Abstract 1686: A Phase 1 dose escalation study to establish the maximum tolerated dose (MTD), pharmacokinetic (PK) and pharmacodynamic (PD) parameters of hydroxychloroquine (HCQ) in combination with vorinostat (V) in patients with advanced solid tumors - final results.
Authors: Mita Monica M. , Mahalingam Devalingam , Sarantopoulos John , Amaravadi Ravi , Mita Alain , Curiel Tyler , Nawrocki Steffan , Giles Frank , Carew Jennifer 
Published: August 2014

Abstract
Background: Autophagy is a cellular process that generates energy to assure cell survival in response to insults such as hypoxia, nutrient deprivation or cytotoxic mediators. Autophagy contributes to cancer cell survival as well as drug resistance. Several anticancer agents, including Vorinostat (V) are reported to induce autophagy as a cytoprotective mechanism. In preclinical models, the addition of Hydroxycholoquine (HCQ) to V inhibited autophagy and significantly increased the anticancer effects of V. The objectives of this trial were to determine the MTD of HCQ in combination with V both administered daily (QD) in patients (pts) with advanced solid tumors, to evaluate PK and PD parameters, and test anti-tumor activity. Biomarkers were evaluated in tumors and peripheral blood mononuclear cells (PBMC) to investigate synergistic antitumor activity of V in combination with HCQ.
Methods: We used a 3+3 dose escalation design of V at 300-400 mg QD plus HCQ QD at 400-1000 mg in 21 day cycles. Patients with advanced solid tumors and no available treatment with ECOG PS 0-2 and adequate organ function were eligible.
Results: 32 patients were enrolled with 27 evaluable for toxicity studies. No dose limiting toxicity (DLT) was observed in cohorts 1 or 2. In cohort 3 (400 mg V/600 mg HCQ), 1/6 pts had DLT of Gr 3 anemia and fatigue. In cohort 4 (400 mg V/800 mg HCQ), 4/8 pts had DLT with Gr 3 fatigue (3 pts) and Gr 2 seizure on C1D8 (1 pt). De-escalation to 400 mg V/600 mg HCQ resulted in no further DLTs, defining the MTD. 10 pts were treated at the MTD. Treatment-related toxicities were Gr 1-2: nausea (11 pts), diarrhea (8), fatigue (6), anorexia (4), weight loss (4), anemia (4), and elevated creatinine (4). Gr 3 toxicities were fatigue (3), anemia, thrombocytopenia and neutropenia (1 each). One pt (renal cell cancer) had a confirmed PR (cohort 2, completed 43 cycles), and 2 pts with colorectal cancer had prolonged SD (&gt;4 cycles). HCQ trough and V plasma concentrations (preliminary) showed no drug interactions compared to previously published data. PD analyses of biomarkers of HCQ and V in PBMCs at baseline compared to weeks 1 and 6 confirmed the results from pre-clinical studies showing accumulation of autophagic vesicles and induction of LC3-II, p21 and cathepsin D. The results of biopsies from 3 patients at MTD demonstrated greater induction of these PD markers in tumor compared to PBMC.
Conclusions: The MTD was established as HCQ 600 mg + V 400 mg. Dose-dependent fatigue represented DLT in several patients. Anti-tumor activity was seen in one patient with RCC and 2 patients with CRC had prolonged SD. Based on these data phase II studies are planned in patients with renal and colorectal cancer.
Citation Format: Monica M. Mita, Devalingam Mahalingam, John Sarantopoulos, Ravi Amaravadi, Alain Mita, Tyler Curiel, Steffan Nawrocki, Frank Giles, Jennifer Carew. A Phase 1 dose escalation study to establish the maximum tolerated dose (MTD), pharmacokinetic (PK) and pharmacodynamic (PD) parameters of hydroxychloroquine (HCQ) in combination with vorinostat (V) in patients with advanced solid tumors - final results. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1686. doi:10.1158/1538-7445.AM2013-1686