AZD0486 as Monotherapy in B-cell Acute Lymphoblastic Leukaemia

Study Overview
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Brief Summary
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This is a Phase 1/2, global multicentre, open-label, single-arm, dose escalation and dose optimisation study of AZD0486 to evaluate the safety, tolerability, and efficacy of AZD0486 monotherapy in participants with R/R B ALL who have received ≥ 2 prior lines of therapies. The study will consist of 3 parts. Part A monotherapy dose escalation. Part B dose optimisation. Part C Dose expansion at the recommended phase 2 dose (RP2D)

Official Title
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A Phase 1/2 Study to Evaluate the Safety and Efficacy of AZD0486 in Adolescent and Adult Participants With Relapsed or Refractory B-Cell Acute Lymphoblastic Leukaemia

Conditions
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B-cell Acute Lymphoblastic Leukemia (B-ALL)

Intervention / Treatment
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* Drug: AZD0486


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age: 16 years and older (Part A), 12 years and older (Parts B and C). Participants with CD19+ B-cell Acute Lymphoblastic Leukemia by local lab with: Bone marrow infiltration with >/= 5% blasts Either relapsed or refractory after a minimum of 2 prior therapies or after 1 prior line of therapy if no SOC available option. Philadelphia positive participants are allowed in Part A if intolerant or refractory to TKIs. Eastern Cooperative Oncology Group (ECOG) Performance Status less than or equal to 2 OR Lansky score more or equal to 50%. The above is a summary, other inclusion criteria details may apply. Exclusion Criteria: Active CNS involvement by B-ALL, defined by presence of ALL blasts in CSF (CNS2 and CNS3 criteria). Isolated extramedullary disease relapse. Testicular leukemia History or presence of clinically relevant CNS pathology such as epilepsy, seizure, paresis, aphasia, stroke, severe brain injuries, dementia, Parkinson's disease, cerebellar disease, organic brain syndrome, or psychosis; or prior Grade 4 neurotoxicity with CAR-T or TCE therapy. History of other malignancy (with certain exceptions). Unresolved AEs >/= Grade 2, from prior therapies Prior therapy with TCEs within 4 weeks, CAR T-cell therapy or autologous HSCT within 8 weeks or prior alloSCT within 12 weeks of start of therapy. GVHD requiring immunosuppressive therapy within 3 weeks prior to AZD0486 treatment. The above is a summary, other exclusion criteria details may apply.

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 80 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: Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: The trial will asses AZD0486 IV infusion in monotherapy. Part A will evaluate ascending dose levels of AZD0486 in participants 16-80 years with B-ALL. Part B will select the RP2D through a dose optimization process of safe-declared dose levels in participants with Ph(-) B-ALL aged 12-82 years. Part C will expand the RP2D dose level cohort to assess efficacy in a large number of subjects.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A: AZD0486 Dose Escalation<br>Ascending dose level cohorts of AZD0486 in B-ALL participants aged 16-80 years. | Drug: AZD0486<br>* Investigational Product administered via intervenous infusion.<br>|
| Experimental: Part B: Dose Optimization<br>Up to 2 cohorts will evaluated prior declared safe-doses and schedules in order to determine the recommended phase 2 dose (RP2D). Participants will receive AZD0486 IV infusions and randomized in a 1:1 ratio. | Drug: AZD0486<br>* Investigational Product administered via intervenous infusion.<br>|
| Experimental: Part C: Dose Expansion<br>Part C will consist of 1 cohort of participants aged 12-80 years, treated with the optimal dose selected in Part B and receive IV AZD0486 monotherapy. | Drug: AZD0486<br>* Investigational Product administered via intervenous infusion.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A: Frequency of DLTs | DLTs are dose-limiting toxicities as defined in the study protocol | 28 days | 
| Parts A, B, C: Safety Evaluation of AZD0486 | Frequency, severity, and relationship to study drug of AEs and SAEs; dose modifications; changes in physical examination and safety procedures. | From signing of informed consent through study completion, an average of 8 months | 
| Parts B & C: Overall Response Rate (ORR) | The Primary analysis for ORR be conducted in RP2D-treated participants (in Part B and C). | From First dose to end of treatment or data cutoff, whichever comes first, assessed up to 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A: Objective Response Rate (ORR) | Overall response rate (ORR) in the evaluable participant set, defined as proportion of participants who achieve overall response (CR/CRi). | From First dose to end of treatment or data cutoff, whichever comes first, assessed up to 12 months | 
| Parts A, B, C: Duration of response (DoR) | Date of first documented CR/CRi until the date of relapse or death | Up to 36 months | 
| Parts A, B, C: CR rate at any time during the study | CR rate as defined as the percentage of participants achieving CR at any time by NCCN criteria | From first dose until end of study, up to 36 months | 
| Parts A, B, C: Event-free survival (EFS) | Event-free survival is defined as the time from the date of the first dose until the date of a relapse after achieving a CR/ CRi, or death due to any cause. | From first dose until end of study, up to 36 months | 
| Parts A, B, C: Overall survival (OS) | OS measured from first dose of study drug until death | From first dose until end of study, up to 36 months | 
| Parts B & C: Subsequent alloSCT | Number of patients who after achieve CR/CR underwent an alloSCT | From first dose until end of study, up to 24 months | 
| Parts B &C: CR MRD-negative rate | Number of patients who achieve CR MRD-negative by NGS at any time on study | First dose until end of study, up to 24 months | 
| Parts A, B, & C: PK characterization of AZD0486 | Derived PK parameter: AUC | From first dose until end of study, up to 36 months | 
| Parts A, B & C: PK Characterization of AZD0486 | Derived PK parameter: Cmax | From first dose until end of study, up to 36 months | 
| Parts A, B, C: PK Characterization of AZD0486 | Derived PK Parameter: tmax | From first dose until end of study, up to 36 months | 
| Parts A, B, C: PK Characterization of AZD0486 | Derived PK parameter: Ctrough | From first dose until end of study, up to 36 months | 
| Parts A, B, C: PK Characterization of AZD0486 | Derived PK Parameter: t1/2 | Pre-defined intervals from day 1 to day 28 | 
| Parts A, B, C: PK Characterization of AZD0486 | Derived PK Parameter: CL of AZD0486 | From first dose until end of study, up to 36 months | 
| Parts A, B, C: ADA characterization of AZD0486 | Number of participants who develop ADA during study. | First dose up to 36 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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B-cell acute lymphoblastic leukemia, Leukemia, B-lymphocytes, AZD0486