Abstract 2521: Combining chemotherapy with autophagy inhibition: Phase I trial of dose-intense temozolomide and hydroxchloroquine in patients with advanced solid tumors
Authors: Fecher Leslie A. , Schuchter Lynn M. , Evans Tracey , Chang Claire Y. , Gallagher Maryann , Kramer Amy , O'Dwyer Peter J. , Amaravadi Ravi K. 
Published: June 2012

Abstract
Background: Therapy-induced autophagy is a key resistance mechanism to alkylating chemotherapy. Hydroxychloroquine (HCQ) is an autophagy inhibitor that augments the antitumor efficacy of chemotherapy in preclinical models. To determine the safety and pharmacodynamic (PD) effects of combining an alkylating chemotherapy with an autophagy inhibitor, we conducted a phase I clinical trial of temozolomide (TMZ) and HCQ in patients with advanced solid tumors. Methods: This was a traditional 3+3 dose escalation study in which patients were treated with 2 weeks daily HCQ followed by combined treatment with TMZ 150 mg/m2 po qd for 7/ 14 days and continuous HCQ. Patients with solid tumors with any number of prior therapies were eligible. Because both drugs cross the blood brain barrier, patients with brain metastases were included. The primary objective was to determine the maximal tolerated dose (MTD) of HCQ in this combination. Secondary objectives included toxicity rate, response rate, and measurement of therapy-induced accumulation of autophagic vesicles (AV) in serial peripheral blood mononuclear cells (PBMC) and tumor tissue. Results: 27 patients including 10 with brain metastases were enrolled with 19 evaluable for toxicity and response. HCQ was successfully dose escalated from 200 mg daily to 600 mg bid in 5 cohorts. There was one dose limiting toxicity at 400 mg bid HCQ of grade 4 neutropenia &gt;7 days which lead to dose expansion. The 400 mg bid cohort was further expanded due to complete heart block in one patient that was thought to be unrelated to study drug. A grade 3 rash lead to dose expansion at 1000 mg daily. Anorexia, nausea, and fatigue were common grade 2 toxicities. In 12 patients with melanoma, partial response and stable disease was achieved in 2, and 3 patients respectively, including complete regression of multiple large extra-cranial tumors in a patient with brain metastases. One patient with 7 prior treatments for metastatic breast cancer with brain metastases had stable disease for 8 months. PD evidence of autophagy inhibition was observed by electron microscopy (EM) in PBMCs in individual patients but not across cohorts. In one patient with advanced melanoma, a post-progression FDG-PET scan demonstrated metabolic compromise and necrosis in the center of tumors, recapitulating preclinical models of autophagy inhibition. Conclusions: Dose- intense TMZ and HCQ demonstrated clinical activity, and a manageable safety profile in a population of patients enriched for brain metastases. Inconsistent evidence of autophagy inhibition in PBMC may reflect limited induction of autophagy by single agent temozolomide in surrogate tissues. Central metabolic compromise of tumor suggests FDG-PET can capture on-target effects of HCQ. The recommended phase II dose, final response rate and EM analysis of serial tumor biopsies 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 2521. doi:10.1158/1538-7445.AM2011-2521