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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Acute Myeloid Leukemia

Intervention / Treatment
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* Drug: Thioridazine


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 55 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Thioridazine<br>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<br> <br> |

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Relapsed Acute Myeloid Leukemia, Refractory Acute Myeloid Leukemia, Thioridazine, Phase I, Clinical Trial