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

Myrna R. Rosenfeld, Xiaobu Ye, Jeffrey G. Supko, Serena Desideri, Stuart A Grossman, Steven Brem, Tom Mikkelson, Daniel Wang, Yunyoung C. Chang, Janice Hu, Quentin McAfee, Joy Fisher, Andrea B. Troxel, Shengfu Piao, Daniel F. Heitjan, Kay See Tan, Laura Pontiggia, Peter J. O'Dwyer, Lisa E. Davis, Ravi K. Amaravadi

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)1359-1368
Number of pages10
JournalAutophagy
Volume10
Issue number8
DOIs
StatePublished - 2014

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temozolomide
Hydroxychloroquine
Glioblastoma
Radiotherapy
Autophagy
Maximum Tolerated Dose
Pharmacokinetics
Vacuoles
Blood Cells

Keywords

  • Autophagy
  • Glioblastoma
  • Hydroxychloroquine

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology
  • Medicine(all)

Cite this

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, Myrna R.; Ye, Xiaobu; Supko, Jeffrey G.; Desideri, Serena; Grossman, Stuart A; Brem, Steven; Mikkelson, Tom; Wang, Daniel; Chang, Yunyoung C.; Hu, Janice; McAfee, Quentin; Fisher, Joy; Troxel, Andrea B.; Piao, Shengfu; Heitjan, Daniel F.; Tan, Kay See; Pontiggia, Laura; O'Dwyer, Peter J.; Davis, Lisa E.; Amaravadi, Ravi K.

In: Autophagy, Vol. 10, No. 8, 2014, p. 1359-1368.

Research output: Contribution to journalArticle

Rosenfeld, MR, Ye, X, Supko, JG, Desideri, S, Grossman, SA, Brem, S, Mikkelson, T, Wang, D, Chang, YC, Hu, J, McAfee, Q, Fisher, J, Troxel, AB, Piao, S, Heitjan, DF, Tan, KS, Pontiggia, L, O'Dwyer, PJ, Davis, LE & Amaravadi, RK 2014, 'A phase I/II trial of hydroxychloroquine in conjunction with radiation therapy and concurrent and adjuvant temozolomide in patients with newly diagnosed glioblastoma multiforme', Autophagy, vol. 10, no. 8, pp. 1359-1368. https://doi.org/10.4161/auto.28984
Rosenfeld, Myrna R. ; Ye, Xiaobu ; Supko, Jeffrey G. ; Desideri, Serena ; Grossman, Stuart A ; Brem, Steven ; Mikkelson, Tom ; Wang, Daniel ; Chang, Yunyoung C. ; Hu, Janice ; McAfee, Quentin ; Fisher, Joy ; Troxel, Andrea B. ; Piao, Shengfu ; Heitjan, Daniel F. ; Tan, Kay See ; Pontiggia, Laura ; O'Dwyer, Peter J. ; Davis, Lisa E. ; Amaravadi, Ravi K. / A phase I/II trial of hydroxychloroquine in conjunction with radiation therapy and concurrent and adjuvant temozolomide in patients with newly diagnosed glioblastoma multiforme. In: Autophagy. 2014 ; Vol. 10, No. 8. pp. 1359-1368.
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