Safety and Efficacy of Imatinib Versus Interferon-α Plus Cytarabine in Patients With Newly Diagnosed Philadelphia Chromosome Positive Chronic Myelogenous Leukemia

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:
NCT00333840
First received: June 2, 2006
Last updated: August 7, 2013
Last verified: August 2013
  Purpose

The purpose of this study is to evaluate and compare the side effects and anti-leukemic benefits of imatinib with those of interferon and Ara-C for patients who have chronic myeloid leukemia (CML) in the chronic phase. Patients in this study will be randomized (1:1) to receive either interferon plus Ara-C or imatinib as initial treatment.


Condition Intervention Phase
Chronic Myelogenous Leukemia
Drug: imatinib mesilate
Drug: interferon-alpha (INF-a)
Drug: cytarabine (ARA-C)
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Crossover Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase III Study of STI571 Versus Interferon-α (IFN-α) Combined With Cytarabine (Ara-C) in Patients With Newly Diagnosed Previously Untreated Philadelphia Chromosome Positive (Ph+) Chronic Myelogenous Leukemia in Chronic Phase (CML-CP)

Resource links provided by NLM:


Further study details as provided by Novartis:

Primary Outcome Measures:
  • Kaplan-Meier Estimates of Overall Survival (All Randomized Participants) [ Time Frame: 12,24,36,48,60,72,84,96,108,120,132 and 144 months ] [ Designated as safety issue: No ]
    Overall survival was defined as the time between date of randomization and death due to any cause. The time was censored at last examination date for patients who were still being treated and at date of last contact for patients who discontinued treatment. Kaplan-Meier estimates of the percentage of participants at each time point was calculated. This outcome was measured in all randomized patients, regardless of whether crossover occurred, i.e., events that occurred in patients, who had crossed over, were attributed following crossover to the original randomized treatment.


Secondary Outcome Measures:
  • Kaplan Meier Estimates of Event Free Survival (All Randomized Participants) [ Time Frame: 12,24,36,48,60,72,84,96,108,120,132 and 144 months ] [ Designated as safety issue: No ]

    Event-free survival is defined as the time between randomization and the earliest of any of the following events on treatment:

    • progression to Accelerated Phase (AP) or Blast Crisis (BC)
    • loss of Complete Hematological Response (CHR)
    • loss of Major Cytogenetic Response (MCyR) confirmed
    • loss of Major Cytogenetic Response (MCyR) unconfirmed
    • increase in white blood cell count (WBC) if approved by the Study Management Committee (SMC)
    • death (due to any cause when reported as primary reason for discontinuation of treatment).

    Kaplan Meier estimates of the percentage of participants with Event Free Survival at the given time point was calculated. This outcome was measured in all randomized patients, regardless of whether crossover occurred, i.e., events that occurred in patients, who had crossed over, were attributed following crossover to the original randomized treatment.


  • Percentage of Participants With Event Free Survival Events (All Randomized Participants) [ Time Frame: 144 months ] [ Designated as safety issue: No ]

    Event-free survival is defined as the time between randomization and the earliest of any of the following events on treatment:

    • progression to Accelerated Phase (AP) or Blast Crisis (BC)
    • loss of Complete Hematological Response (CHR)
    • loss of Major Cytogenic Response (MCyR) confirmed
    • loss of Major Cytogenic Response (MCyR) unconfirmed
    • increase in white blood cell count (WBC) if approved by the Study Management Committee (SMC)
    • death (due to any cause when reported as primary reason for discontinuation of treatment).

    The percentage of participants with Event Free Survival events in each category was calculated. This outcome was measured in all randomized patients, regardless of whether crossover occurred, i.e., events that occurred in patients, who had crossed over, were attributed following crossover to the original randomized treatment.


  • Kaplan Meier Estimates of Time to Progression to Accelerated Phase (AP) or Blast Crisis (BC) (All Randomized Participants) [ Time Frame: 12,24,36,48,60,72,84,96,108,120,132 and 144 months ] [ Designated as safety issue: No ]
    Time to progression to AP/BC is defined as the time between randomization and either of the following events on treatment: death (due to CML when reported as primary reason for discontinuation of treatment) or progression to Accelerated Phase or Blast Crisis and is censored at last examination date for patients without event. No data after discontinuation of study treatment was included. The Kaplan Meier estimates of the percentage of participants with survival without progression to AP/BC at the given time point was calculated. This outcome was measured in all randomized patients, regardless of whether crossover occurred, i.e., events that occurred in patients, who had crossed over, were attributed following crossover to the original randomized treatment.

  • Percentage of Participants With Best Cytogenetic Response (First-line Treatment) [ Time Frame: 144 months ] [ Designated as safety issue: No ]

    Bone marrow aspirate was performed to evaluate cytogenetic results (percentage of Philadelphia chromosome positive (Ph+) metaphases) and amount of blasts and promyelocytes in bone marrow to establish cytogenetic response.

    Major Cytogenetic Response= Complete Response or Partial Response. Complete Cytogenetic Response= 0 % of Ph+ metaphases (out of 20 metaphases). Partial Cytogenetic Response= > 0 and ≤ 35 % of Ph+ metaphases (out of 20 metaphases). The percentage of participants with cytogenetic response in each category was calculated.


  • Percentage of Participants With Best Cytogenetic Response (Second-line Treatment) [ Time Frame: 144 months ] [ Designated as safety issue: No ]

    Bone marrow aspirate was performed to evaluate cytogenetic results (percentage of Ph chromosome (Ph+) containing metaphases) and the amount of blasts and promyelocytes in bone marrow to establish cytogenetic response.

    Major Cytogenetic Response= Complete Response or Partial Response. Complete Cytogenetic Response= 0 % of Ph+ metaphases (out of 20 metaphases). Partial Cytogenetic Response= > 0 and ≤ 35 % Ph+ metaphases (out of 20 metaphases). The percentage of participants with cytogenetic response in each category was calculated.


  • Number of Participants With Serious Adverse Events as a Measure of Safety (First-line Treatment) [ Time Frame: 144 months ] [ Designated as safety issue: Yes ]
    A serious adverse event is any experience that suggests a significant hazard, contraindication, side effect or precaution that: results in death, is life-threatening, requires in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect or is medically significant

  • Number of Participants With Serious Adverse Events as a Measure of Safety (Second-line Treatment) [ Time Frame: 144 months ] [ Designated as safety issue: Yes ]
    A serious adverse event is any experience that suggests a significant hazard, contraindication, side effect or precaution that: results in death, is life-threatening, requires in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect or is medically significant

  • Percentage of Participants With Major Molecular Response (First-line Treatment) [ Time Frame: 12,24,36,48,60,72,84,96,108,120,132 and 144 months ] [ Designated as safety issue: No ]
    Major Molecular Response was determined using a quantitative polymerase chain reaction (PCR) laboratory test and was defined as BCR-ABL protein transcripts of ≤ 0.1% according to the international scale.

  • Percentage of Participants With Major Molecular Response (Second-line Treatment) [ Time Frame: 12,24,36,48,60,72,84,96,108,120,132 and 144 months ] [ Designated as safety issue: No ]
    Major Molecular Response was determined using a quantitative polymerase chain reaction (PCR) laboratory test and was defined as BCR-ABL protein transcripts of ≤ 0.1% according to the international scale.


Enrollment: 1106
Study Start Date: June 2000
Study Completion Date: March 2012
Primary Completion Date: March 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: imatinib (STI571)
In the first-line treatment period participants received imatinib 400 mg orally once daily in the morning. Hydroxyurea was permitted in the first 6 months to keep the white blood cell count (WBC) below 20.0 X 10^9/liter. If protocol specific criteria applied, participants were eligible to crossover to receive interferon-alpha (IFN-a) subcutaneous (SC) injections escalated over 4 weeks to achieve a target dose of 5 MU/m^2/day. After the maximum tolerated dose of IFN-a was achieved, participants also received cytarabine (ARA-C) 20 mg/m^2/day (max 40 mg) SC injection for 10 days every month. Maximum study duration was 11.5 years.
Drug: imatinib mesilate
imatinib supplied as 100 mg and 400 mg tablets or 100 mg capsules.
Other Names:
  • Glivec®
  • Gleevec®
  • STI571
Drug: interferon-alpha (INF-a)
interferon-alpha (IFN-a) subcutaneous (SC) injections escalated over 4 weeks to achieve a target dose of 5 MU/m^2/day.
Other Names:
  • Roferon®-A
  • Intron®-A
Drug: cytarabine (ARA-C)
cytarabine 20 mg/m^2/day (max 40 mg) SC for 10 days every month.
Active Comparator: IFN-a+Ara-C
In the first-line treatment period participants received interferon-alpha (IFN-a) subcutaneous (SC) injections escalated over 4 weeks to achieve a target dose of 5 MU/m^2/day. After the maximum tolerated dose of IFN-a was achieved, participants also received cytarabine (ARA-C) 20 mg/m^2/day (max 40 mg) SC injections for 10 days every month. Hydroxyurea was permitted in the first 6 months to keep the white blood cell count (WBC) below 20.0 X 10^9/liter. If protocol specific criteria applied, participants were eligible to crossover to the second-line treatment period to receive imatinib (STI571). IFN treatment was discontinued with protocol amendment 6. Maximum study duration was 8 years.
Drug: imatinib mesilate
imatinib supplied as 100 mg and 400 mg tablets or 100 mg capsules.
Other Names:
  • Glivec®
  • Gleevec®
  • STI571
Drug: interferon-alpha (INF-a)
interferon-alpha (IFN-a) subcutaneous (SC) injections escalated over 4 weeks to achieve a target dose of 5 MU/m^2/day.
Other Names:
  • Roferon®-A
  • Intron®-A
Drug: cytarabine (ARA-C)
cytarabine 20 mg/m^2/day (max 40 mg) SC for 10 days every month.

  Eligibility

Ages Eligible for Study:   18 Years to 70 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion criteria:

  • Must have signed consent for Amendment 5
  • Must have completed visit 62 of the core IRIS trial or be in follow-up
  • Must be on STI571 treatment
  • If on IFN treatment, must be willing to cross over to STI571 treatment

Exclusion criteria:

  • Patients who have discontinued from the study and are in follow-up
  • Patients who are on IFN treatment and do not want to cross over to STI571 treatment
  • Patients who have not consented to amendment 5
  • Patients who did not complete the amendment 5 protocol

Additional protocol-defined inclusion/exclusion criteria may apply

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00333840

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Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
  More Information

No publications provided by Novartis

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier: NCT00333840     History of Changes
Other Study ID Numbers: CSTI571A 0106
Study First Received: June 2, 2006
Results First Received: March 15, 2013
Last Updated: August 7, 2013
Health Authority: United States: Food and Drug Administration
European Union: European Medicines Agency
Australia: Department of Health and Ageing Therapeutic Goods Administration

Keywords provided by Novartis:
CML
STI571
imatinib
interferon
interferon alpha
cytosine arabinoside
chronic myeloid leukemia
Philadelphia chromosome positive

Additional relevant MeSH terms:
Leukemia
Leukemia, Myeloid
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Philadelphia Chromosome
Neoplasms by Histologic Type
Neoplasms
Myeloproliferative Disorders
Bone Marrow Diseases
Hematologic Diseases
Translocation, Genetic
Chromosome Aberrations
Pathologic Processes
Interferon-alpha
Interferon Alfa-2a
Cytarabine
Interferons
Imatinib
Antiviral Agents
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions
Immunologic Factors
Physiological Effects of Drugs
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Growth Inhibitors
Antineoplastic Agents
Antimetabolites, Antineoplastic
Antimetabolites

ClinicalTrials.gov processed this record on July 23, 2014