A Phase I Study of Oral Asciminib (ABL001) in Patients With CML or Ph+ ALL

Study Overview
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Brief Summary
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The design of a phase I, open label, dose finding study was chosen in order to establish a safe and tolerated dose of single agent ABL001 in CML and Ph+ ALL patients who are relapsed or refractory to or are intolerant of TKIs, and of ABL001+Nilotinib, ABL001+Imatinib and ABL001+Dasatinib in Ph positive CML patients who are relapsed or refractory to TKIs.

Detailed Description
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This first-in-human trial with ABL001 is a dose escalation study whose primary purpose is to estimate the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE) of single agent ABL001 in CML or Ph+ ALL patients, and in combination with either Nilotinib or Imatinib or Dasatinib in Ph positive CML patients. The safety, tolerability and pharmacokinetic (PK) profile of ABL001 and ABL001+Nilotinib, ABL001+Imatinib and ABL001+Dasatinib will be assessed together with an evaluation of pharmacodynamic (PD) changes in peripheral blood mononuclear cells (PBMC) and bone marrow aspirates and all data may contribute to the assessment of the RDE. An understanding of the MTD/RDE, safety profile, PK/PD relationship, and preliminary evidence of anti-CML and ALL activity will be used to inform future development in adults with CML and Ph+ ALL. By virtue of its distinct pharmacological profile and by preclinical pharmacological studies demonstrating an additive effect, a combination of ABL001 and a tyrosine-kinase inhibitor (TKI) has the potential to achieve a deeper molecular response in a higher proportion of CML patients as compared to single agent TKI therapy. Such a combination has the added advantage of targeting the ABL kinase domain at two distinct locations, theoretically preventing single point mutation-associated treatment resistance. The prediction is that a nilotinib+ABL001, imatinib+ABL001 and/or dasatinib+ABL001 combination will increase the percentage of patients who achieve a complete molecular response (CMR) and decrease the time to CMR, thereby increasing the possibility of achieving sustained treatment-free remissions in these patients. In addition, some patients may be intolerant of therapy with TKIs or may develop mutations that promote resistance to TKI therapy. In these patients, ABL001 may provide a novel therapeutic option.

Official Title
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A Phase I, Multicenter, Open-label Study of Oral ABL001 in Patients With Chronic Myelogenous Leukemia (CML) or Philadelphia Chromosome-positive Acute Lymphoblastic Leukemia (Ph+ ALL)

Conditions
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Chronic Myelogenous Leukemia, Philadelphia Chromosome-positive Acute Lymphoblastic Leukemia

Intervention / Treatment
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* Drug: Asciminib (ABL001)
* Drug: Nilotinib
* Drug: Imatinib
* Drug: Dasatinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: For CML patients either: a. Patients with Ph+ CML in chronic or accelerated phase who were previously treated with at least two different tyrosine kinase inhibitors prior to study entry and are relapsed, refractory to or intolerant of TKIs as determined by investigators or b. Patients with CML in chronic or accelerated phase who exhibit relapsed disease associated with the presence of the T315I gatekeeper mutation after at least one TKI are also eligible provided that no other effective therapy exists For ALL and CML-BP patients: Patients with CML BP or Ph+ ALL who have a cytopathologically confirmed diagnosis and are relapsed or refractory to at least one prior TKI or intolerant of TKIs. TKI failure for Ph+ ALL and CML-BP patients is defined as at least the loss of Molecular Response (MR) 4.5 (BCR-ABL ≤ 0.0032%) Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2 Willingness and ability to comply with all study procedures Written informed consent obtained prior to any screening procedures Exclusion Criteria: Wash-out period: Systemic antineoplastic therapy (including cytotoxic chemotherapy, alfa-interferon and toxin immunoconjugates) or any experimental therapy within 14 days or 5 half-lives, whichever is shorter, before the first dose of study treatment Therapy with TKIs as single agent within 5 half-lives before the first dose of study treatment Unconjugated monoclonal antibody therapies within 28 days or 5 half-lives, whichever is shorter, before the first dose of study treatment For patients receiving ABL001 in combination with either nilotinib or imatinib or dasatinib, intolerance to nilotinib, imatinib or dasatinib, respectively Radiotherapy with a wide field of radiation within 4 weeks or radiotherapy with a limited field of radiation for palliation within 1 week of the first dose of study treatment. CNS irradiation for meningeal leukemia, except if radiotherapy occurred > 3 months previously. At least four weeks must have elapsed since prophylactic CNS irradiation given as part of a front-line therapy regimen for ALL Major surgery within 2 weeks before the first dose of study treatment Other protocol-defined inclusion/exclusion criteria may apply

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Asciminib in CML patients<br>Dose escalation study to estimate the MTD and/or RDE of asciminib in adult patients with CML | Drug: Asciminib (ABL001)<br>* Asciminib will be administered orally in a dose escalation schedule.<br>* Other names: ABL001;|
| Experimental: Asciminib+Nilotinib in CML patients<br>Dose escalation study to estimate the MTD and/or RDE of asciminib in combination with Nilotinib in adult CML patients | Drug: Asciminib (ABL001)<br>* Asciminib will be administered orally in a dose escalation schedule.<br>* Other names: ABL001;Drug: Nilotinib<br>* Asciminib and Nilotinib will be administered orally in CML patients<br>|
| Experimental: Asciminib in Ph+ ALL patients<br>Dose escalation study to estimate the MTD and/or RDE of asciminib in adult patients with Ph positive ALL patients | Drug: Asciminib (ABL001)<br>* Asciminib will be administered orally in a dose escalation schedule.<br>* Other names: ABL001;|
| Experimental: Asciminib+Imatinib in CML patients<br>Dose escalation study to estimate the MTD and/or RDE of asciminib in combination with imatinib in adult CML patients | Drug: Asciminib (ABL001)<br>* Asciminib will be administered orally in a dose escalation schedule.<br>* Other names: ABL001;Drug: Imatinib<br>* Asciminib and imatinib will be administered orally in CML patients<br>|
| Experimental: Asciminib+dasatinib in CML patients<br>Dose escalation study to estimate the MTD and/or RDE of asciminib in combination with dasatinib in adult CML patients | Drug: Asciminib (ABL001)<br>* Asciminib will be administered orally in a dose escalation schedule.<br>* Other names: ABL001;Drug: Dasatinib<br>* Asciminib and dasatinib will be administered orally in CML patients<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of dose limiting toxicities (DLTs) during the first cycle of study treatment | Determine the MTD and/or RDE of ABL001 as single agent in CML and Ph+ ALL, and in combination with either nilotinib or imatinib or dasatinib in CML patients | First Cycle is 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hematologic Response |  | At screening and first day of cycle 2 and 3 and every 12 weeks afterwards | 
| Cytogenetic response |  | at screening or when a patient's BCR-ABL ratio has risen to >1% | 
| BCR-ABL transcript level |  | At screening and first day of cycle 2 and 3 and every 12 weeks afterwards | 
| Cmax of ABL001 as measured in plasma |  | Cycle 1 days 1,2,8,15,16 and 22. Cycle 2 days 1 and 2, and subsequent cycles at the begining of each cycle up to cycle 6. | 
| Cmin of ABL001 as measured in plasma |  | Cycle 1 days 1,2,8,15,16 and 22. Cycle 2 days 1 and 2, and subsequent cycles at the begining of each cycle up to cycle 6. | 
| AUCinf of ABL001 as measured in plasma |  | Cycle 1 days 1,2,8,15,16 and 22. Cycle 2 days 1 and 2, and subsequent cycles at the begining of each cycle up to cycle 6. | 
| AUClast of ABL001 as measured in plasma |  | Cycle 1 days 1,2,8,15,16 and 22. Cycle 2 days 1 and 2, and subsequent cycles at the begining of each cycle up to cycle 6. | 
| AUCtau of ABL001 as measured in plasma |  | Cycle 1 days 1,2,8,15,16 and 22. Cycle 2 days 1 and 2, and subsequent cycles at the begining of each cycle up to cycle 6. | 
| T1/2 of ABL001 as measured in plasma |  | Cycle 1 days 1,2,8,15,16 and 22. Cycle 2 days 1 and 2, and subsequent cycles at the begining of each cycle up to cycle 6. | 
| Adverse events |  | Collected from screening visit through post-treatment follow-up period | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CML, Ph+ ALL