title: 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/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.
authors.affiliation: Department of Medicine and Abramson Cancer Center; University of Pennsylvania; Philadelphia, PA USA.
authors.forename: Reshma
authors.initials: R
authors.lastname: Rangwala
authors.affiliation: Department of Medicine and Abramson Cancer Center; University of Pennsylvania; Philadelphia, PA USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Leone
authors.affiliation: Department of Medicine and Abramson Cancer Center; University of Pennsylvania; Philadelphia, PA USA.
authors.forename: Yunyoung C
authors.initials: YC
authors.lastname: Chang
authors.affiliation: Department of Medicine and Abramson Cancer Center; University of Pennsylvania; Philadelphia, PA USA.
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Fecher
authors.affiliation: Department of Medicine and Abramson Cancer Center; University of Pennsylvania; Philadelphia, PA USA.
authors.forename: Lynn M
authors.initials: LM
authors.lastname: Schuchter
authors.affiliation: Department of Medicine and Abramson Cancer Center; University of Pennsylvania; Philadelphia, PA USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Kramer
authors.affiliation: Center for Clinical Epidemiology and Biostatistics; University of Pennsylvania; Philadelphia, PA USA.
authors.forename: Kay-See
authors.initials: KS
authors.lastname: Tan
authors.affiliation: Center for Clinical Epidemiology and Biostatistics; University of Pennsylvania; Philadelphia, PA USA.
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Heitjan
authors.affiliation: Department of Medicine and Abramson Cancer Center; University of Pennsylvania; Philadelphia, PA USA.
authors.forename: Glenda
authors.initials: G
authors.lastname: Rodgers
authors.affiliation: Department of Medicine and Abramson Cancer Center; University of Pennsylvania; Philadelphia, PA USA.
authors.forename: Maryann
authors.initials: M
authors.lastname: Gallagher
authors.affiliation: Department of Medicine and Abramson Cancer Center; University of Pennsylvania; Philadelphia, PA USA.
authors.forename: Shengfu
authors.initials: S
authors.lastname: Piao
authors.affiliation: Center for Clinical Epidemiology and Biostatistics; University of Pennsylvania; Philadelphia, PA USA.
authors.forename: Andrea B
authors.initials: AB
authors.lastname: Troxel
authors.affiliation: Department of Medicine and Abramson Cancer Center; University of Pennsylvania; Philadelphia, PA USA.
authors.forename: Tracey L
authors.initials: TL
authors.lastname: Evans
authors.affiliation: Department of Medicine and Abramson Cancer Center; University of Pennsylvania; Philadelphia, PA USA.
authors.forename: Angela M
authors.initials: AM
authors.lastname: DeMichele
authors.affiliation: Department of Medicine and Abramson Cancer Center; University of Pennsylvania; Philadelphia, PA USA.
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Nathanson
authors.affiliation: Department of Medicine and Abramson Cancer Center; University of Pennsylvania; Philadelphia, PA USA.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: O'Dwyer
authors.affiliation: Philadelphia College of Pharmacy; University of the Sciences; Philadelphia, PA USA.
authors.forename: Jonathon
authors.initials: J
authors.lastname: Kaiser
authors.affiliation: Department of Mathematics, Physics and Statistics; University of the Sciences; Philadelphia, PA USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Pontiggia
authors.affiliation: Department of Medicine and Abramson Cancer Center; University of Pennsylvania; Philadelphia, PA USA; Philadelphia College of Pharmacy; University of the Sciences; Philadelphia, PA USA.
authors.forename: Lisa E
authors.initials: LE
authors.lastname: Davis
authors.affiliation: Department of Medicine and Abramson Cancer Center; University of Pennsylvania; Philadelphia, PA USA.
authors.forename: Ravi K
authors.initials: RK
authors.lastname: Amaravadi
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001343:Autophagy / Q000187:drug effects; D003606:Dacarbazine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D006886:Hydroxychloroquine / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000473:pathology*; D008875:Middle Aged; D009367:Neoplasm Staging; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D000077204:Temozolomide; D016896:Treatment Outcome
chemical_list: D006886:Hydroxychloroquine; D003606:Dacarbazine; D000077204:Temozolomide
keywords: autophagy; chemotherapy; clinical trial; hydroxychloroquine; melanoma