Frontline Asciminib Combination in Chronic Phase CML

Study Overview
=================
Brief Summary
-----------------
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.

Detailed Description
-----------------
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.

Official Title
-----------------
Frontline Asciminib Combination in Chronic Phase CML

Conditions
-----------------
Chronic Myeloid Leukemia

Intervention / Treatment
-----------------
* Drug: Imatinib
* Drug: Nilotinib 300 mg
* Drug: Dasatinib
* Drug: Asciminib


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male or female patients with diagnosis of CP-CML with cytogenetic confirmation of the Ph+ chromosome [t(9;22)(q34;q11)]. Ph-negative cases or patients with variant translocations who are BCR-ABL1 positive in multiplex PCR 35 will be also considered eligible. ECOG performance status of ≤2. Age ≥ 18 years old (no upper age limit is given) Serum levels of potassium, magnesium, total calcium within the normal limits (≥LLN [lower limit of normal] and ≤ULN [upper limit of normal]). Correction of electrolytes levels with supplements to fulfil enrolment criteria is allowed. AST and ALT ≤2.5 x ULN or 5.0 x ULN if considered due to leukemia Alkaline phosphatase ≤2.5 x ULN unless considered due to leukemia Total bilirubin ≤1.5 x ULN, except known Gilbert disease Serum creatinine ≤2 x ULN Written informed consent prior to any study procedures being performed. Exclusion Criteria: Allogeneic stem cell transplantation Known impaired cardiac function, including any of the following: Congenital long QT syndrome History of or presence of clinically significant ventricular or atrial tachyarrhythmia QTc >450 msec on screening ECG Myocardial infarction within 12 months prior to starting therapy Other clinical significant heart disease (e.g. unstable angina, congestive heart failure) Acute or chronic viral hepatitis with moderate or severe hepatic impairment (Child-Pugh scores >6), even if controlled Other concurrent uncontrolled medical conditions (e.g., active or uncontrolled infections, acute or chronic liver and renal disease) that could cause unacceptable safety risks or compromise compliance with the protocol Impaired gastrointestinal function or disease that may alter the absorption of study drug (e.g., ulcerative disease, uncontrolled nausea, vomiting and diarrhea, malabsorption syndrome, small bowel resection or gastric by-pass surgery) Concomitant medications known to be strong inducers or inhibitors of the CYP450 isoenzyme CYP3A4 Patients who have undergone major surgery ≤2 weeks prior to starting study drug or who have not recovered from side effects of such therapy Patients who are pregnant or breastfeeding or women of reproductive potential not employing an effective method of birth control. Women of childbearing potential must have a negative serum pregnancy test within 14 days of study start. Post-menopausal women must be amenorrheic for at least 12 months in order to be considered of non-childbearing potential. Male and female patients must agree to employ an effective method of birth control throughout the study and for up to 2 weeks following discontinuation of study drug Known diagnosis of human immunodeficiency virus (HIV) infection (HIV testing is not mandatory) Known serious hypersensitivity reactions to asciminib, imatinib, nilotinib or dasatinib Patients with a history of another primary malignancy that is currently clinically significant or currently requires active intervention Patients unwilling or unable to comply with the protocol.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: 5 parallel cohorts
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Asciminib 60mg QD<br>Standard therapy of Imatinib 400 mg QD and asciminib 60 mg QD | Drug: Imatinib<br>* Imatinib 400 mg QD and asciminib 60 mg QD<br>* Other names: Imatinib 400 mg QD and asciminib 60 mg QD;Drug: Asciminib<br>* Asciminib 80 mg QD Monotherapy<br>|
| Experimental: Asciminb 20 mg BID<br>Standard therapy of Nilotinib 300 mg BID and asciminib 20 mg BID | Drug: Nilotinib 300 mg<br>* Nilotinib 300 mg BID and asciminib 20 mg BID or 40 mg QD<br>* Other names: Nilotinib 300 mg BID and asciminib 20 mg BID or 40 mg QD;Drug: Asciminib<br>* Asciminib 80 mg QD Monotherapy<br>|
| Experimental: Asciminib 40 mg QD<br>Standard therapy of Nilotinib 300 mg BID and asciminib 40 mg QD | Drug: Nilotinib 300 mg<br>* Nilotinib 300 mg BID and asciminib 20 mg BID or 40 mg QD<br>* Other names: Nilotinib 300 mg BID and asciminib 20 mg BID or 40 mg QD;Drug: Asciminib<br>* Asciminib 80 mg QD Monotherapy<br>|
| Experimental: Asciminib 80 mg QD<br>Standard therapy of Dasatinib 100 mg QD and asciminib 80 mg QD | Drug: Dasatinib<br>* Dasatinib 100 mg QD and asciminib 80 mg QD<br>* Other names: Dasatinib 100 mg QD and asciminib 80 mg QD;Drug: Asciminib<br>* Asciminib 80 mg QD Monotherapy<br>|
| Experimental: Asciminib 80 mg QD monotherapy<br>Asciminib 80 mg QD as a single agent | Drug: Asciminib<br>* Asciminib 80 mg QD Monotherapy<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| deep molecular response (Rate of MR4) | Achievement of deep molecular response (MR4) throught standardized testing of BCR-ABL-transcript Levels | at month 12 after Start of Standard-Therapy | 
| deep molecular Response (Rate of MR4.5) | Achievement of deep molecular response (MR4.5) throught standardized testing of BCR-ABL-transcript Levels | at month 36 after Start of Standard-Therapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| molecular response (MMR and MR4.5) | Achievement of deep molecular response throught standardized testing of BCR-ABL-transcript levels | at and by 6, 12, 18, 24, 36 and 60 months after Start of Therapy | 
| Adverse Events | Incidence of adverse events grade 1-5 and 3-5 | at and by baseline, 3, 6, 12, 15, 18, 21, 24, 36 and 60 months after Start of Therapy | 
| Progression free survival | Progression free survival at the end of the study | at month 60 after Start of Therapy | 
| Overall survival | Overall survival at the end of the study | at month 60 after Start of Therapy | 
| Maintenance of MR4.5 during Asciminib-monotherapy | Achievement of deep molecular response (MR4.5) throught standardized testing of BCR-ABL-transcript Levels | at month 36 and 60 after Start of Therapy | 
| Achievement and durability of treatment-free remission | Achievement of deep molecular response (MR4) throught standardized testing of BCR-ABL-transcript Levels | months 37 and 60 after Start of Therapy |