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

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 thestudy

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 daysprior to screening) is acceptable

• No evidence of extramedullary leukemic involvement, with the exception ofhepatosplenomegaly

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 orponatinib) in case of absence of T315I mutation

• 1 prior ATP site TKI (i.e. imatinib, nilotinib, bosutinib, dasatinib orponatinib) in case of presence of T315I mutation

6. Failure (adapted from the 2020 ELN Recommendations) or intolerance to the mostrecent TKI therapy at the time of screening

• Failure for CML-CP patients (CP at the time of initiation of last therapy) isdefined as meeting at least one of the following criteria.

• Three months after the initiation of therapy: >10% BCR-ABL1 on InternationalScale (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-ABL1mutations which potentially cause resistance to current treatment

• At any time 12 months after the initiation of therapy, BCR-ABL1 ratio ≥ 1% ISor loss of MMR

• At any time after the initiation of therapy, new clonal chromosomeabnormalities in Ph+ cells: CCA/Ph+

• Intolerance is defined as:

• Non-hematologic intolerance: Patients with grade 3 or 4 toxicity while ontherapy, or with persistent grade 2 toxicity, unresponsive to optimalmanagement, including dose adjustments (unless dose reduction is not consideredin the best interest of the patient if response is already suboptimal)

• Hematologic intolerance: Patients with grade 3 or 4 toxicity (absoluteneutrophil count [ANC] or platelets) while on therapy that is recurrent afterdose 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 ofscreening which are amenable to standardized RQ-PCR quantification.

9. Adequate end organ function, within 12 days before the first dose of asciminibtreatment. Patients with mild to moderate renal and hepatic impairment are eligibleif:

• 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 beconsidered not clinically significant and not associated with risk factors foracute 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 productscontaining the juice of each during the entire study and preferably 7 days beforethe first dose of study medications, due to potential CYP3A4 interaction with thestudy medications. Orange juice is allowed.

11. Treatment with medications that meet one of the following criteria is allowed ifused with caution at least one week prior to the start of treatment with studytreatment:

• Moderate or strong inducers of CYP3A

• Moderate or strong inhibitors of CYP3A

12. Patients must have the following electrolyte values (as per central laboratorytests) within normal limits or corrected to be within normal limits with supplementsprior to first dose of study medication:

• Potassium (potassium increase of up to 6.0 mmol/L is acceptable at study entryif associated with creatinine clearance within normal limits)

• Total calcium (corrected for serum albumin); (calcium increase of up to 12.5mg/dl or 3.1 mmol/L is acceptable at study entry if associated with creatinineclearance 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 usingCockcroft-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 myocardialinfarction (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., bifascicularblock, 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 longQT syndrome, or any of the following:

• Risk factors for Torsades de Pointes (TdP) including uncorrected hypokalemia orhypomagnesemia, history of cardiac failure, or history of clinicallysignificant/symptomatic bradycardia

• Concomitant medication(s) with a "Known risk of Torsades de Pointes" perwwwcrediblemeds.org/ that cannot be discontinued or replaced 7 days prior tostarting 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 theinvestigator could cause unacceptable safety risks or compromise compliance with theprotocol (e.g. uncontrolled diabetes, active or uncontrolled infection, pulmonaryhypertension)

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

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

7. History of other active malignancy within 3 years prior to study entry with theexception of previous or concomitant basal cell skin cancer and previous carcinomain situ treated curatively

8. Impairment of gastrointestinal (GI) function or GI disease that may significantlyalter the absorption of study drug (e.g. ulcerative disease, uncontrolled nausea,vomiting, diarrhea, malabsorption syndrome, small bowel resection, or gastric bypasssurgery)

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

10. Participation in a prior investigational study within 30 days prior to randomizationor 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 ofbecoming 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 lifestyleof the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal,post-ovulation methods) and withdrawal are not acceptable methods ofcontraception

• Female sterilization (have had surgical bilateral oophorectomy (with or withouthysterectomy) total hysterectomy or bilateral tubal ligation at least six weeksbefore taking study treatment). In case of oophorectomy alone, only when thereproductive status of the woman has been confirmed by follow up hormone levelassessment

• Male sterilization (at least 6 months prior to screening). The vasectomizedmale partner should be the sole partner for that subject.

• Use of oral, injected or implanted hormonal methods of contraception orplacement of an intrauterine device (IUD) or intrauterine system (IUS) or otherforms 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 samepill for a minimum of 3 months before taking study treatment.

• Women are considered post-menopausal and not of child bearing potential if theyhave had 12 months of natural (spontaneous) amenorrhea with an appropriateclinical profile (e.g. age appropriate, history of vasomotor symptoms) or havehad surgical bilateral oophorectomy (with or without hysterectomy), totalhysterectomy or bilateral tubal ligation at least six weeks before taking studymedication. In the case of oophorectomy alone, women are consideredpost-menopausal and not of child bearing potential only when the reproductivestatus of the woman has been confirmed by follow up hormone level assessment.

13. Sexually active males unwilling to use a condom during intercourse while takingstudy treatment and for 3 days after stopping study (only for patients treated withasciminib). A condom is required for all sexually active male participants onasciminib treatment to prevent them from fathering a child AND to prevent deliveryof study treatment via seminal fluid to their partner. In addition, these maleparticipants 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), inorder 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