First-in-human, dose-escalation, phase 1 study of anti-angiopoietin-2 LY3127804 as monotherapy and in combination with ramucirumab in patients with advanced solid tumours

Abstract

Background: This is the first-in-human study of novel anti-angiopoietin-2 (Ang-2) monoclonal antibody LY3127804 as monotherapy and in combination with ramucirumab in advanced solid tumours.

Methods: Patients received intravenous LY3127804 monotherapy (4, 8, 12, 16, 20 and 27 mg/kg) in part A; LY3127804 (8, 12, 16, 20 and 27 mg/kg) with 8 mg/kg ramucirumab in part B; and LY3127804 (20 mg/kg) with 12 mg/kg ramucirumab in part C. Treatments were administered every 2 weeks (Q2W) during 28-day cycles. Dose-escalation was based on cycle 1 dose-limiting toxicities (DLTs).

Results: Sixty-two patients were treated in part A (n = 20), part B (n = 35) and part C (n = 7). Constipation, diarrhoea and fatigue were the most common treatment-emergent adverse events (TEAEs) in part A; hypertension and peripheral oedema were the most frequent TEAE in parts B and C. No DLT was observed and maximum tolerated dose for LY3127804 was not reached. Four patients achieved partial response with combination therapy (clear cell endometrial carcinoma, cervix squamous cell carcinoma, carcinoma of unknown primary and gastroesophageal junction carcinoma), 29 achieved stable disease, and 24 had progressive disease.

Conclusions: LY3127804 monotherapy and its combination with ramucirumab are well tolerated. LY3127804 20 mg/kg was the recommended Phase 2 dose.

Trial registration: ClinicalTrials.gov NCT02597036.

Conflict of interest statement

J.M.L. received lecture fees from Astellas Pharma, Bristol–Myers Squibb, Merck Sharp & Dohme (MSD), Novartis, Pierre Fabre, Pfizer, and Roche; advisory fees from Bristol–Myers Squibb, MSD, Novartis, Pierre Fabre, and Roche; and travel grants from Bristol–Myers Squibb, MSD, Novartis, Pierre Fabre, Pfizer, Roche and Ipsen. A.H. received honoraria/advisory fees from Gritstone Oncology, Eisai Co., Ltd., Amgen, Servier and Merck Serono. P.A. received honoraria/advisory fees from Novartis, Roche, MacroGenics, G1 Therapeutics, Servier, Synthon, Amcure, Amgen and Boehringer Ingelheim; and travel grants from MSD, Pfizer and Roche. C.J. received travel grants from PharmaMar S.A., Bayer and Ipsen. P Martin-Romano: Principal/sub-Investigator of Clinical Trials for AbbVie, Adaptimmune, Aduro Biotech, Agios Pharmaceuticals, Amgen, Argen-X Bvba, Arno Therapeutics, Astex Pharmaceuticals, AstraZeneca, AstraZeneca Ab, Aveo, Bayer Healthcare Ag, Bbb Technologies Bv, Beigene, Bioalliance Pharma, Biontech Ag, Blueprint Medicines, Boehringer Ingelheim, Boston Pharmaceuticals, Bristol–Myers Squibb, Bristol–Myers Squibb International Corporation, Ca, Celgene Corporation, Cephalon, Chugai Pharmaceutical Co., Clovis Oncology, Cullinan-Apollo, Daiichi Sankyo, Debiopharm S.A., Eisai, Eisai Limited, Eli Lilly, Exelixis, Forma Therapeutics, Gamamabs, Genentech, Gilead Sciences, Glaxosmithkline, Glenmark Pharmaceuticals, H3 Biomedicine, Hoffmann La Roche Ag, Incyte Corporation, Innate Pharma, Institut De Recherche Pierre Fabre, Iris Servier, Janssen Cilag, Janssen Research Foundation, Kura Oncology, Kyowa Kirin Pharm. Dev., Lilly France, Loxo Oncology, Lytix Biopharma As, Medimmune, Menarini Ricerche, Merck Kgaa, Merck Sharp & Dohme Chibret, Merrimack Pharmaceuticals, Merus, Millennium Pharmaceuticals, Molecular Partners Ag, Nanobiotix, Nektar Therapeutics, Nerviano Medical Sciences, Novartis Pharma, Octimet Oncology Nv, Oncoethix, Oncomed, Oncopeptides, Onyx Therapeutics, Orion Pharma, Oryzon Genomics, Ose Pharma, Pfizer, Pharma Mar, Philogen S.P.A., Pierre Fabre Medicament, Plexxikon, Rigontec Gmbh, Roche, Sanofi Aventis, Sierra Oncology, Sotio A.S, Syros Pharmaceuticals, Taiho Pharma, Tesaro, Tioma Therapeutics, Wyeth Pharmaceuticals France, Xencor, Y’s Therapeutics, Research Grants from AstraZeneca, BMS, Boehringer Ingelheim, Janssen Cilag, Merck, Novartis, Pfizer, Roche, Sanofi. P Martin-Romano also disclosed non-financial support (drug supplied) from AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Johnson & Johnson, Lilly, Medimmune, Merck, NH TherAGuiX, Pfizer, Roche. J.R.A. received personal fees and other from Novartis, Kelun Pharmaceuticals/Klus Pharma, Spectrum Pharmaceuticals Inc, Pfizer, Bayer. Personal fees from Eli Lilly and Company, Orion Pharmaceuticals, Roche Pharmaceuticals, Ellipses Pharma, Certera, Ionctura SA. Also conflict with European Journal of Cancer, VHIO/Ministero De Empleo Y Seguridad Social, Chinese University of Hong Kong, SOLTI, Elsevier, GlaxoSmithKline, ESMO, Department of Defense, Merck Sharp & Dohme, Louisiana State University, Huntsman Cancer Institute, Cancer Core Europe, Karolinska Cancer Institute, King Abdullah International Medical Research Center, WIN Consortium, Janssen, Tocagen, Symphogen, BioAlta, GenMab, CytomX, Kelun-Biotech, Takea-Millenium, and Ipsen. J.D.K. and W.Z. are employees and stockholders in Eli Lilly and Company. J.B. received grants and other from Gilead, Genentech/Roche, BMS, Five Prime, Eli Lilly and Company, Merck, MedImmune, Celgene, Taiho, Macrogenics, GlaxoSmithkline, Novartis, OncoMed, LEAP, TG Therapeutics, AstraZeneca, BI, Daiichi Sankyo, Bayer, Incyte, Apexigen, Array, Sanofi, Agios, Ipsen, Merrimack, Oncogenex, Evelo, Forma, Innate, Arch Oncology, Prelude Therapeutics, Amgen, Seattle Genetics, Bicycle Therapeutics, and Relay Therapeutics. Received grants from EMD Serono, Koltan, SynDev Rex, Abbvie, Onyx, Takeda, EISAI, Celldex, Xytomx, Nektar, Armo, Boston Biomedical, Tarveda, Tyrogenex, Marshall Edwards, Pieris, Mersana, Calithera, Blueprint, Merus, Effector, Novocare, Arrys, Tracon, Sierra, Jacobio, Unum Therapeutics, Vyriad, Harpoon, ADC, Pfizer, Millennium, Imclome, Acerta Pharma, Rgenix, Bellicum, Gossamer Bio, Arcus Bio, Tempest Tx, Shattuck Labs, Synthorx, Inc, Revolution Medicines, Inc, and Zymework. Conflict with Phoenix Bio, Cyteir, Molecular Partners, Torque, Tizona, Janssen, Tolero, TD2 (Translational Drug Development), Moderna Therapeutics, Tanabe Research Laboratories, Beigene and Continuum Clinical.

Figures

Fig. 1. Mean (±SD) LY3127804 concentration versus time profile.

The legend indicates LY3127804 dose level in mg/kg.

Fig. 2. Geometric mean (and range) of t1/2, Vd and CL for LY3127804.

All data presented as mean (SD). The parameters are presented after single administration (day 1, n = 56), two doses (day 15, n = 49) and three doses (day 29, n = 37).