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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) (ASC4START)

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ClinicalTrials.gov Identifier: NCT05456191
Recruitment Status : Recruiting
First Posted : July 13, 2022
Last Update Posted : March 13, 2024
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

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).

Condition or disease Intervention/treatment Phase
Philadelphia Chromosome-Positive Chronic Myeloid Leukemia Drug: Asciminib Drug: Nilotinib Phase 3

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 550 participants
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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.
Actual Study Start Date : November 21, 2022
Estimated Primary Completion Date : February 15, 2027
Estimated Study Completion Date : March 15, 2027


Arm Intervention/treatment
Experimental: Asciminib
Participants will receive asciminib 80 mg QD
Drug: Asciminib
Asciminib 80 mg QD administered under fasting conditions.
Other Name: ABL001

Active Comparator: Nilotinib
Participants will receive nilotinib 300 mg BID
Drug: Nilotinib
Nilotinib 300 mg BID administered under fasting conditions.




Primary Outcome Measures :
  1. Time to discontinuation of study treatment due to adverse event (TTDAE). [ Time Frame: From date of first dose to date of treatment discontinuation due to AE, assessed up to 4.5 years ]
    TTDAE is defined as the time from the date of first dose of study treatment to the date of discontinuation of study treatment due to adverse event (AE).


Secondary Outcome Measures :
  1. Percentage of participants with Major Molecular response (MMR) at scheduled data collection time points [ Time Frame: Screening, Week 4, Week 12 and thereafter every 12 weeks until End of Treatment (EOT) and EOT, assessed up to approximately 4.5 years. ]

    MMR will be assessed using fusion gene of the BCR and ABL genes (BCR-ABL) transcript levels measured by realtime quantitative polymerase chain reaction.

    The percentage of participants with MMR at each time point will be assessed.


  2. Percentage of participants with Major Molecular response (MMR) by scheduled data collection time points [ Time Frame: Screening, Week 4, Week 12 and thereafter every 12 weeks until End of Treatment (EOT) and EOT, assessed up to approximately 4.5 years. ]

    MMR will be assessed using BCR-ABL transcript levels measured by realtime quantitative polymerase chain reaction.

    The percentage of participants who meet the criteria for having achieved the endpoint (MMR) at or before the specified visit will be calculated.


  3. Percentage of participants with MR4.0 at scheduled data collection time points [ Time Frame: Screening, Week 4, Week 12 and thereafter every 12 weeks until End of Treatment (EOT) and EOT, assessed up to approximately 4.5 years. ]

    MR4.0 will be assessed using BCR-ABL transcript levels measured by realtime quantitative polymerase chain reaction.

    The percentage of participants with MR4.0 at each time point will be assessed.


  4. Percentage of participants with MR4.0 by scheduled data collection time points [ Time Frame: Screening, week 4, week 12 and thereafter every 12 weeks until End of Treatment (EOT) and EOT, assessed up to approximately 4.5 years ]

    MR4.0 will be assessed using BCR-ABL transcript levels measured by realtime quantitative polymerase chain reaction.

    The percentage of participants who meet the criteria for having achieved the endpoint (MR4.0) at or before the specified visit will be calculated


  5. Percentage of participants with MR4.5 at scheduled data collection time points [ Time Frame: Screening, Week 4, Week 12 and thereafter every 12 weeks until End of Treatment (EOT) and EOT, assessed up to approximately 4.5 years. ]

    MR4.5 will be assessed using BCR-ABL transcript levels measured by realtime quantitative polymerase chain reaction.

    The percentage of participants with MR4.5 at each time point will be assessed.


  6. Percentage of participants with MR4.5 by scheduled data collection time points [ Time Frame: Screening, Week 4, Week 12 and thereafter every 12 weeks until End of Treatment (EOT) and EOT, assessed up to approximately 4.5 years. ]

    MR4.5 will be assessed using BCR-ABL transcript levels measured by realtime quantitative polymerase chain reaction.

    The percentage of participants who meet the criteria for having achieved the endpoint (MR4.5) at or before the specified visit will be calculated


  7. Percentage of participants with Complete Hematological response (CHR) at scheduled data collection time points [ Time Frame: Screening, Week 4, Week 12 and thereafter every 12 weeks until End of Treatment (EOT) and EOT, assessed up to approximately 4.5 years. ]

    Hematologic response will be assessed by complete blood count and physical examination at each visit.

    The percentage of participants with CHR at each time point will be assessed.


  8. Percentage of participants with Complete Hematological response (CHR) by scheduled data collection time points [ Time Frame: Screening, Week 4, Week 12 and thereafter every 12 weeks until End of Treatment (EOT) and EOT, assessed up to approximately 4.5 years. ]

    Hematologic response will be assessed by complete blood count and physical examination at each visit.

    The percentage of participants who meet the criteria for having achieved the endpoint (CHR) at or before the specified visit will be calculated


  9. Percentage of participants with BCR::ABL1 ratio ≤1% by Week 48 and Week 96. [ Time Frame: Week 48 and Week 96 ]
    The percentage of participants who meet the criteria for having achieved BCR::ABL1 ratio ≤1% at or before the specified visit will be calculated

  10. Duration of MMR [ Time Frame: 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. ]
    Duration of MMR is defined as the time between the date of the first documented achievement MMR and the earliest date of loss of MMR, treatment failure, progression to AP/BC, or CML-related death.

  11. Duration of MR4.0 [ Time Frame: 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. ]
    Duration of MR4.0 is defined as the time between the date of the first documented achievement MR4 and the earliest date of loss of MR4, treatment failure, progression to AP/BC, or CML-related death

  12. Duration of MR4.5 [ Time Frame: 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. ]
    Duration of MR4.5 is defined as the time between the date of the first documented achievement MR4.5 and the earliest date of loss of MR4.5, treatment failure, progression to AP/BC, or CML-related death.

  13. Time to first MMR [ Time Frame: From the date of randomization to the date of the first MMR, assessed up to approximately 4.5 years. ]
    Time to first MMR is defined as the time from the date of randomization to the date of the first documented occurrence of MMR.

  14. Time to first MR4.0 [ Time Frame: From the date of randomization to the date of the first MR4, assessed up to approximately 4.5 years. ]
    Time to first MR4.0 is defined as the time from the date of randomization to the date of the first documented occurrence of MR4.

  15. Time to first MR4.5 [ Time Frame: From the date of randomization to the date of the first MR4.5, assessed up to approximately 4.5 years. ]
    Time to first MR4.5 is defined as the time from the date of randomization to the date of the first documented occurrence of MR4.5.

  16. Time to treatment failure (TTF). [ Time Frame: Up to approximately 4.5 years. ]

    TTF is defined as the time from date of randomization to the first/earliest documented date of any of the following events:

    • Treatment failure per European leukemia network (ELN) criteria,
    • Confirmed loss of MMR (in 2 consecutive tests) at any time while on study treatment,
    • Discontinuation from study treatment due to any reason

  17. Event free survival (EFS) [ Time Frame: Up to approximately 4.5 years. ]
    EFS is defined as the time from the date of the first dose of study treatment to the earliest occurrence of treatment failure, confirmed lost of MMR, discontinuation due to AE, progression to AP/BC, and death from any cause.

  18. Progression free survival (PFS). [ Time Frame: Up to approximately 4.5 years. ]
    PFS is defined as the time from the date of randomization to the earliest occurrence of progression to AP/BC or death from any cause.

  19. Overall survival (OS). [ Time Frame: Up to approximately 4.5 years. ]
    OS is defined as the time from the date of randomization to the date of death from any cause.

  20. Time to treatment discontinuation (TTD) due to selected reasons [ Time Frame: Up to approximately 4.5 years ]
    TTD is the time from the date of first dose of study treatment to the date of discontinuation of study treatment due to lack of efficacy, treatment failure, disease progression, suboptimal response or death

  21. 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) [ Time Frame: 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. ]
    Change from baseline in Overall Scores and individual domains of the EORTC QLQ-C30. The EORTC QLQ-C30 contains 30 items and is composed of both multi-item scales and single-item measures based on the participant's experience over the past week. These include five functional scales (physical, role, emotional, cognitive and social functioning), three symptom scales (fatigue, nausea/vomiting, and pain), six single items (dyspnea, insomnia, appetite loss, constipation, diarrhea and financial impact) and a global health status/QoL scale.

  22. Change from baseline in overall scores and individual scales of the European organization for research and treatment of cancer CML module (EORTC QLQ-CML24) [ Time Frame: 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. ]
    Change from baseline in Overall Scores and individual domains of the EORTC QLQ-CML24. The EORTC QLQ-CML24 assesses specific concepts relevant to the experience of patients with CML. The QLQ-CML24 has 24 items which assess symptom burden, impact on daily life and on worry/mood, body image problems, and satisfaction with care and with social life based on the participant's experience over the past week.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05456191


Contacts
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Contact: Novartis Pharmaceuticals 1-888-669-6682 novartis.email@novartis.com
Contact: Novartis Pharmaceuticals +41613241111

Locations
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Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
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Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
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Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT05456191    
Other Study ID Numbers: CABL001J12302
First Posted: July 13, 2022    Key Record Dates
Last Update Posted: March 13, 2024
Last Verified: March 2024
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description:

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com


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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Novartis ( Novartis Pharmaceuticals ):
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
Additional relevant MeSH terms:
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Leukemia
Leukemia, Myeloid
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Philadelphia Chromosome
Neoplasms by Histologic Type
Neoplasms
Hematologic Diseases
Myeloproliferative Disorders
Bone Marrow Diseases
Chronic Disease
Disease Attributes
Pathologic Processes
Translocation, Genetic
Chromosome Aberrations
Nilotinib
Asciminib
Tyrosine Kinase Inhibitors
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action