D7405C00001 (SYRUS)

CD19+ R/R B-ALL (Ph+/Ph−), age ≥12 (weight rules if <16), ≥2 prior lines or 1 prior line with no suitable standard option, ECOG ≤2/Lansky ≥50, adequate hepatic/renal/cardiac function, prior therapy washout met, contraception/pregnancy rules met.

1. Capable of giving signed informed consent as described in Appendix A3, including compliance with ICF/protocol requirements. 2. For participants <18 years: participant and/or legal representative reviewed information/ICF, questions answered, and signed written informed consent. 3. Provision of signed/dated Optional Genetic Research Information consent before optional genetic sample collection. 4. Age at consent: a) Part A only: 16–80 years for dose-escalation cohorts; ≥12 years for backfills. If ≥16 years, body weight ≥40 kg; if ≥12 and <16 years (backfills), body weight ≥30 kg. b) Parts B and C: ≥12 years. If <16 years, body weight ≥30 kg; if ≥16 years, body weight ≥40 kg. 5. Known relapsed/refractory B-ALL with CD19 expression (WHO 2016/NCCN framework), including: a) Morphologic/immunophenotypic evidence of blasts with CD19 expression in peripheral blood or bone marrow by local flow cytometry in current relapse, documented in medical record. b) ≥5% lymphoblasts in bone marrow. • If peripheral blasts >15,000/µL or marrow blasts >50%, pre-phase dexamethasone ± vincristine allowed for disease control; must have <15,000/µL peripheral blasts before C1D1. c) All parts enroll both Ph(+) and Ph(−) B-ALL. 6. At least 2 prior lines with refractory/relapsed disease, or 1 prior line with refractory/relapsed disease plus not eligible/no other standard option. a) Ph(+) B-ALL eligible if TKI-intolerant, had TKI contraindications, or had R/R despite ≥2 different TKIs. b) For Parts B/C, participants refractory to CD19-directed therapies may be limited to ~50% of cohort. Refractory definition includes: • No CR after CD19 CAR-T or relapse within 12 weeks after CD19 CAR-T. • No CR after ≥2 cycles blinatumomab. • Progression/relapse within 8 weeks after last blinatumomab infusion. c) Participant should not be a candidate for any other approved available treatment option. d) Refractory relapse = lack of CR/CRi after salvage treatment. If peripheral blasts >15,000/µL or marrow blasts >50%, pre-phase dexamethasone ± vincristine allowed; must have <15,000/µL peripheral blasts or <50% marrow blasts prior to C1D1. 7. ECOG performance status ≤2 for participants >16 years; participants ≤16 years require Lansky score ≥50%. 8. Washout/timing: prior TCE >4 weeks; prior inotuzumab/ADCs >3 weeks; prior CAR-T or auto-SCT >8 weeks; prior alloSCT >12 weeks; and no immunosuppressive therapy for acute/chronic GVHD within 3 weeks before AZD0486. 9. Adequate liver function: a) Total bilirubin <1.5×ULN (or <3×ULN if Gilbert’s syndrome). b) AST/ALT ≤3×ULN (or <5×ULN if known/suspected liver infiltration). 10. Adequate renal function: a) ≥18 years: CrCl (Cockcroft-Gault) or eGFR (MDRD/CKD-EPI) ≥45 mL/min/1.73m². b) <18 years: age/sex serum creatinine thresholds (per protocol table) or CrCl/eGFR ≥70 mL/min/1.73m². 11. Adequate cardiac function: LVEF ≥45%. 12. Non-hematologic toxicity from prior therapy (except alopecia) resolved to Grade ≤2; prior neurotoxicity or CRS fully resolved. 13. Reproductive criteria: a) Negative serum pregnancy test within 72 hours before study treatment in women of childbearing potential. b) Male participants: barrier contraception throughout study and 90 days after last dose; no sperm donation/banking in same period. c) Female participants: either non-childbearing potential or use protocol-defined highly effective contraception throughout study and 90 days after last dose; monthly pregnancy testing as specified.

Exclude isolated extramedullary relapse, Burkitt, active CNS/testicular ALL, major uncontrolled infection/comorbidity, severe cardiac risk, unresolved significant toxicity, prohibited recent therapy/study exposure, pregnancy/breastfeeding.

1. Isolated extramedullary disease relapse. 2. Burkitt’s lymphoma/leukaemia. 3. Active CNS ALL (CNS2/CNS3). CNS relapse at relapse time is not eligible for Parts A/B; may be eligible for Part C if CNS disease successfully treated and CNS1 confirmed on 2 CSF evaluations ≥1 week apart after CNS therapy. 4. Testicular involvement with ALL. 5. Clinically relevant CNS pathology (eg epilepsy, seizure, paresis, aphasia, stroke, severe brain injury, dementia, Parkinson’s, cerebellar disease, organic brain syndrome, psychosis) or other condition judged high risk/interfering with safe study conduct/results. (Down syndrome not excluded.) 6. Autoimmune disease with potential CNS involvement or current autoimmune disease. 7. Prior Grade 4 neurotoxicity with CAR-T or TCE therapy. 8. Other malignancy whose natural history/treatment may interfere with AZD0486 safety/efficacy assessment (exceptions per protocol). 9. Active infection requiring systemic therapy, including COVID-19 not fully resolved per protocol testing requirements; known/suspected chronic active EBV; known history of HLH; autoimmune diseases as specified. 10. HIV infection, or chronic/active HBV/HCV (with protocol-specified exceptions for controlled HIV, resolved/undetectable HBV/HCV conditions). 11. Major cardiac abnormalities (eg uncontrolled angina, unstable life-threatening arrhythmias, MI ≤12 weeks, NYHA ≥3 CHF, severe cardiac insufficiency, persistent QTcF >480 ms). 12. Unresolved prior anti-cancer therapy AEs ≥Grade 2 (except specified exceptions such as alopecia/fatigue/peripheral neuropathy, with ≥Grade 3 neuropathy excluded). 13. History/another primary malignancy except protocol-specified allowed categories (curatively treated low-risk disease, adequately treated non-melanoma skin cancer/lentigo maligna, carcinoma in situ, locally non-invasive malignancy under surveillance/hormonal control). 14. Prior TCE within 4 weeks, CAR-T/autologous HSCT within 8 weeks, alloSCT within 12 weeks, or acute/extensive chronic GVHD requiring immunosuppression within 3 weeks before AZD0486. 15. Requires chronic systemic immunosuppressive therapy (per protocol table). 16. Prohibited/insufficiently washed-out cancer chemotherapy per protocol windows (TKIs, vincristine/6-MP/6-TG/oral MTX, certain cytotoxics, asparaginase formulations). 17. Non-CNS radiotherapy within 2 weeks before AZD0486. 18. CNS-directed radiotherapy within 8 weeks before AZD0486. 19. Live attenuated vaccine within 28 days before first study dose. 20. COVID-19 vaccination timing concerns around first AZD0486 dose/DLT period (avoidance recommended by protocol). 21. Participation in another clinical study with study intervention in last 28 days or 5 half-lives (whichever shorter). 22. Currently receiving treatment in another investigational study or <30 days since ending such treatment. 23. Known hypersensitivity to AZD0486 or excipients. 24. Involvement in planning/conduct of this study (AstraZeneca/site staff). 25. Investigator judgment that participant is unlikely to comply with study procedures/restrictions/requirements. 26. Previous enrollment in this study. 27. Currently pregnant, breastfeeding, or intending pregnancy/fathering a child during study or within 90 days after last AZD0486 dose.