Clinical trial NCT04971226: A Study of Oral Asciminib Versus Other TKIs in Adult Patients With Newly Diagnosed Ph+ CML-CP
Official title: A Phase III, Multi-center, Open-label, Randomized Study of Oral Asciminib Versus Investigator Selected TKI in Patients With Newly Diagnosed Philadelphia Chromosome Positive Chronic Myelogenous Leukemia in Chronic Phase
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Chronic Myeloid Leukemia (CML) Philadelphia Chromosome Positive
Keywords: Asciminib
Chronic Myeloid Leukemia
CML
Philadelphia Chromosome
TKIs
Bosutinib
Dasatinib
Nilotinib
Imatinib
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2021-07-21
Enrollment: 405
Sex: ALL
Minimum age (years): 18
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The study is designed to compare the efficacy of asciminib 80 mg QD versus Investigator selected Tyrosine Kinase Inhibitor (TKI) for the treatment of newly diagnosed, previously untreated patients with Ph+ CML-CP. The Investigator selected TKI will be one of the following treatment options for first-line treatment of CML-CP - imatinib 400 mg QD or nilotinib 300 mg BID or dasatinib 100 mg QD or bosutinib 400 mg QD.

Detailed description: This study is a phase III, multi-center, open-label, randomized study of oral asciminib 80 mg QD versus Investigator selected TKI (imatinib, nilotinib, dasatinib, or bosutinib) in adult patients with newly diagnosed Ph+ CML-CP. All comparator TKIs will be made available, unless not permitted by local regulations or local Health Authority, or not approved for the treatment of CML in the country.

Approximately 402 patients will be randomized in a 1:1 ratio to asciminib and Investigator selected TKI.

Randomization will be stratified based on the following two stratification factors:

* ELTS score (low versus intermediate versus high)
* Pre-randomization selected TKI (imatinib versus 2G TKI (nilotinib or dasatinib or bosutinib)).

Prior to randomization, the Investigator, in consultation with the patient, considering the current treatment paradigm and patient characteristics and comorbidities, will make a selection of preference for imatinib or 2G TKI (nilotinib or dasatinib or bosutinib) if the patient is randomized to the comparator arm. The stratified randomization based on these two stratification factors will help to achieve a balance across the treatment arms for the possible comorbidities and baseline characteristics of patients enrolled in the study.

To further ensure that the distribution of patients, between imatinib and 2G TKIs (nilotinib or dasatinib or bosutinib), in the Investigator selected TKI arm is reflective of the use of these agents in clinical practice, the enrollment into the strata of imatinib versus 2G TKI (nilotinib or dasatinib or bosutinib) based on the pre-randomization selection of TKI will be managed by Interactive Response Technology to be approximately 50% versus 50%.

Treatment arms: The study will have 2 treatment arms:

* Arm 1: asciminib 80 mg QD under fasting conditions
* Arm 2: Investigator selected TKI that will include one of the below treatments:
* Imatinib 400 mg QD administered with food
* Nilotinib 300 mg BID administered under fasting conditions
* Dasatinib 100 mg QD administered with or without meal
* Bosutinib 400 mg QD administered with food.

No crossover of study treatment across arms and no change of study treatment within the Investigator selected TKI will be allowed.

Duration of Study treatment: Patients on the study will continue to receive the assigned treatment until the End of Study, or until premature discontinuation due to treatment failure, disease progression or intolerance or due to Investigator or participant decision.

Duration of study: The End of Study will occur 5 years from the last patient first treatment in the study. Patients who discontinue study treatment prematurely due to any reason, will be followed up for survival and progression (to AP/BC) until the End of Study.

Eligibility criteria: Inclusion Criteria:

Participants eligible for inclusion in this study must meet all of the following criteria:

* Male or female patients ≥ 18 years of age.
* Participants with CML-CP within 3 months of diagnosis.
* Diagnosis of CML-CP (ELN 2020 criteria) with cytogenetic confirmation of Philadelphia chromosome

Documented chronic phase CML will meet all the below criteria (Hochhaus et al 2020):

* \< 15% blasts in peripheral blood and bone marrow,
* \< 30% blasts plus promyelocytes in peripheral blood and bone marrow,
* \< 20% basophils in the peripheral blood,
* Platelet count ≥ 100 x 10\^9/L (≥ 100,000/mm\^3),
* No evidence of extramedullary leukemic involvement, with the exception of hepatosplenomegaly.

  * Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
  * Adequate end organ function as defined by:
* Total bilirubin \< 3 x ULN; patients with Gilbert's syndrome may only be included if total bilirubin ≤ 3.0 x ULN or direct bilirubin ≤ 1.5 x ULN
* Creatinine clearance (CrCl) ≥ 30 mL/min as calculated using Cockcroft-Gault formula,
* Serum lipase ≤ 1.5 x ULN. For serum lipase \> ULN - ≤ 1.5 x ULN, value must be considered not clinically significant and not associated with risk factors for acute pancreatitis

  - Participants must have the following laboratory values within normal limits or corrected to within normal limits with supplements prior to randomization:
* Potassium (potassium increase of up to 6.0 mmol/L is acceptable if associated with CrCl\* ≥ 90 mL/min)
* Total calcium (corrected for serum albumin); (calcium increase of up to 12.5 mg/dl or 3.1 mmol/L is acceptable if associated with CrCl\* ≥ 90 mL/min)
* Magnesium (magnesium increase of up to 3.0 mg/dL or 1.23 mmol/L if associated with CrCl\* ≥ 90 mL/min)
* For patients with mild to moderate renal impairment (CrCl\* ≥ 30 mL/min and \<90 mL/min) - potassium, total calcium (corrected for serum albumin) and magnesium should be ≥ LLN or corrected to within normal limits with supplements prior to randomization.
* \*CrCl as calculated using Cockcroft-Gault formula

  * Ability to provide written informed consent prior to any study related screening procedures being performed.
  * Evidence of typical BCR-ABL1 transcript \[e14a2 and/or e13a2\] at the time of screening which is amenable to standardized Real time quantitative polymerase chain reaction (RQ-PCR) quantification.

Exclusion Criteria:

* Previous treatment of CML with any other anticancer agents including chemotherapy and/or biologic agents or prior stem cell transplant, with the exception of hydroxyurea and/or anagrelide. Treatment with either imatinib, or nilotinib, or dasatinib or bosutinib for ≤2 weeks is allowed, but no other treatment with other tyrosine kinase inhibitors prior to randomization is permitted.
* Known cytopathologically confirmed CNS infiltration (in absence of suspicion of CNS involvement, lumbar puncture not required).
* Impaired cardiac function or cardiac repolarization abnormality including but not limited to any one 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)
  * QTc ≥ 450 ms (male patients), ≥460 ms (female patients) on the average of three serial baseline ECG (using the QTcF formula) as determined by central reading. If QTcF ≥ 450 ms and electrolytes are not within normal ranges, electrolytes should be corrected and then the patient re-screened for QTc.
  * 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
* 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). Please refer to Section 6.3.1
* History of significant congenital or acquired bleeding disorder unrelated to cancer.
* Major surgery within 4 weeks prior to study entry or who have not recovered from prior surgery.
* 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
* History of acute pancreatitis within 1 year prior to randomization or medical history of chronic pancreatitis.
* History of chronic liver disease leading to severe hepatic impairment, or ongoing acute liver disease.
* Known hypersensitivity to the study treatment

Other protocol-defined Inclusion/exclusion criteria will apply.

Primary outcomes:
measure: Percentage of Participants With Major Molecular Response (MMR) at Week 48 - Ascimimib vs. Investigator Selected TKI
timeFrame: At 48 weeks
measure: Percentage of Participants With Major Molecular Response (MMR) at Week 48 - Asciminib (Imatinib Stratum) vs Investigator Selected TKI (Imatinib Stratum)
timeFrame: At 48 weeks
Secondary outcomes:
measure: Major Molecular Response at Week 96
timeFrame: at 96 weeks (96 weeks after last patient first dose)
measure: Time to Discontinuation of Study Treatment Due to Adverse Events (TTDAE)
timeFrame: 96 weeks after last patient first dose
measure: Major Molecular Response at Scheduled Data Collection Time Points
timeFrame: Planned total follow-up duration of 5 years
measure: Major Molecular Response by Scheduled Data Collection Time Points
timeFrame: Planned total follow-up duration of 5 years
measure: MR4.0 at Scheduled Data Collection Time Points
timeFrame: Planned total follow-up duration of 5 years
measure: MR4.5 at All Scheduled Data Collection Time Points
timeFrame: Planned total follow-up duration of 5 years
measure: MR4.0 by Scheduled Data Collection Time Points
timeFrame: Planned total follow-up duration of 5 years
measure: MR4.5 by All Scheduled Data Collection Time Points
timeFrame: Planned total follow-up duration of 5 years
measure: Complete Hematological Response (CHR) at All Scheduled Data Collection Time Points
timeFrame: Planned total follow-up duration of 5 years
measure: Complete Hematological Response (CHR) by All Scheduled Data Collection Time Points
timeFrame: Planned total follow-up duration of 5 years
measure: Percentage of Participants With Complete Cytogenic Response (CCyR) by Week 48 & Week 96
timeFrame: By week 48 and by week 96 (48 weeks and 96 weeks after last patient first dose); data collection/analysis is ongoing for the 96 week time point, and the data will be reported later
measure: Duration of MMR
timeFrame: Planned total follow-up duration of 5 years
measure: Duration of MR4.0
timeFrame: Planned total follow-up duration of 5 years
measure: Duration of MR4.5
timeFrame: Planned total follow-up duration of 5 years
measure: Time to First MMR
timeFrame: Planned total follow-up duration of 5 years
measure: Time to First MR4.0
timeFrame: Planned total follow-up duration of 5 years
measure: Time to First MR4.5
timeFrame: Planned total follow-up duration of 5 years
measure: BCR-ABL1≤1% at Scheduled Data Collection Time Points
timeFrame: Planned total follow-up duration of 5 years
measure: BCR-ABL1≤1% by Scheduled Data Collection Time Points
timeFrame: Planned total follow-up duration of 5 years
measure: Time to Treatment Failure (TTF)
timeFrame: Planned total follow-up duration of 5 years
measure: Failure Free Survival (FFS)
timeFrame: Planned total follow-up duration of 5 years
measure: Event Free Survival (EFS)
timeFrame: Planned total follow-up duration of 5 years
measure: Progression Free Survival (PFS)
timeFrame: Planned total follow-up duration of 5 years
measure: Overall Survival (OS)
timeFrame: Planned total follow-up duration of 5 years
measure: Trough Plasma Concentrations.
timeFrame: Week 48
measure: Pharmacokinetics (PK) of Asciminib: Cmax
timeFrame: Week 2 (0 hours (h) pre-dose, 1h, 2h, 3h, 4h, 6h, 8h and 12h post dose)
measure: PK of Asciminib: Tmax
timeFrame: Week 2 (0 hours (h) pre-dose, 1h, 2h, 3h, 4h, 6h, 8h and 12h post dose)
measure: PK of Asciminib: AUCtau and AUClast
timeFrame: Week 2 (0 hours (h) pre-dose, 1h, 2h, 3h, 4h, 6h, 8h and 12h post dose)
measure: PK of Asciminib: CL/F
timeFrame: Week 2 (0 hours (h) pre-dose, 1h, 2h, 3h, 4h, 6h, 8h and 12h post dose)
measure: Change From Baseline in Overall Scores (Global Health Status) and Individual Scales of the EORTC QLQ-C30 at Week 48 and Week 96
timeFrame: Baseline, week 48 and week 96
measure: Change From Baseline in EORTC QLQ-CML24 Scales at Week 48 and Week 96
timeFrame: Baseline, week 48 and week 96.
Other outcomes:
Locations:
city: Longmont
country: United States
facility: Rocky Mountain Cancer Centers
state: Colorado
city: Fort Myers
country: United States
facility: Florida Cancer Specialists
state: Florida
city: Tallahassee
country: United States
facility: Florida Cancer Specialists Pan
state: Florida
city: Lexington
country: United States
facility: University of Kentucky
state: Kentucky
city: Worcester
country: United States
facility: Uni of Massachusetts Medical Center
state: Massachusetts
city: Winston-Salem
country: United States
facility: Wake Forest University Baptist Medical Center
state: North Carolina
city: Eugene
country: United States
facility: Williamette Cancer Center
state: Oregon
city: Portland
country: United States
facility: Oregon Health Sciences University
state: Oregon
city: Sioux Falls
country: United States
facility: Avera Cancer
state: South Dakota
city: Chattanooga
country: United States
facility: Chattanooga Onc And Hem Assoc PC
state: Tennessee
city: Dallas
country: United States
facility: Texas Oncology-Baylor USO
state: Texas
city: Dallas
country: United States
facility: Texas Oncology
state: Texas
city: Dallas
country: United States
facility: Texas Oncology
state: Texas
city: Kingswood
country: Australia
facility: Novartis Investigative Site
state: New South Wales
city: Port Macquarie
country: Australia
facility: Novartis Investigative Site
state: New South Wales
city: Adelaide
country: Australia
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state: South Australia
city: SouthPort
country: Australia
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city: Linz
country: Austria
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state: Upper Austria
city: Bruxelles
country: Belgium
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city: Leuven
country: Belgium
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city: Varna
country: Bulgaria
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city: Calgary
country: Canada
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state: Alberta
city: Hamilton
country: Canada
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state: Ontario
city: Ottawa
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state: Ontario
city: Toronto
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state: Ontario
city: Guangzhou
country: China
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state: Guangdong
city: Shenzhen
country: China
facility: Novartis Investigative Site
state: Guangdong
city: Zhengzhou
country: China
facility: Novartis Investigative Site
state: Henan
city: Wuhan
country: China
facility: Novartis Investigative Site
state: Hubei
city: Nanjing
country: China
facility: Novartis Investigative Site
state: Jiangsu
city: Suzhou
country: China
facility: Novartis Investigative Site
state: Jiangsu
city: Xian
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facility: Novartis Investigative Site
state: Shanxi
city: Chengdu
country: China
facility: Novartis Investigative Site
state: Sichuan
city: Hangzhou
country: China
facility: Novartis Investigative Site
state: Zhejiang
city: Wenzhou
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state: Zhejiang
city: Beijing
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country: Denmark
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city: Mannheim
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state: Baden Wuerttemberg
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state: Hessen
city: Aachen
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city: Berlin
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city: Kaposvar
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city: Kecskemet
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city: Delhi
country: India
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city: Petach Tikva
country: Israel
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city: Ramat Gan
country: Israel
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city: Tel Aviv
country: Israel
facility: Novartis Investigative Site
city: Bologna
country: Italy
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state: BO
city: Milano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Reggio Emilia
country: Italy
facility: Novartis Investigative Site
state: RE
city: Roma
country: Italy
facility: Novartis Investigative Site
state: RM
city: Verona
country: Italy
facility: Novartis Investigative Site
state: VR
city: Nagoya
country: Japan
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state: Aichi
city: Toyoake city
country: Japan
facility: Novartis Investigative Site
state: Aichi
city: Fukuoka city
country: Japan
facility: Novartis Investigative Site
state: Fukuoka
city: Fukushima city
country: Japan
facility: Novartis Investigative Site
state: Fukushima
city: Sapporo city
country: Japan
facility: Novartis Investigative Site
state: Hokkaido
city: Kobe
country: Japan
facility: Novartis Investigative Site
state: Hyogo
city: Kurashiki
country: Japan
facility: Novartis Investigative Site
state: Okayama
city: Osaka Sayama
country: Japan
facility: Novartis Investigative Site
state: Osaka
city: Suita
country: Japan
facility: Novartis Investigative Site
state: Osaka
city: Shimotsuke
country: Japan
facility: Novartis Investigative Site
state: Tochigi
city: Chuo
country: Japan
facility: Novartis Investigative Site
state: Yamanashi
city: Akita
country: Japan
facility: Novartis Investigative Site
city: Osaka
country: Japan
facility: Novartis Investigative Site
city: Yamagata
country: Japan
facility: Novartis Investigative Site
city: Uijeongbu si
country: Korea, Republic of
facility: Novartis Investigative Site
state: Gyeonggi Do
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
state: Seocho Gu
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Kuantan
country: Malaysia
facility: Novartis Investigative Site
state: Pahang
city: Subang Jaya
country: Malaysia
facility: Novartis Investigative Site
state: Selangor
city: Pulau Pinang
country: Malaysia
facility: Novartis Investigative Site
city: Selangor
country: Malaysia
facility: Novartis Investigative Site
city: Amsterdam
country: Netherlands
facility: Novartis Investigative Site
city: Bergen
country: Norway
facility: Novartis Investigative Site
city: Oslo
country: Norway
facility: Novartis Investigative Site
city: Porto
country: Portugal
facility: Novartis Investigative Site
city: Vila Nova De Gaia
country: Portugal
facility: Novartis Investigative Site
city: Singapore
country: Singapore
facility: Novartis Investigative Site
city: Singapore
country: Singapore
facility: Novartis Investigative Site
city: Kosice
country: Slovakia
facility: Novartis Investigative Site
city: Granada
country: Spain
facility: Novartis Investigative Site
state: Andalucia
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: El Palmar
country: Spain
facility: Novartis Investigative Site
state: Murcia
city: Pamplona
country: Spain
facility: Novartis Investigative Site
state: Navarra
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Goteborg
country: Sweden
facility: Novartis Investigative Site
city: Lund
country: Sweden
facility: Novartis Investigative Site
city: Stockholm
country: Sweden
facility: Novartis Investigative Site
city: Bellinzona
country: Switzerland
facility: Novartis Investigative Site
city: Taichung
country: Taiwan
facility: Novartis Investigative Site
city: London
country: United Kingdom
facility: Novartis Investigative Site
city: Nottingham
country: United Kingdom
facility: Novartis Investigative Site
city: Oxford
country: United Kingdom
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: