A phase 1 trial evaluating thioridazine in combination with cytarabine in patients with acute myeloid leukemia

Lili Aslostovar; Allison L. Boyd; Mohammed Almakadi; Tony J. Collins; Darryl P. Leong; Rommel G. Tirona; Richard B. Kim; Jim A. Julian; Anargyros Xenocostas; Brian Leber; Mark N. Levine; Ronan Foley; Mickie Bhatia

Blood Advances (Aug 2018)

A phase 1 trial evaluating thioridazine in combination with cytarabine in patients with acute myeloid leukemia

Lili Aslostovar,
Allison L. Boyd,
Mohammed Almakadi,
Tony J. Collins,
Darryl P. Leong,
Rommel G. Tirona,
Richard B. Kim,
Jim A. Julian,
Anargyros Xenocostas,
Brian Leber,
Mark N. Levine,
Ronan Foley,
Mickie Bhatia

Affiliations

Lili Aslostovar: Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON, Canada;; Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada;
Allison L. Boyd: Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON, Canada;
Mohammed Almakadi: Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON, Canada;; Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada;; Division of Malignant Hematology, Department of Oncology, Juravinski Hospital, Hamilton, ON, Canada;
Tony J. Collins: Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON, Canada;
Darryl P. Leong: Division of Cardiology, Department of Medicine, Population Health Research Institute, McMaster University, Hamilton, ON, Canada;
Rommel G. Tirona: Division of Clinical Pharmacology, Department of Medicine, University of Western Ontario, London Health Sciences Centre, London, ON, Canada;
Richard B. Kim: Division of Clinical Pharmacology, Department of Medicine, University of Western Ontario, London Health Sciences Centre, London, ON, Canada;
Jim A. Julian: Department of Oncology, McMaster University, Juravinski Hospital, Hamilton, ON, Canada;
Anargyros Xenocostas: Division of Hematology, Department of Medicine, University of Western Ontario, London Health Sciences Centre, London, ON, Canada;
Brian Leber: Department of Medicine, McMaster University, Juravinski Hospital, Hamilton, ON, Canada
Mark N. Levine: Department of Oncology, McMaster University, Juravinski Hospital, Hamilton, ON, Canada;
Ronan Foley: Department of Pathology and Molecular Medicine, McMaster University, Juravinski Hospital, Hamilton, ON, Canada;; Ronan Foley, Juravinski Hospital and Cancer Centre, 711 Concession St, Second floor laboratory, Room 201, Hamilton, ON L8V 5C2, Canada;
Mickie Bhatia: Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON, Canada;; Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada;; Mickie Bhatia, Stem Cell and Cancer Research Institute, McMaster University, Faculty of Health Sciences, 1280 Main St West, MDCL 5029, Hamilton, ON L8S 4K1, Canada

Journal volume & issue: Vol. 2, no. 15
pp. 1935 – 1945

Abstract

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Abstract: We completed a phase 1 dose-escalation trial to evaluate the safety of a dopamine receptor D2 (DRD2) antagonist thioridazine (TDZ), in combination with cytarabine. Thirteen patients 55 years and older with relapsed or refractory acute myeloid leukemia (AML) were enrolled. Oral TDZ was administered at 3 dose levels: 25 mg (n = 6), 50 mg (n = 4), or 100 mg (n = 3) every 6 hours for 21 days. Intermediate-dose cytarabine was administered on days 6 to 10. Dose-limiting toxicities (DLTs) included grade 3 QTc interval prolongation in 1 patient at 25 mg TDZ and neurological events in 2 patients at 100 mg TDZ (gait disturbance, depressed consciousness, and dizziness). At the 50-mg TDZ dose, the sum of circulating DRD2 antagonist levels approached a concentration of 10 μM, a level noted to be selectively active against human AML in vitro. Eleven of 13 patients completed a 5-day lead-in with TDZ, of which 6 received TDZ with hydroxyurea and 5 received TDZ alone. During this period, 8 patients demonstrated a 19% to 55% reduction in blast levels, whereas 3 patients displayed progressive disease. The extent of blast reduction during this 5-day interval was associated with the expression of the putative TDZ target receptor DRD2 on leukemic cells. These preliminary results suggest that DRD2 represents a potential therapeutic target for AML disease. Future studies are required to corroborate these observations, including the use of modified DRD2 antagonists with improved tolerability in AML patients. This trial was registered at www.clinicaltrials.gov as #NCT02096289.

Published in Blood Advances

ISSN: 2473-9529 (Print); 2473-9537 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Internal medicine: Specialties of internal medicine
Website: https://ashpublications.org/bloodadvances

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