B-cell Acute Lymphoblastic Leukemia (B-ALL)
Conditions
Keywords
Acute lymphoblastic leukemia (B-ALL), Dose escalation, Dose optimization, Cluster of differentiation 22 (CD22), Antibody-drug conjugate (ADC)
Brief summary
The study is intended to assess the safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy of AZD4512 in patients with relapsed/refractory B-Cell acute lymphoblastic leukemia (r/r B-ALL).
Detailed description
In this Phase I/II, open-label multi-center study AZD4512 will be administered to adult/young adult patients (Module 1: \>=16 years; Module 2: \>=12 years) with relapsed/refractory B-Cell acute lymphoblastic leukemia (B-ALL). This study will have 2 parts: Module 1 - Dose Escalation and Module 2 - Dose Optimization.
Interventions
COMBINATION_PRODUCTAZD4512 monotherapy
Patients will receive AZD4512 as monotherapy via intravenous infusion. AZD4512 is an antibody-drug conjugate targeting CD22
Sponsors
AstraZeneca
Fortrea
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* 1\. Age: * 16 years old in Module 1 (US only: ≥18year) * 12 years old in Module 2 2\. Diagnosis: Known Diagnosis of CD22-positive B-ALL based on criteria established by WHO (Alaggio et al. 2022). * Participants must have relapsed or refractory B-ALL ('relapsed' defined as bone marrow blasts \> 5% or reappearance of blasts in PB) * Module 1 (DE): Ph(-) B-ALL and Ph(+) B-ALL - R/R * Backfill of Module 1 and Module 2 (DO): R/R Ph(-) B-ALL 3\. Performance status (ECOG ≤ 2; KPS ≥ 50; LPS ≥ 50) 4\. Peripheral lymphoblast count \< 10,000/µL (may receive cytoreduction prior to C1D1 per protocol-specified criteria) 5\. At least 2 prior therapies with refractoriness or relapse, or 1 prior therapy with refractoriness or relapse and no standard options available. Participants who have received prior CD22 targeted therapies are eligible. * Ph+ B-ALL (Module 1 DE only): intolerant to or have contraindications to TKI therapy or R/R disease despite treatment with at least 2 prior TKIs or at least one 3rd generation TKI 6\. Prior DLI \>4 weeks, prior cell therapy or autoHSCT \>8 weeks, alloHSCT \>12 weeks
Exclusion criteria
1. Burkitt lymphoma and leukemia 2. Isolated extramedullary disease; Active testicular or CNS (\> CNS1) involvement 3. Unresolved non-heme toxicities Grade ≥ 2 (except alopecia, stable Grade ≤ 2 neuropathy, vitiligo, endocrine disorders controlled with therapy) 4. History of drug-induced non-infectious ILD/pneumonitis requiring oral or IV steroids or supplemental oxygen or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening 5. Prior/concomitant therapy * Cytotoxic treatment within 14 days (except ALL maintenance medications or cytoreduction) * Biologic (immuno-oncology) treatment within 28 days or 5 half-lives (whichever is shorter) * Non-CNS radiation within 2 weeks \& CNS radiation within 4 weeks * Medications known to prolong QTc and/or associated with Torsades de Pointes within 5 half-lives * Strong inhibitors of CYP 3A4 within 14 days or 5 half-lives (whichever is longer) * Investigational agents or study interventions in the last 30 days or 5 half-lives prior to the first dose of AZD4512 whichever is longer. If the investigational product is an agent to treat B-ALL and meets the modality criteria, then a specific washout period must be adhered to instead.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Module 1 (Dose Escalation): Number of participants with dose-limiting toxicities (DLTs). | From first dose up to 21 days (DLT period). | DLTs are dose-limiting toxicities as defined in the study protocol. |
| Module 1 (Dose Escalation): Frequency, duration and severity of treatment-emergent adverse events (TEAEs), treatment-related adverse events (TRAEs), and serious adverse events (SAEs) | From date of first dose of AZD4512 up until 30 days post last dose of AZD4512 (on average 6 months) | Assessed by the CTCAE criteria version 5.0 |
| Module 1 (Dose Escalation): Frequency of dose interruptions, modifications, delays, and discontinuations due to AEs | From date of first dose of AZD4512 up until 30 days post last dose of AZD4512 (on average 6 months) | — |
| Module 1 (Dose Escalation): Number of participants with clinically significant changes in laboratory values, ECGs, performance status, and vital signs | From date of first dose of AZD4512 up until 30 days post last dose of AZD4512 (on average 6 months) | — |
| Module 2 (Dose Optimization): Overall response rate (ORR) in participants with R/R Ph(-) B-ALL | From date of first dose of AZD4512 up until end of study, up to 38 months | To evaluate the efficacy based on NCCN response criteria, measured by ORR (CR/CRh) |
| Module 2 (Dose Optimization): Frequency, duration and severity of treatment-emergent adverse events (TEAEs), treatment-related adverse events (TRAEs), and serious adverse events (SAEs) | From date of first dose of AZD4512 up until 30 days post last dose of AZD4512 (on average 6 months) | Assessed by the CTCAE criteria version 5.0 |
| Module 2 (Dose Optimization): Frequency of dose interruptions, modifications, delays, and discontinuations due to AEs | From date of first dose of AZD4512 up until 30 days post last dose of AZD4512 (on average 6 months) | — |
| Module 2 (Dose Optimization): Number of participants with clinically significant changes in laboratory values, ECGs, performance status, and vital signs | From date of first dose of AZD4512 up until 30 days post last dose of AZD4512 (on average 6 months) | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Module 1 (Dose Escalation): Plasma PK parameters of AZD4512 | From date of first dose of AZD4512 up until 30 days post last dose of AZD4512 (on average 6 months) | To characterize the PK of AZD4512 as monotherapy in participants with R/R B-ALL. |
| Module 1 (Dose Escalation): Total antibody and total unconjugated payload | From date of first dose of AZD4512 up until 30 days post last dose of AZD4512 (on average 6 months) | To characterize the PK of AZD4512 as monotherapy in participants with R/R B-ALL. |
| Module 1 (Dose Escalation): Area Under Curve (AUC) | From date of first dose of AZD4512 up until 30 days post last dose of AZD4512 (on average 6 months) | To characterize the PK of AZD4512 as monotherapy in participants with R/R B-ALL. |
| Module 1 (Dose Escalation): Peak Plasma Concentration (Cmax) | From date of first dose of AZD4512 up until 30 days post last dose of AZD4512 (on average 6 months) | To characterize the PK of AZD4512 as monotherapy in participants with R/R B-ALL. |
| Module 1 (Dose Escalation): Time to max concentration (Tmax) | From date of first dose of AZD4512 up until 30 days post last dose of AZD4512 (on average 6 months) | To characterize the PK of AZD4512 as monotherapy in participants with R/R B-ALL. |
| Module 1 (Dose Escalation): Half life (T1/2) | From date of first dose of AZD4512 up until 30 days post last dose of AZD4512 (on average 6 months) | To characterize the PK of AZD4512 as monotherapy in participants with R/R B-ALL. |
| Module 1 (Dose Escalation): Clearance (CL) | From date of first dose of AZD4512 up until 30 days post last dose of AZD4512 (on average 6 months) | To characterize the PK of AZD4512 as monotherapy in participants with R/R B-ALL. |
| Module 1 (Dose Escalation): Volume of distribution (Vz) | From date of first dose of AZD4512 up until 30 days post last dose of AZD4512 (on average 6 months) | To characterize the PK of AZD4512 as monotherapy in participants with R/R B-ALL. |
| Module 1 (Dose Escalation): Number and percentage of participants who develop anti-drug antibodies (ADAs) | From date of first dose of AZD4512 up until 30 days post last dose of AZD4512 (on average 6 months) | To determine the immunogenicity of AZD4512 as monotherapy in participants with R/R B-ALL. |
| Module 1 (Dose Escalation): Objective Response Rate (ORR): proportion of participants with CR or CRh | From date of first dose of AZD4512 up until end of study, up to 38 months | To evaluate the preliminary efficacy of AZD4512 as monotherapy in participants with R/R B-ALL \[Ph(-) and Ph(+)\] as defined by NCCN guidelines |
| Module 1 (Dose Escalation): Composite Complete Remission (CRc) rate: proportion of participants with CR, CRh, or CRi | From date of first dose of AZD4512 up until end of study, up to 38 months | To evaluate the preliminary efficacy of AZD4512 as monotherapy in participants with R/R B-ALL \[Ph(-) and Ph(+)\] as defined by NCCN guidelines |
| Module 1 (Dose Escalation): Complete Remission (CR) rate | From date of first dose of AZD4512 up until end of study, up to 38 months | To evaluate the preliminary efficacy of AZD4512 as monotherapy in participants with R/R B-ALL \[Ph(-) and Ph(+)\] as defined by NCCN guidelines |
| Module 1 (Dose Escalation): Time to Response (TTR) | From date of first dose of AZD4512 up until end of study, up to 38 months | To evaluate the preliminary efficacy of AZD4512 as monotherapy in participants with R/R B-ALL \[Ph(-) and Ph(+)\] as defined by NCCN guidelines |
| Module 1 (Dose Escalation): Duration of Response (DoR) | From date of first dose of AZD4512 up until end of study, up to 38 months | \- To evaluate the preliminary efficacy of AZD4512 as monotherapy in participants with R/R B-ALL \[Ph(-) and Ph(+)\] as defined by NCCN guidelines |
| Module 1 (Dose Escalation): Event-Free Survival (EFS) | From date of first dose of AZD4512 up until end of study, up to 38 months | \- To evaluate the preliminary efficacy of AZD4512 as monotherapy in participants with R/R B-ALL \[Ph(-) and Ph(+)\] as defined by NCCN guidelines |
| Module 1 (Dose Escalation): Overall Survival (OS) | From date of first dose of AZD4512 up until end of study, up to 38 months | \- To evaluate the preliminary efficacy of AZD4512 as monotherapy in participants with R/R B-ALL \[Ph(-) and Ph(+)\] as defined by NCCN guidelines |
| Module 1 (Dose Escalation): Percentage of participants who receive subsequent allogeneic hematopoietic stem cell transplant (HSCT) | From date of first dose of AZD4512 up until end of study, up to 38 months | \- To evaluate the preliminary efficacy of AZD4512 as monotherapy in participants with R/R B-ALL \[Ph(-) and Ph(+)\] as defined by NCCN guidelines |
| Module 2 (Dose Optimization): Complete Remission (CR) rate | From date of first dose of AZD4512 up until end of study, up to 38 months | To evaluate the efficacy of AZD4512 as monotherapy in participants with R/R B-ALL \[Ph(-)\] as defined by NCCN guidelines |
| Module 2 (Dose Optimization):Composite Complete Remission (CRc) rate: proportion of participants with CR, CRh, or CRi | From date of first dose of AZD4512 up until end of study, up to 38 months | To evaluate the efficacy of AZD4512 as monotherapy in participants with R/R B-ALL \[Ph(-)\] as defined by NCCN guidelines |
| Module 2 (Dose Optimization):Time to Response (TTR) | From date of first dose of AZD4512 up until end of study, up to 38 months | To evaluate the efficacy of AZD4512 as monotherapy in participants with R/R B-ALL \[Ph(-)\] as defined by NCCN guidelines |
| Module 2 (Dose Optimization): Duration of Response (DoR) | From date of first dose of AZD4512 up until end of study, up to 38 months | To evaluate the efficacy of AZD4512 as monotherapy in participants with R/R B-ALL \[Ph(-)\] as defined by NCCN guidelines |
| Module 2 (Dose Optimization):Event-Free Survival (EFS) | From date of first dose of AZD4512 up until end of study, up to 38 months | To evaluate the efficacy of AZD4512 as monotherapy in participants with R/R B-ALL \[Ph(-)\] as defined by NCCN guidelines |
| Module 2 (Dose Optimization): Overall Survival (OS) | From date of first dose of AZD4512 up until end of study, up to 38 months | To evaluate the efficacy of AZD4512 as monotherapy in participants with R/R B-ALL \[Ph(-)\] as defined by NCCN guidelines |
| Module 2 (Dose Optimization): Percentage of participants who receive subsequent allogeneic hematopoietic stem cell transplant (HSCT) | From date of first dose of AZD4512 up until end of study, up to 38 months | To evaluate the efficacy of AZD4512 as monotherapy in participants with R/R B-ALL \[Ph(-)\] as defined by NCCN guidelines |
| Module 2 (Dose Optimization): MRD-negative CR rate, CR/CRh (ORR), CR/CRi/CRh (CRc) rate | From date of first dose of AZD4512 up until end of study, up to 38 months | To evaluate the impact of AZD4512 on MRD as assessed by NGS (central) |
| Module 2 (Dose Optimization): Plasma PK parameters of AZD4512 | From date of first dose of AZD4512 up until 30 days post last dose of AZD4512 (on average 6 months) | To characterize the PK of AZD4512 as monotherapy in participants with R/R B-ALL \[Ph(-)\] |
| Module 2 (Dose Optimization): total antibody and total unconjugated payload | From date of first dose of AZD4512 up until 30 days post last dose of AZD4512 (on average 6 months) | To characterize the PK of AZD4512 as monotherapy in participants with R/R B-ALL \[Ph(-)\] |
| Module 2 (Dose Optimization): Area Under Curve (AUC) | From date of first dose of AZD4512 up until 30 days post last dose of AZD4512 (on average 6 months) | To characterize the PK of AZD4512 as monotherapy in participants with R/R B-ALL \[Ph(-)\] |
| Module 2 (Dose Optimzation): Peak Plasma Concentration (Cmax) | From date of first dose of AZD4512 up until 30 days post last dose of AZD4512 (on average 6 months) | To characterize the PK of AZD4512 as monotherapy in participants with R/R B-ALL \[Ph(-)\] |
| Module 2 (Dose Optimization): Time to max concentration (Tmax) | From date of first dose of AZD4512 up until 30 days post last dose of AZD4512 (on average 6 months) | To characterize the PK of AZD4512 as monotherapy in participants with R/R B-ALL \[Ph(-)\] |
| Module 2 (Dose Optimization): Half life (T1/2) | From date of first dose of AZD4512 up until 30 days post last dose of AZD4512 (on average 6 months) | To characterize the PK of AZD4512 as monotherapy in participants with R/R B-ALL \[Ph(-)\] |
| Module 2 (Dose Optimization): Clearance (CL) | From date of first dose of AZD4512 up until 30 days post last dose of AZD4512 (on average 6 months) | To characterize the PK of AZD4512 as monotherapy in participants with R/R B-ALL \[Ph(-)\] |
| Module 2 (Dose Optimization): Volume of distribution (Vz) | From date of first dose of AZD4512 up until 30 days post last dose of AZD4512 (on average 6 months) | To characterize the PK of AZD4512 as monotherapy in participants with R/R B-ALL \[Ph(-)\] |
| Module 2 (Dose Optimization): Summary of of pre-existing and treatment induced ADAs for AZD4512 (positive or negative, titers) | From date of first dose of AZD4512 up until 30 days post last dose of AZD4512 (on average 6 months) | To determine the immunogenicity of AZD4512 as monotherapy in participants with R/R B-ALL \[Ph(-)\] |
Countries
Australia, Canada, China, Japan, South Korea, Spain, Taiwan, United Kingdom, United States
Contacts
CONTACTAstraZeneca Clinical Study Information Center
Outcome results
None listed