This study is a multicenter Phase 2, non-randomized, open-label single-group frontline study administering asciminib in patients with newly diagnosed Chronic Myeloid Leukemia-Chronic Phase (CML-CP). The aim of this study is to evaluate the efficacy and safety of asciminib in newly diagnosed CML-CP. Patients will receive asciminib 80 mg orally once daily during the single asciminib phase. Response is determined by PCR (polymerase chain reaction) blood test during the study. Patients who have not achieved a response after 24 months (but no later than 36 months) of single agent asciminib will be offered the addition of a low dose tyrosine kinase inhibitor (low-TKI) namely dasatinib, imatinib, or nilotinib at the investigator's discretion. The following doses of the TKIs will be used:
1. Dasatinib 50 mg daily 2. Imatinib 300 mg daily 3. Nilotinib 300 mg daily
Patients will discontinue study treatment if they experience disease progression, or unacceptable toxicity.
Age ≥18 years old
Willing and able to give informed consent
Newly diagnosed with CML in chronic phase within 6 months from confirmed diagnosis via bone marrow biopsy/aspirate and have either the b3a2 (e14a2) or b2a2 (e13a2) variants that give rise to the p210 BCR::ABL1 protein. Subtype classification whether b3a2 (e14a2) or b2a2 (e13a2) is not required for study eligibility.
Minimal prior CML therapy with a TKI for less than or equal to 30 days. Treatment with hydroxyurea, busulfan, anagrelide or other non-specific chemotherapy agents is allowed with no time restrictions within the eligible time from diagnosis.
Patients with accelerated or blast phase CML (refer to appendix 4)
Active second malignancy requiring active treatment
History of recent (within 12 months) acute pancreatitis or chronic pancreatitis
Subjects who have previously received treatment with asciminib.
Single group
Single Agent Asciminib
Drugtaken orally once a day starting cycle 1 day 1 for up to 24 months during the single agent asciminib phase. Asciminib is a potent allosteric inhibitor of BCR::ABL1.
Low TKI
Combination productLow dose tyrosine kinase inhibitor (lowTKI) (dasatinib 50 mg daily or imatinib 300 mg daily or nilotinib 300 mg daily) at investigators discretion, may be added to asciminib in the following situations: * Patients who have treatment failure at any time based on ELN criteria (Appendix 7) * Patients who have a warning response after 12 months of single agent asciminib based on ELN criteria (Appendix 7) * Patients who have not achieved MR4.5 after 24 months, but no later than 36 months, of single agent asciminib.
Elective Free Treatment
Other interventionOnce central eligibility has been obtained the patient should discontinue asciminib and if applicable lowTKI within 14 days.
Primary Outcome Measure 1: Deep Molecular Response
The proportion of patients achieving BCR::ABL1 \<0.01% IS (MR4.0) within 12 months of treatment with single agent asciminib
Digital Droplet PCR
Digital droplet PCR (ddPCR). Our Consortium work in the LAST study showed that ddPCR is more sensitive than conventional PCR and is very important in predicting TFR in detecting BCR::ABL1 in cases without detectable disease by conventional PCR29. Thus, samples taken for BCR::ABL1 monitoring in this trial will also be tested by ddPCR using the Bio-Rad platform. This will allow for a head to head comparison of these two methods.
The rates of BCR::ABL1 IS ≤10%, ≤1% (MR2), ≤0.1% (MMR), ≤0.01% (MR4), and ≤0.0032% MR4.5
The rates of BCR::ABL1 IS ≤10%, ≤1% (MR2), ≤0.1% (MMR), ≤0.01% (MR4), and ≤0.0032% MR4.5 by 3, 6, 12, 18, and 24 months of therapy
Time to complete hematological response.
Time to complete hematological response (CHR), MR1, MR2, MMR, MR4.0, MR4.5
Duration of MR1, MR2, MMR, MR4.0, MR4.5, and undetectable BCR::ABL1.
Duration of MR1, MR2, MMR, MR4.0, MR4.5, and undetectable BCR::ABL1.
FFS, TFS, EFS, and OS
4\. Failure-free (FFS), transformation-free (TFS), event-free (EFS), and overall (OS) survival.
Adverse Events when low TKI added
The rates of adverse events with asciminib + low dose TKI
Loss of MMR
Evaluate rate of loss of MMR after treatment discontinuation for patients reaching sustained MR4.5 with asciminib and lowTKI 6 and 24 months from stopping therapy
Evaluate the rates of BCR::ABL1
Evaluate the rates of BCR::ABL1 IS ≤10% (MR1), ≤1% (MR2), ≤0.1% (MMR), ≤0.01% (MR4), and ≤0.0032% (MR4.5) by 3, 6, 12, 18, and 24 months of combination therapy for patients who experience treatment failure at any time with asciminib alone
Rate of MR4.5 after addition of low TKI
Evaluate the rate of MR4.5 by 6 and 12 months after addition of lowTKI for patients not in MR4.5 after 24 months of asciminib alone.
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University of Alabama at Birmingham
Lead sponsor
H. Jean Khoury Cure CML Consortium
Collaborator
