Temsirolimus and Imatinib Mesylate in Treating Patients With Chronic Myelogenous Leukemia

Sponsor

National Cancer Institute (NCI) (NIH)

Overall Status

Terminated

CT.gov ID

NCT00101088

Collaborator

(none)

Enrollment

Location

Arm

Study Details

Study Description

Brief Summary

This phase I trial is studying the side effects and best dose of temsirolimus when given with imatinib mesylate in treating patients with chronic myelogenous leukemia. Drugs used in chemotherapy, such as temsirolimus, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Imatinib mesylate may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving temsirolimus with imatinib mesylate may kill more cancer cells

Condition or Disease	Intervention/Treatment	Phase
Accelerated Phase Chronic Myelogenous Leukemia Blastic Phase Chronic Myelogenous Leukemia Chronic Myelogenous Leukemia, BCR-ABL1 Positive Chronic Phase Chronic Myelogenous Leukemia Relapsing Chronic Myelogenous Leukemia	Drug: imatinib mesylate Drug: temsirolimus Other: laboratory biomarker analysis	Phase 1

Detailed Description

OBJECTIVES:

Determine the safety and tolerability of temsirolimus when administered with imatinib mesylate in patients with chronic myelogenous leukemia.
Determine potential dose-limiting toxic effects of this regimen in these patients.
Determine, preliminarily, hematologic and cytogenetic response rates in patients treated with this regimen.

OUTLINE: This is a multicenter, dose-escalation study of temsirolimus.

Patients receive temsirolimus intravenously (IV) over 30 minutes once on days 1, 8, 15, and 22 and oral imatinib mesylate once daily on days 1-28. Courses repeat every 28 days in the absence of unacceptable toxicity or disease progression. Patients receive 2 additional courses beyond maximal response. Cohorts of 3-6 patients receive escalating doses of temsirolimus until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.

Patients are followed for survival.

Study Design

Study Type:

Interventional

Actual Enrollment :

21 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase I Study of CCI-779 in Combination With Imatinib Mesylate in Chronic Myelogenous Leukemia

Study Start Date :

Apr 1, 2005

Actual Primary Completion Date :

Jun 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment (imatinib mesylate, temsirolimus) Patients receive temsirolimus IV over 30 minutes once on days 1, 8, 15, and 22 and oral imatinib mesylate once daily on days 1-28. Courses repeat every 28 days in the absence of unacceptable toxicity or disease progression	Drug: imatinib mesylate Given orally Other Names: CGP 57148 Gleevec Glivec Drug: temsirolimus Given IV Other Names: CCI-779 cell cycle inhibitor 779 Torisel Other: laboratory biomarker analysis Correlative studies

Arm

Intervention/Treatment

Experimental: Treatment (imatinib mesylate, temsirolimus)

Patients receive temsirolimus IV over 30 minutes once on days 1, 8, 15, and 22 and oral imatinib mesylate once daily on days 1-28. Courses repeat every 28 days in the absence of unacceptable toxicity or disease progression

Drug: imatinib mesylate

Given orally

Other Names:

CGP 57148

Gleevec

Glivec

Drug: temsirolimus

Given IV

Other Names:

CCI-779

cell cycle inhibitor 779

Torisel

Other: laboratory biomarker analysis

Correlative studies

Outcome Measures

Primary Outcome Measures

Unacceptable toxicity graded according to the NCI CTCAE version 3.0 [Up to 5 years]

Secondary Outcome Measures

Disease progression [Up to 5 years]
Duration of response [Up to 5 years]
Presented using descriptive statistics.
Survival [Up to 5 years]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Histologically confirmed chronic myelogenous leukemia (CML)
Philadelphia chromosome-positive OR Bcr-Abl-positive disease, meeting 1 of the following criteria:
Accelerated phase, defined by at least 1 of the following:
10-19% blasts in the peripheral blood or bone marrow
At least 20% basophils in peripheral blood or bone marrow
Platelet count < 100,000/mm^3 (unrelated to therapy)
Platelet count > 1,000,000/mm^3 (unresponsive to therapy)
Increasing splenomegaly AND increasing WBC count (unresponsive to therapy)
Clonal evolution
Blast phase, defined by 1 of the following:
At least 20% blasts in peripheral blood or bone marrow
Extramedullary disease
Chronic phase, defined by all of the following:
Less than 10% blasts in peripheral blood or bone marrow
Less than 20% basophils in peripheral blood or bone marrow
Platelet count > 100,000/mm^3
Absence of clonal evolution
May have received and/or failed prior imatinib mesylate therapy
Patients not previously treated with imatinib mesylate receive oral imatinib mesylate once daily 14 days before beginning study drug
Must be able to tolerate 600 mg per day of imatinib mesylate before starting CCI-779
Patients with chronic phase disease must have failed prior imatinib mesylate at a dose ≥ 600 mg/day, as defined by 1 of the following:
Must not have achieved or must have lost hematologic response within 3 months after the start of imatinib mesylate
Must not have achieved or must have lost cytogenetic response after 6 months of treatment with imatinib mesylate
Must not have achieved or must have lost major cytogenetic response after 12 months of treatment with imatinib mesylate
Must have lost complete cytogenetic response
Bone marrow aspirate and biopsy with cytogenetics and fluorescent in situ hybridization confirming t(9;22) completed within the past 28 days
Performance status - SWOG 0-2
More than 3 months
See Disease Characteristics
Bilirubin normal
AST and ALT < 2.5 times upper limit of normal (ULN) (5 times ULN if suspected liver involvement with leukemia)
Creatinine normal
Creatinine clearance > 60 mL/min
No symptomatic congestive heart failure
No unstable angina pectoris
No cardiac arrhythmia
Ejection fraction ≥ 50% by echocardiogram or MUGA scan for patients with known positive cardiac history (e.g., heart failure, coronary artery disease, cardiomegaly on prior chest x-ray, or valvular heart disease)
Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective contraception
Fasting cholesterol ≤ 350 mg/dL
Fasting triglycerides ≤ 400 mg/dL
No history of allergic reaction attributed to compounds of similar chemical or biologic composition to temsirolimus or imatinib mesylate
No active or ongoing infection
No psychiatric illness or social situation that would preclude study compliance
No other active malignancy except nonmelanoma skin cancer
No other uncontrolled illness
At least 48 hours since prior interferon alfa for CML
At least 6 weeks since prior stem cell transplantation
No concurrent biologic agents
No concurrent prophylactic colony-stimulating factors
At least 24 hours since prior hydroxyurea for CML
At least 7 days since prior mercaptopurine or vinca alkaloids for CML
At least 7 days since prior low-dose cytarabine (< 30 mg/m^2 every 12-24 hours) for CML
At least 14 days since prior homoharringtonine for CML
At least 14 days since prior moderate-dose cytarabine (100-200 mg/m^2 for 5-7 days) for CML
At least 21 days since prior anthracyclines, mitoxantrone, cyclophosphamide, etoposide, or methotrexate for CML
At least 28 days since prior high-dose cytarabine (1-3 g/m^2 every 12-24 hours for 6-12 doses) for CML
At least 6 weeks since prior busulfan for CML
No concurrent hydroxyurea
No other concurrent chemotherapy
At least 7 days since prior steroids for CML
No prior organ transplantation
More than 2 weeks since prior major surgery (e.g., thoracotomy or intra-abdominal surgery)
Recovered from all prior therapy
Prior experimental therapy allowed provided completion of treatment corresponds to a duration > 5 half-lives of the experimental drug or any known active metabolite before study
No concurrent cyclosporine
No concurrent anagrelide
No concurrent oral anticoagulants, including warfarin
No concurrent CYP3A4 inducers or inhibitors
No concurrent tacrolimus
No concurrent plasmapheresis
No concurrent combination antiretroviral therapy for HIV-positive patients
No other concurrent investigational agents
No other concurrent anticancer therapies