Unknown

Dataset Information

0

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


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 ?M, 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.

SUBMITTER: Aslostovar L 

PROVIDER: S-EPMC6093733 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

altmetric image

Publications

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

Aslostovar Lili L   Boyd Allison L AL   Almakadi Mohammed M   Collins Tony J TJ   Leong Darryl P DP   Tirona Rommel G RG   Kim Richard B RB   Julian Jim A JA   Xenocostas Anargyros A   Leber Brian B   Levine Mark N MN   Foley Ronan R   Bhatia Mickie M  

Blood advances 20180801 15


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 grad  ...[more]

Similar Datasets

| S-EPMC8967916 | biostudies-literature
| S-EPMC2930809 | biostudies-literature
| S-EPMC7787346 | biostudies-literature
| S-EPMC4803139 | biostudies-literature
| S-EPMC8580622 | biostudies-literature
| S-EPMC6839888 | biostudies-literature
| S-EPMC7539618 | biostudies-literature
| S-EPMC9746059 | biostudies-literature
| S-EPMC5756334 | biostudies-literature
| S-EPMC3110171 | biostudies-literature