@article {Sanborne002446, author = {Rachel E Sanborn and Omid Hamid and Elisabeth GE de Vries and Patrick A Ott and Javier Garcia-Corbacho and Valentina Boni and Johanna Bendell and Karen A Autio and Daniel C Cho and Ruth Plummer and Mark Stroh and Lawrence Lu and Fiona Thistlethwaite}, title = {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}, volume = {9}, number = {7}, elocation-id = {e002446}, year = {2021}, doi = {10.1136/jitc-2021-002446}, publisher = {BMJ Specialist Journals}, abstract = {Background Probody{\textregistered} therapeutics are antibody prodrugs designed to be activated by tumor-associated proteases. This conditional activation restricts antibody binding to the tumor microenvironment, thereby minimizing {\textquoteleft}off-tumor{\textquoteright} 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.Methods Adults (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).Results Twenty-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{\textendash}4 adverse events (AEs) and grade 3{\textendash}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.Conclusions The 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.All data relevant to the study are included in the article or uploaded as online supplemental information. The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.}, URL = {https://jitc.bmj.com/content/9/7/e002446}, eprint = {https://jitc.bmj.com/content/9/7/e002446.full.pdf}, journal = {Journal for ImmunoTherapy of Cancer} }