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Standard therapy of Imatinib 400 mg QD and asciminib 60 mg QD

Standard therapy of Nilotinib 300 mg BID and asciminib 20 mg BID

Standard therapy of Nilotinib 300 mg BID and asciminib 40 mg QD

Standard therapy of Dasatinib 100 mg QD and asciminib 80 mg QD

Imatinib 400 mg QD and asciminib 60 mg QD

Imatinib

Nilotinib 300 mg BID and asciminib 20 mg BID or 40 mg QD

Nilotinib 300 mg

Dasatinib 100 mg QD and asciminib 80 mg QD

Thomas Ernst, Prof. Dr.

Adult male and female patients with newly diagnosed Philadelphia chromosome positive (Ph+) and/or BCR-ABL1 positive CML can be included in the study until 3 months after diagnosis. A \<4 week pretreatment with hydroxyurea is permitted. Patients treated for \<6 weeks with nilotinib 300 mg BID, imatinib 400 mg QD, dasatinib 100 mg QD or without any therapy are eligible for recruitment and will be allocated to the respective cohort. All patients must provide written informed consent to be enrolled in the trial. Cohorts were designed to allow assessment of QD and BID asciminib based combinations to optimize quality of life and compliance. Patients will not be randomized. In general, cohorts will be filled consecutively. Asciminib therapy will be commenced 12 weeks after start of nilotinib, imatinib or dasatinib and after recovery of hematopoiesis or in case of no therapy so far 6 weeks after diagnosis as first line treatment. Referred patients already treated with imatinib, nilotinib or dasatinib will remain on the initial drug and will be allocated to the respective cohort.

Despite the dramatic progress made over the past decade with TKIs in the treatment of CML, allogeneic stem cell transplant remains the only proven curative therapy. To achieve cure or benefit from treatment-free remissions with pharmacologically-based therapies, it is estimated that patients will likely need to achieve a sustained reduction in tumor burden corresponding to a deep molecular response of at least 4 logs (MR4). Currently, only 30.8% of patients achieve a deep molecular response after 12 months of treatment with single agent nilotinib.

The development of the novel and potent BCR-ABL1 allosteric inhibitor, asciminib, presents an opportunity to assess the effect of a different mechanism of inhibition of BCR-ABL1 in the first-line treatment of CML to enhance speed of response and to increase the patient population benefitting from deep molecular response. Dosing a combination of asciminib with an ATP-site inhibitor also has the potential to prevent the emergence of resistance due to point mutations being acquired in one of the binding sites.

The safety, tolerability and pharmacokinetic profile of asciminib as a single agent and in combination with either nilotinib or imatinib or dasatinib was assessed in a phase-I study. At the doses chosen here, all three combination treatments were well tolerated.

Since in all patient cohorts the standard of care therapy will remain the backbone of initial therapy, there is no reason to expect an efficacy problem with the combination therapies.

Frontline Asciminib Combination in Chronic Phase CML

Achievement of deep molecular response (MR4) throught standardized testing of BCR-ABL-transcript Levels

Achievement of deep molecular response (MR4.5) throught standardized testing of BCR-ABL-transcript Levels

Achievement of deep molecular response throught standardized testing of BCR-ABL-transcript levels

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Frontline Asciminib Combination in Chronic Phase CML	NCT03906292	Chronic Myeloid...	Imatinib Nilotinib 300 m... Dasatinib Asciminib	18 Years -	University of Jena
Frontline Asciminib Combination in Chronic Phase CML	NCT03906292	Chronic Myeloid...	Imatinib Nilotinib 300 m... Dasatinib Asciminib	18 Years -	University of Jena

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