Clinical trial NCT04948333: Asciminib Treatment Optimization in ≥ 3rd Line CML-CP
Official title: A Phase 3b, Multi-center, Open-label, Treatment Optimization Study of Oral Asciminib in Patients With Chronic Myelogenous Leukemia in Chronic Phase (CML-CP) Previously Treated With 2 or More Tyrosine Kinase Inhibitors
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Chronic Myelogenous Leukemia
Keywords: ABL001
Phase 3
tyrosine kinase inhibitor
Chronic myelogenous leukemia (CML)
chronic myeloid leukemia (CML)
chronic myelocytic leukemia (CML)
chronic granulocytic leukemia (CGL)
cancer of the white blood cells
clonal bone marrow stem cell disorder
proliferation of mature granulocytes
Treatment optimization
Asciminib
European Leukemia Network (ELN) Recommendations 2020
Major Molecular Response (MMR) rate at 48 weeks
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2021-07-01
Enrollment: 199
Sex: ALL
Minimum age (years): 18
Maximum age (years): 99
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The purpose of the study is to optimize the treatment of asciminib in patients with chronic myelogenous leukemia in chronic phase (CML-CP) previously treated with 2 or more Tyrosine Kinase Inhibitors (TKIs).

Detailed description: This study consists of a screening period of up to 28 days, a treatment period of 144 weeks and a post-treatment safety follow-up period of 4 weeks.

Patients will receive asciminib as study treatment continuously for up to 144 weeks or until disease progression, treatment failure or intolerance to treatment. At treatment initiation, asciminib will be provided to all trial patients at a total daily dose of 80 mg. All patients will be randomly assigned 1:1 to 2 groups with 80 mg given either as 40 mg b.i.d. or 80 mg q.d., using IRT to avoid any selection bias.

In patients not achieving Major Molecular Responses (MMR) at 48 weeks or losing the response after the week 48 assessment up to week 108, asciminib dose may be escalated to 200 mg q.d. if in the investigator's opinion the patient may benefit from the escalation. In addition, there must not be any grade 3 or 4 toxicity while on therapy, or persistent grade 2 toxicity, possibly related to asciminib and unresponsive to optimal management.

The trial will enroll a total of approximately 186 patients:

* 156 patients with CML-CP not in MMR at baseline who were treated with two or more TKIs and who were either resistant (ELN 2020 warning or failure) or intolerant to the last treatment will be enrolled. For this population, the primary endpoint for MMR at 48 weeks will be assessed.
* Up to 30 additional patients intolerant only to their last TKI treatment and in MMR at baseline will also be enrolled. This patient population will not be part of primary endpoint analysis; however, all assessments will be done as with the 156 patients from the population of the primary endpoint analysis.

Eligibility criteria: Key Inclusion criteria:

* Signed informed consent must be obtained prior to participation in the study
* Male or female patients with a diagnosis of CML-CP ≥ 18 years of age
* Treatment with a minimum of 2 or more prior TKIs (i.e. imatinib, nilotinib, dasatinib, bosutinib, radotinib or ponatinib)
* Warning or failure (adapted from the 2020 ELN Recommendations) or intolerance to the most recent TKI therapy at the time of screening
* Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0, 1, or 2
* Adequate end organ function (as per central laboratory tests)

Key Exclusion criteria:

* Known presence of the BCR::ABL1 T315I mutation at any time prior to study entry
* Known second chronic phase of CML after previous progression to AP/BC
* Previous treatment with a hematopoietic stem-cell transplantation
* Patient planning to undergo allogeneic hematopoietic stem cell transplantation
* Uncontrolled cardiac repolarization abnormality
* 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
* History of acute pancreatitis within 1 year of study entry or past medical history of chronic pancreatitis
* Testing for Hepatitis B surface antigen (HbsAg) and Hepatitis B core antibody (HBcAb / anti HBc) will be performed at screening. Patients with active Hepatitis B Virus (HBV) infection (hepatitis B surface antigen \[HbsAg\] positive) will be excluded

Other Inclusion/Exclusion criteria may apply.

Primary outcomes:
measure: Major Molecular Response (MMR) Rate at Week 48 for All Patients With no Evidence of MMR at Baseline
timeFrame: Week 48
Secondary outcomes:
measure: MMR Rate at Week 12, 24, 36, 72, 96 and 144 for Patients With no MMR at Baseline
timeFrame: Week 12, 24, 36, 72, 96 and 144
measure: Major Molecular Response (MMR) Rate at Week 48 for Patients With MMR at Baseline
timeFrame: Week 48.
measure: Time to MMR for Subjects Without MMR at Baseline
timeFrame: From the date of enrollment to the date of first documented MMR, assessed up to 144 weeks
measure: Rate of BCR::ABL1 ≤ 10% for Subjects Without MMR at Baseline
timeFrame: Week 12, 24, 36 and 48
measure: Rate of BCR::ABL1 ≤ 1% for Subjects Without MMR at Baseline
timeFrame: Week 12, 24, 36 and 48.
measure: Deep Molecular Responses (MR4) Rate for Subjects Without MMR at Baseline
timeFrame: Week 12, 24, 36, 48, 72, 96 and 144.
measure: Deep Molecular Responses (MR4.5) Rate for Subjects Without MMR at Baseline
timeFrame: Week 12, 24, 36, 48, 72, 96 and 144.
measure: Rate of Complete Cytogenetic Response (CCyR) for Subjects Without MMR at Baseline
timeFrame: Week 48 and end of treatment (up to 144 weeks)
measure: Occurrence of High-risk Additional Chromosomal Abnormalities (ACA) for Subjects Without MMR at Baseline
timeFrame: Up to 144 weeks
measure: Cumulative Molecular Response Rate of BCR::ABL1 ≤ 10% for Subjects Without MMR at Baseline
timeFrame: From enrollment to end of treatment up to 144 weeks.
measure: Cumulative Molecular Response Rate of BCR::ABL1 ≤1% for Subjects Without MMR at Baseline
timeFrame: From enrollment to end of treatment up to 144 weeks.
measure: Cumulative Molecular Response Rate of MMR for Subjects Without MMR at Baseline
timeFrame: From enrollment to end of treatment up to 144 weeks.
measure: Cumulative Molecular Response Rate of MR4 for Subjects Without MMR at Baseline
timeFrame: From enrollment to end of treatment up to 144 weeks.
measure: Cumulative Molecular Response Rate of MR4.5 for Subjects Without MMR at Baseline
timeFrame: From enrollment to end of treatment up to 144 weeks.
measure: Duration of MMR
timeFrame: From the date of the first documented molecular response at MMR level to the date of first documented loss of the response level or death due to any cause, whichever occurs first, assessed up to 144 weeks.
measure: Duration of MR4 Without Loss of MMR
timeFrame: From the date of first documented MR4 without loss of MMR to the date of first documented loss of the response level or death due to any cause, whichever occurs first, assessed up to 144 weeks.
measure: Progression-Free Survival (PFS) for Subjects Without MMR at Baseline
timeFrame: Up to 144 weeks.
measure: Overall Survival (OS) for Subjects Without MMR at Baseline
timeFrame: Up to 144 weeks.
measure: Time to Treatment Failure (TTF) for Subjects Without MMR at Baseline
timeFrame: Up to 144 weeks.
measure: Change in Symptom Burden and Interference From Baseline Over Time According to the MDASI-CML PRO Instrument
timeFrame: Week 4, 12, 24, 48, 72, 96, 120 and at end of treatment (up to 144 weeks).
Other outcomes:
Locations:
city: Caba
country: Argentina
facility: Novartis Investigative Site
state: Buenos Aires
city: Buenos Aires
country: Argentina
facility: Novartis Investigative Site
city: Graz
country: Austria
facility: Novartis Investigative Site
city: Linz
country: Austria
facility: Novartis Investigative Site
city: Wien
country: Austria
facility: Novartis Investigative Site
city: Rio de Janeiro
country: Brazil
facility: Novartis Investigative Site
state: RJ
city: Sao Paulo
country: Brazil
facility: Novartis Investigative Site
city: Vancouver
country: Canada
facility: Novartis Investigative Site
state: British Columbia
city: Toronto
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: Bordeaux
country: France
facility: Novartis Investigative Site
city: Lyon
country: France
facility: Novartis Investigative Site
city: Montpellier
country: France
facility: Novartis Investigative Site
city: Nantes
country: France
facility: Novartis Investigative Site
city: Paris 10
country: France
facility: Novartis Investigative Site
city: Mannheim
country: Germany
facility: Novartis Investigative Site
state: Baden Wuerttemberg
city: Frankfurt am Main
country: Germany
facility: Novartis Investigative Site
state: Hessen
city: Berlin
country: Germany
facility: Novartis Investigative Site
city: Jena
country: Germany
facility: Novartis Investigative Site
city: Kiel
country: Germany
facility: Novartis Investigative Site
city: Muenchen
country: Germany
facility: Novartis Investigative Site
city: Thessaloniki
country: Greece
facility: Novartis Investigative Site
state: GR
city: Athens
country: Greece
facility: Novartis Investigative Site
city: Monza
country: Italy
facility: Novartis Investigative Site
state: MB
city: Roma
country: Italy
facility: Novartis Investigative Site
state: RM
city: Verona
country: Italy
facility: Novartis Investigative Site
state: VR
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Taegu
country: Korea, Republic of
facility: Novartis Investigative Site
city: Kota Kinabalu
country: Malaysia
facility: Novartis Investigative Site
state: Sabah
city: Johor Bahru
country: Malaysia
facility: Novartis Investigative Site
city: Pulau Pinang
country: Malaysia
facility: Novartis Investigative Site
city: Selangor
country: Malaysia
facility: Novartis Investigative Site
city: Muscat
country: Oman
facility: Novartis Investigative Site
city: Katowice
country: Poland
facility: Novartis Investigative Site
city: Warszawa
country: Poland
facility: Novartis Investigative Site
city: Singapore
country: Singapore
facility: Novartis Investigative Site
city: Singapore
country: Singapore
facility: Novartis Investigative Site
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Santiago De Compostela
country: Spain
facility: Novartis Investigative Site
state: Galicia
city: Bilbao
country: Spain
facility: Novartis Investigative Site
state: Pais Vasco
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Santa Cruz de Tenerife
country: Spain
facility: Novartis Investigative Site
city: Leeds
country: United Kingdom
facility: Novartis Investigative Site
state: West Yorkshire
city: Cambridge
country: United Kingdom
facility: Novartis Investigative Site
city: London
country: United Kingdom
facility: Novartis Investigative Site
city: London
country: United Kingdom
facility: Novartis Investigative Site
city: Hanoi
country: Vietnam
facility: Novartis Investigative Site
city: Ho Chi Minh
country: Vietnam
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: