (range 41-76 years) have been treated in 4 cohorts. Doses have been escalated as follows; Cohort 1 (5/100, n = 3), Cohort 2 (10/100, n = 6), Cohort 3 (20/100, n = 3), Cohort 4 (40/100, n =2). Median number of cycles was 3 (range 0-4 cycles). One grade 3 DLT (dyspnea/hypoxia) occurred in a pt with extensive bronchoalveolar disease in cohort 2. Other grade 3 toxicities included leucopenia in a pt in cohort 1 and a pt in cohort 3, weight loss that occurred after 4 cycles in a pt in cohort 1, fatigue that occurred after 3 cycles in a pt in cohort 2, and anemia in a pt in cohort 2. Two pts with non-small cell lung cancer (NSCLC) had a partial response (PR) and showed evidence of decreased 18FDG uptake on PET scanning at the end of cycle one. The MTD has not yet been reached and enrollment continues on cohort 4. Conclusions: Low dose weekly oral R in combination with intravenous A seems to be well tolerated. Enrollment and dose escalation is continuing, and PD and PK analysis will be performed once all samples are available to assure uniformity. PK and PD analyses and PET scan data will be presented. 1 Camp R, Chung G, and Rimm L. Automated subcellular localization and quantification of protein expression in tissue microarrays. Nat Med 2002; 8:1323-1327. 2 Harris L, You F, Schnitt S, et al. Predictors of resistance to preoperative trastuzumab and vinorelbine for HER2-positive early breast cancer. Clin Cancer Res. 2007; 13(4):1198-207.