A Phase 1 study of the anti-tissue factor antibody-drug conjugate XB002 in patients with advanced solid tumors (JEWEL-101): initial results from the dose-escalation stage

Background: XB002 is an antibody-drug conjugate (ADC) composed of a high-affinity tissue factor (TF)-directed human monoclonal antibody conjugated to a novel cytotoxic payload, ZymeLink Auristatin. TF, a transmembrane protein, functions as a FVIIa receptor, initiating the extrinsic coagulation cascade. TF is also expressed in multiple tumor types. XB002 demonstrated antitumor activity in pre-clinical studies across multiple tumor types and did not perturb coagulation. Presented here are initial results from the dose-escalation stage of the JEWEL-101 study with XB002 in advanced solid tumors. Materials and methods: This phase 1, open-label, multicenter, first-in-human trial (NCT04925284) consists of dose-escalation and tumor-specific cohort-expansion stages. Pts ≥18 years with advanced solid tumors and limited treatment options are being enrolled. Pts must have ECOG PS 0–1 and adequate organ function. In the dose-escalation stage, cohorts of 3– 12 pts are being enrolled using an interval 3 + 3 design. The primary objective for this stage is to determine the maximum tolerated dose (MTD) and recommended dose (RD) of XB002. Results: At cutoff on 13 May 2022, 15 pts were enrolled across four dose levels (XB002 IV Q3W): 0.16 mg/kg (n = 3); 0.5 mg/kg (n = 3); 1.0 mg/kg (n = 6); 1.5 mg/kg (n = 3). Median age was 63 years (range 45–79); 67% had an ECOG PS of 1. Median prior lines of non-radiation anticancer therapy was 3 (range 2–8). No dose-limiting toxicity was observed; an MTD/RD has not yet been determined. The most common reason for treatment discontinuation was radiographic progression (n = 8). All pts had a treatment-emergent adverse event (TEAE), but no grade 4 or 5 TEAEs were seen. All 5 (33%) grade 3 TEAEs were unrelated to XB002. No bleeding events or peripheral neuropathy were observed. All treatment-related AEs (TRAEs) were grade £2 and resolved prior to next dose: these included ocular toxicities (n = 2, grade 1 dry eyes and grade 2 conjunctivitis in the same pt at 1.0 mg/kg and grade 2 conjunctivitis at 1.5 mg/kg), fatigue and nausea (n = 2 each, all grade 1), and chills, peripheral edema, skin infection, and vomiting (n = 1 each, all grade 1). Two serious AEs unrelated to XB002 occurred with 1.0 mg/kg (COVID-19 pneumonia and diarrhea). Pharmacokinetic (PK) analysis showed that XB002 Cmax and AUC increased with increasing dose. Total antibody and intact ADC PK were similar, suggesting XB002 is stable in vivo. Free payload levels were over 300-fold lower than intact ADC at all doses (<0.5 ng/mL). Conclusions: XB002 Q3W was well tolerated at multiple dose levels with manageable TRAEs, all grade £2 including ocular toxicities, and no bleeding events or neuropathy. PK analysis revealed appropriate exposure with very low levels of free payload. Dose-escalation is ongoing and updated data will be presented. Conflict of interest: Ownership: Shailaja Uttamsingh, Jing Li, and Mustafa Syed: Exelixis. Anthony Tolcher: Pyxis (Inst). Advisory Board: Susanna Ulahannan: Array BioPharma Bayer Eisai Incyte Syros Pharmaceuticals Exelixis. Research Funding - Abbvie (Inst) Adlai Nortye (Inst) ArQule (Inst) Astex Pharmaceuticals (Inst) AstraZeneca (Inst) atreca (Inst) Boehringer Ingelheim (Inst) Bristol-Myers Squibb (Inst) Celgene (Inst) CicloMed (Inst) Erasca, Inc (Inst) evelo biosciences (Inst) Exelixis (Inst) G1 Therapeutics (Inst) GlaxoSmithKline (Inst) IgM Biosciences (Inst) Incyte (Inst) Klus Pharma (Inst) Macrogenics (Inst) Merck (Inst) Mersana (Inst) OncoMed (Inst) Pfizer (Inst) Regeneron (Inst) Revolution Medicines (Inst) Synermore biologics (Inst) Takeda (Inst) Takeda (Inst) Tarveda Therapeutics (Inst) Tempest Therapeutics (Inst) Tesaro (Inst) Vigeo Therapeutics (Inst). Melissa Johnson: Abbvie (Inst) Amgen (Inst) Astellas Pharma (Inst) AstraZeneca (Inst) Axelia Oncology (Inst) Black Diamond Therapeutics (Inst) Boehringer Ingelheim (Inst) Bristol-Myers Squibb (Inst) Calithera Biosciences (Inst) CytomX Therapeutics (Inst) Daiichi Sankyo (Inst) EcoR1 Capital (Inst) Editas Medicine (Inst) Eisai (Inst) EMD Serono (Inst) G1 Therapeutics (Inst) Genentech/Roche (Inst) Genmab (Inst) GlaxoSmithKline (Inst) Gritstone Bio (Inst) IDEAYA Biosciences (Inst) ITeos Therapeutics (Inst) Janssen Oncology (Inst) Lilly (Inst) Merck (Inst) Mirati Therapeutics (Inst) Oncorus (Inst) Regeneron (Inst) Ribon Therapeutics (Inst) Sanofi (Inst) Turning Point Therapeutics (Inst) WindMIL (Inst). Anthony Tolcher: AbbVie (Inst) Aclaris Therapeutics (Inst) Adagene (Inst) Agenus (Inst) Aro Biotherapeutics (Inst) Asana Biosciences (Inst) Ascentage Pharma (Inst) Aximmune (Inst) Bayer (Inst) BioInvent (Inst) BluPrint Oncology (Inst) Boehringer Ingelheim (Inst) Daiichi Sankyo, Inc. (Inst) Deka Biosciences (Inst) Eleven Biotherapeutics (Inst) Elucida Oncology (Inst) EMD Serono (Inst) Gilde Healthcare (Inst) HBM Partners (Inst) HiberCell (Inst) IDEA Pharma (Inst) Ikena Oncology (Inst) Immuneering (Inst) Immunome (Inst) Immunomet (Inst) IMPACT Therapeutics (Inst) Janssen (Inst) Jazz Pharmaceuticals (Inst) Karma Oncology (Inst) Lengo Therapeutics (Inst) Lilly (Inst) Mekanistic Therapeutics (Inst) Menarini (Inst) Mersana (Inst) Mirati Therapeutics (Inst) Nanobiotix (Inst) NBE Therapeutics (Inst) Ocellaris Pharma (Inst) Partner Therapeutics (Inst) Pelican Therapeutics (Inst) Pfizer (Inst) Pieris Pharmaceuticals (Inst) Pierre Fabre (Inst) Pyxis (Inst) Ryvu Therapeutics (Inst) Seattle Genetics (Inst) Senti Biosciences (Inst) SK Life Sciences (Inst) Sotio (Inst) Spirea (Inst) Sunshine Guojian (Inst) Transcenta (Inst) Transgene (Inst) Trillium Therapeutics (Inst) Vincerx Pharma (Inst) Zentalis (Inst) ZielBio (Inst) Zymeworks (Inst). Corporate-sponsored Research: Melissa Johnson: Abbvie (Inst) Acerta Pharma (Inst) Adaptimmune (Inst) Amgen (Inst) Apexigen (Inst) Arcus Biosciences (Inst) Array BioPharma (Inst) Artios (Inst) AstraZeneca (Inst) Atreca (Inst) BeiGene (Inst) BerGenBio (Inst) BioAtla (Inst) Black Diamond Therapeutics (Inst) Boehringer Ingelheim (Inst) Calithera Biosciences (Inst) Carisma Therapeutics (Inst) Checkpoint Therapeutics (Inst) Corvus Pharmaceuticals (Inst) Curis (Inst) CytomX Therapeutics (Inst) Daiichi Sankyo (Inst) Dracen (Inst) Dynavax Technologies (Inst) Elicio Therapeutics (Inst) EMD Serono (Inst) Erasca, Inc (Inst) Exelixis (Inst) Fate Therapeutics (Inst) Genentech/Roche (Inst) Genmab (Inst) Genocea Biosciences (Inst) GlaxoSmithKline (Inst) Gritstone Bio (Inst) Guardant Health (Inst) Harpoon (Inst) Helsinn Healthcare (Inst) Hengrui Pharmaceutical (Inst) Hutchison MediPharma (Inst) IDEAYA Biosciences (Inst) IGM Biosciences (Inst) Immunocore (Inst) Impact Therapeutics (Inst) Incyte (Inst) Janssen (Inst) Jounce Therapeutics (Inst) Kadmon (Inst) Kartos Therapeutics (Inst) Lilly (Inst) Loxo (Inst) Lycera (Inst) Memorial Sloan-Kettering Cancer Center (Inst) Merck (Inst) Merus (Inst) Mirati Therapeutics (Inst) NeoImmuneTech (Inst) Neovia Oncology (Inst) Novartis (Inst) Numab (Inst) Nuvalent, Inc. (Inst) OncoMed (Inst) Palleon Pharmaceuticals (Inst) Pfizer (Inst) PMV Pharma (Inst) Rain Therapeutics (Inst) RasCal (Inst) Regeneron (Inst) Relay Therapeutics (Inst) Revolution Medicines (Inst) Ribon Therapeutics (Inst) Rubius Therapeutics (Inst) Sanofi (Inst) Seven and Eight Biopharmaceuticals (Inst) Shattuck Labs (Inst) Silicon Therapeutics (Inst) Stem CentRx (Inst) Syndax (Inst) Takeda (Inst) Tarveda Therapeutics (Inst) TCR2 Therapeutics (Inst) Tempest Therapeutics (Inst) Tizona Therapeutics, Inc. (Inst) Tmunity Therapeutics, Inc. (Inst) Turning Point Therapeutics (Inst) University of Michigan (Inst) Vyriad (Inst) WindMIL (Inst) Y-mAbs Therapeutics (Inst). Haeseong Park: Ambrx (Inst) Amgen (Inst) Aprea Therapeutics (Inst) Array BioPharma (Inst) AstraZeneca (Inst) Bayer (Inst) BeiGene (Inst) BJ Bioscience (Inst) Bristol-Myers Squibb (Inst) Daiichi Sankyo (Inst) EMD Serono (Inst) Five Prime Therapeutics (Inst) Genentech (Inst) Gilead Sciences (Inst) GlaxoSmithKline (Inst) Gossamer Bio (Inst) ImmuneOncia (Inst) Immunomedics (Inst) Incyte (Inst) Jounce Therapeutics (Inst) Lilly (Inst) MabSpace Biosciences (Inst) Macrogenics (Inst) MedImmune (Inst) Medivation (Inst) Merck (Inst) Millennium (Inst) Mirati Therapeutics (Inst) Novartis (Inst) Oncologie (Inst) Pfizer (Inst) PsiOxus Therapeutics (Inst) Puma Biotechnology (Inst) Regeneron (Inst) Roche (Inst) Seattle Genetics (Inst) Synermore Biologics (Inst) Taiho Pharmaceutical (Inst) TopAlliance Biosciences (Inst) Turning Point Therapeutics (Inst) Vedanta Biosciences (Inst) Vertex (Inst) Xencor (Inst). Andrae Vandross: Mabwell (Shanghai) (Inst) Abbvie (Inst) Astra Zeneca (Inst) Aminex Therapeutics (Inst) Ascentage Pharma (Inst) Asana Bio (Inst) BioOneCure (Inst) BJ Bioscience Inc (Inst) Elpiscience Biopharma (Inst) Nanjing Immunophage Biotech (Inst) Chugai Pharmaceuticals (Inst) Lyvgen Biopharma (Inst) NGMBio (Inst) Zhuhai Yufan Biotechnologies (Inst) siRNAomics (Inst) Sorrento therapeutics (Inst) Exelixis (Inst) Xilio (Inst) ZielBio (Inst). Anthony Tolcher: - AbbVie (Inst) ABL Bio (Inst) Adagene (Inst) ADC Therapeutics (Inst) Agenus (Inst) Aminex (Inst) Amphivena (Inst) Apros Therapeutics (Inst) Arcellx (Inst) ARMO BioSciences (Inst) Arrys Therapeutics (Inst) Artios (Inst) Asana Biosciences (Inst) Ascentage Pharma (Inst) Astex Pharmaceuticals (Inst) Basilea (Inst) Bioinvent (Inst) Birdie (Inst) BJ Bioscience (Inst) Boehringer Ingelheim (Inst) Boston Biomedical (Inst) CStone Pharmaceuticals (Inst) Daiichi Sankyo, Inc. (Inst) Deciphera (Inst) eFFECTOR Therapeutics (Inst) EMD Serono (Inst) Gilead Sciences (Inst) GlaxoSmithKline (Inst) ImmuneOncia (Inst) Inhibrx (Inst) Innate Pharma (Inst) Janssen Research & Development (Inst) K-Group Beta (Inst) Kechow Pharma (Inst) Kiromic (Inst) Merck Sharp & Dohme (Inst) Mersana (Inst) Mirati Therapeutics (Inst) Naturewise (Inst) NBE Therapeutics (Inst) NextCure (Inst) Nitto BioPharma (Inst) Odonate Therapeutics (Inst) ORIC Pharmaceuticals (Inst) Pfizer (Inst) Pieris Pharmaceuticals (Inst) Qilu Puget Sound Biotherapeutics (Inst) Samumed (Inst) Seattle Genetics (Inst) Shanghai HaiHe Pharmaceutical (Inst) Spring Bank (Inst) Sunshine Guojian (Inst) Symphogen (Inst) Syndax (Inst) Synthorx (Inst) Takeda (Inst) Tizona Therapeutics, Inc. (Inst) Zymeworks (Inst). Other Substantive Relationships: Melissa Johnson: Travel, Accommodations, Expenses - Abbvie AstraZeneca Genentech Incyte Merck Pfizer Sanofi. Haeseong Park: Travel, Accommodations, Expenses - Bayer Daiichi Sankyo Vedanta Biosciences. Anthony Tolcher: Employment - Next Oncology. Leadership - Next Oncology. Expert Testimony – Immunogen. Travel, Accommodations, Expenses - Sotio (Inst). Shailaja Uttamsingh, Jing Li, and Mustafa Syed: Employment: Exelixis.