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

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/m2 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.

Antitumor adaptive immunity remains intact following inhibition of autophagy and antimalarial treatment

“…Most studies investigating autophagy in cancer have focused on its cellintrinsic effects, including aiding cancer cell survival during extrinsic stress (2,3) as well as promoting drug resistance (4). Importantly, several clinical trials have combined traditional chemotherapy or targeted therapy with antimalarial lysosomotropic agents, such as hydroxychloroquine, which block the late stages of autophagic proteolysis (5)(6)(7)(8)(9)(10)(11)(12). Despite interest in inhibiting autophagy in the clinical oncology setting in combination with chemotherapies or other targeted therapies, emerging evidence has raised questions with regard to the efficacy of such approaches to cancer treatment.…”

Casein kinase 1α–dependent feedback loop controls autophagy in RAS-driven cancers

“…A growing number of clinical trials have been conducted to investigate whether inhibition of autophagic recycling by hydroxychloroquine (HCQ) or CQ can sensitize cancer cells to various types of anticancer drugs (12)(13)(14)(15)(16)(17). Given that autophagy plays context-dependent roles in cancer, the clinical benefits of targeting autophagy may be unpredictable.…”

Autophagy Inhibition Enhances Sunitinib Efficacy in Clear Cell Ovarian Carcinoma

“…Although HCQ demonstrated promising results in recent phase I/II clinical trials, the development of more potent autophagy inhibitors that display greater in vivo activity is urgently needed (2)(3)(4)(5)(6). Indeed, a recent report investigating sunitinib in combination with HCQ demonstrated that the MTD of HCQ, albeit through unknown mechanisms, inconsistently inhibited autophagy, thereby warranting the development of more potent and specific autophagy inhibitors (34).…”

“…As such, phase I and II clinical trials investigating HCQ in combination with chemotherapies or targeted therapies are ongoing. Early reports have indicated that HCQ may have modest clinical activity (2)(3)(4)(5)(6). However, in the absence of a specific autophagy inhibitor, targeting other events upstream or downstream of autophagy may improve clinical responses.…”