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

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

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.

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.