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

Primary Purpose

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

Status
Completed
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
STI571 400 mg
STI571 600 mg
Sponsored by
Novartis Pharmaceuticals
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Philadelphia Positive Chronic Myeloid Leukemia focused on measuring Chronic Myelogenous Leukemia, CML, Philadelphia Chromosome, Accelerated phase, Acute Myelogenous Leukemia, AML, Acute Lymphoblastic Leukemia, ALL, Imatinib mesylate

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Dana Faber Cancer Institute
  • New York Presbyterian Hospital
  • Oregon Health & Sciences University
  • MD Anderson Cancer Center, University of Texas
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm 7

Arm Type

Experimental

Experimental

Experimental

Experimental

Experimental

Experimental

Experimental

Arm Label

Accelerated Phase Chronic Myeloid/Myelogenous Leukemia 400 mg

Lymphoid Blast Crisis 400 mg

Acute Lymphoblastic Leukemia 400 mg

Accelerated Phase Chronic Myeloid/Myelogenous Leukemia 600 mg

Lymphoid Blast Crisis 600 mg

Acute Lymphoblastic Leukemia 600 mg

Acute Myeloid/Myelogenous Leukemia 600 mg

Arm Description

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.

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.

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.

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.

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.

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.

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.

Outcomes

Primary Outcome Measures

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).

Secondary Outcome Measures

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.
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).
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.
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.
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.
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.

Full Information

First Posted
September 12, 2005
Last Updated
July 1, 2021
Sponsor
Novartis Pharmaceuticals
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1. Study Identification

Unique Protocol Identification Number
NCT00171249
Brief Title
An Extension Study to Determine the Safety and Anti-Leukemic Effects of Imatinib Mesylate in Adult Participants With Ph+ Leukemia
Official Title
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
Study Type
Interventional

2. Study Status

Record Verification Date
July 2021
Overall Recruitment Status
Completed
Study Start Date
August 9, 1999 (Actual)
Primary Completion Date
September 23, 2013 (Actual)
Study Completion Date
September 23, 2013 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Novartis Pharmaceuticals

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Philadelphia Positive Chronic Myeloid Leukemia, Acute Lymphoblastic Leukemia, Acute Myeloid Leukemia
Keywords
Chronic Myelogenous Leukemia, CML, Philadelphia Chromosome, Accelerated phase, Acute Myelogenous Leukemia, AML, Acute Lymphoblastic Leukemia, ALL, Imatinib mesylate

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
293 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Accelerated Phase Chronic Myeloid/Myelogenous Leukemia 400 mg
Arm Type
Experimental
Arm Description
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.
Arm Title
Lymphoid Blast Crisis 400 mg
Arm Type
Experimental
Arm Description
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.
Arm Title
Acute Lymphoblastic Leukemia 400 mg
Arm Type
Experimental
Arm Description
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.
Arm Title
Accelerated Phase Chronic Myeloid/Myelogenous Leukemia 600 mg
Arm Type
Experimental
Arm Description
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.
Arm Title
Lymphoid Blast Crisis 600 mg
Arm Type
Experimental
Arm Description
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.
Arm Title
Acute Lymphoblastic Leukemia 600 mg
Arm Type
Experimental
Arm Description
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.
Arm Title
Acute Myeloid/Myelogenous Leukemia 600 mg
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
STI571 400 mg
Other Intervention Name(s)
Imatinib mesylate, Glivec®, GleevecTM
Intervention Description
STI571 capsules and tablets
Intervention Type
Drug
Intervention Name(s)
STI571 600 mg
Other Intervention Name(s)
Imatinib mesylate, Glivec®, GleevecTM
Intervention Description
STI571 capsules and tablets
Primary Outcome Measure Information:
Title
Percentage of Participants With Hematologic Response in Accelerated Phase Chronic Myeloid/Myelogenous Leukemia
Description
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).
Time Frame
Up to 3 years after start of treatment
Secondary Outcome Measure Information:
Title
Percentage of Participants With Cytogenetic Response in Accelerated Phase Chronic Myeloid/Myelogenous Leukemia
Description
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.
Time Frame
Up to 3 years after start of treatment
Title
Time to Response in Participants With Accelerated Phase Chronic Myeloid/Myelogenous Leukemia
Description
Time to response was defined for all participants as the time until first documented response (which was confirmed ≥4 weeks later).
Time Frame
Up to 3 years after start of treatment
Title
Duration of Response in Participants With Accelerated Phase Chronic Myeloid/Myelogenous Leukemia
Description
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.
Time Frame
Up to 3 years after start of treatment
Title
Time to Progression to Blast Crisis in Participants With Accelerated Phase Chronic Myeloid/Myelogenous Leukemia
Description
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.
Time Frame
Up to 3 years after start of treatment
Title
Overall Survival by Disease
Description
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.
Time Frame
12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, and 156 months after start of treatment
Title
Overall Survival by Dose in Participants With Accelerated Phase Chronic Myeloid/Myelogenous Leukemia
Description
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.
Time Frame
12, 24, 36, 48, 60, 72, 84, 96, 108, 120, and 132 months after start of treatment

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Novartis Pharmaceuticals
Organizational Affiliation
Novartis Pharmaceuticals
Official's Role
Study Director
Facility Information:
Facility Name
Dana Faber Cancer Institute
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02115
Country
United States
Facility Name
New York Presbyterian Hospital
City
New York
State/Province
New York
ZIP/Postal Code
10021
Country
United States
Facility Name
Oregon Health & Sciences University
City
Portland
State/Province
Oregon
ZIP/Postal Code
97239
Country
United States
Facility Name
MD Anderson Cancer Center, University of Texas
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Facility Name
Novartis Investigative Site
City
Pessac
Country
France
Facility Name
Novartis Investigative Site
City
Poitiers
Country
France
Facility Name
Novartis Investigative Site
City
Frankfurt
Country
Germany
Facility Name
Novartis Investigative Site
City
Leipzig
Country
Germany
Facility Name
Novartis Investigative Site
City
Mainz
Country
Germany
Facility Name
Novartis Investigative Site
City
Mannheim
Country
Germany
Facility Name
Novartis Investigative Site
City
Monza
Country
Italy
Facility Name
Novartis Investigative Site
City
London
Country
United Kingdom

12. IPD Sharing Statement

Learn more about this trial

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

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