A phase 1, dose-escalation, open-label study, evaluating the safety and tolerability of ZI-MA4-1, a TCR-NK cell therapy, in HLA A*02:01 positive patients with inoperable, locally advanced, or metastatic MAGE-A4 expressing solid malignancies
Ovarian cancer, squamous non-small-cell lung cancer, synovial sarcoma, head and neck cancer.
This is an open-label, first-in-human, Phase 1 dose-escalation study (3+3 design) evaluating the safety and tolerability of ZI-MA4-1, an allogeneic TCR-NK cell therapy, in patients with advanced solid tumours. There are no randomised treatment arms. All participants receive lymphodepleting chemotherapy consisting of cyclophosphamide (300 mg/m²/day) and fludarabine (30 mg/m²/day), administered intravenously prior to study treatment. ZI-MA4-1 is administered intravenously in three doses on Days 1, 4 and 8 of Cycle 1. Dose levels are evaluated sequentially in a 3+3 dose-escalation design to determine the maximum tolerated dose and/or recommended Phase 2 dose. An optional second treatment cycle may be administered following safety review. Participants are hospitalised during the dosing period for monitoring. The primary evaluation period includes a dose-limiting toxicity (DLT) assessment window through Day 28 of Cycle 1. Participants are subsequently followed for response and safety for up to 2 years after first dose, with long-term follow-up for up to 5 years. No randomisation is performed in this study.
Pre-Screening Inclusion Criteria 1. Participant has signed the Pre-Screening ICF 2. Participant is HLA-A*02:01 positive (assessed by the hospital’s own laboratory vendor) 3. Participant’s tumour(s) show expression of the MAGE-A4 protein of ≥30% tumour cells at ≥2+ intensity (assessed by sponsors central lab) 4. Participant meets, or is expected to comply with all Screening Inclusion Criteria Screening Inclusion Criteria (Part A and Part B) 5. Participant must be capable of giving signed informed consent as described in Section 10.3 which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. 6. 18 to ≤75 years of age, at the time of signing the informed consent. 7. Histopathological or cytological diagnosis of inoperable Locally Advanced or Metastatic malignant disease: ovarian cancer, squamous non-small cell lung cancer (NSCLC), synovial sarcoma or head and neck cancer. 8. No approved therapy with demonstrated clinical benefit is indicated or available to treat the patients, or the patient is intolerant of or has refused standard of care therapy. Patients should not have been withdrawn from any treatment (considered necessary for the clinical management of the patient) with the only purpose being fulfilling the study eligibility criteria. 9. Patients must have documented imaging confirmed disease progression while on or within 6 months after the end of the most recent therapy. 10. Patients must have received ≥2 prior lines of cancer therapy except for patient with synovial sarcoma for whom ≥1 prior lines of cancer therapy are required. 11. Patients have measurable disease according to RECIST v1.1 criteria. 12. An ECOG PS of 0 or 1 with no deterioration over the previous 2 weeks, and an anticipated life expectancy of >3 months following lymphodepletion. 13. Adequate haematological, renal, and hepatic function within 7 days of the start of lymphodepletion 14. Patients must not have evidence of
Pre-Screening Exclusion Criteria 1. Participant currently meets, or is expected to meet, any of the Main Exclusion Criteria. Screening Exclusion Criteria (Part A and Part B) 1. Patients have received any prior cellular or gene therapy. 2. Receiving experimental investigational products within 4 weeks of lymphodepletion. 3. Recent therapies prior to lymphodepletion including: a. Within 4 weeks or 5 half‑lives (whichever is longer) of the start of lymphodepletion: biologic agents (such as monoclonal antibodies including marketed drugs), anti-cancer immunotherapy including monoclonal antibodies against PD-1 receptor or ligand. b. Within 4 weeks of lymphodepletion: Bone/soft tissue directed palliative radiotherapy, c. Within 3 weeks of lymphodepletion: Cytotoxic chemotherapy or loco-regional therapy, liver directed radiation therapy within 3 months. d. Within 2 weeks of lymphodepletion: Systemic corticosteroids, other types of radiotherapy not stated above, or any other immunosuppressive therapy. e. Any other therapy, which in the opinion of the investigator presents as a contra indication to lymphodepletion. f. Treatment with biologic agents (such as monoclonal antibodies including marketed drugs) within 4 weeks or 5 half‑lives (whichever is longer) of the start of lymphodepletion in this study. 4. Residual toxicities ≥2 CTCAE grade due to prior therapy, that in the opinion of the investigator may interfere with study conduct. 5. Patients have had any other active malignancy besides the tumour under study within 3 years prior to screening except for in situ removal of basal cell carcinoma or adequately treated cervix carcinoma in-situ. 6. Active or documented history of autoimmune disease or any other diseases requiring immunosuppressive therapy or corticosteroid therapy (defined as >10 mg/day prednisone or equivalent). Physiological replacement, topical, and inhaled steroids are permitted. 7. Significant CNS disorders including Uncontrolled seizures and CNS meta