RATIONALE: Drugs used in chemotherapy, such as CCI-779, 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 CCI-779 with imatinib mesylate may kill more cancer cells.

PURPOSE: This phase I trial is studying the side effects and best dose of CCI-779 when given with imatinib mesylate in treating patients with chronic myelogenous leukemia.

Condition	Treatment or Intervention	Phase
accelerated phase chronic myelogenous leukemia blastic phase chronic myelogenous leukemia Philadelphia chromosome positive chronic myelogenous leukemia	Drug: CCI-779  Drug: imatinib mesylate  Procedure: chemotherapy  Procedure: enzyme inhibitor therapy  Procedure: protein tyrosine kinase inhibitor therapy	Phase I

Further Study Details: 

OBJECTIVES:

• Determine the safety and tolerability of CCI-779 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 CCI-779.

Patients receive CCI-779 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 CCI-779 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.

PROJECTED ACCRUAL: A total of 3-21 patients will be accrued for this study within 2 years.

Ages Eligible for Study:  18 Years and above,  Genders Eligible for Study:  Both

Criteria

DISEASE CHARACTERISTICS:

• 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
• 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
• Bone marrow aspirate and biopsy with cytogenetics and fluorescent in situ hybridization confirming t(9;22) completed within the past 28 days

PATIENT CHARACTERISTICS: Age

• Over 18

Performance status

• SWOG 0-2

Life expectancy

• More than 6 months

Hematopoietic

• See Disease Characteristics

Hepatic

• Bilirubin normal
• AST and ALT < 2.5 times upper limit of normal (ULN) (5 times ULN if suspected liver involvement with leukemia)

Renal

• Creatinine normal OR
• Creatinine clearance > 60 mL/min

Cardiovascular

• No symptomatic congestive heart failure
• No unstable angina pectoris
• No cardiac arrhythmia

Other

• 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 CCI-779 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

PRIOR CONCURRENT THERAPY: Biologic therapy

• 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

Chemotherapy

• 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

Endocrine therapy

• At least 7 days since prior steroids for CML

Radiotherapy

• Not specified

Surgery

• No prior organ transplantation
• More than 2 weeks since prior major surgery (e.g., thoracotomy or intra-abdominal surgery)

Other

• Recovered from all prior therapy
• At least 28 days since prior experimental therapy
• 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

Study chairs or principal investigators

Tiong S. Ong, MD,  Study Chair,  Chao Family Comprehensive Cancer Center   

Study ID Numbers:  CDR0000406631; UCIRVINE-UCI-04-04; NCI-6619; NCT00101088
Record last reviewed:  February 2005
Last Updated:  April 4, 2005
Record first received:  January 7, 2005
ClinicalTrials.gov Identifier:  NCT00101088
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-04-08