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A phase 2, multi-center, open-label study of cinrebafusp alfa (PRS-343) in patients with HER2-high and HER2-low gastric or gastroesophageal junction (GEJ) adenocarcinoma
Background
For patients (pts) with HER2-overexpressing metastatic gastric cancer, trastuzumab + chemotherapy +/- pembrolizumab is a standard first-line option but only provides an incremental overall survival (OS) benefit vs chemotherapy. Anticalin® proteins are recombinant human proteins based on lipocalins. Cinrebafusp alfa, a first-in-class bispecific antibody-Anticalin fusion protein, targets HER2 and the co-stimulatory immune receptor 4-1BB on T cells. In a previous phase 1 study cinrebafusp alfa monotherapy was generally well tolerated and showed deep and durable responses in patients with HER2-positive gastrointestinal malignancies at doses of 8mg/kg Q2W and 18mg/kg Q2W. Significant induction of plasma 4-1BB as well as increase of CD8+ cells was observed in on-treatment tumor biopsies at active dose levels (Piha-Paul, SITC 2020). Based on pharmacokinetics (PK), pharmacodynamics (PD) and clinical efficacy data, a phase 2 dose of 18mg/kg Q2W in C1 followed by 8mg/kg Q2W maintenance was chosen.
Trial design
This is a global, open-label, multicenter, two-arm phase 2 trial of cinrebafusp alfa in patients with metastatic gastric or gastroesophageal junction cancer. Arm 1 is enrolling patients with HER2 high (Immunohistochemistry (ICH) 3+ or IHC 2+ with HER2/neu gene amplification) disease. Pts who have received one prior treatment regimen for metastatic disease, including HER2-directed therapy such as trastuzumab are eligible. Pts will receive cinrebafusp alfa in combination with ramucirumab and paclitaxel. Arm2 is enrolling patients with HER2 low (IHC 1+ or 2+ without HER2/neu gene amplification) disease. Pts who have received at least one prior treatment regimen for metastatic disease are eligible. Pts will receive cinrebafusp alfa in combination with tucatinib. After a run-in consisting of 3 pts in each arm, an additional 17 patients will be enrolled in each arm. For Arm 1, an additional 40 patients may be enrolled after a futility analysis has been conducted. Treatment will continue until disease progression, unacceptable toxicity, or consent withdrawal. Primary endpoint is confirmed overall response rate per RECIST 1.1 and key secondary endpoints are duration of response, progression free survival, overall survival, safety, PK, and immunogenicity. Recruitment is ongoing. Approximately 10 sites in 3 countries in US, Asia and Europe are expected to participate.
Clinical trial identification
NCT05190445.
Legal entity responsible for the study
Pieris Pharmaceuticals.
Funding
Pieris Pharmaceuticals.
Disclosures
G. Ku: Advisory / Consultancy: BMS, Eli Lilly, Merck, Pieris; Research grant / Funding (institution): Arog, AstraZeneca, BMS, Daiichi Sankyo, Merck, Oncolys, Pieris, Zymeworks. S. Piha-Paul: Advisory / Consultancy: CRC Oncology; Research grant / Funding (institution): AbbVie, Inc.; ABM Therapeutics, Inc.; Acepodia, Inc; Alkermes; Aminex Therapeutics; Amphivena Therapeutics, Inc.; BioMarin Pharmaceutical, Inc; Boehringer Ingelheim; Bristol Myers Squib; Cerulean Pharma, Inc.; Chugai Pharmaceutical Co., Ltd; Curis, , Cyclacel Pharmaceuticals; Daiichi Sankyo; Eli Lilly; ENB Therapeutics; Five Prime Therapeutics; F-Star Beta Limited; F-Star Therapeutics; Gene Quantum; Genmab A/S; Gilead Sciences, Inc.; GlaxoSmithKline; Helix BioPharma Corp.; HiberCell, Inc., Immunomedics, Inc.; Incyte Corp.; Jacobio Pharmaceuticals Co., Ltd.; Lytix Biopharma AS; Medimmune, LLC.; Medivation, Inc.; Merck Sharp and Dohme Corp.; Novartis Pharmaceuticals; Pieris Pharmaceuticals, Inc.; Pfizer; Principia Biopharma, Inc.; Puma . Y. Kang: Advisory / Consultancy: Ono, BMS. K. Aviano: Full / Part-time employment: Pieris Pharmaceuticals. T. Demuth: Leadership role: Pieris Pharmaceuticals; Shareholder / Stockholder / Stock options: Pieris Pharmaceuticals; Officer / Board of Directors: Pieris Pharmaceuticals. All other authors have declared no conflicts of interest.
