CX-072 (pacmilimab), a Probody PD-L1 inhibitor, in combination with ipilimumab in patients with advanced solid tumors (PROCLAIM-CX-072): a first-in-human, dose-finding study
| العنوان: | CX-072 (pacmilimab), a Probody PD-L1 inhibitor, in combination with ipilimumab in patients with advanced solid tumors (PROCLAIM-CX-072): a first-in-human, dose-finding study |
|---|---|
| المؤلفون: | Ruth Plummer, Rachel E. Sanborn, Fiona C Thistlethwaite, Omid Hamid, Daniel C. Cho, Lawrence Lu, Valentina Boni, Johanna C. Bendell, Mark Stroh, Elisabeth G.E. de Vries, Karen A. Autio, Patrick A. Ott, Javier Garcia-Corbacho |
| المساهمون: | Guided Treatment in Optimal Selected Cancer Patients (GUTS) |
| المصدر: | Journal for Immunotherapy of Cancer Journal for ImmunoTherapy of Cancer, Vol 9, Iss 7 (2021) Journal for immunotherapy of cancer, 9(7):002446. BMC |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | 0301 basic medicine, Male, Cancer Research, Gastroenterology, B7-H1 Antigen, 0302 clinical medicine, Neoplasms, Antineoplastic Combined Chemotherapy Protocols, Immunology and Allergy, Prodrugs, Immune Checkpoint Inhibitors, RC254-282, Clinical/Translational Cancer Immunotherapy, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Antibodies, Monoclonal, Middle Aged, Oncology, Tolerability, Response Evaluation Criteria in Solid Tumors, 030220 oncology & carcinogenesis, Toxicity, Molecular Medicine, Female, immunotherapy, medicine.drug, Adult, CTLA-4 antigen, medicine.medical_specialty, Combination therapy, Immunology, therapies, Ipilimumab, investigational, 03 medical and health sciences, Internal medicine, medicine, Humans, Testicular cancer, Pneumonitis, Aged, Pharmacology, Dose-Response Relationship, Drug, business.industry, medicine.disease, 030104 developmental biology, NIVOLUMAB PLUS IPILIMUMAB, PD-L1 inhibitor, business |
| الوصف: | BackgroundProbody® therapeutics are antibody prodrugs designed to be activated by tumor-associated proteases. This conditional activation restricts antibody binding to the tumor microenvironment, thereby minimizing ‘off-tumor’ toxicity. Here, we report the phase 1 data from the first-in-human study of CX-072 (pacmilimab), a Probody immune checkpoint inhibitor directed against programmed death-ligand 1 (PD-L1), in combination with the anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4) antibody ipilimumab.MethodsAdults (n=27) with advanced solid tumors (naive to PD-L1/programmed cell death protein 1 or CTLA-4 inhibitors) were enrolled in the phase 1 combination therapy dose-escalation portion of this multicenter, open-label, phase 1/2 study (NCT03013491). Dose-escalation pacmilimab/ipilimumab followed a standard 3+3 design and continued until the maximum tolerated dose (MTD) was determined. Pacmilimab+ipilimumab was administered intravenously every 3 weeks for four cycles, followed by pacmilimab administered every 2 weeks as monotherapy. The primary objective was identification of dose-limiting toxicities and determination of the MTD. Other endpoints included the rate of objective response (Response Evaluation Criteria In Solid Tumors v.1.1).ResultsTwenty-seven patients were enrolled in pacmilimab (mg/kg)+ipilimumab (mg/kg) dose-escalation cohorts: 0.3+3 (n=6); 1+3 (n=3); 3+3 (n=3); 10+3 (n=8); 10+6 (n=6); and 10+10 (n=1). Dose-limiting toxicities occurred in three patients, one at the 0.3+3 dose level (grade 3 dyspnea/pneumonitis) and two at the 10+6 dose level (grade 3 colitis, grade 3 increased aspartate aminotransferase). The MTD and recommended phase 2 dose was pacmilimab 10 mg/kg+ipilimumab 3 mg/kg administered every 3 weeks. Pacmilimab-related grade 3–4 adverse events (AEs) and grade 3–4 immune-related AEs were reported in nine (33%) and six (22%) patients, respectively. Three patients (11%) discontinued treatment because of AEs. The overall response rate was 19% (95% CI 6.3 to 38.1), with one complete (anal squamous cell carcinoma) and four partial responses (cancer of unknown primary, leiomyosarcoma, mesothelioma, testicular cancer). Responses lasted for >12 months in four patients.ConclusionsThe MTD and recommended phase 2 dose of pacmilimab (10 mg/kg)+ipilimumab (3 mg/kg) every 3 weeks is active and has a favorable tolerability profile. |
| وصف الملف: | application/pdf |
| تدمد: | 2051-1426 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::8f59b5f6c6c998d04c0063e8f4efa570Test https://pubmed.ncbi.nlm.nih.gov/34301808Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....8f59b5f6c6c998d04c0063e8f4efa570 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 20511426 |
|---|