Abstract
Abstract Background: Therapy-induced autophagy may be a key resistance mechanism that explains the low rates of clinical benefit observed in trials of mTOR inhibitors in multiple cancers. For example, the mTOR inhibitor temsirolimus produced a 0% stable disease rate in a prior phase II trial in patients with metastatic melanoma. Hydroxychloroquine (HCQ) is an autophagy inhibitor that augments the antitumor efficacy of a number of anticancer therapies including mTOR inhibitors in preclinical models. To determine the safety and pharmacodynamic (PD) effects of combining an mTOR inhibitor with an autophagy inhibitor, we report the results of a phase I clinical trial of temsirolimus and HCQ in patients with advanced solid tumors. Methods: We conducted a traditional 3+3 phase I dose escalation clinical trial in which patients were treated with 1 week single agent temsirolimus 25 mg IV weekly followed by combined weekly temsirolimus with increasing doses of daily continuous HCQ. Patients with advanced solid tumors with any number of prior therapies were eligible. The primary objective was to determine the maximal tolerated dose (MTD) of HCQ in this combination. Secondary objectives included toxicity rate, response rate, measurement of therapy-induced accumulation of autophagic vesicles (AV) in serial peripheral blood mononuclear cells (PBMC) and tumor tissue, and pharmacokinetic (PK) analysis of temsirolimus, sirolimus and HCQ to explore drug interactions and establish a PK-PD relationship. A 12 patient expansion at the MTD or HCQ 600 mg bid (final planned dose level) in patients with metastatic melanoma with serial FDG-PET scans is planned. Results: 23 patients were enrolled with 14 evaluable for response and toxicity. The median number of prior treatments was 4. HCQ was successfully dose escalated from 200 mg daily to 600 mg bid in 4 cohorts. There was one dose limiting toxicity (DLT) at 200 mg HCQ, grade 4 thrombocytopenia with bleeding, that lead to dose expansion. The 800 mg dose cohort was also expanded due to a death from streptococcal pneumonia in month 3 of treatment. No additional bleeding, infections, or other DLTs were observed. Anorexia, nausea, and fatigue were common grade 2 toxicities. Stable disease was achieved in 10/14 evaluable patients, including 4/5 patients with metastatic melanoma. After 6 weeks of treatment, a significant accumulation of AV was observed in PBMC of patients treated with this combination compared to pretreatment samples providing PD evidence of consistent autophagy inhibition. Conclusions: The combination of temsirolimus and HCQ demonstrated significant clinical activity, and a manageable safety profile in a highly treatment-refractory patient population. PD evidence of autophagy inhibition was observed. The recommended phase II dose, PK-PD analysis, response rate, and FDG-PET results in the melanoma expansion will be presented. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4500. doi:10.1158/1538-7445.AM2011-4500
Published Version
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