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.

Combined autophagy and HDAC inhibition

“…Consistent with this finding, we did not observe a significant increase in AVs in PBMCs following VOR 400 mg po qd plus HCQ 600 mg po qd treatment. This is in contrast to a modest but significant increase in AV observed in PBMC in patients with glioma treated with temozolomide, whole brain radiation, and HCQ (Rosenfeld et al, this issue 23 ), suggesting that either the anticancer backbone may be important to elicit a significant signal in the PBMC-based EM assay or the sample size for the VOR and HCQ study was not powered to detect a significant therapy-associated increase in AV in PBMC. Collectively, these results suggest that PBMCs may not be ideal for the evaluation of biomarkers associated with autophagy inhibition and that future clinical trials focused on autophagy inhibitor-based therapeutic combinations should consider utilizing tumor specimens for correlative analysis of PD endpoints.…”

MIR517C inhibits autophagy and the epithelial-to-mesenchymal (-like) transition phenotype in human glioblastoma through KPNA2-dependent disruption of TP53 nuclear translocation

“…MIR517C prevented the activity of autophagy inducers in U87 cells through inhibition of autophagy and the EMT phenotype Since low MIR517C expression was associated with poor prognoses in patients with GBM, and based on the results of our previous study, 13 we further investigated whether MIR517C played a functional role in U87 and U251 cells. Interestingly, lentiviral-mediated introduction of MIR517C, negative control (NC), or a MIR517C inhibitor caused morphological differences in U87 cells.…”

“…9,10 Increasing evidence has shown that IR and TMZ inhibit tumor growth in GBM by inducing a type of programmed cell death that is dependent of autophagy. [11][12][13][14] Autophagy is a survival-promoting pathway that captures, degrades, and recycles intracellular proteins and organelles in lysosomes. However, excessive levels of autophagy may also lead to cell death.…”

Autophagy Inhibition Enhances Sunitinib Efficacy in Clear Cell Ovarian Carcinoma

“…Although HCQ demonstrated promising results in recent phase I/II clinical trials, the development of more potent autophagy inhibitors that display greater in vivo activity is urgently needed (2)(3)(4)(5)(6). Indeed, a recent report investigating sunitinib in combination with HCQ demonstrated that the MTD of HCQ, albeit through unknown mechanisms, inconsistently inhibited autophagy, thereby warranting the development of more potent and specific autophagy inhibitors (34).…”

“…As such, phase I and II clinical trials investigating HCQ in combination with chemotherapies or targeted therapies are ongoing. Early reports have indicated that HCQ may have modest clinical activity (2)(3)(4)(5)(6). However, in the absence of a specific autophagy inhibitor, targeting other events upstream or downstream of autophagy may improve clinical responses.…”