1071TiP - Phase I study of the investigational CD228 x 4-1BB costimulatory antibody anticalin bispecific SGN-BB228 (PF-08046049) in advanced melanoma and other solid tumors

Background

Clinical development of 4-1BB agonists faces challenges achieving specificity and therapeutic effects without off-target activity or poor tolerability (Salek-Ardakani 2023). SGN-BB228 is an investigational costimulatory bispecific molecule composed of a CD228-directed fully humanized antibody and 4-1BB-directed Anticalin® proteins designed to provide a costimulatory bridge between tumor-reactive cytotoxic T cells and CD228-expressing tumor cells. This may localize activity to the tumor microenvironment and expand the therapeutic window for 4-1BB agonism by limiting potential for off-target toxicity. 4-1BB costimulation enhances antitumor T cell activity by a mechanism distinct from but complementary to the blocking of inhibitory receptors (Updegraff 2023).

Trial design

The primary objectives of this phase 1, open label multicenter study are to evaluate the safety and tolerability of SGN-BB228 and identify a recommended dose and schedule in patients (pts) ≥18 years of age. The study involves dose escalation (Part A), dose optimization (Part B: weekly, biweekly, or other options), and dose expansion in disease-specific cohorts (Part C) with potential for future combination dosing. Parts A and B will enrol histologically/cytologically confirmed metastatic/unresectable cutaneous melanoma; a biology backfill cohort may enrol with pre-treatment and on-treatment biopsies required. Part C will enrol pts with melanoma, mesothelioma, pancreatic, colorectal, or NSCLC. Pts must be relapsed/refractory, or intolerant to SOC therapies, have adequate organ function, and an ECOG PS 0-1. Pts with acral or uveal melanoma, active CNS metastases or prior therapies targeting CD228 or 4-1BB are excluded. Pts with cutaneous melanoma must have prior anti PD(L)-1 treatment. Pts with a targetable BRAF mutation must have received, been intolerant to, or deemed ineligible for treatment with BRAF/MEK therapy. Primary endpoints: AEs, laboratory abnormalities, DLTs, cumulative safety by dose level. Secondary endpoints: PK, ORR, DoR, PFS, OS, and incidence of ADAs. Enrolment is ongoing in the US, Canada and Europe. NCT05571839.

Clinical trial identification

NCT05571839.

Editorial acknowledgement

Editorial support was provided by David Sunter PhD of Engage Scientific Solutions.

Legal entity responsible for the study

Pfizer.

Funding

This study was sponsored by Seagen Inc., which was acquired by Pfizer in December 2023.

Disclosure

R. Dummer: Financial Interests, Personal, Other, Consulting and/or advisory role: Novartis, Merck Sharp & Dohme (MSD), Bristol Myers Squibb (BMS), Roche, Amgen, Takeda, Pierre Fabre, Sun Pharma, Sanofi, Catalym, Second Genome, Regeneron, MaviVAX SA, T3 Pharma, Pfizer, Simcere. A. Daud: Financial Interests, Personal, Other: EMD Serono, Inovio Pharmaceuticals; Financial Interests, Personal, Speaker, Consultant, Advisor: Genoptix, GSK, Oncosec, Caris, Eisai, GLG; Financial Interests, Institutional, Research Funding: Bristol Myers Squibb, Checkmate Pharmaceuticals, Checkmate Pharmaceuticals, Genentech/Roche, GSK, Incyte, Merck/Schering Plough, Novartis, Oncosec, Pfizer. T.K. Eigentler: Financial Interests, Personal, Speaker, Consultant, Advisor: Anaveon, CureVac, Bristol Myers Squibb, MSD, Novartis, Pierre Fabre, Sanofi. T.R.J. Evans: Financial Interests, Institutional, Advisory Board for GI cancers and melanoma (immune checkpoint inhibitors): Bristol Myers Squibb; Financial Interests, Institutional, Invited Speaker, Invited speaker - GI cancers, melanoma, immunotherapy: Bristol Myers Squibb; Financial Interests, Institutional, Advisory Boards - GI cancers, melanoma: Roche/Genentech; Financial Interests, Institutional, Invited speaker GI cancer, melanoma: Roche/Genentech; Financial Interests, Institutional, Advisory Board (Lenvatinib): Eisai; Financial Interests, Institutional, Invited Speaker, Speaker's fees (lenvatinib): Eisai; Financial Interests, Institutional, Advisory Board: MSD, AstraZeneca, Bayer, Bicycle Therapeutics, Clovis; Financial Interests, Institutional, Invited Speaker, Speaker's fees: MSD, AstraZeneca, Bayer; Financial Interests, Institutional, Advisory Board: Nucana; Financial Interests, Institutional, Invited Speaker, speaker's fees: Nucana; Financial Interests, Institutional, Advisory Board; Chair of Scientific Advisory Council (HCC & MIV-818): Medivir; Financial Interests, Institutional, Invited Speaker, speaker's fees (and presentation to potential investors): Medivir; Financial Interests, Personal, Other, Support to attend international conferences: Bristol Myers Squibb, Roche/Genentech, MSD, Nucana, Bayer, Celgene, Pierre Fabre; Financial Interests, Institutional, Advisory Board for Upper GI Cancer: Ascelia; Financial Interests, Institutional, Advisory Board for Oesophageal Cancer: Seagen; Financial Interests, Institutional, Coordinating PI, Educational grant (supply of study agents) for investigator-led study and reimbursement of study costs for commercial studies: AstraZeneca; Financial Interests, Institutional, Local PI, reimbursement of study costs for commercial studies: Astellas, Bayer, Basilea, Celgene, GSK, Roche, Medivir, Starpharma, Immunocore, Novartis, Sapience Therapeutics, MiNa Therapeutics, Lilly, Bicycle Therapeutics, Sierra, CytomX, BeiGene, Pfizer, Johnson & Johnson, UCB, Codiak, Avacta, Nurix, T3P, Amgen, Moderna; Financial Interests, Institutional, Coordinating PI, reimbursement of study costs for commercial studies: Adaptimmune, Bristol Myers Squibb, Eisai, MSD, Nucana, iOnctura, Sanofi; Financial Interests, Institutional, Local PI, support for non-commercial investigator-led study: Verastem; Financial Interests, Institutional, Local PI, reimbursement for costs of commercial studies: Boehringer Ingelheim; Financial Interests, Institutional, Local PI, reimbursement of costs of commercial study: Seagen; Financial Interests, Institutional, Funding, reimbursement of study costs for commercial studies; lead investigator for infrastructure investment to NHS Research Scotland: BioNTech; Financial Interests, Institutional, Local PI, reimbursement of study sots for commercial studies: Exelixis; Non-Financial Interests, Other, Member of Scientific Advisory Panel: Pancreatic Cancer Research Fund; Non-Financial Interests, Other, Annual Meeting abstracts committee: International Liver Cancer Association; Non-Financial Interests, Institutional, Product Samples, Supply of investigational and licensed compounds for a non-commercial study for which I'm Chief Investigator: AstraZeneca; Non-Financial Interests, Member, Cancer Society Member: American Society of Clinical Oncology, America Association for Cancer Research, British Association for Cancer Research, Association of Cancer Physicians (UK), European Association for Cancer Research, International Liver Cancer Association; Other, Editor-in-Chief: British Journal of Cancer; Other, Chair of Independent Data Monitoring Committee for a phase 1 trial - honorarium payable to the employing institution: Genmab; Other, Chair and panel member, Scientific Evaluation Committee: early phase trials (Amgen, Merck, AstraZeneca); Chair and panel member, CLIP (early phase trial centres) 5-year review: Institut National du Cancer (France); Other, Panel Member, Pancreas Cancer funding committee, 2023: Fondation ARC; Other, NHS Research Scotland cancer research network national clinical lead: NHS Research Scotland. J. Henry: Financial Interests, Institutional, Research Funding: Abbiscko Therapeutics, ABl Bio, Accutar Biotech ADC therapeutics, Agenus, Aileron Therapeutics, Amgen i, Artios, Astrazenaca, Bayer, Bicycle therapeutics, BioAlta, BioInvent, Biomea Fusion, Biosplice Therapeutics, Black Diamond Therapeutics, Boehringer, Centessa, Cyteir, Daiichi Sankyo, Eli Lilly, Epizyme, Erasca, Exelixis, FujiFilm, GSK, Harbour Biomed, Hutchison MediPharma, ICON plc, IGM Biosciences, Immuneering Corporation, Immunitas, Immunogen, Incyte, Ingelheim, Jazz Pharmaceuticals, Jacobio Pharmaceuticals, Jounce Pharma, Jubilant Therapeutics, Kineta, Kura Oncology, Loxo Oncology, Merck& CO, Metabomed, Mirati, Molecular Templates, Navire Pharma, Nikang Pharmaceuticals, NGM, Oncorus, Phanes, Poseida, Prelude, PureTech, Pyxis, Pyramid, Rascal, Regeneron, Relay Therapeutics, Rgenix inc, Roche, Ribon Therapeutics, Sapience, Sarah Cannon Development Innovations, Seagen, Simcha Therapeutics, Siranomics, Stingthera, Synthorx inc, Tachyon Therapeutics, Tarus Therapeutics, Takeda, Tallac Therapeutics, Tarveda, Teneothree, Tesaro, Turning Point Pharma, Vista Therapeutics, Xencor; Financial Interests, Personal, Stocks/Shares: HCA. F.S. Hodi: Financial Interests, Personal, Speaker, Consultant, Advisor: Bristol Myers Squibb, Merck, Novartis, Compass Therapeutics, Apricity, Bicara, Checkpoint Therapeutics, Bioentre, Gossamer, Iovance, Catalym, Immunocore, Kairos, Rheos, Bayer, Zumutor, Corner Therapeutics, Puretech, Curis, AstraZeneca, Solu Therapeutics; Financial Interests, Personal, Stocks/Shares: Apricity, Apricity, Bicara, Checkpoint Therapeutics, Solu Therapeutics; Financial Interests, Institutional, Research Funding: Bristol Myers Squibb, Merck, Genentech, Seattle Genetics. W.H. Miller: Financial Interests, Personal, Speaker, Consultant, Advisor: BMS, Merck, Roche, Novartis, GSK, Amgen, Mylan, EMD Serono, Sanofi; Financial Interests, Institutional, Research Grant: CIHR, CRS, SWCRF; Financial Interests, Institutional, Research Funding: Merck, BMS, Novartis, GSK, Roche, AstraZeneca, Methlgene, MedImmune, Sanofi, Array, MiMic, Ocellaris, Astellas, Pfizer, Genentech, Seagen. C. Robert: Financial Interests, Personal, Advisory Board, Consultancy fees: BMS, Roche, Pierre Fabre, Novartis, Sanofi, MSD, Pfizer, Sun Pharma, Merck, Ultimovacs, Regeneron, EGLE, Philogen, MAAT Pharma; Financial Interests, Personal, Other, Steering Committee: Novartis, Regeneron, Pfizer, IO Biotech; Financial Interests, Personal, Other, IDMC: Ultimovacs; Financial Interests, Personal, Invited Speaker: Pierre Fabre, Sanofi, BMS, MSD, Novartis. S. Saibil: Financial Interests, Personal, Invited Speaker: Medison, Novartis. L. Tachiki: Financial Interests, Institutional, Research Grant: Seagen, Merck. M. Nayeri, B. Xing: Financial Interests, Personal, Stocks or ownership: Pfizer. J.M. Mehnert: Financial Interests, Institutional, Research Grant: Seagen, Merck, BMS, Regeneron; Financial Interests, Personal, Advisory Board: Merck, Seagen.