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

Leukemia, Myelogenous, Chronic, BCR-ABL Positive Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00171223
• Other study ID #: CSTI571A0110E2
• Secondary ID: 2005-001382-33
• Status: Completed
• Phase: Phase 2
• Start date: December 6, 1999
• Est. completion date: November 29, 2013

Study information

• Verified date: July 2021
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 532
• Est. completion date: November 29, 2013
• Est. primary completion date: November 29, 2013
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Leukemia
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive
• Leukemia, Myeloid

Intervention

Drug:
• STI571
STI571 oral capsules or tablets.

Locations

Country	Name	City	State
France	Novartis Investigative Site	Lille
France	Novartis Investigative Site	Pessac
France	Novartis Investigative Site	Poitiers
Germany	Novartis Investigative Site	Frankfurt
Germany	Novartis Investigative Site	Leipzig
Germany	Novartis Investigative Site	Mainz
Germany	Novartis Investigative Site	Mannheim
Italy	Novartis Investigative Site	Bologna
Italy	Novartis Investigative Site	Milano
Italy	Novartis Investigative Site	Monza
Italy	Novartis Investigative Site	Orbassano
Italy	Novartis Investigative Site	Pavia
Italy	Novartis Investigative Site	Rome
Italy	Novartis Investigative Site	Udine
Switzerland	Novartis Investigative Site	Basel
United Kingdom	Novartis Investigative Site	London
United Kingdom	Novartis Investigative Site	Newcastle upon Tyne
United States	University of Michigan	Ann Arbor	Michigan
United States	Johns Hopkins Oncology Center	Baltimore	Maryland
United States	Dana Faber Cancer Institute	Boston	Massachusetts
United States	Northwestern Univ meical School/Robert H. Lurie Comprehensive Cancer Center	Chicago	Illinois
United States	Wayne State University/Kamanos Cancer Center	Detroit	Michigan
United States	MD Anderson Cancer Center, University of Texas	Houston	Texas
United States	UCLA Medical Center	Los Angeles	California
United States	New York Presbyterian Hospital	New York	New York
United States	Oregon Health & sciences University	Portland	Oregon
United States	C/O V. Ward - Washington Univ. school of Medicine	Saint Louis	Missouri
United States	H. Lee Moffet Cancer Center & Research Institute/Univ of South Florida	Tampa	Florida

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

United States,  France,  Germany,  Italy,  Switzerland,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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