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Autophagy. 2014 Aug;10(8):1359-68. doi: 10.4161/auto.28984. Epub 2014 May 20.

A phase I/II trial of hydroxychloroquine in conjunction with radiation therapy and concurrent and adjuvant temozolomide in patients with newly diagnosed glioblastoma multiforme.

Author information

1
Adult Brain Tumor Consortium; Department of Neurology; University of Pennsylvania; Philadelphia, PA USA.
2
Adult Brain Tumor Consortium; Sidney Kimmel Comprehensive Cancer Center; Johns Hopkins University; Baltimore, MD USA.
3
Adult Brain Tumor Consortium; Massachusetts General Hospital; Harvard Medical School; Boston, MA USA.
4
Adult Brain Tumor Consortium; H Lee Moffitt Cancer Center Department of Neurosurgery; Tampa, FL USA.
5
Adult Brain Tumor Consortium; Henry Ford Hospital Hermelin Brain Tumor Center/Neurology; Detroit, MI USA.
6
Division of Hematology-Oncology; Department of Medicine; Perelman School of Medicine; Philadelphia, PA USA.
7
Center for Clinical Epidemiology and Biostatistics; University of Pennsylvania; Philadelphia, PA USA.
8
Department of Mathematics, Physics, and Statistics; University of the Sciences.
9
Division of Hematology-Oncology; Department of Medicine; Perelman School of Medicine; Philadelphia, PA USA; Abramson Cancer Center, University of Pennsylvania; Philadelphia, PA USA.
10
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.

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.

KEYWORDS:

autophagy; glioblastoma; hydroxychloroquine

PMID:
24991840
PMCID:
PMC4203513
DOI:
10.4161/auto.28984
[Indexed for MEDLINE]
Free PMC Article
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