Everolimus and Imatinib Mesylate in Treating Patients With Chronic Phase Chronic Myelogenous Leukemia Who Are Not in Complete Cytogenetic Remission After Previous Imatinib Mesylate
RATIONALE: Drugs used in chemotherapy, such as everolimus, work in different ways to stop cancer cells from dividing so they stop growing or die. Imatinib mesylate may stop the growth of cancer cells by blocking the enzymes necessary for their growth. Combining everolimus with imatinib mesylate may be effective in killing cancer cells that have become resistant to imatinib mesylate.
PURPOSE: This phase I/II trial is studying the side effects and best dose of everolimus when given together with imatinib mesylate and to see how well they work in treating patients with chronic phase chronic myelogenous leukemia who are not in complete cytogenetic remission after previous imatinib mesylate.
|Study Design:||Masking: Open Label
Primary Purpose: Treatment
|Official Title:||A Phase I-II, Study of RAD001 in Combination With Imatinib (Glivec®/Gleevec™) in Patients With Chronic Myelogenous Leukemia (CML) in Chronic Phase Who Are Not In Complete Cytogenetic Response to Imatinib-Alone at Study Entry|
- Tolerability and biological activity of everolimus and imatinib mesylate every 6 months after completion of study treatment
- Cytogenetic improvements at 3 and 6 months and then every 6 months after completion of study treatment
- Changes in the amounts of the Bcr-Abl transcripts as measured by quantitative real time reverse transcriptase PCR (QT-PCR) every 6 months after completion of study treatment
- mTOR pathway activity at baseline and during treatment measured by molecular pathological examination of blood and bone marrow cells every 6 months after completion of study treatment
- Disease-related mutations and gene expression changes in blood, bone marrow cells, and in plasma every 6 months after completion of study treatment
- Effects of genetic variation in drug metabolism genes, leukemia genes, and drug target genes on patient response measured every 6 months after completion of study treatment
- Pharmacokinetics of combination everolimus and imatinib every 6 months after completion of study treatment
|Study Start Date:||August 2004|
|Study Completion Date:||August 2006|
|Primary Completion Date:||August 2006 (Final data collection date for primary outcome measure)|
- Determine the safety, tolerability, and biological activity of everolimus when combined with imatinib mesylate in patients with chronic phase chronic myelogenous leukemia that is not in complete cytogenetic remission after prior imatinib mesylate. (Phase I)
- Determine, preliminarily, the clinical efficacy of this regimen, in terms of 3-month improvement by at least one cytogenetic category and the duration of cytogenetic improvements, in these patients. (Phase II)
- Determine the 6-month rate of cytogenetic improvements in patients treated with this regimen.
- Determine the rate of confirmed cytogenetic improvements in patients treated with this regimen.
- Determine the rate and duration of major cytogenetic response in patients treated with this regimen.
- Determine the rate and kinetics of molecular response in patients treated with this regimen.
- Correlate genetic variation in drug metabolism genes, leukemia genes, and drug target genes with response in patients treated with this regimen.
- Determine the pharmacokinetics of this regimen in these patients.
- Determine whether the mTOR pathway activity, as determined by molecular pathologic examination before and during treatment with this regimen, is predictive of response in these patients.
OUTLINE: This is a phase I, non-randomized, open-label, multicenter, dose-escalation study of everolimus followed by a phase II study. Patients are stratified according to baseline cytogenetic status (Philadelphia chromosome-positive cells in bone marrow) (>0% and ≤ 95% vs > 95%).
- Phase I: Patients receive oral everolimus once daily (or once weekly) and oral imatinib mesylate once daily beginning on day 1. Treatment continues in the absence of disease progression or unacceptable toxicity.
Cohorts of 4-6 patients receive escalating doses of everolimus until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 6 patients experience dose-limiting toxicity.
- Phase II: Patients receive everolimus and imatinib mesylate as in phase I at the MTD.
Patients are followed every 6 months.
PROJECTED ACCRUAL: A total of 4-98 patients (4-34 for phase I and up to 64 for phase II [34 patients with > 0% and ≤ 95% Philadelphia chromosome (Ph)-positive cells and 30 patients with > 95% Ph-positive cells]) will be accrued for this study.
Please refer to this study by its ClinicalTrials.gov identifier: NCT00093639
|United States, New York|
|Roswell Park Cancer Institute|
|Buffalo, New York, United States, 14263-0001|
|Principal Investigator:||Meir Wetzler, MD||Roswell Park Cancer Institute|