Study of AZD4512 Monotherapy or in Combination With Anticancer Agents in Participants With Acute Lymphoblastic Leukemia

Phase 2RecruitingNCT07109219

AstraZeneca83 enrolled

Overview

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).

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.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

B-cell Acute Lymphoblastic Leukemia (B-ALL)

Interventions

AZD4512 monotherapyCOMBINATION_PRODUCT

Patients will receive AZD4512 as monotherapy via intravenous infusion. AZD4512 is an antibody-drug conjugate targeting CD22

Eligibility

Sex: ALLMin age: 12 Years

Medical Language ↔ Plain English

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.

Locations (26)

Research Site

Duarte, California, United States

Outcomes

Primary Outcomes

Module 1 (Dose Escalation): Number of participants with dose-limiting toxicities (DLTs).

DLTs are dose-limiting toxicities as defined in the study protocol.

Time frame: From first dose up to 21 days (DLT period).

Module 1 (Dose Escalation): Frequency, duration and severity of treatment-emergent adverse events (TEAEs), treatment-related adverse events (TRAEs), and serious adverse events (SAEs)

Assessed by the CTCAE criteria version 5.0

Time frame: From date of first dose of AZD4512 up until 30 days post last dose of AZD4512 (on average 6 months)

Module 1 (Dose Escalation): Frequency of dose interruptions, modifications, delays, and discontinuations due to AEs

Time frame: 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

Time frame: 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

To evaluate the efficacy based on NCCN response criteria, measured by ORR (CR/CRh)

Time frame: From date of first dose of AZD4512 up until end of study, up to 38 months

Module 2 (Dose Optimization): Frequency, duration and severity of treatment-emergent adverse events (TEAEs), treatment-related adverse events (TRAEs), and serious adverse events (SAEs)

Assessed by the CTCAE criteria version 5.0

Time frame: From date of first dose of AZD4512 up until 30 days post last dose of AZD4512 (on average 6 months)

Module 2 (Dose Optimization): Frequency of dose interruptions, modifications, delays, and discontinuations due to AEs

Central Contacts

AstraZeneca Clinical Study Information Center

CONTACT

1-877-240-9479 information.center@astrazeneca.com

Data from ClinicalTrials.gov

This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.

Secondary Outcomes

Module 1 (Dose Escalation): Plasma PK parameters of AZD4512

To characterize the PK of AZD4512 as monotherapy in participants with R/R B-ALL.

Time frame: From date of first dose of AZD4512 up until 30 days post last dose of AZD4512 (on average 6 months)

Module 1 (Dose Escalation): Total antibody and total unconjugated payload

To characterize the PK of AZD4512 as monotherapy in participants with R/R B-ALL.

Time frame: From date of first dose of AZD4512 up until 30 days post last dose of AZD4512 (on average 6 months)

Module 1 (Dose Escalation): Area Under Curve (AUC)

To characterize the PK of AZD4512 as monotherapy in participants with R/R B-ALL.

Time frame: From date of first dose of AZD4512 up until 30 days post last dose of AZD4512 (on average 6 months)

Module 1 (Dose Escalation): Peak Plasma Concentration (Cmax)

To characterize the PK of AZD4512 as monotherapy in participants with R/R B-ALL.

Time frame: From date of first dose of AZD4512 up until 30 days post last dose of AZD4512 (on average 6 months)

Module 1 (Dose Escalation): Time to max concentration (Tmax)

To characterize the PK of AZD4512 as monotherapy in participants with R/R B-ALL.

Time frame: From date of first dose of AZD4512 up until 30 days post last dose of AZD4512 (on average 6 months)

Module 1 (Dose Escalation): Half life (T1/2)

To characterize the PK of AZD4512 as monotherapy in participants with R/R B-ALL.

Time frame: From date of first dose of AZD4512 up until 30 days post last dose of AZD4512 (on average 6 months)

Module 1 (Dose Escalation): Clearance (CL)

To characterize the PK of AZD4512 as monotherapy in participants with R/R B-ALL.

Time frame: From date of first dose of AZD4512 up until 30 days post last dose of AZD4512 (on average 6 months)

Module 1 (Dose Escalation): Volume of distribution (Vz)

To characterize the PK of AZD4512 as monotherapy in participants with R/R B-ALL.

Time frame: 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 and percentage of participants who develop anti-drug antibodies (ADAs)

To determine the immunogenicity of AZD4512 as monotherapy in participants with R/R B-ALL.

Time frame: From date of first dose of AZD4512 up until 30 days post last dose of AZD4512 (on average 6 months)

Module 1 (Dose Escalation): Objective Response Rate (ORR): proportion of participants with CR or CRh

To evaluate the preliminary efficacy of AZD4512 as monotherapy in participants with R/R B-ALL \[Ph(-) and Ph(+)\] as defined by NCCN guidelines

Time frame: From date of first dose of AZD4512 up until end of study, up to 38 months

Module 1 (Dose Escalation): Composite Complete Remission (CRc) rate: proportion of participants with CR, CRh, or CRi

To evaluate the preliminary efficacy of AZD4512 as monotherapy in participants with R/R B-ALL \[Ph(-) and Ph(+)\] as defined by NCCN guidelines

Time frame: From date of first dose of AZD4512 up until end of study, up to 38 months

Module 1 (Dose Escalation): Complete Remission (CR) rate

To evaluate the preliminary efficacy of AZD4512 as monotherapy in participants with R/R B-ALL \[Ph(-) and Ph(+)\] as defined by NCCN guidelines

Time frame: From date of first dose of AZD4512 up until end of study, up to 38 months

Module 1 (Dose Escalation): Time to Response (TTR)

To evaluate the preliminary efficacy of AZD4512 as monotherapy in participants with R/R B-ALL \[Ph(-) and Ph(+)\] as defined by NCCN guidelines

Time frame: From date of first dose of AZD4512 up until end of study, up to 38 months

Module 1 (Dose Escalation): Duration of Response (DoR)

\- To evaluate the preliminary efficacy of AZD4512 as monotherapy in participants with R/R B-ALL \[Ph(-) and Ph(+)\] as defined by NCCN guidelines

Time frame: From date of first dose of AZD4512 up until end of study, up to 38 months

Module 1 (Dose Escalation): Event-Free Survival (EFS)

\- To evaluate the preliminary efficacy of AZD4512 as monotherapy in participants with R/R B-ALL \[Ph(-) and Ph(+)\] as defined by NCCN guidelines

Time frame: From date of first dose of AZD4512 up until end of study, up to 38 months

Module 1 (Dose Escalation): Overall Survival (OS)

\- To evaluate the preliminary efficacy of AZD4512 as monotherapy in participants with R/R B-ALL \[Ph(-) and Ph(+)\] as defined by NCCN guidelines

Time frame: From date of first dose of AZD4512 up until end of study, up to 38 months

Module 1 (Dose Escalation): Percentage of participants who receive subsequent allogeneic hematopoietic stem cell transplant (HSCT)

\- To evaluate the preliminary efficacy of AZD4512 as monotherapy in participants with R/R B-ALL \[Ph(-) and Ph(+)\] as defined by NCCN guidelines

Time frame: From date of first dose of AZD4512 up until end of study, up to 38 months

Module 2 (Dose Optimization): Complete Remission (CR) rate

To evaluate the efficacy of AZD4512 as monotherapy in participants with R/R B-ALL \[Ph(-)\] as defined by NCCN guidelines

Time frame: From date of first dose of AZD4512 up until end of study, up to 38 months

Module 2 (Dose Optimization):Composite Complete Remission (CRc) rate: proportion of participants with CR, CRh, or CRi

To evaluate the efficacy of AZD4512 as monotherapy in participants with R/R B-ALL \[Ph(-)\] as defined by NCCN guidelines

Time frame: From date of first dose of AZD4512 up until end of study, up to 38 months

Module 2 (Dose Optimization):Time to Response (TTR)

To evaluate the efficacy of AZD4512 as monotherapy in participants with R/R B-ALL \[Ph(-)\] as defined by NCCN guidelines

Time frame: From date of first dose of AZD4512 up until end of study, up to 38 months

Module 2 (Dose Optimization): Duration of Response (DoR)

To evaluate the efficacy of AZD4512 as monotherapy in participants with R/R B-ALL \[Ph(-)\] as defined by NCCN guidelines

Time frame: From date of first dose of AZD4512 up until end of study, up to 38 months

Module 2 (Dose Optimization):Event-Free Survival (EFS)

To evaluate the efficacy of AZD4512 as monotherapy in participants with R/R B-ALL \[Ph(-)\] as defined by NCCN guidelines

Time frame: From date of first dose of AZD4512 up until end of study, up to 38 months

Module 2 (Dose Optimization): Overall Survival (OS)

To evaluate the efficacy of AZD4512 as monotherapy in participants with R/R B-ALL \[Ph(-)\] as defined by NCCN guidelines

Time frame: From date of first dose of AZD4512 up until end of study, up to 38 months

Module 2 (Dose Optimization): Percentage of participants who receive subsequent allogeneic hematopoietic stem cell transplant (HSCT)

To evaluate the efficacy of AZD4512 as monotherapy in participants with R/R B-ALL \[Ph(-)\] as defined by NCCN guidelines

Time frame: From date of first dose of AZD4512 up until end of study, up to 38 months

Module 2 (Dose Optimization): MRD-negative CR rate, CR/CRh (ORR), CR/CRi/CRh (CRc) rate

To evaluate the impact of AZD4512 on MRD as assessed by NGS (central)

Time frame: From date of first dose of AZD4512 up until end of study, up to 38 months

Module 2 (Dose Optimization): Plasma PK parameters of AZD4512

To characterize the PK of AZD4512 as monotherapy in participants with R/R B-ALL \[Ph(-)\]

Time frame: From date of first dose of AZD4512 up until 30 days post last dose of AZD4512 (on average 6 months)

Module 2 (Dose Optimization): total antibody and total unconjugated payload

To characterize the PK of AZD4512 as monotherapy in participants with R/R B-ALL \[Ph(-)\]

Time frame: From date of first dose of AZD4512 up until 30 days post last dose of AZD4512 (on average 6 months)

Module 2 (Dose Optimization): Area Under Curve (AUC)

To characterize the PK of AZD4512 as monotherapy in participants with R/R B-ALL \[Ph(-)\]

Time frame: From date of first dose of AZD4512 up until 30 days post last dose of AZD4512 (on average 6 months)

Module 2 (Dose Optimzation): Peak Plasma Concentration (Cmax)

To characterize the PK of AZD4512 as monotherapy in participants with R/R B-ALL \[Ph(-)\]

Time frame: From date of first dose of AZD4512 up until 30 days post last dose of AZD4512 (on average 6 months)

Module 2 (Dose Optimization): Time to max concentration (Tmax)

To characterize the PK of AZD4512 as monotherapy in participants with R/R B-ALL \[Ph(-)\]

Time frame: From date of first dose of AZD4512 up until 30 days post last dose of AZD4512 (on average 6 months)

Module 2 (Dose Optimization): Half life (T1/2)

To characterize the PK of AZD4512 as monotherapy in participants with R/R B-ALL \[Ph(-)\]

Time frame: From date of first dose of AZD4512 up until 30 days post last dose of AZD4512 (on average 6 months)

Module 2 (Dose Optimization): Clearance (CL)

To characterize the PK of AZD4512 as monotherapy in participants with R/R B-ALL \[Ph(-)\]

Time frame: From date of first dose of AZD4512 up until 30 days post last dose of AZD4512 (on average 6 months)

Module 2 (Dose Optimization): Volume of distribution (Vz)

To characterize the PK of AZD4512 as monotherapy in participants with R/R B-ALL \[Ph(-)\]

Time frame: From date of first dose of AZD4512 up until 30 days post last dose of AZD4512 (on average 6 months)

Module 2 (Dose Optimization): Summary of of pre-existing and treatment induced ADAs for AZD4512 (positive or negative, titers)

To determine the immunogenicity of AZD4512 as monotherapy in participants with R/R B-ALL \[Ph(-)\]

Time frame: From date of first dose of AZD4512 up until 30 days post last dose of AZD4512 (on average 6 months)