Asciminib in Monotherapy for Chronic Myeloid Leukemia in Chronic Phase (CML-CP) With and Without T315I Mutation

Phase 3

Completed

Conditions: Chronic Myelogenous Leukemia - Chronic Phase

Interventions: Drug: ABL001

Registration Number: NCT04666259

Lead Sponsor: Novartis Pharmaceuticals

Brief Summary: This study was a multicenter Phase IIIb open-label, three-cohort study of asciminib in patients with CML-CP without T315I mutation who have had at least 2 prior TKIs and CML-CP harboring the T315I mutation with at least 1 prior TKI

Detailed Description: This trial consisted of three periods: screening and baseline for up to 21 days, active treatment for up to 72 weeks and a safety follow up period for 30 days.

One hundred and fifteen (115) patients with chronic myeloid leukemia in chronic phase (CML-CP) without T315I mutation who have had at least 2 prior Tyrosine Kinase Inhibitors (TKIs) and CML-CP with the T315I mutation with at least 1 prior TKI were planned for this study, however the study was finally completed with 56 participants due to enrollment issues.

Informed consent was obtained before any procedures were performed for the study including eligibility assessments. The results of the real time quantitative polymerase chain reaction (RQ-PCR) must be available prior to randomization and first dose of study treatment.

Patients with CML-CP without T315I mutation were randomly assigned to either cohort A or B. Patients with the T315I mutation were enrolled in cohort C. During treatment period asciminib was taken orally: Cohort A was administered 40 mg twice a day, Cohort B was administered 80 mg once a day and Cohort C was administered 200 mg twice a day. The patients were treated up to end of study treatment period defined as up to 72 weeks after the last patient receives the first dose. Patients may have been discontinued from treatment with the study drug at any time due to unacceptable toxicity, disease progression and/or at the discretion of the investigator or the patient.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 56

Inclusion Criteria

Not provided

Exclusion Criteria

Patients eligible for this study must not meet any of the following criteria:

Known second chronic phase of CML after previous progression to AP/BC
Previous treatment with a hematopoietic stem-cell transplantation
Cardiac or cardiac repolarization abnormality, including any of the following:
- History within 6 months prior to starting study treatment of myocardial infarction (MI), angina pectoris, coronary artery bypass graft (CABG)
- Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), complete left bundle branch block, high-grade AV block (e.g., bifascicular block, Mobitz type II and third degree AV block)
- QTcF at screening ≥450 msec (male patients), ≥460 msec (female patients)
- Long QT syndrome, family history of idiopathic sudden death or congenital long QT syndrome, or any of the following:
- Risk factors for Torsades de Pointes (TdP) including uncorrected hypokalemia or hypomagnesemia, history of cardiac failure, or history of clinically significant/symptomatic bradycardia
- Concomitant medication(s) with a "Known risk of Torsades de Pointes" per wwwcrediblemeds.org/ that cannot be discontinued or replaced 7 days prior to starting study drug by safe alternative medication.
- Inability to determine the QTcF interval
Severe and/or uncontrolled concurrent medical disease that in the opinion of the investigator could cause unacceptable safety risks or compromise compliance with the protocol (e.g. uncontrolled diabetes, active or uncontrolled infection, pulmonary hypertension)
History of acute pancreatitis within 1 year of study entry or past medical history of chronic pancreatitis
Known presence of significant congenital or acquired bleeding disorder unrelated to cancer
History of other active malignancy within 3 years prior to study entry with the exception of previous or concomitant basal cell skin cancer and previous carcinoma in situ treated curatively
Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of study drug (e.g. ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection, or gastric bypass surgery)
Previous treatment with or known/ suspected hypersensitivity to asciminib or any of its excipients.
Participation in a prior investigational study within 30 days prior to randomization or within 5 half-lives of the investigational product, whichever is longer
Pregnant or nursing (lactating) women
Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception.

Highly effective contraception methods include:
- Total abstinence (when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception
- Female sterilization (have had surgical bilateral oophorectomy (with or without hysterectomy) total hysterectomy or bilateral tubal ligation at least six weeks before taking study treatment). In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment
- Male sterilization (at least 6 months prior to screening). The vasectomized male partner should be the sole partner for that subject.
- Use of oral, injected or implanted hormonal methods of contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS) or other forms of hormonal contraception that have comparable efficacy (failure rate <1%), for example hormone vaginal ring or transdermal hormone contraception.
- In case of use of oral contraception women should have been stable on the same pill for a minimum of 3 months before taking study treatment.
- Women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy or bilateral tubal ligation at least six weeks before taking study medication. In the case of oophorectomy alone, women are considered post-menopausal and not of child bearing potential only when the reproductive status of the woman has been confirmed by follow up hormone level assessment.
Sexually active males unwilling to use a condom during intercourse while taking study treatment and for 3 days after stopping study (only for patients treated with asciminib). A condom is required for all sexually active male participants on asciminib treatment to prevent them from fathering a child AND to prevent delivery of study treatment via seminal fluid to their partner. In addition, these male participants must not donate sperm for the time period specified above.
If a patient is presenting with symptoms suggestive of possible COVID-19 infection, we advise ruling it out by appropriate testing recommended by health authorities.
- Nucleic acid amplification tests for viral RNA (polymerase chain reaction), in order to measure current infection with SARS-CoV-2
- Antigen tests for rapid detection of SARS-CoV-2
- Antibody (serology) tests to detect the presence of antibodies to SARS-CoV-2

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Cohort B	ABL001	80 mg asciminib orally once daily (QD)
Cohort A	ABL001	40 mg asciminib orally twice daily (BID)
Cohort C	ABL001	200 mg asciminib orally twice daily (BID)

Primary Outcome Measures

Name	Time	Method
Number of Participants With Adverse Events and Serious Adverse Events for Cohorts A and B up to 24 Weeks	Baseline to up to 24 Weeks	Adverse events (AEs) and serious adverse events (SAEs) are summarized by cohort. Clinically significant findings for vitals, laboratory values and electrocardiogram (ECG) are reported as adverse events and or serious adverse events as determined by the investigator.

Secondary Outcome Measures

Name	Time	Method
Number of Participants With Adverse Events and Serious Adverse Events for Cohorts A, B and C by Week 48	Baseline up to 48 weeks	Adverse events (AEs) and serious adverse events (SAEs) were summarized by cohort. Clinically significant findings for vitals, laboratory values and electrocardiogram (ECG) were reported as adverse events and or serious adverse events as determined by the investigator.
Number of Participants With Adverse Events and Serious Adverse Events for Cohorts A, B and C by Week 72	Baseline up to 72 weeks	Adverse events (AEs) and serious adverse events (SAEs) were summarized by cohort. Clinically significant findings for vitals, laboratory values and electrocardiogram (ECG) were reported as adverse events and or serious adverse events as determined by the investigator.
Percentage of Patients Achieving Complete Hematologic Response (CHR) for Cohorts A, B and C	Baseline to 12, 24, 48, 72 weeks	A complete hematologic response (CHR) is defined as all of the following present for ≥ 4 weeks: * White blood cell count (WBC) \<10 x 10\^9/L * Platelet count \<450 x 10\^9/L * Basophils \<5%, * No blasts and promyelocytes in peripheral blood * Myelocytes + metamyelocytes \< 5% in peripheral blood * No evidence of extramedullary disease, including spleen and liver The estimated cumulative incidence rates were presented.
Percentage of Patients Achieving Major Molecular Response (MMR) for Cohorts A, B and C	Baseline up to 12, 24, 48, 72 weeks	The rate of major molecular response (MMR) by 12, 24, 48 and 72 weeks after the start of first study medication is defined as ≥ 3 log reduction of BCR-ABL (transcript from standardized baseline or ≤0.1% BCR-ABL/ABL % by international scale, measured by real-time quantitative polymerase chain reaction (RQ-PCR). BCR-ABL fusion gene is also called the Philadelphia chromosome. The estimated cumulative incidence rates were presented.
Percentage of Patients Achieving Molecular Response (MR2) for Cohorts A, B and C	Baseline up to 12, 24, 48, 72 weeks	The rate of molecular response (MR2) by 12, 24, 48 and 72 weeks after the start of first study medication is defined as ≥ 2 log reduction of BCR-ABL (transcript from standardized baseline or ≤ 1% BCR-ABL/ABL % by international scale, measured by real-time quantitative polymerase chain reaction (RQ-PCR). BCR-ABL fusion gene is also called the Philadelphia chromosome. The estimated cumulative incidence rates were presented.
Percentage of Patients Achieving Molecular Response 4 (MR4) for Cohorts A, B and C	Baseline up to 12, 24, 48, 72 weeks	The rate of molecular response (MR4) by 12, 24, 48 and 72 weeks after the start of first study medication is defined as ≥ 4 log reduction of BCR-ABL (transcript from standardized baseline or ≤ 0.01% BCR-ABL/ABL % by international scale, measured by real-time quantitative polymerase chain reaction (RQ-PCR). BCR-ABL fusion gene is also called the Philadelphia chromosome. The estimated cumulative incidence rates were presented.
Duration of CHR, MR2, MMR, MR4 and MR4.5 for Cohorts A, B and C	Baseline up 72 weeks	Duration of Response (DOR) is the time from the date of the first documented molecular response level to the date of first documented loss of the response level or death due to any cause, whichever occurs first. DOR for each response level was analyzed using the Kaplan-Meier Product-Limit method. Participants continuing without that event were censored at the date of their last adequate response assessment.
Percentage of Patients Achieving Molecular Response 4.5 (MR4.5) for Cohorts A, B and C	Baseline up to 12, 24, 48, 72 weeks	The rate of molecular response (MR4.5) by 12, 24, 48 and 72 weeks after the start of first study medication is defined as ≥ 4.5 log reduction of BCR-ABL (transcript from standardized baseline or ≤ 0.0032% BCR-ABL/ABL % by international scale, measured by real-time quantitative polymerase chain reaction (RQ-PCR). BCR-ABL fusion gene is also called the Philadelphia chromosome. The estimated cumulative incidence rates were presented.
Time to Achieve CHR, MR2, MMR, MR4, MR4.5 for Cohorts A, B and C	Baseline up to 72 weeks	Time to achieving a response level is defined as the time from the date of the first dose of study medication to the first documented achievement of each defined response level. Time to achieve a specific response level was analyzed using the Kaplan-Meier Product-Limit method. Patients who are known to be without achieving that response level were censored at the last adequate assessment.
Progression Free Survival (PFS) for Cohorts A, B and C	Baseline up to 72 weeks	Progression Free Survival (PFS) is defined as time from the first dose of study medication to disease progression to accelerated phase/blast crisis (AP/BC) or death due to any cause, whichever occurs first. PFS was analyzed using the Kaplan-Meier Product-Limit method. Subjects who did not progress were censored at the last adequate assessment.
Overall Survival Overall Survival (OS) for Cohorts A, B and C	Baseline up to 72 weeks	Overall Survival (OS) is defined as the time from the first dose of study medication to death due to any cause during study. If a patient was not known to have died, then OS was censored at the latest date the patient was known to be alive. OS was analyzed using the Kaplan-Meier Product-Limit method

Trial Locations

Locations (26): Alaska Oncology and Hematology
🇺🇸
Anchorage, Alaska, United States
Arizona Oncology Associates
🇺🇸
Phoenix, Arizona, United States
Lundquist Inst BioMed at Harbor
🇺🇸
Torrance, California, United States
Rocky Mountain Cancer Centers
🇺🇸
Boulder, Colorado, United States
Memorial Cancer Institute
🇺🇸
Hollywood, Florida, United States
Florida Cancer Specialists
🇺🇸
Sarasota, Florida, United States
Florida Cancer Specialists Pan
🇺🇸
Tallahassee, Florida, United States
Indiana Blood and Marrow Institute
🇺🇸
Beech Grove, Indiana, United States
Michigan Med University of Michigan
🇺🇸
Ann Arbor, Michigan, United States
Siteman Cancer Center
🇺🇸
Saint Louis, Missouri, United States
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Alaska Oncology and Hematology
🇺🇸Anchorage, Alaska, United States