B-cell Acute Lymphoblastic Leukemia (B-ALL)
Conditions
Keywords
B-cell acute lymphoblastic leukemia, Leukemia, B-lymphocytes, AZD0486
Brief summary
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)
Detailed description
This dose escalation and optimization study is evaluating the safety, tolerability, PK, PD and clinical activity of AZD0486 monotherapy in r/r B-ALL.
Interventions
DRUGAZD0486
Investigational Product administered via intravenous infusion.
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
The trial will assess AZD0486 IV infusion in monotherapy. Part A will evaluate ascending dose levels of AZD0486 in participants 12 years and above with B-ALL. Part B will evaluate up to 2 safe-declared dose levels in participants with both Ph(+) and Ph(-) B-ALL aged 12 years and above to select the RP2D. Part C will expand the RP2D dose level cohort to assess efficacy in a large number of subjects.
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age: 12 years and above (Parts A, B and C). * Participants with B-cell Acute Lymphoblastic Leukemia with CD19 expression by local lab with: 1. Bone marrow infiltration with \>/= 5% blasts 2. Either relapsed or refractory after a minimum of 2 prior therapies or after 1 prior line of therapy if no SOC available option. 3. Philadelphia positive participants are allowed in all parts of the study, if intolerant or refractory to TKIs. * For participants older than 16 years, Eastern Cooperative Oncology Group (ECOG) Performance Status less than or equal to 2. For Participants 16 years or younger, 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part A: Frequency of DLTs | Up to 28 days | DLTs are dose-limiting toxicities as defined in the study protocol |
| Parts A & B: Safety Evaluation of AZD0486 | From signing of informed consent through data cutoff, up to 42 months | Frequency, severity, and relationship to study drug of AEs and SAEs; dose modifications; changes in laboratory evaluations; QTc, and vital signs changes. |
| Parts B & C: Rate of CR within 3 cycles | Up to three cycles of 28 days each | To evaluate the efficacy of AZD0486 based on NCCN response criteria (in Part B and C). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part A,B,C: Rate of CR/CRh and CR/CRh/CRi within 3 cycles | Up to 3 cycles of 28 days each | proportion of participants achieving CR/CRh/CRi within 3 cycles based on NCCN response criteria by investigators (Part A) based on the response evaluable population, and by central review confirmation (Parts B and C) based on the FAS. |
| Parts A, B, C: Rate of CR, CR/CRh and CR/CRh/CRi at any time during the study | From first dose to end of treatment or data cutoff, whichever comes first, assessed up to 42 months | Rate of CR, CR/CRh and CR/CRh/CRi at any time during study (Best CR, best CR/CRh and best CR/CRh/CRi) |
| Parts A, B, C: Duration of CR, CR/CRh and CR/CRh/CRi | From first dose to last progression or data cutoff, whichever comes first, assessed up to 42 months | the time from the date of first documented CR, CR/CRh, or CR/CRh/CRi response, respectively, until the date of documented relapse or death due to any cause in the absence of disease progression or relapse, whichever occurs earlier. |
| Parts A, B, C: Event-free survival (EFS) | From First dose to last progression or data cutoff, whichever comes first, assessed up to 42 months | 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/CRh/CRi, or death due to any cause, whichever occurs first. |
| Parts A, B, C: Overall Survival (OS) | From First dose to data cutoff, up to 42 months | The OS is defined as the time from date of first dose until death due to any cause regardless of whether the participant withdraws from treatment or receives a TTNT. |
| Parts A, B, C: ADA characterization of AZD0486 | From First dose to EOT, up to 42 months | Summary of pre-existing and treatment-induced ADAs for AZD0486 (positive or negative, titres) |
| Part A, B, C:MRD-negative rate of CR | From First dose to data cutoff, up to 42 months | To evaluate the impact of AZD0486 on MRD-negative rate of CR, CR/CRh and CR/CRi |
| Parts A, B, & C: PK characterization of AZD0486 | From first dose to data cutoff, up to 42 months | Derived PK parameter: AUC |
| Parts A, B & C: PK Characterization of AZD0486 | From first dose to data cutoff, up to 42 months | Derived PK parameter: Cmax |
| Parts A, B, C: PK Characterization of AZD0486 | From first dose to data cutoff, up to 42 months | Derived PK Parameter: tmax |
| Parts B &C: Subsequent alloSCT or donor lymphocyte infusion if used as an alloSCT substitute | From first dose to EOT, up to 42 Months | Percentage of participants who received a subsequent alloSCT, or DLI if used as an alloSCT substitute, post AZD0486 treatment |
| Part C: Safety Evaluation of AZD0486 | From signing of informed consent through completion of study treatment, an average of 6 months | Frequency, severity, and relationship to study drug of AEs and SAEs; dose modifications; changes in laboratory evaluations; QTc, and vital signs changes. |
| Part A: Rate of CR within 3 cycles | Up to 3 cycles of 28 days each | the percentage of participants with a best response of CR within 3 cycles based on NCCN response criteria by investigators |
Countries
Australia, Brazil, Canada, China, France, Germany, Italy, Japan, South Korea, Spain, Taiwan, United Kingdom, United States
Contacts
Primary ContactAstraZeneca Clinical Study Information Center
Outcome results
None listed