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

Sponsor

Jonsson Comprehensive Cancer Center (Other)

Overall Status

Unknown status

CT.gov ID

NCT00335868

Collaborator

National Cancer Institute (NCI) (NIH)

Enrollment

Location

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Leukemia	Drug: danusertib Other: laboratory biomarker analysis Other: pharmacological study	Phase 2

Detailed Description

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

16 participants

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Study Start Date :

Mar 1, 2007

Anticipated Primary Completion Date :

Dec 1, 2009

Outcome Measures

Primary Outcome Measures

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 []

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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