An open-label randomised, Phase II trial of datopotamab deruxtecan plus durvalumab versus datopotamab deruxtecan in patients with PDL1-negative metastatic triple-negative breast cancer
Locally advanced or metastatic PD-L1 negative, triple-negative breast cancer
Arm A: Datopotamab deruxtecan 6 mg/kg plus durvalumab 1120 mg on day 1 Q3W, both administered via IV Arm B: Datopotamab deruxtecan only 6 mg/kg on day 1 Q3W, administered via IV Patients will be randomised in a 1:1 manner to receive one of the two above treatment arms via randomisation on the Interactive Response Technology (IRT) system. Once the screening data has been entered on the eCRF and checked by the sponsor, authorisation will be given to the site staff to randomise the patient. Treatment for both arms will continue unless there is evidence of unacceptable toxicity, disease progression, voluntary patient withdrawal or death. Upon completion of the study treatment, patients will enter a follow-up period during which data on cancer therapy, disease status and survival status will be collected. All patients will be followed up for survival every 6 months for a period of 2 years post the last patient treatment discontinuation.
1. Willing and able to provide written informed consent 2. Ability to comply with the protocol 3. Female and male ≥18 years of age 4. Triple-negative disease, defined as tumour cells being: 4.1. Negative for ER with <10% of tumour cells positive for ER on IHC or IHC score (Allred) of ≤3 4.2. Negative for PR with <10% of tumour cells positive for PR on IHC or IHC score (Allred) of ≤3 or PR unknown, and 4.3. Negative for HER2 with 0, 1+ or 2+ intensity on IHC and no evidence of amplification on ISH 5. PDL1 negative, defined as 22C3 CPS<10 6. Patients must have: 6.1. At least one lesion, not previously irradiated, that can be measured accurately at baseline as ≥10 mm in the longest diameter (except lymph nodes which must have short axis ≥ 15mm) with computed tomography (CT) or magnetic resonance imaging (MRI) performed within 28 days prior to randomisation which is suitable for accurate repeated measurements, or 6.2. Lytic or mixed (lytic + sclerotic) bone lesions in the absence of measurable disease as defined above; patients with sclerotic/osteoblastic bone lesions only in the absence of measurable disease are not eligible Patients who cannot be assessed by the CT or MRI should be excluded from the study. 7. Representative formalin-fixed paraffin-embedded (FFPE) breast tumour samples with an associated pathology report from the primary or recurrent cancer that are determined to be available and sufficient for central testing OR tumour accessible for biopsy. 8. ECOG performance status 0-1 9. Adequate haematologic and end-organ function within 28 days prior to the first study treatment defined by the following: 9.1. ANC ≥1500 cells/μL (1.5 x 10e9/L) (without granulocyte colony-stimulating factor support within 2 weeks prior to Cycle 1, Day 1) 9.2. WBC >2500/μL (2.5 x 10e9/L) 9.3. Platelet count ≥100,000/μL (100 x 10e9/L) (transfusion not permitted within 28 days of study medication) 9.4. Haemoglobin ≥9.0 g/dL (90 g/L) with no blood transfusions (packed red blood cells
1. Prior chemotherapy, immunotherapy (including durvalumab) or treatment with PARP inhibitors for advanced or metastatic breast cancer 2. Prior treatment with immune checkpoint inhibitors (eg atezolizumab, pembrolizumab) or DNA topoisomerase I or TROP2- or HER2-targeting ADCs and TROP2 targeted therapy in the (neo)adjuvant setting within 6 months from the end of treatment and randomisation into this study 3. Patients with prior allogeneic stem cell or solid organ transplantation. 4. Patients must not have a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent), or had oral or IV steroids for 14 days prior to the first dose of study drug 5. Administration of a live vaccine within 30 days prior to the first dose of study drug. 6. Active or prior documented autoimmune or inflammatory disorders 7. History of idiopathic pulmonary fibrosis, drug-induced pneumonitis, radiation pneumonitis, organizing pneumonia requiring steroids, or evidence of active pneumonitis on screening chest CT scan. 8. Active infection requiring systemic therapy. 9. History of HIV infection 10. Known active hepatitis infection or hepatitis C. 11. Known history of active tuberculosis 12. Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that, in the investigator’s opinion, gives reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug, may affect the interpretation of the results, render the patient at high risk from treatment complications or interferes with obtaining informed consent. 13. Psychological, familial, sociological, or geographical conditions that do not permit compliance with the study protocol. 14. Concurrent treatment with other experimental drugs or participation in another clinical trial with therapeutic intent within 28 days prior to randomisation. 15. Pregnant and lactating female patients. 16. Ma