ASC2ESCALATE: Asciminib Monotherapy, With Dose Escalation, for 2nd Line Chronic Myelogenous Leukemia

Sponsor

Novartis Pharmaceuticals (Industry)

Overall Status

Not yet recruiting

CT.gov ID

NCT05384587

Collaborator

(none)

Enrollment

Arm

42.1

Anticipated Duration (Months)

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
Chronic Myelogenous Leukemia - Chronic Phase	Drug: asciminib	Phase 2

Detailed Description

This trial consists of three periods: screening and baseline for up to 28 days, active treatment for up to 104 weeks and a safety follow up period for 30 days.

Ninety-two (92) patients with chronic myeloid leukemia in chronic phase (CML-CP) without T315I mutation who have had 1 prior Tyrosine Kinase Inhibitors (TKIs) will be considered for the current study.

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

Patients with CML-CP without T315I mutation will be enrolled in the single-arm, open label study. For the first 6 months of the treatment period,80 mg asciminib will be taken orally once a day. At six months, patients who have achieved Major Molecular Response (MMR, BCR-ABL1IS <1%) will continue on the 80 mg once a day dosage. For those who did not achieve MMR, patients will increase dosage to 200 mg once a day. At the 12 month or 52 week mark, patients will either continue on 80 mg once a day, 200 mg once a day, or increase to 200 mg twice a day dependent on MMR. Investigators also have the choice to choose the patients dosage at 12 months.

The patients will be treated up to end of study treatment period defined as up to 104 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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

92 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Anticipated Study Start Date :

Aug 26, 2022

Anticipated Primary Completion Date :

Feb 27, 2025

Anticipated Study Completion Date :

Feb 26, 2026

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Asciminib 80 mg initial oral dose taken once a day with possible dose escalation	Drug: asciminib Supplied in 20 mg and 40 mg tablets for oral use to be taken daily. Dose may be increased at 6 and 12 months based on molecular response with BCR-ABL1 Polymerase Chain Reaction testing. Other Names: ABL001

Arm

Intervention/Treatment

Experimental: Asciminib

80 mg initial oral dose taken once a day with possible dose escalation

Drug: asciminib

Supplied in 20 mg and 40 mg tablets for oral use to be taken daily. Dose may be increased at 6 and 12 months based on molecular response with BCR-ABL1 Polymerase Chain Reaction testing.

Other Names:

ABL001

Outcome Measures

Primary Outcome Measures

Percentage of participants who achieve Major Molecular Response (MMR) [Baseline up to 12 months]
MMR is defined as BCR-ABL1IS ≤ 0.1%).

Secondary Outcome Measures

Percentage of participants achieving Molecular Response (MR4.5) [Baseline up to 24 months]
Molecular response (MR) will be assessed. The rate of MR4.5 where MR4.5 is defined as a ≥ 4.5 log reduction in BCR-ABL1 transcripts compared to the standardized baseline equivalent to ≤ 0.0032% BCR-ABL1/ABL % by international scale as measured by real time Polymerase Chain Reaction (PCR).
Number of Adverse Events and Serious Adverse Events [Baseline up to 24 months]
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.
MMR Rate - All scheduled time points [Baseline up to 3, 6, 18, and 24 months]
Percentage of participants who achieve MMR at or before the specified visit, i.e., if a patient achieves an MMR but then loses it before or at the visit, h/she will still be considered as achieving MMR by that time point.
Time to MMR [Baseline up to 24 months]
Time to MMR is defined and calculated as date of first documented MMR - start date of study treatment +1 day.
Duration of MMR [Baseline up to 24 months]
Duration of MMR is defined as the time from the date of first documented MMR to the earliest date of loss of MMR, progression to Accelerated Phase (AP) or Blast Crisis (BC), or CML-related death.
Time to Treatment Failure (TTF) [Baseline up to 24 months]
Time to treatment failure (TTF) is defined as the time from date of randomization to an event of treatment failure.
Progression Free Survival (PFS) [Baseline up to 24 months]
Time from the first dose of study treatment to the earliest occurrence of documented progression to Accelerated Phase (AP) or Blast Crisis (BC) or the date of death from any cause, before the end of the treatment phase.
Overall Survival (OS) [Baseline up to 24 months.]
Time from the first dose of study treatment to death due to any cause during the study.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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:

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

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.

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.