Phase I trial of hydroxychloroquine with dose-intense temozolomide in patients with advanced solid tumors and melanoma

Reshma Rangwala, Robert Leone, Yunyoung C Chang, Leslie A Fecher, Lynn M Schuchter, Amy Kramer, Kay-See Tan, Daniel F Heitjan, Glenda Rodgers, Maryann Gallagher, Shengfu Piao, Andrea B Troxel, Tracey L Evans, Angela M DeMichele, Katherine L Nathanson, Peter J O'Dwyer, Jonathon Kaiser, Laura Pontiggia, Lisa E Davis, Ravi K Amaravadi, Reshma Rangwala, Robert Leone, Yunyoung C Chang, Leslie A Fecher, Lynn M Schuchter, Amy Kramer, Kay-See Tan, Daniel F Heitjan, Glenda Rodgers, Maryann Gallagher, Shengfu Piao, Andrea B Troxel, Tracey L Evans, Angela M DeMichele, Katherine L Nathanson, Peter J O'Dwyer, Jonathon Kaiser, Laura Pontiggia, Lisa E Davis, Ravi K Amaravadi

Abstract

Blocking autophagy with hydroxychloroquine (HCQ) augments cell death associated with alkylating chemotherapy in preclinical models. This phase I study evaluated the maximum tolerated dose (MTD), safety, preliminary activity, pharmacokinetics, and pharmacodynamics of HCQ in combination with dose-intense temozolomide (TMZ) in patients with advanced solid malignancies. Forty patients (73% metastatic melanoma) were treated with oral HCQ 200 to 1200 mg daily with dose-intense oral TMZ 150 mg/m (2) daily for 7/14 d. This combination was well tolerated with no recurrent dose-limiting toxicities observed. An MTD was not reached for HCQ and the recommended phase II dose was HCQ 600 mg twice daily combined with dose-intense TMZ. Common toxicities included grade 2 fatigue (55%), anorexia (28%), nausea (48%), constipation (20%), and diarrhea (20%). Partial responses and stable disease were observed in 3/22 (14%) and 6/22 (27%) patients with metastatic melanoma. In the final dose cohort 2/6 patients with refractory BRAF wild-type melanoma had a near complete response, and prolonged stable disease, respectively. A significant accumulation in autophagic vacuoles (AV) in peripheral blood mononuclear cells was observed in response to combined therapy. Population pharmacokinetics (PK) modeling, individual PK simulations, and PK-pharmacodynamics (PD) analysis identified a threshold HCQ peak concentration that predicts therapy-associated AV accumulation. This study indicates that the combination of high-dose HCQ and dose-intense TMZ is safe and tolerable, and is associated with autophagy modulation in patients. Prolonged stable disease and responses suggest antitumor activity in melanoma patients, warranting further studies of this combination, or combinations of more potent autophagy inhibitors and chemotherapy in melanoma.

Keywords: autophagy; chemotherapy; clinical trial; hydroxychloroquine; melanoma.

Figures

https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4203514/bin/auto-10-1369-g1.jpg
Figure 1. Antitumor activity of dose-intense TMZ and HCQ. (A) Treatment induced clearance of 2 large FDG-avid gallbladder and mesenteric metastases in a melanoma patient with brain metastases. (B) Durable near complete response of all extra CNS lesions in a metastatic melanoma patient with leptomeningeal disease. Red arrows: melanoma metastases. (C) Progression-free survival of patients.
https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4203514/bin/auto-10-1369-g2.jpg
Figure 2. Pharmacokinetic analysis of HCQ in patients receiving dose-intense TMZ and HCQ. (A) Observed vs. individually predicted concentrations of HCQ based on the population PK model. (B) Estimated peak concentrations (Cmax). (C) Estimated average concentrations (Cavg). (D) PK-response relationship. AUC, area under curve.
https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4203514/bin/auto-10-1369-g3.jpg
Figure 3. Pharmacodynamic effects of TMZ and HCQ on autophagic vacuole accumulation in PBMC, and PK-PD correlation. (A) Mixed-effects model of mean ± SD autophagic vacuoles (AVs)/cell in PBMC. Dotted line: regression line. (B) Representative electron micrographs of serial PBMC; red arrows: AV (C) Classification tree from CART analysis. (D) Histogram of AV change at 2 wk in patients with estimated HCQ Cmax above or below 1554 ng/mL.

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