.  Autophagy. 2014 May 20;10(8). [Epub ahead of print]

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

Rosenfeld MR1, Ye X2, Supko JG3, Desideri S2, Grossman SA2, Brem S4, Mikkelson T5, Wang D6, Chang YC6, Hu J6, McAfee Q6, Fisher J2, Troxel A7, Piao S6, Heitjan DF7, Tan KS7, Pontiggia L8, O'Dwyer PJ9, Davis LE10, Amaravadi RK9.

Author information: 

1Adult Brain Tumor Consortium; Department of Neurology; University of Pennsylvania; Philadelphia, PA USA.

2Adult Brain Tumor Consortium; Sidney Kimmel Comprehensive Cancer Center; Johns Hopkins University; Baltimore, MD USA.

3Adult Brain Tumor Consortium; Massachusetts General Hospital; Harvard Medical School; Boston, MA USA.

4Adult Brain Tumor Consortium; H Lee Moffitt Cancer Center Department of Neurosurgery;Tampa, FL USA.

5Adult Brain Tumor Consortium; Henry Ford Hospital Hermelin Brain Tumor Center/Neurology; Detroit, MI USA.

6Division of Hematology-Oncology; Department of Medicine; Perelman School of Medicine; Philadelphia, PA USA.

7Center for Clinical Epidemiology and Biostatistics; University of Pennsylvania; Philadelphia, PA USA.

8Department of Mathematics, Physics, and Statistics; University of the Sciences.

9Division of Hematology-Oncology; Department of Medicine; Perelman School of Medicine; Philadelphia, PA USA; Abramson Cancer Center, University of Pennsylvania; Philadelphia, PA USA.

10Division 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.

 

 PMID: 24991840 [PubMed - as supplied by publisher] 

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