A phase 1 trial evaluating thioridazine in combination with cytarabine in patients with acute myeloid leukemia
| Autor: | Ronan Foley, Mickie Bhatia, Mark Levine, Darryl P. Leong, Brian Leber, Richard B. Kim, Mohammed Almakadi, Rommel G. Tirona, Anargyros Xenocostas, Jim A. Julian, Allison L. Boyd, Tony J. Collins, Lili Aslostovar |
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| Rok vydání: | 2018 |
| Předmět: |
Male
0301 basic medicine medicine.medical_specialty Myeloid Clinical Trials and Observations Thioridazine Gastroenterology 03 medical and health sciences 0302 clinical medicine Internal medicine Antineoplastic Combined Chemotherapy Protocols medicine Humans Hydroxyurea Aged business.industry Cytarabine Antagonist Myeloid leukemia Hematology Middle Aged medicine.disease Dopamine D2 Receptor Antagonists Leukemia Myeloid Acute Leukemia 030104 developmental biology medicine.anatomical_structure Tolerability 030220 oncology & carcinogenesis Female business Progressive disease medicine.drug |
| Zdroj: | Paediatrics Publications |
| ISSN: | 2473-9537 2473-9529 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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