title: A phase I/II trial of hydroxychloroquine in conjunction with radiation therapy and concurrent and adjuvant temozolomide in patients with newly diagnosed glioblastoma multiforme.
abstract: Preclinical studies indicate autophagy inhibition with hydroxychloroquine (HCQ) can augment the efficacy of DNA-damaging therapy. The primary objective of this trial was to determine the maximum tolerated dose (MTD) and efficacy of HCQ in combination with radiation therapy (RT) and temozolomide (TMZ) for newly diagnosed glioblastoma (GB). A 3 + 3 phase I trial design followed by a noncomparative phase II study was conducted in GB patients after initial resection. Patients received HCQ (200 to 800 mg oral daily) with RT and concurrent and adjuvant TMZ. Quantitative electron microscopy and immunoblotting were used to assess changes in autophagic vacuoles (AVs) in peripheral blood mononuclear cells (PBMC). Population pharmacokinetic (PK) modeling enabled PK-pharmacodynamic correlations. Sixteen phase I subjects were evaluable for dose-limiting toxicities. At 800 mg HCQ/d, 3/3 subjects experienced Grade 3 and 4 neutropenia and thrombocytopenia, 1 with sepsis. HCQ 600 mg/d was found to be the MTD in this combination. The phase II cohort (n = 76) had a median survival of 15.6 mos with survival rates at 12, 18, and 24 mo of 70%, 36%, and 25%. PK analysis indicated dose-proportional exposure for HCQ. Significant therapy-associated increases in AV and LC3-II were observed in PBMC and correlated with higher HCQ exposure. These data establish that autophagy inhibition is achievable with HCQ, but dose-limiting toxicity prevented escalation to higher doses of HCQ. At HCQ 600 mg/d, autophagy inhibition was not consistently achieved in patients treated with this regimen, and no significant improvement in overall survival was observed. Therefore, a definitive test of the role of autophagy inhibition in the adjuvant setting for glioma patients awaits the development of lower-toxicity compounds that can achieve more consistent inhibition of autophagy than HCQ.
authors.affiliation: Adult Brain Tumor Consortium; Department of Neurology; University of Pennsylvania; Philadelphia, PA USA.
authors.forename: Myrna R
authors.initials: MR
authors.lastname: Rosenfeld
authors.affiliation: Adult Brain Tumor Consortium; Sidney Kimmel Comprehensive Cancer Center; Johns Hopkins University; Baltimore, MD USA.
authors.forename: Xiaobu
authors.initials: X
authors.lastname: Ye
authors.affiliation: Adult Brain Tumor Consortium; Massachusetts General Hospital; Harvard Medical School; Boston, MA USA.
authors.forename: Jeffrey G
authors.initials: JG
authors.lastname: Supko
authors.affiliation: Adult Brain Tumor Consortium; Sidney Kimmel Comprehensive Cancer Center; Johns Hopkins University; Baltimore, MD USA.
authors.forename: Serena
authors.initials: S
authors.lastname: Desideri
authors.affiliation: Adult Brain Tumor Consortium; Sidney Kimmel Comprehensive Cancer Center; Johns Hopkins University; Baltimore, MD USA.
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Grossman
authors.affiliation: Adult Brain Tumor Consortium; H Lee Moffitt Cancer Center Department of Neurosurgery; Tampa, FL USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Brem
authors.affiliation: Adult Brain Tumor Consortium; Henry Ford Hospital Hermelin Brain Tumor Center/Neurology; Detroit, MI USA.
authors.forename: Tom
authors.initials: T
authors.lastname: Mikkelson
authors.affiliation: Division of Hematology-Oncology; Department of Medicine; Perelman School of Medicine; Philadelphia, PA USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Wang
authors.affiliation: Division of Hematology-Oncology; Department of Medicine; Perelman School of Medicine; Philadelphia, PA USA.
authors.forename: Yunyoung C
authors.initials: YC
authors.lastname: Chang
authors.affiliation: Division of Hematology-Oncology; Department of Medicine; Perelman School of Medicine; Philadelphia, PA USA.
authors.forename: Janice
authors.initials: J
authors.lastname: Hu
authors.affiliation: Division of Hematology-Oncology; Department of Medicine; Perelman School of Medicine; Philadelphia, PA USA.
authors.forename: Quentin
authors.initials: Q
authors.lastname: McAfee
authors.affiliation: Adult Brain Tumor Consortium; Sidney Kimmel Comprehensive Cancer Center; Johns Hopkins University; Baltimore, MD USA.
authors.forename: Joy
authors.initials: J
authors.lastname: Fisher
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: Division of Hematology-Oncology; Department of Medicine; Perelman School of Medicine; 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: Daniel F
authors.initials: DF
authors.lastname: Heitjan
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: Department of Mathematics, Physics, and Statistics; University of the Sciences.
authors.forename: Laura
authors.initials: L
authors.lastname: Pontiggia
authors.affiliation: Division of Hematology-Oncology; Department of Medicine; Perelman School of Medicine; Philadelphia, PA USA; Abramson Cancer Center, University of Pennsylvania; Philadelphia, PA USA.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: O'Dwyer
authors.affiliation: Division of Hematology-Oncology; Department of Medicine; Perelman School of Medicine; 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: Division of Hematology-Oncology; Department of Medicine; Perelman School of Medicine; Philadelphia, PA USA; 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 / Q000627:therapeutic use; D001343:Autophagy / Q000187:drug effects; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy*; D059248:Chemoradiotherapy; D017024:Chemotherapy, Adjuvant; D003131:Combined Modality Therapy; D003606:Dacarbazine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D003710:Demography; D005260:Female; D005909:Glioblastoma / Q000175:diagnosis / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*; D006801:Humans; D006886:Hydroxychloroquine / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D016019:Survival Analysis; D000077204:Temozolomide; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D006886:Hydroxychloroquine; D003606:Dacarbazine; D000077204:Temozolomide
keywords: autophagy; glioblastoma; hydroxychloroquine