Thioridazine in combination with cytarabine in patients with acute myeloid leukemia (THORIDAL)

The results of a phase I dose-escalation study (NCT02096289) evaluating the safety and feasibility of oral thioridazine, a dopamine receptor D2 (DRD2) antagonist, in combination with cytarabine in patients 55 years and older with relapsed or refractory (R/R) acute myeloid leukemia (AML) were reported by a group of Canadian researchers in the August 2018 issue of Blood Advances.

In this phase I study, 13 patients aged 55 years or older with R/R AML (n = 9) or AML with myelodysplastic-related changes (AML-MRC; n = 4) were enrolled between July 2014 and September 2016. Patients received oral thioridazine at 25 mg (dose level I; n = 6), 50 mg (dose level II; n = 4), and 100 mg (dose level III; n = 3) every 6 hours alone for 21 consecutive days (days 1–22) and also in combination with intermediate-dose cytarabine (1 g/m² for five consecutive days, days 6–10).

To evaluate the response to thioridazine in AML patients, a lead-in phase with thioridazine alone (days 1–5) and cytarabine (days 1–6) was performed. Bone marrow and peripheral blood samples were collected on day 5 to evaluate response to thioridazine alone, on day 22 after termination of thioridazine and on day 36 for the end of response assessment. DRD2 expression was measured at baseline using flow cytometry and correlated with response.

Key findings:

Safety

• Dose-limiting toxicity (DLT) of grade 3 QTc interval prolongation to 535 ms on day 7 occurred in one patient in dose level I
• Dose escalation from 100 mg to 50 mg thioridazine every 6 hours occurred in one patient enrolled in dose level II due to grade 2 QTc interval prolongation
• DLT of grade 3 depressed level of consciousness, grade 2 dizziness and gait disturbance occurred in one patient each enrolled in dose level III
• Maximum tolerated dose of thioridazine: 50 mg every 6 hours

Response assessment

• On Day 5, 72% (8/11) of patients who completed the 5-day portion of the study had a reduction of peripheral leukemic burden ranging from 19%–55%
• Eight of the nine patients who harbored > 1% DRD2 expression, displayed blast reduction during this 5-day interval
• Patients with < 1% DRD2 expression at baseline associated with a lack of biological response
• Three patients showed progressive disease
• After day 5, peripheral leukemic burden continued to decrease with the addition of cytarabine
• After day 22, there was an increase in blasts as patients approached day 36

In summary, the findings of this study suggest that thioridazine at a dose of 50 mg every 6 hours can be safely combined with intermediate-dose cytarabine in older patients with R/R AML.

The researchers noted that the anti-leukemic effect of thioridazine was observed predominantly in the peripheral blood compared to the bone marrow and did not meet the “established clinical remission criteria in AML.” Additionally, these measurements were quite similar to those obtained in early generation FLT3 inhibitors. They further concluded by stating that the preliminary findings of this study suggest that “DRD2 represents a valid target in AML.”