A Phase II Multicenter, Open-label, Single-arm Dose Escalation Study of Asciminib Monotherapy in 2nd Line Chronic Phase - Chronic Myelogenous Leukemia

• Status: Not yet recruiting
• Trial end date: 2026-02-26
• Target enrollment: 0
• Participant gender: All

Summary

This study will be a single arm multicenter Phase II open-label, dose escalation study of asciminib in patients with CML-CP without T315I mutation who have had 1 prior TKIs for which they did not respond to treatment or were intolerant to treatment.

• Phase: Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Novartis Pharmaceuticals

Criteria

Inclusion Criteria:

Signed informed consent must be obtained prior to participation in the study 2. Chronic Myelogenous Leukemia (CML-CP,) no previous Accelerated Phase (AP) or Blast Crisis (BC) 3. ≥ 18 years of age 4. For CML-CP patients with treatment failure/resistance to first line (1L) Tyrosine Kinase Inhibitor (TKI,) BCR-ABL1IS at screening:

1. >10% if 1L treatment duration between 6 and 12 months

2. >1% if 1L treatment longer than 12 months 5. For CML-CP patients with treatment intolerance to 1L TKI, BCR-ABL1IS > 0.1% at screening 6. Previously treated with 1 Adenosine triphosphate- (ATP)-binding site TKI for at least 6 months of therapy 7. Intolerance of TKI therapy and/or resistance to TKI therapy (European Leukemia Network (ELN) 2020)

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

Resistance/Failure is defined for CML-CP patients (CP at the time of initiation of last therapy) as follows . Patients must meet at least 1 of the following criteria:

• Three months after the initiation of therapy: No Complete Hematological Response (CHR) or > 95% Philadelphia Chromosome Positive (Ph+) metaphases

• Six months after the initiation of therapy: BCR-ABL1 ratio > 10% IS and/or >65% Ph+ metaphases

• Twelve months after initiation of therapy: BCR-ABL1 ratio > 1% IS and/or >35% Ph+ metaphases

• At any time after the initiation of therapy, loss of CHR, Complete Cytogenetic Response (CCyR) or Partial Cytogenetic Response (PCyR)

• At any time after the initiation of therapy, the development of new BCR-ABL1 mutations which potentially cause resistance to study treatment

• At any time after the initiation of therapy, confirmed loss of Major Molecular Response (MMR) in 2 consecutive tests, of which one must have a BCR-ABL1 ratio ≥ 1% IS

• At any time after the initiation of therapy, new clonal chromosome abnormalities in Ph+ cells: CCA/Ph+ 8. 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 and ≤ 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

Exclusion Criteria:

• 1. Previous treatment with 2 or more ATP-binding site TKIs 2. Previous treatment with asciminib 3. Known presence of the T315I mutation at any time prior to study entry 4. Known second chronic phase of CML after previous progression to AP/BC 5. Previous treatment with a hematopoietic stem-cell transplantation 6. Patient planning to undergo allogeneic hematopoietic stem cell transplantation 7. 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 www.crediblemeds.org that cannot be discontinued or replaced 7 days prior to starting study drug by safe alternative medication.

• Inability to determine the QTcF interval 8. History of acute pancreatitis within 1 year of study entry or past medical history of chronic pancreatitis 9. Participation in a prior investigational study within 30 days prior to randomization or within 5 half-lives of the investigational product, whichever is longer 10. Treatment with medications that meet one of the following criteria is not allowed and should be switched to an alternative at least one week prior to the start of treatment with study treatment:

• Strong inducers of CYP3A for patients on the dose of 80 mg QD and 200mg QD

• Strong inducers and inhibitors of CYP3A for patients on the dose of 200 mg BID

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.

• Highly effective contraception for women should be maintained throughout the study and for at least 7 days after the last dose.

13. Sexually active males unwilling to use a condom during intercourse while taking study treatment and for 7 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.