Clinical trial NCT05456191: A Study to Investigate Tolerability and Efficacy of Asciminib (Oral) Versus Nilotinib (Oral) in Adult Participants (≥18 Years of Age) With Newly Diagnosed Philadelphia Chromosome Positive Chronic Myelogenous Leukemia in Chronic Phase (Ph+ CML-CP)
Official title: A Phase IIIb, Multi-center, Open-label, Randomized Study of Tolerability and Efficacy of Oral Asciminib Versus Nilotinib 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: Philadelphia Chromosome-Positive Chronic Myeloid Leukemia
Keywords: Chronic Myelogenous Leukemia
Chronic Myeloid Leukemia
Leukemia
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
Chronic Myeloproliferative Disorders
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2022-07-13
Enrollment: 568
Sex: ALL
Minimum age (years): 18
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The study is designed to compare the tolerability of asciminib versus nilotinib for the treatment of newly diagnosed, previously untreated patients with Positive Chronic Myelogenous Leukemia in Chronic Phase (Ph+ CML-CP).

Detailed description: This study is a phase IIIb, multi-center, open-label, randomized study of oral asciminib 80 mg once daily (QD) versus nilotinib 300 mg twice daily (BID) in adult patients with newly diagnosed Ph+ CML-CP.

Participants will be randomized in the study in a 1:1 ratio to asciminib or nilotinib. No crossover of study treatment across arms will be allowed.

Participants will be treated until unacceptable toxicity, disease progression and/or at the discretion of the investigator or the participants. A safety follow up visit/call will be performed approximately 30 days after end of treatment visit. Participants who discontinue study treatment prematurely due to any reason, will be followed up for survival and progression (to Accelerated Phase (AP)/Blast Crisis (BC)) up until end of study.

Eligibility criteria: Inclusion Criteria:

1. Patients with CML-CP within 3 months of diagnosis.
2. Diagnosis of CML-CP (ELN 2020 criteria) with cytogenetic confirmation of the Philadelphia chromosome

   Documented chronic phase CML will meet all the below criteria Baccarani et al 2013:
   * \< 15% blasts in peripheral blood and bone marrow,
   * \< 30% blasts plus promyelocytes in peripheral blood and bone marrow,
   * \< 20% basophils in the peripheral blood,
   * PLT count ≥ 100 x 10\^9/L (≥ 100,000/mm3), except treatment induced thrombocytopenia
   * No evidence of extramedullary leukemic involvement, with the exception of hepatosplenomegaly.
3. Evidence of typical BCR::ABL1 transcript \[e14a2 and/or e13a2\] which is amenable to standardized RQ-PCR quantification by the central laboratory assessment.
4. ECOG performance status of 0 or 1.
5. Adequate end organ function as defined by:

   * Total bilirubin (TBL) \< 3 x ULN; patients with Gilbert's syndrome may only be included if TBL ≤ 3.0 x ULN or direct bilirubin ≤ 1.5 x ULN,
   * 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.
6. Patients 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 within normal limits or corrected to within normal limits with supplements prior to randomization.

     * CrCl as calculated using Cockcroft-Gault formula. \*\*Pseudohyperkaliemia in case of thrombocytosis is not an exclusion criterion.

Exclusion Criteria:

1. 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.
2. Known cytopathologically confirmed CNS infiltration (in absence of suspicion of CNS involvement, lumbar puncture not required).
3. Impaired cardiac function or cardiac repolarization abnormality including but not limited to any one of the following:

   * History of myocardial infarction (MI), angina pectoris, coronary artery bypass graft (CABG) within 6 months prior to starting study treatment.
   * 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 ≥ 450 ms on the average of three serial baseline ECG (using the QTcF formula). If QTcF ≥ 450 ms and electrolytes are not within normal ranges, electrolytes should be corrected and then the patient re-screened for QTcF.
   * 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.
4. 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).
5. History of significant congenital or acquired bleeding disorder unrelated to cancer.
6. Major surgery within 4 weeks prior to study entry or patients who have not recovered from prior surgery.
7. 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.
8. History of acute pancreatitis within 1 year prior to randomization or medical history of chronic pancreatitis.
9. History of chronic liver disease leading to severe hepatic impairment, or ongoing acute liver disease.
10. Known history of chronic Hepatitis B (HBV), or chronic Hepatitis C (HCV) infection. Testing for Hepatitis B surface antigen (HBs Ag) and Hepatitis B core antibody (HBc Ab/anti HBc) will be performed at screening. If anti-HBc is positive, HBV-DNA evaluation will be carried out at screening. A patient having positive HBV-DNA will not be enrolled in the study. Also, a patient with positive HBsAg will not be enrolled in the study. HCV Ab testing will also be performed at screening. For details on the criteria see Appendix 4.
11. History of Human Immunodeficiency Virus (HIV) unless well-controlled on a stable dose of anti-retroviral therapy at the time of screening.

Other protocol-defined Inclusion/exclusion criteria will apply.

Primary outcomes:
measure: Time to discontinuation of study treatment due to adverse event (TTDAE).
timeFrame: From date of first dose to date of treatment discontinuation due to AE, assessed up to 4.5 years
Secondary outcomes:
measure: Percentage of participants with Major Molecular response (MMR) at scheduled data collection time points
timeFrame: Screening, Week 4, Week 12 and thereafter every 12 weeks until End of Treatment (EOT) and EOT, assessed up to approximately 4.5 years.
measure: Percentage of participants with Major Molecular response (MMR) by scheduled data collection time points
timeFrame: Screening, Week 4, Week 12 and thereafter every 12 weeks until End of Treatment (EOT) and EOT, assessed up to approximately 4.5 years.
measure: Percentage of participants with MR4.0 at scheduled data collection time points
timeFrame: Screening, Week 4, Week 12 and thereafter every 12 weeks until End of Treatment (EOT) and EOT, assessed up to approximately 4.5 years.
measure: Percentage of participants with MR4.0 by scheduled data collection time points
timeFrame: Screening, week 4, week 12 and thereafter every 12 weeks until End of Treatment (EOT) and EOT, assessed up to approximately 4.5 years
measure: Percentage of participants with MR4.5 at scheduled data collection time points
timeFrame: Screening, Week 4, Week 12 and thereafter every 12 weeks until End of Treatment (EOT) and EOT, assessed up to approximately 4.5 years.
measure: Percentage of participants with MR4.5 by scheduled data collection time points
timeFrame: Screening, Week 4, Week 12 and thereafter every 12 weeks until End of Treatment (EOT) and EOT, assessed up to approximately 4.5 years.
measure: Percentage of participants with Complete Hematological response (CHR) at scheduled data collection time points
timeFrame: Screening, Week 4, Week 12 and thereafter every 12 weeks until End of Treatment (EOT) and EOT, assessed up to approximately 4.5 years.
measure: Percentage of participants with Complete Hematological response (CHR) by scheduled data collection time points
timeFrame: Screening, Week 4, Week 12 and thereafter every 12 weeks until End of Treatment (EOT) and EOT, assessed up to approximately 4.5 years.
measure: Percentage of participants with BCR::ABL1 ratio ≤1% by Week 48 and Week 96.
timeFrame: Week 48 and Week 96
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 MMR or death due to any cause, whichever occurs first, assessed up to approximately 4.5 years.
measure: Duration of MR4.0
timeFrame: From the date of the first documented molecular response at MR4 level to the date of first documented loss of the response level or death due to any cause, whichever occurs first, assessed up to approximately 4.5 years.
measure: Duration of MR4.5
timeFrame: From the date of the first documented molecular response at MR4.5 level to the date of first documented loss of the response level or death due to any cause, whichever occurs first, assessed up to approximately 4.5 years.
measure: Time to first MMR
timeFrame: From the date of randomization to the date of the first MMR, assessed up to approximately 4.5 years.
measure: Time to first MR4.0
timeFrame: From the date of randomization to the date of the first MR4, assessed up to approximately 4.5 years.
measure: Time to first MR4.5
timeFrame: From the date of randomization to the date of the first MR4.5, assessed up to approximately 4.5 years.
measure: Time to treatment failure (TTF).
timeFrame: Up to approximately 4.5 years.
measure: Event free survival (EFS)
timeFrame: Up to approximately 4.5 years.
measure: Progression free survival (PFS).
timeFrame: Up to approximately 4.5 years.
measure: Overall survival (OS).
timeFrame: Up to approximately 4.5 years.
measure: Time to treatment discontinuation (TTD) due to selected reasons
timeFrame: Up to approximately 4.5 years
measure: Change from baseline in overall scores and individual scales of the European organization for research and treatment of cancer - quality of life questionnaire (EORTC QLQ-C30)
timeFrame: Baseline, every 4 weeks from Week 4 to Week 12, after Week 24, Week 48, Week 96, EOT and every 4 weeks until 12 weeks after EOT, assessed up to approximately 4.5 years.
measure: Change from baseline in overall scores and individual scales of the European organization for research and treatment of cancer CML module (EORTC QLQ-CML24)
timeFrame: Baseline, every 4 weeks from Week 4 to Week 12, after Week 24, Week 48, Week 96, EOT and every 4 weeks until 12 weeks after EOT, assessed up to approximately 4,5 years.
Other outcomes:
Locations:
city: Boulder
country: United States
facility: Rocky Mountain Cancer Centers
state: Colorado
city: Peoria
country: United States
facility: Illinois Cancer Care
state: Illinois
city: Saint Paul
country: United States
facility: Regions Hospital
state: Minnesota
city: Asheville
country: United States
facility: Messino Cancer Centers
state: North Carolina
city: Cincinnati
country: United States
facility: Oncology Hematology Care Inc
state: Ohio
city: Eugene
country: United States
facility: Williamette Cancer Center
state: Oregon
city: Bedford
country: United States
facility: Texas Oncology P A
state: Texas
city: Bedford
country: United States
facility: Texas Oncology PA Bedford
state: Texas
city: Norfolk
country: United States
facility: Virginia Oncology Associates
state: Virginia
city: Caba
country: Argentina
facility: Novartis Investigative Site
state: Buenos Aires
city: Caba
country: Argentina
facility: Novartis Investigative Site
state: Buenos Aires
city: Buenos aires
country: Argentina
facility: Novartis Investigative Site
city: Buenos Aires
country: Argentina
facility: Novartis Investigative Site
city: Buenos Aires
country: Argentina
facility: Novartis Investigative Site
city: Pleven
country: Bulgaria
facility: Novartis Investigative Site
city: Plovdiv
country: Bulgaria
facility: Novartis Investigative Site
city: Sofia
country: Bulgaria
facility: Novartis Investigative Site
city: Sofia
country: Bulgaria
facility: Novartis Investigative Site
city: Varna
country: Bulgaria
facility: Novartis Investigative Site
city: London
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: Toronto
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: Praha 2
country: Czechia
facility: Novartis Investigative Site
state: Czech Republic
city: Brno Bohunice
country: Czechia
facility: Novartis Investigative Site
city: Plzen-Bory
country: Czechia
facility: Novartis Investigative Site
city: Praha 10
country: Czechia
facility: Novartis Investigative Site
city: Bordeaux
country: France
facility: Novartis Investigative Site
city: Caen
country: France
facility: Novartis Investigative Site
city: Clermont Ferrand
country: France
facility: Novartis Investigative Site
city: Lille
country: France
facility: Novartis Investigative Site
city: Lyon
country: France
facility: Novartis Investigative Site
city: Marseille
country: France
facility: Novartis Investigative Site
city: Nantes
country: France
facility: Novartis Investigative Site
city: Nice
country: France
facility: Novartis Investigative Site
city: Paris 10
country: France
facility: Novartis Investigative Site
city: Poitiers
country: France
facility: Novartis Investigative Site
city: Strasbourg
country: France
facility: Novartis Investigative Site
city: Toulouse
country: France
facility: Novartis Investigative Site
city: Vandoeuvre Les Nancy
country: France
facility: Novartis Investigative Site
city: Mannheim
country: Germany
facility: Novartis Investigative Site
state: Baden Wuerttemberg
city: Muenchen
country: Germany
facility: Novartis Investigative Site
state: Bayern
city: Frankfurt am Main
country: Germany
facility: Novartis Investigative Site
state: Hessen
city: Velbert
country: Germany
facility: Novartis Investigative Site
state: North Rhine-Westphalia
city: Halle Saale
country: Germany
facility: Novartis Investigative Site
state: Sachsen-Anhalt
city: Dresden
country: Germany
facility: Novartis Investigative Site
state: Sachsen
city: Leipzig
country: Germany
facility: Novartis Investigative Site
state: Sachsen
city: Aachen
country: Germany
facility: Novartis Investigative Site
city: Augsburg
country: Germany
facility: Novartis Investigative Site
city: Bad Saarow
country: Germany
facility: Novartis Investigative Site
city: Bayreuth
country: Germany
facility: Novartis Investigative Site
city: Berlin
country: Germany
facility: Novartis Investigative Site
city: Bonn
country: Germany
facility: Novartis Investigative Site
city: Bremen
country: Germany
facility: Novartis Investigative Site
city: Chemnitz
country: Germany
facility: Novartis Investigative Site
city: Erlangen
country: Germany
facility: Novartis Investigative Site
city: Essen
country: Germany
facility: Novartis Investigative Site
city: Freiburg
country: Germany
facility: Novartis Investigative Site
city: Hamburg
country: Germany
facility: Novartis Investigative Site
city: Hannover
country: Germany
facility: Novartis Investigative Site
city: Heidelberg
country: Germany
facility: Novartis Investigative Site
city: Jena
country: Germany
facility: Novartis Investigative Site
city: Luebeck
country: Germany
facility: Novartis Investigative Site
city: Magdeburg
country: Germany
facility: Novartis Investigative Site
city: Marburg
country: Germany
facility: Novartis Investigative Site
city: Muenchen
country: Germany
facility: Novartis Investigative Site
city: Paderborn
country: Germany
facility: Novartis Investigative Site
city: Regensburg
country: Germany
facility: Novartis Investigative Site
city: Tuebingen
country: Germany
facility: Novartis Investigative Site
city: Ulm
country: Germany
facility: Novartis Investigative Site
city: Wuerzburg
country: Germany
facility: Novartis Investigative Site
city: Athens
country: Greece
facility: Novartis Investigative Site
state: Attiki
city: Ioannina
country: Greece
facility: Novartis Investigative Site
state: GR
city: Thessaloniki
country: Greece
facility: Novartis Investigative Site
state: GR
city: Athens
country: Greece
facility: Novartis Investigative Site
city: Patras
country: Greece
facility: Novartis Investigative Site
city: Budapest
country: Hungary
facility: Novartis Investigative Site
city: Budapest
country: Hungary
facility: Novartis Investigative Site
city: Eger
country: Hungary
facility: Novartis Investigative Site
city: Ahmedabad
country: India
facility: Novartis Investigative Site
state: Gujrat
city: Chennai
country: India
facility: Novartis Investigative Site
state: Tamilnadu
city: Varanasi
country: India
facility: Novartis Investigative Site
state: Uttar Pradesh
city: Rishikesh
country: India
facility: Novartis Investigative Site
state: Uttarakhand
city: New Delhi
country: India
facility: Novartis Investigative Site
city: Meldola
country: Italy
facility: Novartis Investigative Site
state: FC
city: Milano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Pisa
country: Italy
facility: Novartis Investigative Site
state: PI
city: Roma
country: Italy
facility: Novartis Investigative Site
state: RM
city: Torino
country: Italy
facility: Novartis Investigative Site
state: TO
city: Amman
country: Jordan
facility: Novartis Investigative Site
city: Bundang Gu
country: Korea, Republic of
facility: Novartis Investigative Site
state: Gyeonggi Do
city: Uijeongbu si
country: Korea, Republic of
facility: Novartis Investigative Site
state: Gyeonggi Do
city: Alor Setar
country: Malaysia
facility: Novartis Investigative Site
state: Kedah
city: Kuching
country: Malaysia
facility: Novartis Investigative Site
state: Sarawak
city: Petaling Jaya
country: Malaysia
facility: Novartis Investigative Site
state: Selangor Darul Ehsan
city: Kuala Lumpur
country: Malaysia
facility: Novartis Investigative Site
city: Dordrecht
country: Netherlands
facility: Novartis Investigative Site
city: Muscat
country: Oman
facility: Novartis Investigative Site
city: Bucharest
country: Romania
facility: Novartis Investigative Site
state: District 2
city: Targu Mures
country: Romania
facility: Novartis Investigative Site
state: Mures
city: Bucharest
country: Romania
facility: Novartis Investigative Site
city: Bucuresti
country: Romania
facility: Novartis Investigative Site
city: Cluj-Napoca
country: Romania
facility: Novartis Investigative Site
city: Craiova
country: Romania
facility: Novartis Investigative Site
city: Sibiu
country: Romania
facility: Novartis Investigative Site
city: Timisoara
country: Romania
facility: Novartis Investigative Site
city: Singapore
country: Singapore
facility: Novartis Investigative Site
city: Singapore
country: Singapore
facility: Novartis Investigative Site
city: Singapore
country: Singapore
facility: Novartis Investigative Site
city: Bratislava
country: Slovakia
facility: Novartis Investigative Site
city: Soweto
country: South Africa
facility: Novartis Investigative Site
state: Gauteng
city: Pretoria
country: South Africa
facility: Novartis Investigative Site
city: Geneve 14
country: Switzerland
facility: Novartis Investigative Site
city: Istanbul
country: Turkey
facility: Novartis Investigative Site
state: TUR
city: Ankara
country: Turkey
facility: Novartis Investigative Site
city: Izmir
country: Turkey
facility: Novartis Investigative Site
city: Abu Dhabi
country: United Arab Emirates
facility: Novartis Investigative Site
city: Glasgow
country: United Kingdom
facility: Novartis Investigative Site
city: Gloucester
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: Newport
country: United Kingdom
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: