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

Official title

A Modular Phase I/II, Open-label, Multi-center Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Immunogenicity, and Preliminary Efficacy of AZD4512 Monotherapy or in Combination With Anticancer Agent(s) in Participants With Acute Lymphoblastic Leukemia

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).

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

Primary outcome measures

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

Secondary outcome measures (12)

• Module 1 (Dose Escalation): Plasma PK parameters of AZD4512 [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 [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) [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) [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) [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) [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) [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) [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) [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 [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 [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 [Time frame: From date of first dose of AZD4512 up until end of study, up to 38 months]

Eligibility criteria

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

• Burkitt lymphoma and leukemia
• Isolated extramedullary disease; Active testicular or CNS (> CNS1) involvement
• Unresolved non-heme toxicities Grade ≥ 2 (except alopecia, stable Grade ≤ 2 neuropathy, vitiligo, endocrine disorders controlled with therapy)
• 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
• 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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Sequential

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 6 centers

• Research Site — Duarte
• Research Site — Jacksonville
• Research Site — Chicago
• Research Site — Iowa City
• Research Site — Franklin
• Research Site — Houston

Spain · 5 centers

• Research Site — Badalona(Barcelona)
• Research Site — Barcelona
• Research Site — Salamanca
• Research Site — Santander
• Research Site — Valencia

South Korea · 4 centers

• Research Site — Seoul
• Research Site — Seoul
• Research Site — Seoul
• Research Site — Seoul

Canada · 2 centers

• Research Site — Vancouver
• Research Site — Toronto

China · 2 centers

• Research Site — Guangzhou
• Research Site — Tianjin

Japan · 2 centers

• Research Site — Bunkyō City
• Research Site — Chūōku

Taiwan · 2 centers

• Research Site — Taichung
• Research Site — Taipei

United Kingdom · 2 centers

• Research Site — Bloomsbury
• Research Site — Manchester

Australia · 1 center

• Research Site — Melbourne

Identifiers

NCT: NCT07109219 · D9891C00001 · 2025-522372-93-00

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗