Safety Study of Thioridazine in Combination With Cytarabine to Treat Relapsed or Refractory Acute Myeloid Leukemia (THORIDAL)

A Phase I Trial Evaluating Oral Thioridazine in Combination With Intermediate Dose Cytarabine in Patients 55 Years and Older With Acute Myeloid Leukemia Who Have Relapsed or Have Refractory Disease

This is a Phase I trial investigating the safety of using thioridazine in addition to cytarabine in elderly patients with relapsed or refractory Acute Myeloid Leukemia.

Study Overview

• Status: Completed
• Conditions: Acute Myeloid Leukemia
• Intervention / Treatment: Drug: Thioridazine

• Study Type: Interventional
• Enrollment (Actual): 13
• Phase: Phase 1

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Hamilton, Ontario, Canada, L8V 1C3
      • Juravinski Hospital & Cancer Centre

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 55 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Have a diagnosis of AML according to the WHO Classification1

• AML is refractory or relapsed (requiring at least 5% leukemic blasts in the bone marrow, regardless of the presence of other features such as new or recurrent dysplastic changes or extra medullary disease) according to the following definitions:

  • Relapsed (defined as ≥ 5% leukemic blasts in the bone marrow) after three months from receiving up to three prior induction regimens.
  • Refractory (defined as ≥ 5% leukemic blasts in the bone marrow) to not more than one prior induction regimen (defined as failure to achieve a CR or CRi following induction therapy).
• 55 years of age or older.

Exclusion Criteria:

• Receiving any other systemic anti-leukemic therapy (standard or investigational).
• Having received more than two prior chemotherapy lines for AML. Induction/consolidation therapy and bone marrow transplant are each considered a line of therapy.
• Having received previous AML therapy within four weeks of the first dose of study drug, with the exception of hydroxyurea.
• Clinical evidence suggestive of CNS involvement with leukemia unless a lumbar puncture confirms the absence of leukemic blasts in the CSF.
• Acute promyelocytic leukemia.
• An ECOG performance status of 3 or more.
• Inadequate renal function (i.e., estimated GFR < 60 mL/min/1.73m2).
• Inadequate hepatic function (i.e., serum bilirubin > 1.5×ULN; AST, ALT and alkaline phosphatase > 2.5×ULN).
• Presence of acute or chronic GVHD.
• Presence of a systemic fungal, bacterial, viral or other infection not controlled (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment).
• Having any other severe concurrent disease, or have a history of serious organ dysfunction or disease involving the heart, kidney, liver or other organ system that may place the patient at undue risk to undergo induction therapy.
• Diagnosed with a condition that can prolong the QT interval (e.g., long QT syndrome) or have a QTc interval ≥ 470ms if male, or ≥ 480ms if female.
• Left ventricular ejection fraction less than 45%.
• History of uncontrolled cardiac arrhythmia.
• Known severe hypotensive or hypertensive heart disease.
• Prior malignancy, unless the patient has been disease-free for at least five years following curative intent therapy, with the following exceptions: Patients with treated non-melanoma skin cancer, in situ carcinoma, or cervical intraepithelial neoplasia, regardless of the disease-free duration, if definitive treatment for the condition has been completed; or patients with organ-confined prostate cancer with no evidence of recurrent or progressive disease based on prostate-specific antigen (PSA) values if hormonal therapy has been initiated or a radical prostatectomy has been performed.
• Known HIV positivity.
• Known pregnancy or lactating female.
• Presence of a psychiatric disorder that would interfere with consent, study participation, or follow-up.
• Unable to provide informed consent.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Thioridazine; Up to 3 dose levels of thioridazine will be assessed sequentially: 25 mg Q6H (Level I), 50 mg Q6H (Level II) and 100 mg Q6H (Level III). The duration of thioridazine therapy is for a total of 21 days (Days 1-22 on study). All patients will receive cytarabine 1 g/m2 administered as a 2 hour infusion for 5 consecutive days (Days 6-10 on study).	Drug: Thioridazine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety	Both acute and late toxicities will be determined according to NCI-CTCAE version 4.03	Up to 36 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Assessment of Functional Leukemia Stem Cells	Bone marrow and peripheral blood samples obtained from patients treated with thioridazine and cytarabine will be analyzed in four separate assays.	Up to 36 days
Pharmacokinetic Analysis of Thioridazine Serum Trough Levels	Pharmacokinetic modeling will be performed to estimate values for individual C min levels.	Up to 36 days
Assessment of Objective Tumor Response	Tumor responses are categorized as either a complete remission, a complete remission with incomplete count recovery, a partial remission, a treatment failure, or as not evaluable	Up to 36 days
Pharmacogenetic Analysis of Thioridazine Serum Trough Levels	Cytochrome P450 2D6 genotype will be determined to examine genetic contribution to thioridazine Cmin levels.	Up to 36 days

Collaborators and Investigators

• Sponsor: Ontario Clinical Oncology Group (OCOG)
• Collaborators: Hamilton Health Sciences Corporation; Juravinski Cancer Centre Foundation
• Investigators: Study Director: Mark N Levine, MD, Ontario Clinical Oncology Group, McMaster University; Principal Investigator: Ronan Foley, MD, Hamilton Health Sciences, McMaster University

Publications and helpful links

General Publications

• Aslostovar L, Boyd AL, Almakadi M, Collins TJ, Leong DP, Tirona RG, Kim RB, Julian JA, Xenocostas A, Leber B, Levine MN, Foley R, Bhatia M. A phase 1 trial evaluating thioridazine in combination with cytarabine in patients with acute myeloid leukemia. Blood Adv. 2018 Aug 14;2(15):1935-1945. doi: 10.1182/bloodadvances.2018015677.

Study record dates

Study Major Dates

• Study Start: July 1, 2014
• Primary Completion (Actual): August 1, 2016
• Study Completion (Actual): September 1, 2016

Study Registration Dates

• First Submitted: March 20, 2014
• First Submitted That Met QC Criteria: March 21, 2014
• First Posted (Estimate): March 26, 2014

Study Record Updates

• Last Update Posted (Estimate): December 7, 2016
• Last Update Submitted That Met QC Criteria: December 6, 2016
• Last Verified: December 1, 2016

More Information

Terms related to this study

• Keywords: Phase I; Clinical Trial; Relapsed Acute Myeloid Leukemia; Refractory Acute Myeloid Leukemia; Thioridazine
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Antipsychotic Agents; Tranquilizing Agents; Psychotropic Drugs; Dopamine Agents; Dopamine Antagonists; Thioridazine
• Other Study ID Numbers: OCOG-2013-THORIDAL