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Everolimus and Imatinib Mesylate in Treating Patients With Chronic Phase Chronic Myelogenous Leukemia Who Are Not in Complete Cytogenetic Remission After Previous Imatinib Mesylate

This study has been completed.
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals ) Identifier:
First received: October 6, 2004
Last updated: April 30, 2013
Last verified: April 2013

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.

Condition Intervention Phase
Drug: everolimus
Drug: imatinib mesylate
Phase 1
Phase 2

Study Type: Interventional
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

Resource links provided by NLM:

Further study details as provided by Novartis:

Primary Outcome Measures:
  • Tolerability and biological activity of everolimus and imatinib mesylate every 6 months after completion of study treatment

Secondary Outcome Measures:
  • 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)
Detailed Description:



  • 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.


Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No


  • Histologically confirmed chronic myelogenous leukemia (CML)

    • In chronic phase
    • Philadelphia chromosome (Ph)-positive
    • No accelerated or blastic phase

      • Accelerated phase CML is defined as ≥ 15% but < 30% blasts in peripheral blood or bone marrow OR ≥ 30% blasts and promyelocytes in peripheral blood or bone marrow provided that < 30% blasts were present OR ≥ 20% peripheral basophils OR platelet count < 100,000/mm^3, unrelated to therapy
  • No less than 20 metaphases in the bone marrow sample
  • No evidence of complete cytogenetic response to imatinib mesylate (complete cytogenetic response defined as 0% Ph-positive cells in bone marrow)
  • Receiving continuous imatinib mesylate therapy for ≥ the past 9 months

    • Dosage ≥ 600 mg/day for ≥ the past 3 months
    • Stable dose of 600 mg/day for ≥ the past 4 weeks
  • Achieved and maintained hematological response to imatinib mesylate as defined by all of the following:

    • WBC < 20,000/mm^3
    • Basophils < 20%
    • Less than 5% myelocytes and metamyelocytes in peripheral blood
    • No blasts or promyelocytes in peripheral blood
    • No evidence of disease-related symptoms or extramedullary disease, including enlarged spleen or liver



  • 18 and over

Performance status

  • WHO 0-2

Life expectancy

  • Not specified


  • See Disease Characteristics
  • Absolute neutrophil count ≥ 1,500/mm^3
  • Platelet count ≥ 100,000/mm^3
  • Hemoglobin ≥ 9 g/dL


  • AST and ALT < 1.5 times upper limit of normal (ULN)
  • Bilirubin < 1.5 times ULN (except for patients with Gilbert's disease)
  • PTT < 1.5 times ULN (except for patients on oral anticoagulation therapy)
  • INR < 1.5 times ULN (except for patients on oral anticoagulation therapy)


  • Creatinine < 1.5 times ULN


  • No angina
  • No New York Heart Association class III or IV cardiac disease


  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use effective barrier contraception during and for 3 months after study participation
  • HIV negative
  • No history of non-compliance with medical regimens
  • No hypercholesterolemia or hypertriglyceridemia (fasting state) ≥ grade 2 (despite lipid-lowering therapy)
  • No diabetes mellitus
  • No thyroid dysfunction
  • No neuropsychiatric disorders
  • No infection
  • No other severe and/or uncontrolled medical condition that would preclude study participation
  • No other malignancy within the past 5 years except adequately treated basal cell or squamous cell skin cancer or carcinoma in situ of the cervix


Biologic therapy

  • No prior allogeneic, syngeneic, or autologous bone marrow transplantation or stem cell transplantation for CML
  • No concurrent prophylactic hematopoietic growth factors (e.g., filgrastim [G-CSF], sargramostim [GM-CSF], or epoetin alfa)


  • No prior chemotherapy regimens used in transplantation

Endocrine therapy

  • Not specified


  • Not specified


  • Recovered from prior major surgery


  • No prior sirolimus in combination with imatinib mesylate
  • At least 4 weeks since prior investigational agents used in combination with imatinib mesylate and recovered
  • No other concurrent investigational therapies
  • No other concurrent anticancer agents
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Please refer to this study by its identifier: NCT00093639

United States, New York
Roswell Park Cancer Institute
Buffalo, New York, United States, 14263-0001
Sponsors and Collaborators
Novartis Pharmaceuticals
Principal Investigator: Meir Wetzler, MD Roswell Park Cancer Institute
  More Information

Responsible Party: Novartis Pharmaceuticals Identifier: NCT00093639     History of Changes
Other Study ID Numbers: NOVARTIS-CRAD001C2207
CDR0000389252 ( Registry Identifier: PDQ (Physician Data Query) )
NCI-2010-00894 ( Registry Identifier: CTRP (Clinical Trials Reporting System) )
Study First Received: October 6, 2004
Last Updated: April 30, 2013

Keywords provided by Novartis:
chronic phase chronic myelogenous leukemia
chronic myelogenous leukemia, BCR-ABL1 positive

Additional relevant MeSH terms:
Leukemia, Myeloid
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Leukemia, Myeloid, Chronic-Phase
Neoplasms by Histologic Type
Myeloproliferative Disorders
Bone Marrow Diseases
Hematologic Diseases
Imatinib Mesylate
Antineoplastic Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antifungal Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action processed this record on April 28, 2017