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; Mohammed Milhem

doi:10.18632/oncotarget.21269

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

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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, …

Oncotarget, Vol.8(51), pp.89182-89193

10/24/2017

DOI: 10.18632/oncotarget.21269

PMCID: PMC5687680

PMID: 29179510

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Abstract

Epigenetic modifications play an important role in progression and development of resistance in BRAF 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 BRAF positive metastatic melanoma with or without any prior treatment. 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. 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. The combination of oral vemurafenib with subcutaneous decitabine is safe and showed activity in BRAF 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.

Epigenetics

vemurafenib

melanoma

BRAF

decitabine

Details

Title: Subtitle: Targeting epigenetics for treatment of BRAF mutated metastatic melanoma with decitabine in combination with vemurafenib: A phase lb study
Creators: Yousef Zakharia - Department 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
Varun Monga - Department 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
Umang Swami - Department 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
Aaron D Bossler - Department of Pathology, University of Iowa Hospitals and Clinics, Iowa City, IA 52242, USA
Michele Freesmeier - Department 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
Melanie Frees - Department 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
Mirza Khan - Department of Internal Medicine, University of Iowa Hospitals and Clinics, Iowa City, IA 52242, USA
Noah Frydenlund - The University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
Rithu Srikantha - The University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
Marion Vanneste - Department of Molecular Physiology and Biophysics, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
Michael Henry - Department of Molecular Physiology and Biophysics, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
Mohammed Milhem - Department 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
Resource Type: Journal article
Publication Details: Oncotarget, Vol.8(51), pp.89182-89193
DOI: 10.18632/oncotarget.21269
PMID: 29179510
PMCID: PMC5687680
NLM abbreviation: Oncotarget
ISSN: 1949-2553
eISSN: 1949-2553
Publisher: United States
Grant note: P30 CA086862 / NCI NIH HHS T32 CA078586 / NCI NIH HHS
Language: English
Date published: 10/24/2017
Academic Unit: Molecular Physiology and Biophysics; Hematology, Oncology, and Blood & Marrow Transplantation; Pathology; Radiation Oncology; Radiation Research Laboratory; Urology; Internal Medicine
Record Identifier: 9984046933102771

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