Clinical trial NCT00335868: PHA-739358 in Treating Patients With Chronic Myelogenous Leukemia That Relapsed After Imatinib Mesylate or c-ABL Therapy
Official title: A Pilot Phase II Study of PHA-739358 in Patients With Chronic Myeloid Leukemia Relapsing on Gleevec or c-ABL Therapy
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Leukemia
Keywords: accelerated phase chronic myelogenous leukemia
blastic phase chronic myelogenous leukemia
chronic phase chronic myelogenous leukemia
relapsing chronic myelogenous leukemia
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
Collaborators: name: National Cancer Institute (NCI)
First posted: 2006-06-12
Enrollment: 16
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Primary purpose: TREATMENT

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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Antileukemic response in terms of complete hematological response, no evidence of leukemia, or return to chronic phase
measure: Overall safety profile of PHA-739358 by type, severity, timing, and relatedness of adverse events and laboratory abnormalities
measure: Pharmacokinetics of this drug and its N-oxide metabolite PHA-816359 by measuring their plasma concentration at different times after dosing
measure: Changes in histone H3 and CRKL phosphorylation
measure: Correlation between changes in degree of histone H3 and CRKL phosphorylation and concurrent PHA-739358 concentrations and/or hematological response
measure: Complete, partial, or minor cytogenetic response in bone marrow
Secondary outcomes:
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Jonsson Comprehensive Cancer Center at UCLA
state: California
Study officials:
affiliation: Jonsson Comprehensive Cancer Center
name: Ronald Paquette, MD
role: STUDY_CHAIR
References: