A phase I study of the mTOR inhibitor sirolimus in combination with nanoparticle albumin-bound paclitaxel (nab-P).
Authors: M. M. Abu-Khalaf, S. N. Gettinger, V. N. Trieu, H. A. Deshpande, M. DiGiovanna, M. Azodi, N. Desai, W. K. Kelly, P. E. Schwartz, L. Harris
Journal: Journal of Clinical Oncology (2010)

2534^ Background: Preclinical data suggest that mTOR inhibitors potentiate the efficacy of taxanes. Sirolimus (Rapamycin, R) is an FDA-approved mTORC1 inhibitor for prevention of renal allograft rejection. nab-P has greater efficacy and less toxicity than cremophor-based P. Primary aim is to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT). Secondary aims are to evaluate pharmacokinetics (PK) and biologic effect of R on Akt pathway in pre\/post therapy tumor samples. Methods: Cohorts (C) of 3-6 patients (pts) were enrolled and treated. Oral R doses were escalated; C1 (5 mg, n = 3), C2 (10 mg, n = 6), C3 (20 mg, n = 3), C4 (40 mg, n =6), C5 (60 mg, n=5) on day -7, 2, 9, 16 and nab-P 100 mg/m2 on day -14, 1, 8, 15 of 28-day cycle. Pre- and posttherapy biopsies were performed on 10 and 9 pts. Results: 23 pts (10 lung, 2 sarcoma, 3 ovarian, 3 breast, 3 endometrial, 1 melanoma, 1 head and neck) with median age of 61 (range 41-78) were treated. Median number of cycles is 3 (range 1-8). The following DLT occurred: a grade 3 DLT dyspnea/hypoxia (C2); ANC<1,500ul > 2 wk (C4); grade 4 pericardial effusion and grade 3 fatigue (C5). Other grade 3 non-hematologic toxicities included weight loss (C1); elevated AST/ALT (C4); hypertriglyceridemia, diarrhea, subcutaneous edema, deep vein thrombosis (C5). One grade 4 neutropenia occurred (C4). MTD is 40 mg. Best response is partial response in 6 pts (2 lung, 2 breast, 1 endometrial, 1 ovarian)[4/6 confirmed]; stable disease in 9 and progression in 7 pts. There were proportionate increases in AUC and Cmax with increasing dose of R (Cmax = 4,700, 3,810, 1,733, 10,036, 10,307, 43,256 ng/mL and AUCinf = 5,099, 5,310, 3,059, 8,460, 16,776 hr*ng/mL at R dose levels of 5, 10, 20, 40, 60 mg, respectively) and no evidence of drug accumulation at cycle 2. There were high correlations between baseline AKT pathway markers (mTOR, Akt, pAkt, S6K1 and pS6K1; Spearman's rho-0.406-0.867). This correlation was lost in post therapy samples. There was a trend for higher levels of mTOR to predict resistance to therapy (p 0.08). Conclusions: R in doses up to 40 mg can be safely combined with nab-P 100 mg/m2on day 1, 8, and 15 q 28 day with promising activity in solid tumors. Post-therapy change in marker expression suggests biologic effect of R. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Amgen, Genomic Health, sanofi-aventis Amgen, Genomic Health, sanofi-aventis In compliance with the guidelines established by the ASCO Conflict of Interest Policy (J Clin Oncol. 2006 Jan 20;24[3]:519-521) and the Accreditation Council for Continuing Medical Education (ACCME), ASCO strives to promote balance, independence, objectivity, and scientific rigor through disclosure of financial and other interests, and identification and management of potential conflicts. According to the ASCO Conflict of Interest Policy, the following financial and other relationships must be disclosed: employment or leadership position, consultant or advisory role, stock ownership, honoraria, research funding, expert testimony, and other remuneration (J Clin Oncol. 2006 Jan 20;24[3]:520). The ASCO Conflict of Interest Policy disclosure requirements apply to all authors who submit abstracts to the Annual Meeting. For clinical trials that began accrual on or after April 29, 2004, ASCO's Policy places some restrictions on the financial relationships of principal investigators (J Clin Oncol. 2006 Jan 20;24[3]:521). If a principal investigator holds any restricted relationships, his or her abstract will be ineligible for placement in the 2010 Annual Meeting unless the ASCO Ethics Committee grants an exception. Among the circumstances that might justify an exception are that the principal investigator (1) is a widely acknowledged expert in a particular therapeutic area; (2) is the inventor of a unique technology or treatment being evaluated in the clinical trial; or (3) is involved in international clinical oncology research and has acted consistently with recognized international standards of ethics in the conduct of clinical research. NIH-sponsored trials are exempt from the Policy restrictions. Abstracts for which authors requested and have been granted an exception in accordance with ASCO's Policy are designated with a caret symbol (^) in the Annual Meeting Proceedings. For more information about the ASCO Conflict of Interest Policy and the exceptions process, please visit www.asco.org/conflictofinterest.