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 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.

Conflict of interest statement

Conflict-of-interest disclosure: The authors declare no competing financial interests.

© 2018 by The American Society of Hematology.

Figures

Graphical abstract

Figure 1.

Study design. (A) Patients received TDZ daily at 3 dose levels including 25 mg every 6 hours (dose level I), 50 mg every 6 hours (dose level II), and 100 mg every 6 hours (dose level III) for 21 consecutive days, spanning days 1 to 22 of the study. Intermediate-dose cytarabine at 1 g/m2 was administered as a 2-hour infusion for 5 consecutive days between days 6 and 10 of the study. (B) Summary of screened and enrolled patients. PO, orally.

Figure 2.

Pharmacokinetic analysis. (A) TDZ trough concentrations were measured on days 1, 5, 8, 10, 17, 22, 29, and 36 for each study cohort. Plasma TDZ concentrations reached a steady state by day 5, and TDZ remained detectable up to day 29. In cohort III, TDZ was discontinued early for patients 12 and 13, and only patient 11 received doses to achieve steady-state plasma TDZ concentrations. This patient received TDZ at dose level III (100 mg every 6 hours) for the first 10 days (solid line), after which TDZ was deescalated to 50 mg every 6 hours (broken line) up to day 16 and discontinued thereafter. Data for cohorts I and II are displayed as mean ± standard error at each assessment point. (B) Plasma TDZ levels at steady state in relation to the target 10 μM concentration (conc.), previously shown to be effective against human AML in vitro. Data are expressed as cohort means and 95% CI. (C) Sum of plasma TDZ and its 2 active metabolites (2-sulfoxide and 2-sulfone) with DRD2 antagonistic effects in relation to the target concentration of 10 μM. Data are expressed as cohort means and 95% CI. (D) Sum of circulating DRD2 antagonist levels for individual patients normalized to daily dose of TDZ. Patient variation in plasma DRD2 antagonist level was associated with CYP2D6 genotype and its predicted drug metabolism phenotypes (difference between group means: 18.22, 95% CI: 4.1 to 32.3; P = .01).

Figure 3.

Response. (A) Response to a 5-day treatment with TDZ as a monotherapy was monitored at the level of peripheral blood ABC. Response for patients 2 and 9 was determined by percent bone marrow blast due to a lack of circulating blasts as indicated by the asterisk. Patients 12 and 13 were excluded from this analysis because they did not complete the 5-day treatment with TDZ. Red curves indicate disease progression based on ABC prior to the start of TDZ treatment. Blue color coding indicates TDZ dose level. Insets depict percent change in blast counts at day 5 compared with day 1. “+HU” indicates concurrent use of hydroxyurea during the 5-day treatment with TDZ. (B) Absolute neutrophil counts after exposure to up to 100 mg of TDZ every 6 hours based on data from 11 patients that completed the 5-day monotherapy with TDZ. Data are expressed as cohort means and 95% CI (mean change from day 1 to day 5: −1.00, 95% CI: −2.7 to 0.7, P = .22). (C) Platelet counts after a 5-day treatment with up to 100 mg of TDZ every 6 hours. Data points include patients that did not receive platelet transfusions within the first 5 days of TDZ, or up to 4 days prior to the start of the trial. Data are expressed as cohort means and 95% CI (mean change from day 1 to day 5: −23.00, 95% CI: −45.4 to −0.54, P = .04). (D) Baseline levels of DRD2 protein expression in MNCs of patients that showed no blast response vs patients that showed blast reduction after the 5-day treatment with TDZ (difference between group means: 1.20, 95% CI: 0.56 to 1.84; P = .002). The shaded area indicates the upper and lower 99% CI for DRD2 levels in healthy primitive cells as defined in supplemental Figure 3D. (E) DRD2 protein expression in MNCs of 20 AML patient samples (16 diagnosis and 4 relapse cases) not including on-study patients. The shaded area indicates the upper and lower 99% CI for DRD2 levels in healthy primitive cells (CD34+) as defined in supplemental Figure 3D. Inset depicts a representative flow cytometry plot for DRD2 expression in AML (red histogram), overlayed on the staining control (dotted histogram).