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

Study Overview
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Brief Summary
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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.

Official Title
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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)

Conditions
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Chronic Myelogenous Leukemia

Intervention / Treatment
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* Drug: imatinib mesilate
* Drug: interferon-alpha (INF-a)
* Drug: cytarabine (ARA-C)


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: imatinib (STI571)<br>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<br>* imatinib supplied as 100 mg and 400 mg tablets or 100 mg capsules.<br>* Other names: STI571;Drug: interferon-alpha (INF-a)<br>* interferon-alpha (IFN-a) subcutaneous (SC) injections escalated over 4 weeks to achieve a target dose of 5 MU/m^2/day.<br>* Other names: Intron®-A;Drug: cytarabine (ARA-C)<br>* cytarabine 20 mg/m^2/day (max 40 mg) SC for 10 days every month.<br>|
| Active Comparator: IFN-a+Ara-C<br>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<br>* imatinib supplied as 100 mg and 400 mg tablets or 100 mg capsules.<br>* Other names: STI571;Drug: interferon-alpha (INF-a)<br>* interferon-alpha (IFN-a) subcutaneous (SC) injections escalated over 4 weeks to achieve a target dose of 5 MU/m^2/day.<br>* Other names: Intron®-A;Drug: cytarabine (ARA-C)<br>* cytarabine 20 mg/m^2/day (max 40 mg) SC for 10 days every month.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Kaplan-Meier Estimates of Overall Survival (All Randomized Participants) | 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. | 12,24,36,48,60,72,84,96,108,120,132 and 144 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Kaplan Meier Estimates of Event Free Survival (All Randomized Participants) | 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. | 12,24,36,48,60,72,84,96,108,120,132 and 144 months | 
| Percentage of Participants With Event Free Survival Events (All Randomized Participants) | 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. | 144 months | 
| Kaplan Meier Estimates of Time to Progression to Accelerated Phase (AP) or Blast Crisis (BC) (All Randomized Participants) | 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. | 12,24,36,48,60,72,84,96,108,120,132 and 144 months | 
| Percentage of Participants With Best Cytogenetic Response (First-line Treatment) | 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. | 144 months | 
| Percentage of Participants With Best Cytogenetic Response (Second-line Treatment) | 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. | 144 months | 
| Number of Participants With Serious Adverse Events as a Measure of Safety (First-line Treatment) | 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 | 144 months | 
| Number of Participants With Serious Adverse Events as a Measure of Safety (Second-line Treatment) | 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 | 144 months | 
| Percentage of Participants With Major Molecular Response (First-line Treatment) | 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. | 12,24,36,48,60,72,84,96,108,120,132 and 144 months | 
| Percentage of Participants With Major Molecular Response (Second-line Treatment) | 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. | 12,24,36,48,60,72,84,96,108,120,132 and 144 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CML, STI571, imatinib, interferon, interferon alpha, cytosine arabinoside, chronic myeloid leukemia, Philadelphia chromosome positive