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Phase I study of 5-aza-2′-deoxycytidine in combination with valproic acid in non-small-cell lung cancer

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Abstract

Purpose

Non-small-cell lung cancer (NSCLC) accounts for the majority of lung cancer and is the most common cause of cancer death in industrialized countries. Epigenetic modifications are observed universally during the tumorigenesis of lung cancer. The development of epigenetic-modulating agents utilizing the synergism between hypomethylating agents and histone deacetylase (HDAC) inhibitors provides a novel therapeutic approach in treating NSCLC.

Methods

We performed a phase I trial combining 5-aza-2′-deoxycytidine (decitabine) and valproic acid (VPA), in patients with advanced stage NSCLC. Patients were treated with escalating doses of decitabine (5–15 mg/m2) IV for 10 days in combination with VPA (10–20 mg/kg/day) PO on days 5–21 of a 28-day cycle. Pharmacokinetic and pharmacodynamic analysis included decitabine pharmacokinetics and fetal hemoglobin expression.

Results

Eight patients were accrued to this phase I study. All patients had advanced NSCLC and had received prior chemotherapy. Eastern Cooperative Oncology Group performance status was 0–2. Major toxicities included myelosuppression and neurotoxicity. Dose-limiting toxicity was seen in two patients suffering grade 3 neurotoxicity during cycle one including disorientation, lethargy, memory loss, and ataxia at dose level 1. One patient had grade 3 neutropenia at the de-escalated dose. No objective response was observed, and stable disease was seen in one patient. Fetal hemoglobin levels increased after cycle one in all seven patients with evaluable results.

Conclusions

We observed that decitabine and valproic acid are an effective combination in reactivating hypermethylated genes as demonstrated by re-expressing fetal hemoglobin. This combination in patients with advanced stage IV NSCLC, however, is limited by unacceptable neurological toxicity at a relatively low dosage. Combining hypomethylating agents with alternative HDAC inhibitors that lack the toxicity of VPA should be explored further.

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Acknowledgments

This study is supported in part by the research funding from NIH U01 CA76576-02, NIH 3P30CA016058-35S2, and V-Foundation Translational Research Award. Authors of this publication have no conflict of interest or disclosure relevant to this work.

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Correspondence to G. A. Otterson.

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B. F. Chu and M. J. Karpenko contributed equally to the work.

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Chu, B.F., Karpenko, M.J., Liu, Z. et al. Phase I study of 5-aza-2′-deoxycytidine in combination with valproic acid in non-small-cell lung cancer. Cancer Chemother Pharmacol 71, 115–121 (2013). https://doi.org/10.1007/s00280-012-1986-8

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  • DOI: https://doi.org/10.1007/s00280-012-1986-8

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