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

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

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.

Study Overview

• Status: Completed
• Conditions: Acute Myeloid Leukemia; Acute Lymphoblastic Leukemia; Philadelphia Positive Chronic Myeloid Leukemia
• Intervention / Treatment: Drug: STI571 400 mg; Drug: STI571 600 mg

• Study Type: Interventional
• Enrollment (Actual): 293
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Pessac, France
    • Novartis Investigative Site
  • Poitiers, France
    • Novartis Investigative Site
• Germany
  • Frankfurt, Germany
    • Novartis Investigative Site
  • Leipzig, Germany
    • Novartis Investigative Site
  • Mainz, Germany
    • Novartis Investigative Site
  • Mannheim, Germany
    • Novartis Investigative Site
• Italy
  • Monza, Italy
    • Novartis Investigative Site
• United Kingdom
  • London, United Kingdom
    • Novartis Investigative Site
• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Dana Faber Cancer Institute
  • New York
    • New York, New York, United States, 10021
      • New York Presbyterian Hospital
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health & Sciences University
  • Texas
    • Houston, Texas, United States, 77030
      • MD Anderson Cancer Center, University of Texas

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

7

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Accelerated Phase Chronic Myeloid/Myelogenous Leukemia 400 mg; 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; STI571 capsules and tablets; Other Names: Glivec®; Imatinib mesylate; GleevecTM
Experimental: Lymphoid Blast Crisis 400 mg; 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; STI571 capsules and tablets; Other Names: Glivec®; Imatinib mesylate; GleevecTM
Experimental: Acute Lymphoblastic Leukemia 400 mg; 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; STI571 capsules and tablets; Other Names: Glivec®; Imatinib mesylate; GleevecTM
Experimental: Accelerated Phase Chronic Myeloid/Myelogenous Leukemia 600 mg; 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; STI571 capsules and tablets; Other Names: Glivec®; Imatinib mesylate; GleevecTM
Experimental: Lymphoid Blast Crisis 600 mg; 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; STI571 capsules and tablets; Other Names: Glivec®; Imatinib mesylate; GleevecTM
Experimental: Acute Lymphoblastic Leukemia 600 mg; 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; STI571 capsules and tablets; Other Names: Glivec®; Imatinib mesylate; GleevecTM
Experimental: Acute Myeloid/Myelogenous Leukemia 600 mg; 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; STI571 capsules and tablets; Other Names: Glivec®; Imatinib mesylate; GleevecTM

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Actual): August 9, 1999
• Primary Completion (Actual): September 23, 2013
• Study Completion (Actual): September 23, 2013

Study Registration Dates

• First Submitted: September 12, 2005
• First Submitted That Met QC Criteria: September 12, 2005
• First Posted (Estimate): September 15, 2005

Study Record Updates

• Last Update Posted (Actual): July 22, 2021
• Last Update Submitted That Met QC Criteria: July 1, 2021
• Last Verified: July 1, 2021

More Information

Terms related to this study

• Keywords: AML; ALL; Acute Lymphoblastic Leukemia; CML; Acute Myelogenous Leukemia; Chronic Myelogenous Leukemia; Imatinib mesylate; Philadelphia Chromosome; Accelerated phase
• Additional Relevant MeSH Terms: Pathologic Processes; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Bone Marrow Diseases; Hematologic Diseases; Myeloproliferative Disorders; Chromosome Aberrations; Translocation, Genetic; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Philadelphia Chromosome; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Imatinib Mesylate
• Other Study ID Numbers: CSTI571A0109E2; 2005-001381-14 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No