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
Background Probody® 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...
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BMJ Publishing Group
2021-07-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/9/7/e002446.full |
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| author | Omid Hamid Fiona Thistlethwaite Johanna Bendell Ruth Plummer Patrick A Ott Rachel E Sanborn Karen A Autio Valentina Boni Elisabeth GE de Vries Javier Garcia-Corbacho Daniel C Cho Mark Stroh Lawrence Lu |
| author_facet | Omid Hamid Fiona Thistlethwaite Johanna Bendell Ruth Plummer Patrick A Ott Rachel E Sanborn Karen A Autio Valentina Boni Elisabeth GE de Vries Javier Garcia-Corbacho Daniel C Cho Mark Stroh Lawrence Lu |
| author_sort | Omid Hamid |
| collection | DOAJ |
| description | Background Probody® 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.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 3–4 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.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. |
| format | Article |
| id | doaj-art-bede17be06fa40b884678abba71d0fbe |
| institution | DOAJ |
| issn | 2051-1426 |
| language | English |
| publishDate | 2021-07-01 |
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| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-bede17be06fa40b884678abba71d0fbe2025-08-20T02:49:53ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262021-07-019710.1136/jitc-2021-002446CX-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 studyOmid Hamid0Fiona Thistlethwaite1Johanna Bendell2Ruth Plummer3Patrick A Ott4Rachel E Sanborn5Karen A Autio6Valentina Boni7Elisabeth GE de Vries8Javier Garcia-Corbacho9Daniel C Cho10Mark Stroh11Lawrence Lu12Department of Medical Oncology, The Angeles Clinic and Research Institute, A Cedars-Sinai Affiliate, Los Angeles, California, USAThe Christie Hospital NHS Foundation Trust and University of Manchester, Manchester, UKSarah Cannon Research Institute/Tennessee Oncology, Nashville, Tennessee, USADepartment of Medical Oncology, Northern Centre for Cancer Care, Newcastle Hospitals NHS Trust and Newcastle University, Newcastle upon Tyne, UKDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USAEarle A Chiles Research Institute, Portland, Oregon, USAMemorial Sloan Kettering Cancer Center, New York, New York, USASTART Madrid-CIOCC, Centro Integral Oncológico Clara Campal, Hospital Universitario HM Sanchinarro, Madrid, SpainDepartment of Medical Oncology, Universitair Medisch Centrum Groningen, University of Groningen, Groningen, NetherlandsDepartment of Medical Oncology, Hospital Clinic Barcelona/IDIBAPS, Barcelona, SpainDepartment of Medicine, Perlmutter Cancer Center at NYU Langone Medical Center, New York, New York, USACytomX Therapeutics Inc, South San Francisco, California, USACytomX Therapeutics Inc, South San Francisco, California, USABackground Probody® 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.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 3–4 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.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.https://jitc.bmj.com/content/9/7/e002446.full |
| spellingShingle | Omid Hamid Fiona Thistlethwaite Johanna Bendell Ruth Plummer Patrick A Ott Rachel E Sanborn Karen A Autio Valentina Boni Elisabeth GE de Vries Javier Garcia-Corbacho Daniel C Cho Mark Stroh Lawrence Lu 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 Journal for ImmunoTherapy of Cancer |
| 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| url | https://jitc.bmj.com/content/9/7/e002446.full |
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