Abstract
Epigenetic therapies may modulate the tumor microenvironment. We evaluated the safety and optimal sequence of combination DNA methyltransferase inhibitor guadecitabine with a granulocyte macrophage-colony-stimulating-factor (GM-CSF) secreting colon cancer (CRC) vaccine (GVAX) using a primary endpoint of change in CD45RO + T cells. 18 patients with advanced CRC enrolled, 11 underwent paired biopsies and were evaluable for the primary endpoint. No significant increase in CD45RO + cells was noted. Grade 3-4 toxicities were expected and manageable. Guadecitabine + GVAX was tolerable but demonstrated no significant immunologic activity in CRC. We report a novel trial design to efficiently evaluate investigational therapies with a primary pharmacodynamic endpoint.Trial registry Clinicaltrials.gov: NCT01966289. Registered 21 October, 2013.
Keywords:
Colorectal cancer; Epigenetic therapy; GVAX; Immunotherapy.
Publication types
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Randomized Controlled Trial
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adult
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Aged
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Aged, 80 and over
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Azacitidine / administration & dosage
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Azacitidine / adverse effects
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Azacitidine / analogs & derivatives*
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Azacitidine / pharmacology
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Azacitidine / therapeutic use
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Biopsy
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Cancer Vaccines / administration & dosage
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Cancer Vaccines / adverse effects
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Cancer Vaccines / pharmacology*
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Colorectal Neoplasms / drug therapy*
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Colorectal Neoplasms / genetics*
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Colorectal Neoplasms / immunology
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Colorectal Neoplasms / pathology
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Combined Modality Therapy / methods
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DNA (Cytosine-5-)-Methyltransferase 1 / antagonists & inhibitors*
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DNA Methylation / drug effects
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Epigenomics / methods
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Feasibility Studies
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Female
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Granulocyte-Macrophage Colony-Stimulating Factor / metabolism
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Humans
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Immunotherapy / methods
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Immunotherapy, Active / methods
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Leukocyte Common Antigens / drug effects
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Leukocyte Common Antigens / metabolism
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Male
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Middle Aged
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Safety
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Severity of Illness Index
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Tumor Microenvironment
Substances
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Cancer Vaccines
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GVAX vaccine
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guadecitabine
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Granulocyte-Macrophage Colony-Stimulating Factor
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DNA (Cytosine-5-)-Methyltransferase 1
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DNMT1 protein, human
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Leukocyte Common Antigens
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Azacitidine
Associated data
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ClinicalTrials.gov/NCT01966289