Study of Brexucabtagene Autoleucel Plus Dasatinib in Adults With Acute Lymphoblastic Leukemia

Study Overview
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Brief Summary
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To assess the feasibility of oral dasatinib pulses (3 consecutive days per week) during the first month following infusion of brexucabtagene autoleucel (Tecartus) in adults with relapsed or refractory B-cell acute lymphoblastic leukemia.

Official Title
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Phase 1b Study of Brexucabtagene Autoleucel Plus Dasatinib in Adults With Acute Lymphoblastic Leukemia

Conditions
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Lymphoblastic Leukemia

Intervention / Treatment
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* Drug: Dasatinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Relapsed or refractory B-precursor ALL defined as one of the following: Primary refractory disease (>=5% blasts or persistent extramedullary disease following induction therapy) First or later relapse of marrow or extramedullary disease Persistence of MRD defined as detectable ALL by flow cytometry, PCR, or next-generation sequencing Relapsed or refractory disease after allogeneic transplant provided individual is at least 100 days from transplant at time of enrollment Patients with isolated, asymptomatic CNS relapse will be eligible Age >=18 years Eastern cooperative oncology group (ECOG) performance status of 0-2 Adequate renal, hepatic, pulmonary and cardiac function defined as: Creatinine clearance (as estimated by Cockcroft Gault) ≥ 60 cc/min Serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) ≤ 2.5 x upper limit of normal (ULN) Total bilirubin ≤ 1.5 mg/dl, except in individuals with Gilbert's syndrome. Cardiac ejection fraction ≥ 50%, no evidence of clinically significant pericardial effusion, and no clinically significant arrhythmias Baseline oxygen saturation > 92% on room air QTc ≤ 500ms In individuals previously treated with blinatumomab, CD19 tumor expression in bone marrow or peripheral blood by flow cytometry or extramedullary site by IHC or flow cytometry Negative serum or urine beta-HCG test in females of childbearing potential within 3 weeks of enrollment Subjects of childbearing or child fathering potential must be willing to practice birth control from the time of enrollment on this study Page 10 of 83 Version 1.0 dated 27-April-2023 and for six (6) months after receiving the preparative conditioning regimen. Must be able to give informed consent. Legal authorized representative (LAR) is permitted if subject is cognitively able to provide verbal assent. Exclusion Criteria: History of dasatinib intolerance Known sensitivity or allergy to aminoglycosides or any agents/reagents used in this study Blast count > 75% in the bone marrow. History of malignancy other than non-melanoma skin cancer or carcinoma in situ (e.g. cervix, bladder, breast) unless disease free for at least 2 years Presence of CNS-3 disease with neurological changes History or presence of any CNS disorder such as a seizure disorder, cerebrovascular ischemia/hemorrhage with clinical signs or symptoms History of concomitant genetic syndrome such as Fanconi anemia, Kostmann syndrome, Shwachman-Diamond or any known bone marrow failure syndrome History of myocardial infarction, cardiac angioplasty or stenting, unstable angina, or other clinically significant cardiac disease within 12 months of enrollment Primary immunodeficiency Known infection with HIV, hepatitis B (HBsAg positive) or untreated hepatitis C virus Presence of fungal, bacterial, viral, or other infection that is uncontrolled or requiring IV antimicrobials for management. Salvage chemotherapy including TKIs for Ph+ ALL within 1 week prior to enrollment Pregnant or breast feeding Patients with known autoimmune disease requiring the use of systemic immunosuppressive therapy within the last year Corticosteroid therapy within 7 days prior to enrollment Acute or chronic GVHD requiring systemic treatment within 4 weeks prior to enrollment Live vaccine ≤ 4 weeks prior to enrollment Any medical condition that in the judgement of the investigator is likely to interfere with assessment of safety or efficacy of study treatment

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: Dasatinib<br>Oral dasatinib 100mg | Drug: Dasatinib<br>* 3 pulses of oral dasatinib (100 mg daily) beginning on Day 4 (+up to 2 days) for 3 days (with 4 days off), repeated weekly. The weekly 3-day pulse schedule of dasatinib may continue for up to 3 months in subjects who continue to meet the dasatinib eligibility criteria and who do not meet off treatment/off study criteria<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Feasibility of dasatinib pulses | Feasibility of administering oral dasatinib pulses (3 consecutive doses per week) during the first month following Tecartus infusion. Feasibility will be defined as the ability of 8 out of 20 subjects to miss no more than one cycle (defined as one week of at least three consecutive days of dasatinib) within the first month following Tecartus infusion. | 1 month | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety of oral dasatinib pulses | Defined by a description of adverse events and serious adverse events at least possibly related to dasatinib following CAR T cell therapy; it will include an analysis of the sequential toxicity boundaries in that the analysis does not lead to a pause in the study; further defined as no reports of suspected death on study. | 2 years | 
| Overall response rate | The definitions for response are primarily based on the standardized response criteria defined by National Comprehensive Cancer Network (NCCN) Guidelines (NCCN, 2021 v.2). | 3 months | 
| Complete Response (CR) | The definitions for response are primarily based on the standardized response criteria defined by National Comprehensive Cancer Network (NCCN) Guidelines (NCCN, 2021 v.2). | 3 months | 
| MRD-negative Complete Response (CR) | The definitions for response are primarily based on the standardized response criteria defined by National Comprehensive Cancer Network (NCCN) Guidelines (NCCN, 2021 v.2). | 3 months | 
| Duration of CR in responders |  | 2 years | 
| Progression Free Survival (PFS) following Tecartus plus dasatinib | PFS is defined as the time from the start of the investigational therapy to the date of radiographic progression | 2 years | 
| Overall Survival (OS) following Tecartus plus dasatinib | OS is defined as the time from the date of initial disease diagnosis to the date of death from any cause | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Leukemia, CAR T cell therapy, Brexucabtagene Autoleucel, Dasatinib