An Extension Study to Determine the Safety and Anti-Leukemic Effects of Imatinib Mesylate in Adult Participants With Ph+ Leukemia

Study Overview
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Brief Summary
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The objectives of Part 1 of the study were: To determine the rate of hematologic response (HR) lasting ≥4 weeks in participants with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in the accelerated phase (AP). To evaluate duration of HR, overall survival, cytogenetic response (CyR), time to blast crisis in CML participants in the AP, improvement of symptomatic parameters, tolerability and safety of STI571 treatment. The objective of the extension (Part 2) was: -To enable participants to have access to study drug and continue study treatment and to decrease data collection to include only overall survival and serious adverse events.

Official Title
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An Extension to a Phase II Study to Determine the Safety and Anti-Leukemic Effects of STI571 in Adult Patients With Philadelphia Chromosome Positive Leukemia Including Acute Lymphoblastic Leukemia, Acute Myeloid Leukemia, and Accelerated Phase Chronic Myeloid Leukemia

Conditions
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Philadelphia Positive Chronic Myeloid Leukemia, Acute Lymphoblastic Leukemia, Acute Myeloid Leukemia

Intervention / Treatment
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* Drug: STI571 400 mg
* Drug: STI571 600 mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female participants, aged ≥18 years, with a histologically confirmed diagnosis of Ph+ leukemia of one of the following types: Accelerated phase chronic myeloid/myelogenous leukemia (CML). Acute lymphoid/lymphoblastic leukemia (ALL) or acute myeloid/myelogenous leukemia (AML) in first or subsequent relapse after either standard chemotherapy, autologous or allogeneic bone marrow transplantation, or high-dose treatment with peripheral blood stem cell support, or ALL or AML refractory to standard chemotherapy (no complete remission achieved after two courses of conventional induction chemotherapy). Lymphoid blastic phase of CML in first or subsequent relapse or refractory to standard chemotherapy. With serum serum glutamate oxaloacetate transaminase (aspartate aminotransferase) and serum glutamate pyruvate transaminase (alanine aminotransferase) not more than 3 x upper limit of normal (ULN) (or not more than 5xULN if clinically suspected leukemic involvement of the liver), serum creatinine concentration not more than 2xULN, and total serum bilirubin level not more than 3xULN (bilirubin limit was 1.5xULN before protocol amendment 1) Exclusion Criteria: Participants who had an Eastern Cooperative Oncology Group (ECOG) performance status score ≥3. Participants with known leukemic involvement of the central nervous system (CNS). Participants who had received treatment with any of the following agents: interferon-alpha within 48 hours, hydroxyurea within 24 hours, homoharringtonine within 14 days, low-dose, moderate dose or high dose cytosine arabinoside within 7, 14 or 28 days respectively, 6-mercaptopurine, vinca alkaloids or steroids within 7 days, anthracyclines, mitoxantrone, etoposide, methotrexate, cyclophosphamide within 21 days, or busulfan within 6 weeks. Participants who had undergone hematopoietic stem cell transplantation within six weeks of Day 1, or who had not achieved full hematopoietic recovery following the transplant. Participants with grade 3/4 cardiac disease or any serious, concomitant, medical condition. Participants with a history of non-compliance to medical regimens or who were considered potentially unreliable. Other protocol-defined inclusion/exclusion criteria may apply.

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
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Accelerated Phase Chronic Myeloid/Myelogenous Leukemia 400 mg<br>Participants with accelerated phase chronic myeloid/myelogenous leukemia received STI571 400 mg, orally, once daily, until death, the development of intolerable toxicity, or the investigator felt it was no longer in the participant's best interest to continue therapy, whichever came first. | Drug: STI571 400 mg<br>* STI571 capsules and tablets<br>* Other names: GleevecTM;|
| Experimental: Lymphoid Blast Crisis 400 mg<br>Participants with lymphoid blast crisis received STI571 400 mg, orally, once daily, until death, the development of intolerable toxicity, or the investigator felt it was no longer in the participant's best interest to continue therapy, whichever came first. | Drug: STI571 400 mg<br>* STI571 capsules and tablets<br>* Other names: GleevecTM;|
| Experimental: Acute Lymphoblastic Leukemia 400 mg<br>Participants with acute lymphoblastic leukemia received STI571 400 mg, orally, once daily, until death, the development of intolerable toxicity, or the investigator felt it was no longer in the participant's best interest to continue therapy, whichever came first. | Drug: STI571 400 mg<br>* STI571 capsules and tablets<br>* Other names: GleevecTM;|
| Experimental: Accelerated Phase Chronic Myeloid/Myelogenous Leukemia 600 mg<br>Participants with accelerated phase chronic myeloid/myelogenous leukemia received STI571 600 mg, orally, once daily, until death, the development of intolerable toxicity, or the investigator felt it was no longer in the participant's best interest to continue therapy, whichever came first. | Drug: STI571 600 mg<br>* STI571 capsules and tablets<br>* Other names: GleevecTM;|
| Experimental: Lymphoid Blast Crisis 600 mg<br>Participants with lymphoid blast crisis received STI571 600 mg, orally, once daily, until death, the development of intolerable toxicity, or the investigator felt it was no longer in the participant's best interest to continue therapy, whichever came first. | Drug: STI571 600 mg<br>* STI571 capsules and tablets<br>* Other names: GleevecTM;|
| Experimental: Acute Lymphoblastic Leukemia 600 mg<br>Participants with acute lymphoblastic leukemia received STI571 600 mg, orally, once daily, until death, the development of intolerable toxicity, or the investigator felt it was no longer in the participant's best interest to continue therapy, whichever came first. | Drug: STI571 600 mg<br>* STI571 capsules and tablets<br>* Other names: GleevecTM;|
| Experimental: Acute Myeloid/Myelogenous Leukemia 600 mg<br>Participants with acute myeloid/myelogenous leukemia received STI571 600 mg, orally, once daily, until death, the development of intolerable toxicity, or the investigator felt it was no longer in the participant's best interest to continue therapy, whichever came first. | Drug: STI571 600 mg<br>* STI571 capsules and tablets<br>* Other names: GleevecTM;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Hematologic Response in Accelerated Phase Chronic Myeloid/Myelogenous Leukemia | Hematologic response was evaluated from hematology measurements in the peripheral blood (PB) and bone marrow (BM) and assessments of extramedullary leukemic involvement (EMD) at physical examination. Response was defined as complete hematologic remission (CHR), no evidence of leukemia (NEL), or return to chronic phase (RTC). | Up to 3 years after start of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Cytogenetic Response in Accelerated Phase Chronic Myeloid/Myelogenous Leukemia | Bone marrow (BM) cytogenetic analysis was required at baseline, after 12 weeks (visit 22) and after 24 weeks (visit 28) to evaluate Ph chromosome positivity. In several participants, this was also done after 4 and 8 weeks. Based on the percentage of Philadelphia chromosome positive (Ph+) cells = (positive cells/examined cells)x100, at each BM assessment the cytogenetic response was classified as: Complete, 0% Ph+ cells; Partial, >0 - 35% Ph+ cells; Minor, >35 - 65% Ph+ cells; Minimal, >65 - 95% Ph+ cells; None, >95% Ph+ cells; Not done: <20 metaphases were examined and/or response could not be assigned. Cytogenetic response was defined as confirmed complete or partial response. A BM sample was considered as assessable for cytogenetic response only if it contained ≥20 metaphases. However, an assessment of partial response was retained in a sample with <20 metaphases when it was immediately preceded or followed by a complete or partial response in another sample with ≥20 metaphases. | Up to 3 years after start of treatment | 
| Time to Response in Participants With Accelerated Phase Chronic Myeloid/Myelogenous Leukemia | Time to response was defined for all participants as the time until first documented response (which was confirmed ≥4 weeks later). | Up to 3 years after start of treatment | 
| Duration of Response in Participants With Accelerated Phase Chronic Myeloid/Myelogenous Leukemia | Duration of response was defined as the time between first documented response (which was confirmed ≥4 weeks later) and the earliest date of the following: loss of response (when any of the criteria for response were no longer fulfilled); progression to blast crisis (≥30% blasts in peripheral blood or bone marrow, extramedullary involvement other than liver/spleen enlargement); discontinuation due to adverse event, laboratory abnormality, unsatisfactory therapeutic effect or death. | Up to 3 years after start of treatment | 
| Time to Progression to Blast Crisis in Participants With Accelerated Phase Chronic Myeloid/Myelogenous Leukemia | Progression to blast crisis was defined as ≥30% blasts in peripheral blood or bone marrow or as extramedullary involvement other than liver or spleen enlargement. | Up to 3 years after start of treatment | 
| Overall Survival by Disease | To evaluate overall survival, all participants were followed after the last dose of study drug every month for the first three months and thereafter every three months until death. Overall survival was calculated for all participants as the time between start of treatment and death due to any reason. The time was censored at the date of last contact for participants who discontinued treatment and were in survival follow-up. For participants without survival follow-up information, the time was censored at last available visit/treatment date. | 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, and 156 months after start of treatment | 
| Overall Survival by Dose in Participants With Accelerated Phase Chronic Myeloid/Myelogenous Leukemia | To evaluate overall survival, all participants were followed after the last dose of study drug every month for the first three months and thereafter every three months until death. Overall survival was calculated for all participants as the time between start of treatment and death due to any reason. The time was censored at the date of last contact for participants who discontinued treatment and were in survival follow-up. For participants without survival follow-up information, the time was censored at last available visit/treatment date. | 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, and 132 months after start of treatment | 

 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