D7400C00006

Adults (generally 18–80; >80 in approved cohorts), biopsy-proven CD19+ measurable B-NHL (DLBCL/FL), ECOG <=2, adequate marrow/renal/hepatic function, prior therapy requirements per RR vs 1L FL cohorts.

1) Age: Subject is between 18 and 80 years at ICF signing; subjects >80 years may enroll in cohorts as determined by SMG approval based on emerging safety data and BOIN guidance. 2) Disease: Biopsy-proven B-NHL per WHO criteria. For this trial, B-NHL includes DLBCL NOS (including protocol-listed subtypes such as PMBCL, T-cell/histiocyte-rich LBCL, transformed indolent lymphoma except Richter’s transformation, HGBL NOS including MYC/BCL2 and/or BCL6 rearranged, and FL grade 3b) or FL grade 1–3. Certain cohorts are designated DLBCL or FL; eligibility is based on most recent biopsy. 3) CD19 positivity: Disease must be CD19-positive (IHC or flow cytometry). Local assessment is acceptable. If previously treated with CD19-targeted therapy, examined biopsy material must be collected after relapse/recurrence. 4) Measurable disease: >=1 measurable disease site by RECIL 2017. 5) Prior therapy by cohort: - RR cohorts: At least 2 prior lines, refractory or relapsed; not candidates for regimens known to provide clinical benefit in B-NHL. CAR T-naive subjects may enroll if they declined, are ineligible, or have no timely CAR T access. - 1L FL cohorts: Biopsy-proven FL grade 1–3a per WHO 2016, stage II–IV, FLIPI 2–5, no prior systemic lymphoma-directed therapy, and requiring treatment by GELF criteria. - Radiation to localized disease before entry is allowed; last radiation dose must not be within 14 days before first AZD0486 dose; subject must have recovered from radiation toxicity. 6) ECOG performance status <=2. 7) Able to understand/comply with protocol and sign informed consent. 8) Adequate bone marrow function: - ANC >=1000/mm3 - Platelets >=50,000/mm3 - Hemoglobin >=8.0 g/dL Transfusion/growth factor support is permitted before assessment, but counts must be stable >=72 hours after transfusion/growth factor; if long half-life growth factor used (eg, peg-GCSF), corresponding count stability >=7 days. 9) Renal function: eGFR >=50 mL/min (MDRD). 10) Hepatic function: Total bilirubin <1.5 x ULN (or <3 x ULN for known Gilbert’s syndrome); AST/ALT <=3 x ULN (or <5 x ULN for known Gilbert’s syndrome).

Active CNS lymphoma, leukemic presentation, severe prior CRS/ICANS with TCE/CAR-T, recent investigational/anticancer therapy or transplant within restricted windows, uncontrolled infection/comorbidity, pregnancy/breastfeeding.

1) Another malignancy whose natural history/treatment may interfere with safety or efficacy assessment (non-interfering prior/concurrent malignancy may be eligible). 2) Active CNS involvement by B-NHL (distant, adequately treated CNS history with no recurrence within 6 months may be eligible). 3) History of leukemic presentation (>5000 circulating lymphoma cells/µL). 4) Clinically significant CNS pathology (eg, epilepsy/seizure/stroke/paresis/aphasia/severe brain injury/dementia/neurodegenerative disorder/organic brain syndrome/psychosis/severe mental illness). 5) CNS involvement from active or history of autoimmune disease. 6) Prior Grade >=3 CRS (ASTCT) after prior T-cell engager or CAR T-cell therapy. 7) Prior Grade >=2 neurotoxicity/ICANS (ASTCT) after prior T-cell engager or CAR T-cell therapy. 8) Another investigational drug within 5 x half-life of that agent or within 28 days of enrollment (whichever is shorter). 9) Peripheral autologous SCT within 12 weeks, or allogeneic SCT within 1 year before first dose, or SCT with ongoing immunosuppression. 10) CD19 CAR T therapy within 3 months before first dose. 11) Chronic immunosuppressive therapy required (including steroids >10 mg prednisone/day), with only protocol-allowed short corticosteroid course; required washout of immunosuppressive therapy 14 days or 5 half-lives (whichever shorter). 12) Medical/psychiatric condition that places subject at unacceptable risk or interferes with study/safety interpretation (examples include significant bleeding history, major psychiatric illness, active alcoholism, active GVHD, known allergy/hypersensitivity to study drug components). 13) Any cancer therapy (radiation, chemotherapy, biologics, cellular therapy) or major surgery within 14 days (or within 5 half-lives of anticancer drug), whichever is shorter; protocol allows RR debulking chemotherapy outside this washout for bulky disease risk mitigation. 14) Known serious active infection requiring treatment (may become eligible after treatment completion and symptom resolution per investigator judgment). 15) HIV, chronic/active HBV, or HCV, except protocol-allowed controlled/cured cases: - HIV on effective ART with undetectable viral load within 6 months may be eligible. - Chronic HBV with undetectable viral load on suppressive therapy, or documented cure (HBsAg negative), may be eligible. - HCV with documented cure (undetectable HCV RNA 24 weeks after end of treatment) may be eligible. 16) Major cardiac abnormalities (eg, uncontrolled angina, unstable life-threatening arrhythmias, MI <=12 weeks before screening, NYHA class >=3 CHF, severe cardiac insufficiency, persistent QTcF >480 msec). 17) Female subject pregnant or breastfeeding. 18) Unresolved AEs >=Grade 2 (CTCAE v5.0) from prior anticancer therapy, except protocol-listed exceptions (eg, alopecia; certain neuropathy/anemia/thrombocytopenia conditions). 19) Irreversible toxicity not reasonably expected to worsen with study drugs may be included only after Medical Monitor consultation.