Title

Intravenous 5-fluoro-2'-deoxycytidine administered with tetrahydrouridine increases the proportion of p16-expressing circulating tumor cells in patients with advanced solid tumors

Authors

Geraldine O. Coyne, Division of Cancer Treatment and Diagnosis, National Cancer Institute
Lihua Wang, Frederick National Laboratory for Cancer Research
Jennifer Zlott, Division of Cancer Treatment and Diagnosis, National Cancer Institute
Lamin Juwara, Frederick National Laboratory for Cancer Research
Joseph M. Covey, Division of Cancer Treatment and Diagnosis, National Cancer Institute
Jan H. Beumer, University of Pittsburgh School of Pharmacy
Mihaela C. Cristea, Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center
Edward M. Newman, Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center
Stephen Koehler, City of Hope Medical Group
Jorge J. Nieva, University of Southern California Norris Comprehensive Cancer Center
Agustin A. Garcia, University of Southern California Norris Comprehensive Cancer Center
David R. Gandara, University of California Davis Cancer Center
Brandon Miller, Frederick National Laboratory for Cancer Research
Sonny Khin, Frederick National Laboratory for Cancer Research, Frederick
Sarah B. Miller, Division of Cancer Treatment and Diagnosis, National Cancer Institute
Seth M. Steinberg, Center for Cancer Research, National Cancer Institute
Larry Rubinstein, Division of Cancer Treatment and Diagnosis, National Cancer Institute
Ralph E. Parchment, Frederick National Laboratory for Cancer Research
Robert J. Kinders, Clinical Pharmacodynamic Biomarkers Program, Applied/Developmental Research Directorate, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
Richard L. Piekarz, Division of Cancer Treatment and Diagnosis, National Cancer Institute, 31 Center Drive, Bldg. 31 Room 3A-44, Bethesda, MD, 20892, USA.
Shivaani Kummar, Division of Cancer Treatment and Diagnosis, National Cancer Institute, 31 Center Drive, Bldg. 31 Room 3A-44, Bethesda, MD, 20892, USA.
Alice P. Chen, Division of Cancer Treatment and Diagnosis, National Cancer Institute, 31 Center Drive, Bldg. 31 Room 3A-44, Bethesda, MD, 20892, USA.
James H. Doroshow, Division of Cancer Treatment and Diagnosis, National Cancer Institute

Document Type

Article

Publication Date

5-1-2020

Publication Title

Cancer chemotherapy and pharmacology

Abstract

PURPOSE: Following promising responses to the DNA methyltransferase (DNMT) inhibitor 5-fluoro-2'-deoxycytidine (FdCyd) combined with tetrahydrouridine (THU) in phase 1 testing, we initiated a non-randomized phase 2 study to assess response to this combination in patients with advanced solid tumor types for which tumor suppressor gene methylation is potentially prognostic. To obtain pharmacodynamic evidence for DNMT inhibition by FdCyd, we developed a novel method for detecting expression of tumor suppressor protein p16/INK4A in circulating tumor cells (CTCs). METHODS: Patients in histology-specific strata (breast, head and neck [H&N], or non-small cell lung cancers [NSCLC] or urothelial transitional cell carcinoma) were administered FdCyd (100 mg/m) and THU (350 mg/m) intravenously 5 days/week for 2 weeks, in 28-day cycles, and progression-free survival (PFS) rate and objective response rate (ORR) were evaluated. Blood specimens were collected for CTC analysis. RESULTS: Ninety-three eligible patients were enrolled (29 breast, 21 H&N, 25 NSCLC, and 18 urothelial). There were three partial responses. All strata were terminated early due to insufficient responses (H&N, NSCLC) or slow accrual (breast, urothelial). However, the preliminary 4-month PFS rate (42%) in the urothelial stratum exceeded the predefined goal-though the ORR (5.6%) did not. An increase in the proportion of p16-expressing cytokeratin-positive CTCs was detected in 69% of patients evaluable for clinical and CTC response, but was not significantly associated with clinical response. CONCLUSION: Further study of FdCyd + THU is potentially warranted in urothelial carcinoma but not NSCLC or breast or H&N cancer. Increase in the proportion of p16-expressing cytokeratin-positive CTCs is a pharmacodynamic marker of FdCyd target engagement.

First Page

979

Last Page

993

DOI

10.1007/s00280-020-04073-5

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