An Extension Study to Determine the Efficacy and Safety of STI571 in Participants With Chronic Myeloid Leukemia Who Are Refractory to or Intolerant of Interferon-Alpha

Study Overview
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Brief Summary
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During the Core Phase of the study, participants received STI571 at a dose of 400 milligrams (mg) daily for up to 12 months. Participants completing 12 months of therapy were eligible to continue treatment in the Extension Phase of the study provided that, in the opinion of the investigator, they had benefited from treatment with STI571 and there were no safety concerns.

Official Title
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An Extension to a Phase II Study to Determine the Efficacy and Safety of STI571 in Patients With Chronic Myeloid Leukemia Who Are Refractory to or Intolerant of Interferon-Alpha

Conditions
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive

Intervention / Treatment
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* Drug: STI571


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants included in the study were: Consenting males or females greater than or equal to (≥)18 years of age with Philadelphia chromosome positive (Ph+) chronic myeloid leukemia (CML). With a documented failure of interferon-alpha (IFN) or an IFN-containing therapy, characterized as resistance or refractoriness defined as any of the following: Hematologic Resistance - Failure to achieve a complete hematological response (CHR), lasting for at least 1 month despite 6 or more months of IFN or an IFN-containing regimen, in which IFN was administered at a dose of at least 25 million international units (MIU) per week. During this treatment period the cumulative duration of hydroxyurea therapy may not have exceeded 50% of the treatment period with the IFN-containing regimen. Cytogenetic Resistance - Bone marrow cytogenetics showing ≥65% Ph+ after one year of IFN-based therapy, Cytogenetic Refractoriness - An increase in the Ph+ chromosome in BM cells by at least 30 percentage points (e.g. from 20% to 50%, or from 30% to 60%) confirmed by two samples at least 1 month apart, or an absolute increase to ≥65%, Hematologic Refractoriness - A rising white blood cell count (WBC) [to a level ≥20 x 10^9/L confirmed by two samples taken at least two weeks apart] for participants achieving a complete hematologic response while receiving IFN or an IFN-containing regimen. This regimen must have included IFN at a dose of at least 25 MIU administered per week. During this treatment period the cumulative duration of hydroxyurea therapy may not have exceeded 50% of the treatment period with the IFN-containing regimen. In this report all refractory populations were referred to as relapsed populations. With a documented intolerance to IFN therapy defined as a ≥Grade 3 non-hematologic toxicity persisting for at least one month, for participants receiving IFN or an IFN- containing regimen. IFN was to be administered at a dose of at least 25 MIU/week. Participants who were intolerant of IFN were to have been diagnosed ≥6 months prior to the time of entry into the study. Exclusion Criteria: Participants excluded from the study were: Females of childbearing potential without a negative pregnancy test prior to the initiation of study drug. Barrier contraceptive precautions were to be used throughout the trial in both sexes. With serum bilirubin and creatinine concentrations more than twice the upper limit of the normal range (ULN). With serum glutamic oxaloacetic transaminase (SGOT) and serum glutamic pyruvic transaminase (SGPT) more than twice the ULN. With >15% of blasts or basophils in peripheral blood (PB) or bone marrow (BM). With ≥30% of blasts plus promyelocytes in PB or BM. With a platelet count of less than (<)100 x 10^9/L. With an Eastern Cooperative Oncology Group (ECOG) Performance Status Score ≥3. Receiving busulfan within 6 weeks of Day 1. Receiving treatment with IFN or cytosine arabinoside (Ara-C) within 14 days of Day 1. Receiving treatment with hydroxyurea within 7 days of Day 1. Receiving other investigational agents within 28 days of Day 1. With prior marrow or stem cell transplantation.

Ages Eligible for Study
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Minimum Age: 18 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: All Participants With Chronic Myeloid Leukemia<br>Participants received STI571, capsules or tablets, orally, once a day at a dose of 400 mg. During the Core Phase of the study, participants received STI571 daily for up to 12 months. Participants completing 12 months of therapy were eligible to continue treatment in the Extension Phase of the study, and they continued STI571 for as long as the therapy was beneficial or until death, intolerable toxicity or the decision to discontinue by the investigator, whichever came first. (Maximum duration on study was approximately 14 years). | Drug: STI571<br>* STI571 oral capsules or tablets.<br>* Other names: Imatinib Mesylate;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Cytogenetic Response (Complete Cytogenetic Response and Major Cytogenetic Response) to STI571 | Response was evaluated from bone marrow aspirates and biopsy samples. Bone marrow cytogenetic studies were performed every 3 months during the core phase of the study, then twice yearly, then annually to evaluate Philadelphia chromosome positive (Ph+). Cytogenetic response was defined as the best response the participant achieved during study. Based on the percentage of Ph+ cells = (positive cells/ examined cells) x100, at each BM assessment the cytogenetic response was classified as: Complete Cytogenetic Response (CCyR):, 0% Ph+ cells; Partial Cytogenetic Response (PCyR):, >0 - 35% Ph+ cells; Minor: >35 - 65% Ph+ cells; and Minimal: >65 - 95% Ph+ cells, None: >95 % Ph+ cells and Not done: <20 metaphases were examined and/or response could not be assigned. Major Cytogenetic Response (MCyR) was defined as sum of the CCyR plus PCyR rates. | Up to 6 years after the start of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Complete Hematologic Response to STI571 | Hematologic response was evaluated from hematology measurements in the peripheral blood. Complete hematological response was defined as normalization of peripheral blood counts [WBC and platelet count < upper limit of normal (ULN) at the laboratory where the analysis was performed], with a normal WBC differential, and no immature granulocytes present, lasting for 4 weeks. | 12 months after the start of treatment | 
| Duration of Complete Hematologic Response to STI571 | Duration of hematologic response was defined as the time from the first documentation of the complete hematologic response to the date the loss of complete hematologic response is documented. Loss of complete hematological response was defined as a rising WBC count (increased to a level above the ULN at the laboratory where the analysis was performed confirmed by two samples obtained one month apart). The mean survival time and its standard error were underestimated because the largest observation was censored and the estimation was restricted to the largest event time. Complete hematological response was defined as normalization of peripheral blood counts (WBC and platelet count < ULN at the laboratory where the analysis was performed), with a normal WBC differential, and no immature granulocytes present, lasting for 4 weeks. | 12 months after the start of treatment | 
| Time to Complete Hematologic Response to STI571 | Time to Complete Hematologic Response was defined for all participants with calculated confirmed complete hematologic response as the time until first documented response (which was confirmed >= 4 weeks). Complete hematological response was defined as normalization of peripheral blood counts (WBC and platelet count < ULN at the laboratory where the analysis was performed), with a normal WBC differential, and no immature granulocytes present, lasting for 4 weeks. | 12 months after the start of treatment | 
| Number of Participants With Common Toxicity Criteria Grade 3 or 4 Cancer-related Symptoms | National Cancer Institute (NCI)/ National Institute of Health (NIH) provides a grading (severity) scale for each adverse event (AE) term, the Common Toxicity Criteria (CTC). Grade 3 refers to severe AE and Grade 4 refers to life-threatening or disabling AE. Cancer-related symptoms included fever, night sweats, bone pain, arthralgia, abdominal discomfort, fatigue and anorexia. | Up to 9 months after the start of treatment | 
| Number of Participants With Grade 3 or 4 Eastern Cooperative Oncology Group (ECOG) Performance Status | The ECOG performance status was recorded at baseline and every 3 months during the core study. The ECOG Performance Scale has 5 grades. 0 = Fully active, able to carry out all pre-disease activities; 1 = Restricted in strenuous activity but ambulatory and able to carry out work of light or sedentary nature; 2 = Ambulatory and capable of all self-care but unable to carry out work activities. Active about 50% of waking hours; 3 = Capable of limited self-care, confined to bed/chair more than 50% of waking hours; 4 = Completely disabled; cannot carry on self-care. Totally confined to bed/chair. | Up to 9 months after the start of treatment | 
| Percentage of Participants Alive Over Time Based on Kaplan-Meier Estimates | Overall survival was defined as the time from the first dose of STI571 to the death of the participant. If a participant is not known to have died, survival was censored at the time of last contact. Kaplan-Meier estimates of the percentage of participants at each time point was calculated. | 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144 and 156 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Chronic Myelogenous Leukemia, CML, Philadelphia Chromosome, Accelerated phase, Acute Myelogenous Leukemia, AML, Acute Lymphoblastic Leukemia, ALL, Imatinib mesylate