Safety and activity of CY-101 in patients with advanced solid tumors: The phase I/IIa CICILIA trial

BackgroundCY-101 is a synthetic peptide that inhibits the oncogenic Wnt/β-catenin pathway by activating Axin2 and has a pore-forming membranolytic effect on cancer cells that triggers a tumor-specific immune response. Here, we report findings from a phase I/IIa trial evaluating intratumoral (IT) administration of CY-101 monotherapy and in combination with pembrolizumab in patients (pts) with heavily pretreated advanced solid tumors.MethodsEligible pts received biweekly (Q2W) IT injections with CY-101 into 1-3 accessible metastatic lesion(s). The primary endpoint was safety and tolerability, with anti-tumor and immunomodulatory activity as secondary objectives. Dose-escalation (2, 8, and 20 mg) followed a ‘3+3 design’ with a 6-week dose-limiting toxicity (DLT) observation period. The recommended dose for further development (R2PD) was explored across three expansion cohorts: A) CY-101 Q2W monotherapy, B) CY-101 plus pembrolizumab 400 mg Q6W, and C) CY-101 Q2W monotherapy in intrahepatic lesions. Response assessment was performed every 8 weeks.ResultsNo DLTs were observed in the dose escalation part. The R2PD was defined at 20 mg. In the dose-expansion phase, 45 pts were enrolled among the 3 cohorts A (n=18), B (n=15), and C (n=12). Common grade 1-2 treatment-related adverse events (TRAE) included pain at the injection site (63.6%), fatigue (20.1%), pyrexia (11.4%) and injection site reaction (9.1%). One grade 3 TRAE, due to pain related to IT administration (2.2%), was noted. Histopathologic examination of post-treatment biopsies revealed enlarged necrotic areas and tumor infiltrating lymphocytes in 70%. Across tumor types, the disease control rate was 31%, with 36% having an ongoing response beyond six months. Abscopal partial responses were seen in three pts (2 monotherapy, 1 combination). Notably, among six pts with adrenocortical carcinoma (monotherapy), a disease control rate of 50% (n = 3/6) was observed, with durable responses (> 6 months) in two pts. Both pts expressed β-catenin (IHC) and had somatic mutations in the Wnt/β-catenin pathway (WES).ConclusionsCY-101 is well tolerated at the RP2D of 20 mg and demonstrated early signs of antitumor activity, especially in tumors with dysregulated Wnt/β-catenin signaling.Clinical trial identificationNCT04260529; Release date: 05-02-2020.Legal entity responsible for the studyCytovation AS.FundingCytovation ASA.DisclosureS. Champiat: Non-Financial Interests, Institutional, Invited Speaker: Amgen, Astellas, AstraZeneca, Bristol Myers Squibb, Eisai, Genmab, Janssen, Merck, MSD, Novartis, Roche, Servier, Takeda; Non-Financial Interests, Institutional, Principal Investigator: AbbVie, Amgen, Boehringen Ingelheim, Bolt, Biotherapeutics, Centessa Pharmaceuticals, Cytovation, Eisai, GSK, Imcheck Therapeutics, Immunocore, Molecular Partners Ag, MSD, Ose Immunotherapeutics, Pierre Fabre, Replimune, Roche, Sanofi Aventis, Seagen, Sotio AS, Transgene; Non-Financial Interests, Institutional, Advisory Board: Acces Trial, Alderaan Biotechnology, Amgen, AstraZeneca, Avacta, BeiGene, BioNTech, Celanese, Domain Therapeutics, Ellipses Pharma, Genmab, Harpoon therapeutics, Immunicom, Inc., Mariana Oncology, Mima Health, Nanobiotix, Nextcure, Oncovita, Pierre Fabre, Seagen, Takeda, Tatum Bioscience, Tollys, UltraHuman8, UltraHuman8. V. Moreno Garcia: Financial Interests, Personal, Advisory Board: BMS, Janssen, Roche, Basilea, Bayer, AstraZeneca; Financial Interests, Personal, Full or part-time Employment: START; Financial Interests, Institutional, Local PI, AbbVie, AceaBio, Adaptimmune, ADC Therapeutics, Aduro, Agenus, Amcure, Amgen, Astellas, AstraZeneca Bayer BeiGene BioInvent International AB, BMS, Boehringer, Boheringer, Boston, Celgene, Daiichi Sankyo, Debiopharm, Eisai, e-Terapeutics, Exelisis, Forma Therapeutics, Genmab, GSK, Harpoon, Hutchison, Immutep, Incyte, Inovio, Iovance, Janssen, Kyowa Kirin, Lilly, Loxo, MedSir, Menarini, Merck, Merus, Millennium, MSD, Nanobiotix, Nektar, Novartis, Odonate Therapeutics, Pfizer, PharmaMar, Principia, PsiOxus, Puma, Regeneron, Rigontec, Roche, Sanofi, Sierra Oncology, Synthon, Taiho, Takeda, Tesaro, Transgene, Turning Point Therapeutics, Upshersmith: Multiple. F. Opdam: Non-Financial Interests, Principal Investigator: GSK, Int1B3, AstraZeneca, Cytovation, Relay, Taiho, Roche, Merus, Boehringer ingelheim, Crescendo, Pierre Fabre, Lilly, RevMed, Incyte. H. Gelderblom: Financial Interests, Institutional, Local PI: Deciphera, Cytovation; Financial Interests, Institutional, Coordinating PI: Boehringer Ingelheim, AmMax Bio, Debiopharm, Abbisko. M. Chaney: Financial Interests, Personal, Full or part-time Employment: Merck and Co., Inc; Financial Interests, Personal, Stocks/Shares: Merck and Co., Inc; Non-Financial Interests, Member: ASCO, AACR. L. Prestegarden: Financial Interests, Personal, Full or part-time Employment: Cytovation. All other authors have declared no conflicts of interest.