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

Leukemia Clinical Trial

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT00335868
• Other study ID #: CDR0000486219
• Secondary ID: UCLA-0601009-01N
• Status: Active, not recruiting
• Phase: Phase 2
• First received: June 8, 2006
• Last updated: December 17, 2013
• Start date: March 2007

Study information

• Verified date: July 2009
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 16
• Est. primary completion date: December 2009
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

Study Design

Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Leukemia
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive
• Leukemia, Myeloid

Intervention

Drug:
• danusertib

Other:
• laboratory biomarker analysis

• pharmacological study

Locations

Country	Name	City	State
United States	Jonsson Comprehensive Cancer Center at UCLA	Los Angeles	California

Sponsors (2)

Lead Sponsor	Collaborator
Jonsson Comprehensive Cancer Center	National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

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