Clinical Research Papers:

Targeting epigenetics for treatment of BRAF mutated metastatic melanoma with decitabine in combination with vemurafenib: A phase lb study

Yousef Zakharia, Varun Monga, Umang Swami, Aaron D. Bossler, Michele Freesmeier, Melanie Frees, Mirza Khan, Noah Frydenlund, Rithu Srikantha, Marion Vanneste, Michael Henry and Mohammed Milhem _

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Oncotarget. 2017; 8:89182-89193. https://doi.org/10.18632/oncotarget.21269

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Yousef Zakharia1, Varun Monga1, Umang Swami1, Aaron D. Bossler4, Michele Freesmeier1, Melanie Frees1, Mirza Khan5, Noah Frydenlund2, Rithu Srikantha2, Marion Vanneste3, Michael Henry3 and Mohammed Milhem1

1Department of Hematology, Oncology and Blood and Marrow Transplantation and the Holden Comprehensive Cancer Center, University of Iowa Hospitals and Clinics, Iowa City, IA 52242, USA

2The University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA

3Department of Molecular Physiology and Biophysics, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA

4Department of Pathology, University of Iowa Hospitals and Clinics, Iowa City, IA 52242, USA

5Department of Internal Medicine, University of Iowa Hospitals and Clinics, Iowa City, IA 52242, USA

Correspondence to:

Mohammed Milhem, email: [email protected]

Keywords: vemurafenib, decitabine, epigenetics, BRAF, melanoma

Received: June 16, 2017     Accepted: September 16, 2017     Published: September 26, 2017


Introduction: Epigenetic modifications play an important role in progression and development of resistance in V600EBRAF positive metastatic melanoma. Therefore, we hypothesized that the action of vemurafenib (BRAF inhibitor) can be made more effective by combining with low dose decitabine (a DNA methyltransferase inhibitor). The primary objective of this phase lb study was to determine the dose limiting toxicity and maximum tolerated dose of combination of subcutaneous decitabine with oral vemurafenib in patients with V600EBRAF positive metastatic melanoma with or without any prior treatment.

Experimental Design: The study employed 3+3 dose escalation combining subcutaneous decitabine at different doses and schedules (4 cohorts) with the standard oral dose of vemurafenib 960 mg twice daily. Preclinical assessment and further analysis were also performed in A375 melanoma cell line.

Results: Fourteen patients received study treatment. No dose limiting toxicity was encountered and maximum tolerated dose was not reached. Important toxicities included fatigue, increased creatinine, neutropenia, leucopenia, hypophosphatemia, rash and hyperuricemia. Three patients achieved complete response, three had partial response and five had stable disease. Preclinical assessment demonstrated action of the combination which delayed the development of acquired resistance and improved duration of treatment sensitivity.

Conclusions: The combination of oral vemurafenib with subcutaneous decitabine is safe and showed activity in V600EBRAF positive metastatic melanoma. Since most responses were seen in cohort 1, which utilized low-dose, long-term decitabine, future studies of this combination treatment should utilize longer duration of decitabine, at the lowest dose of 0.1 mg/kg.

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