Asciminib Monotherapy, With Dose Escalation, for 2nd and 1st Line Chronic Myelogenous Leukemia

A Phase II Multicenter, Open-label, Single-arm Dose Escalation Study of Asciminib Monotherapy in 2nd and 1st Line Chronic Phase - Chronic Myelogenous Leukemia (ASC2ESCALATE)

This will be a multicenter Phase II open-label study of asciminib in CML-CP patients who have been previously treated with one prior ATP- binding site TKI with discontinuation due to treatment failure, warning or intolerance. (2L patient cohort). In addition, newly diagnosed CML-CP patients who may have received up to 4 weeks of prior TKI are included in a separate 1L patient cohort.

This trial consists of three periods: screening and baseline for up to 28 days, active treatment for up to 156 weeks and a safety follow up period for 30 days.

Ninety-two (92) 2L patients with CML-CP without T315I mutation who had 1 prior ATP-binding site TKI discontinued due to treatment failure, warning or intolerance will be considered for the current study. Patients will be tested at screening for the T315I mutation and excluded if the mutation is found.

To gain additional insights into the effect of asciminib in the 1L setting, an additional cohort of newly diagnosed CML-CP patients will be enrolled in the study. Based on the number of participating sites, it is approximated that between 60 and 90 patients could be enrolled. Enrollment of the 1L cohort will be stopped when a maximum of 90 patients have been enrolled or when approximately 60 patients have been enrolled and the 2L cohort is fully recruited, whichever comes first.

Informed consent will be obtained before any procedures are performed for the study including eligibility assessments.

All eligible patients will be initially treated with asciminib at 80 mg QD. At 6 months of study treatment, patients who have achieved BCR-ABL1IS ≤1% will continue on the same dose whereas those who have not will increase dose to 200mg QD.

At 12 months of study treatment, patients will be evaluated for the primary endpoint of the study (MMR at 12 month in 2L patient cohort) and will pursue one of the following:

• Continue on the current dose of asciminib if MMR is achieved
• Increase dose to 200 mg QD if on 80 mg QD dosing and MMR is not achieved
• Increase dose to 200 mg BID if on 200 mg QD dosing and MMR is not achieved
• Take the patient off the study and switch to Investigator's agent of choice if MMR is not achieved and it is in the interest of the patient based on investigator's clinical judgment of prospect treatment benefit.

Key Inclusion Criteria:

Participants eligible for inclusion in this study must meet the following criteria: Criteria #1-5 are common to both patient cohorts (2L and 1L):

1. Signed informed consent must be obtained prior to participation in the study

2. CML-CP, no previous AP or BC

3. ≥ 18 years of age

4. ECOG performance status of 0, 1 or 2

5. Adequate end organ function within 14 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

   Criteria #6 and 7 are specific to the 2L patient cohort. These are meant to be either/or. It is not required to have both criteria satisfied.

6. Warning or failure (according to 2020 ELN Recommendations; Hochhaus et al) to 1L TKI therapy at the time of screening

   a. Warning is defined as: i. Six months after the initiation of treatment: BCR::ABL1IS >1-10% ii. Twelve months after the initiation of treatment: BCR::ABL1IS >0.1-1% b. Treatment failure/resistance to 1L TKI is defined as: i. BCR::ABL1IS >10% if 1L treatment duration between 6 and 12 months ii. BCR::ABL1IS >1% if 1L treatment longer than 12 months treatment iii. Beyond 12 months after initiation of treatment: loss of MMR

7. Treatment intolerance to 1L TKI,

   1. BCR::ABL1IS > 0.1% at screening
   2. Intolerance is defined as:

   i. 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) ii. 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

   Criteria #8 is specific to the 1L patient cohort

8. Patients with newly diagnosed CML-CP (treatment with a prior TKI (imatinib, or nilotinib, or dasatinib or bosutinib) for ≤ 4 weeks is allowed)

Key Exclusion Criteria:

1. Previous treatment

   1. With 2 or more ATP-binding site TKIs (for 2L patient cohort)
   2. More than 4 weeks with 1-ATP-binding site TKIs (for 1L patient cohort)

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), ≥450 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 enrollment 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 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).

14. 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; uncontrolled arterial or pulmonary hypertension, uncontrolled clinically significant hyperlipidemia).

15. 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.

16. Known hypersensitivity to the study treatment.