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 will be 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 consists 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 will be considered for the current study

Informed consent will be obtained before any procedures are 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 will be randomly assigned to either cohort A or B. Patients with the T315I mutation will be enrolled in cohort C. During treatment period asciminib will be taken orally: Cohort A will be administered 40 mg twice a day, Cohort B will be administered 80 mg once a day and Cohort C will be administered 200 mg twice a day. The patients will be treated up to end of study treatment period defined as up to 72 weeks after the last patient receives the first dose. Patients may be 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.

Basic Information
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Recruitment & Eligibility
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Study & Design
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Trial Locations
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Related News

Study Timeline

• Study First Submitted: 2020-12-07
• Study First Submitted QC: 2020-12-07
• Study First Posted: 2020-12-14
• Study Start: 2021-05-25
• Primary Completion: 2023-06-20
• Results First Submitted: 2024-06-14
• Study Completion: 2024-06-26
• Status Verified: 2024-07
• Results First Submitted QC: 2024-07-11
• Last Update Submitted: 2024-07-11
• Results First Posted: 2024-07-12
• Last Update Posted: 2024-07-12

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 56

Inclusion Criteria

Not provided

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Exclusion Criteria

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

1. Known second chronic phase of CML after previous progression to AP/BC

2. Previous treatment with a hematopoietic stem-cell transplantation

3. 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

4. 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)

5. History of acute pancreatitis within 1 year of study entry or past medical history of chronic pancreatitis

6. Known presence of significant congenital or acquired bleeding disorder unrelated to cancer

7. 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

8. 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)

9. Previous treatment with or known/ suspected hypersensitivity to asciminib or any of its excipients.

10. Participation in a prior investigational study within 30 days prior to randomization or within 5 half-lives of the investigational product, whichever is longer

11. Pregnant or nursing (lactating) women

12. 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.

13. 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.

14. 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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Cohort A	ABL001	40 mg asciminib orally twice daily (BID)
Cohort B	ABL001	80 mg asciminib orally once daily (QD)
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
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 count (WBC) \<10 x 109/L, platelet count \<450 x 109/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
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 is not known to have died, then OS will be censored at the latest date the patient was known to be alive. OS will be analyzed using the Kaplan-Meier Product-Limit method
Number of Adverse Events and Serious Adverse Events for Cohorts A, B and C	Baseline up to 48 and 72 weeks	Adverse events (AEs) and serious adverse events (SAEs) will be summarized by cohort. Clinically significant findings for vitals, laboratory values and electrocardiogram (ECG) will be reported as adverse events and or serious adverse events as determined by the investigator.
Percentage of Patients Achieving Molecular Response (MR2), Major Molecular Response (MMR) and Molecular Response of MR4 and MR4.5 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. Rate for MMR is defined as ≥ 3 log reduction, MR4 is defined as ≥ 4 log reduction and MR4.5 is defined as ≥ 4.5 log reduction.
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 a 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 will be analyzed using the Kaplan-Meier Product-Limit method. Participants continuing without that event will be censored at the date of their last adequate response assessment.
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 a each defined response level. Time to achieve a specific response level will be analyzed using the Kaplan-Meier Product-Limit method. Patients who are known to be without achieving that response level will be 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 will be analyzed using the Kaplan-Meier Product-Limit method

Trial Locations

Locations (22)

Univ of TX MD Anderson Cancer Cntr .; 🇺🇸 Houston, Texas, United States

Uni of Cincinnati Medical Center .; 🇺🇸 Cincinnati, Ohio, United States

Oncology Hematology Care Inc .; 🇺🇸 Cincinnati, Ohio, United States

Medical College of Wisconsin; 🇺🇸 Milwaukee, Wisconsin, United States

Alaska Oncology and Hematology AOH 2; 🇺🇸 Anchorage, Alaska, United States

Cancer Treatment Centers of America; 🇺🇸 Phoenix, Arizona, United States

Lundquist Inst BioMed at Harbor .; 🇺🇸 Torrance, California, United States

Pacific Shores Medical Group; 🇺🇸 Long Beach, California, United States

Memorial Healthcare System .; 🇺🇸 Hollywood, Florida, United States

Rocky Mountain Cancer Centers USOR; 🇺🇸 Boulder, Colorado, United States

Florida Cancer Specialists-North; 🇺🇸 Saint Petersburg, Florida, United States

Florida Cancer Specialists East; 🇺🇸 Stuart, Florida, United States

University of Kentucky; 🇺🇸 Lexington, Kentucky, United States

Uni of Massachusetts Medical Center; 🇺🇸 Worcester, Massachusetts, United States

Siteman Cancer Center .; 🇺🇸 Saint Louis, Missouri, United States

Cancer Institute of New Jersey; 🇺🇸 New Brunswick, New Jersey, United States

Northwest Cancer Specialists HematologyCln ProvidenceOffice; 🇺🇸 Portland, Oregon, United States

Texas Oncology, P.A. .; 🇺🇸 Fort Worth, Texas, United States

Texas Oncology .; 🇺🇸 Dallas, Texas, United States

Indiana Blood and Marrow Institute .; 🇺🇸 Beech Grove, Indiana, United States

Michigan Med University of Michigan .; 🇺🇸 Ann Arbor, Michigan, United States

Wake Forest Uni Baptist MC Outpatient Comprehensive Can C; 🇺🇸 Winston-Salem, North Carolina, United States