Overview
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.
Principal investigator
Eligibility criteria
Inclusion Criteria:
* 1\. Age:
* 16 years old in Module 1
* 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 (BM blasts \>5%) 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 21 days or 5 half-lives (whichever is longer)
* Strong inhibitors of CYP 3A4 within 21 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.
* 1\. Age:
* 16 years old in Module 1
* 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 (BM blasts \>5%) 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 21 days or 5 half-lives (whichever is longer)
* Strong inhibitors of CYP 3A4 within 21 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.
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