Temsirolimus and Imatinib Mesylate in Treating Patients With Chronic Myelogenous Leukemia

Study Overview
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Brief Summary
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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

Detailed Description
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OBJECTIVES: I. Determine the safety and tolerability of temsirolimus when administered with imatinib mesylate in patients with chronic myelogenous leukemia. II. Determine potential dose-limiting toxic effects of this regimen in these patients. III. 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.

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

Conditions
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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

Intervention / Treatment
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* Drug: imatinib mesylate
* Drug: temsirolimus
* Other: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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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

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (imatinib mesylate, temsirolimus)<br>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<br>* Given orally<br>* Other names: Glivec;Drug: temsirolimus<br>* Given IV<br>* Other names: Torisel;Other: laboratory biomarker analysis<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Unacceptable toxicity graded according to the NCI CTCAE version 3.0 |  | Up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease progression |  | Up to 5 years | 
| Duration of response | Presented using descriptive statistics. | Up to 5 years | 
| Survival |  | Up to 5 years |