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

Abstract

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.

Peptide–Antibody Fusions Engineered by Phage Display Exhibit an Ultrapotent and Broad Neutralization of SARS-CoV-2 Variants

“…These anticancer biologics are very similar in format to the antiviral peptide–IgG fusions we report here . Critically, anticancer peptide–IgG fusions have exhibited good pharmacokinetic profiles and tissue penetration, and they have been well tolerated in the clinic . Taken together, our results establish peptide–IgG fusions as a powerful means for greatly enhancing the potency and coverage of next-generation biologics for the treatment of diseases caused by SARS-CoV-2 and its variants.…”

CX-072 (pacmilimab), a Probody®PD-L1 inhibitor, in advanced or recurrent solid tumors (PROCLAIM-CX-072): an open-label dose-finding and first-in-human study

“…These preliminary findings with pacmilimab in patients with pretreated advanced solid tumors are encouraging and support further clinical evaluation. The tolerability and clinical activity of pacmilimab in combination with ipilimumab within the current study is reported separately 30 .…”

Extracellular Vesicle-Derived Protein File from Peripheral Blood Predicts Immune-Related Adverse Events in Gastric Cancer Patients Receiving Immunotherapy

“…ICOS and IDO1 are proteins related to immunotherapy; relevant target drugs have been produced [ 30 , 31 ], and several studies support that they were associated with allergic diseases [ 32 ]. It has been reported that activation of ICOS + Tregs mediates allergic airway diseases, and targeting the ICOS/ICOS-L pathway may disrupt T follicular helper cell responses and ameliorate allergic asthma by disrupting the disease [ 33 , 34 ].…”