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

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

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.

Eligibility Criteria:
Inclusion Criteria

Participants eligible for inclusion in this study must meet all of the following criteria:

1. Written informed consent must be obtained and signed prior to participation in the study
2. Male or female patients with a diagnosis of CML-CP ≥ 18 years of age
3. Patients must meet all of the following laboratory values at the screening visit:

   * \< 15% blasts in peripheral blood and/or bone marrow
   * \< 30% blasts plus promyelocytes in peripheral blood and/or bone marrow
   * \< 20% basophils in the peripheral blood
   * ≥ 50 x 109/L (≥ 50,000/ mm3) platelets
   * Transient prior therapy related thrombocytopenia (\< 50,000/mm3 for ≤ 30 days prior to screening) is acceptable
   * No evidence of extramedullary leukemic involvement, with the exception of hepatosplenomegaly
4. Mutation Analysis testing performed 6 months before study entry
5. Prior treatment with a minimum of:

   * 2 prior ATP-site TKIs (i.e. imatinib, nilotinib, bosutinib, dasatinib or ponatinib) in case of absence of T315I mutation
   * 1 prior ATP site TKI (i.e. imatinib, nilotinib, bosutinib, dasatinib or ponatinib) in case of presence of T315I mutation
6. Failure (adapted from the 2020 ELN Recommendations) or intolerance to the most recent TKI therapy at the time of screening

   * Failure for CML-CP patients (CP at the time of initiation of last therapy) is defined as meeting at least one of the following criteria.
   * Three months after the initiation of therapy: \>10% BCR-ABL1 on International Scale (IS) if confirmed within 1-3 months
   * Six months after the initiation of therapy: BCR-ABL1 ratio \> 10% IS
   * Twelve months after initiation of therapy: BCR-ABL1 ratio \> 1% IS
   * At any time after the initiation of therapy, loss of CHR, MR2
   * At any time after the initiation of therapy, the development of new BCR-ABL1 mutations which potentially cause resistance to current treatment
   * At any time 12 months after the initiation of therapy, BCR-ABL1 ratio ≥ 1% IS or loss of MMR
   * At any time after the initiation of therapy, new clonal chromosome abnormalities in Ph+ cells: CCA/Ph+
   * Intolerance is defined as:
   * Non-hematologic intolerance: Patients with grade 3 or 4 toxicity while on therapy, or with persistent grade 2 toxicity, unresponsive to optimal management, including dose adjustments (unless dose reduction is not considered in the best interest of the patient if response is already suboptimal)
   * Hematologic intolerance: Patients with grade 3 or 4 toxicity (absolute neutrophil count \[ANC\] or platelets) while on therapy that is recurrent after dose reduction to the lowest doses recommended by manufacturer
7. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0, 1, or 2
8. Evidence of typical BCR-ABL1 transcript \[e14a2 and/or e13a2\] at the time of screening which are amenable to standardized RQ-PCR quantification.
9. Adequate end organ function, within 12 days before the first dose of asciminib treatment. Patients with mild to moderate renal and hepatic impairment are eligible if:

   * Total bilirubin ≤ 3.0 x ULN without AST/ALT increase
   * Aspartate transaminase (AST) ≤ 5.0 x ULN
   * Alanine transaminase (ALT) ≤ 5.0 x ULN
   * Serum lipase ≤ 1.5 x ULN. For serum lipase \> ULN - ≤ 1.5 x ULN, value should be considered not clinically significant and not associated with risk factors for acute pancreatitis
   * Alkaline phosphatase ≤ 2.5 x ULN
   * Creatinine clearance ≥ 30 mL/min as calculated using Cockcroft-Gault formula
10. Patients must avoid consumption of grapefruit, Seville oranges or products containing the juice of each during the entire study and preferably 7 days before the first dose of study medications, due to potential CYP3A4 interaction with the study medications. Orange juice is allowed.
11. Treatment with medications that meet one of the following criteria is allowed if used with caution at least one week prior to the start of treatment with study treatment:

    * Moderate or strong inducers of CYP3A
    * Moderate or strong inhibitors of CYP3A
12. Patients must have the following electrolyte values (as per central laboratory tests) within normal limits or corrected to be within normal limits with supplements prior to first dose of study medication:

    * Potassium (potassium increase of up to 6.0 mmol/L is acceptable at study entry if associated with creatinine clearance within normal limits)
    * Total calcium (corrected for serum albumin); (calcium increase of up to 12.5 mg/dl or 3.1 mmol/L is acceptable at study entry if associated with creatinine clearance within normal limits)
    * Magnesium, with the exception of magnesium increase \> ULN - 3.0 mg/dL; \> ULN - 1.23 mmol/L associated with creatinine clearance (calculated using Cockcroft-Gault formula) within normal limits.

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