PHA-739358 in Treating Patients With Chronic Myelogenous Leukemia That Relapsed After Imatinib Mesylate or c-ABL Therapy

Study Overview
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Brief Summary
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RATIONALE: PHA-739358 may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. PURPOSE: This phase II trial is studying how well PHA-739358 works in treating patients with chronic myelogenous leukemia that relapsed after imatinib mesylate or c-ABL therapy.

Detailed Description
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OBJECTIVES: Explore the clinical efficacy of PHA-739358, in terms of hematological response lasting ≥ 4 weeks, in patients with chronic myelogenous leukemia that relapsed after imatinib mesylate or c-ABL therapy. Explore the safety profile of this drug in these patients. Explore the pharmacokinetic profile of this drug and its N-oxide metabolite PHA-816359 in plasma. Explore the modulation of histone H3 and CRKL phosphorylation after PHA-739358 administration. Explore the relationship between plasma drug levels and the modulation of histone H3 and CRKL phosphorylation. Explore the clinical efficacy of this drug, in terms of cytogenetic response in bone marrow. Explore response depending on status of T315I mutation in BCR-ABL kinase. OUTLINE: This is a pilot, open-label, multicenter study. Patients receive PHA-739358 IV over 6 hours on days 1, 8, and 15. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients benefitting from treatment may receive additional courses at the discretion of the investigator. Patients undergo blood collection and bone marrow biopsies periodically for pharmacologic and biomarker correlative studies. After completion of study treatment, patients are followed every 3 months for 1 year. PROJECTED ACCRUAL: A total of 16 patients will be accrued for this study.

Official Title
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A Pilot Phase II Study of PHA-739358 in Patients With Chronic Myeloid Leukemia Relapsing on Gleevec or c-ABL Therapy

Conditions
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Leukemia

Intervention / Treatment
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* Drug: danusertib
* Other: laboratory biomarker analysis
* Other: pharmacological study


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Diagnosis of chronic myelogenous leukemia confirmed by bone marrow biopsy Chronic, accelerated, or blastic phase disease May have T315I mutation in BCR-ABL kinase Relapsed after prior imatinib mesylate or c-ABL therapy No CNS leukemia PATIENT CHARACTERISTICS: ECOG performance status 0-2 Blood pressure ≤ 140/90 mm Hg (with or without hypertension treatment for ≥ 1 week) Transaminases ≤ 2.5 times upper limit of normal (ULN) Bilirubin ≤ 1.5 times ULN Creatinine ≤ 1.5 times ULN No known history of HIV infection No active uncontrolled infection No grade 3 or 4 bleeding LVEF ≥ 45% by MUGA or ≥ 40% by transthoracic echocardiography No medical or psychiatric condition or laboratory abnormalities that would limit study compliance or increase risk during study participation Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception during and for 90 (female) or 180 (male) days after completion of study treatment No significant cardiovascular disease (i.e., uncontrolled arrhythmias or unstable angina) within the past 6 months No major thromboembolic event within the past 6 months, including any of the following: Myocardial infarction Stroke Transient ischemic attack Pulmonary embolism Noncatheter-related deep-vein thrombosis PRIOR CONCURRENT THERAPY: Recovered from all acute toxic effects (excluding alopecia) of prior therapy More than 2 weeks since prior chemoimmunotherapy Hydroxyurea must be discontinued 1 day prior to study therapy More than 4 weeks since prior major surgery No other concurrent approved or investigational anticancer treatment, including chemotherapy, biologic response modifiers, hormones, or immunotherapy No other concurrent investigational drugs No concurrent participation in another treatment clinical trial

Ages Eligible for Study
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Minimum Age: 18 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
Masking: None (Open Label)


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: danusertib|nan|
|Other: laboratory biomarker analysis|nan|
|Other: pharmacological study|nan|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Antileukemic response in terms of complete hematological response, no evidence of leukemia, or return to chronic phase |  |  | 
| Overall safety profile of PHA-739358 by type, severity, timing, and relatedness of adverse events and laboratory abnormalities |  |  | 
| Pharmacokinetics of this drug and its N-oxide metabolite PHA-816359 by measuring their plasma concentration at different times after dosing |  |  | 
| Changes in histone H3 and CRKL phosphorylation |  |  | 
| Correlation between changes in degree of histone H3 and CRKL phosphorylation and concurrent PHA-739358 concentrations and/or hematological response |  |  | 
| Complete, partial, or minor cytogenetic response in bone marrow |  |  | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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accelerated phase chronic myelogenous leukemia, blastic phase chronic myelogenous leukemia, chronic phase chronic myelogenous leukemia, relapsing chronic myelogenous leukemia