Phase 1 study of ARV-393, a PROTAC BCL6 degrader, as monotherapy in patients with advanced non-Hodgkin lymphoma (NHL) or combined with glofitamab in patients with diffuse large B-cell lymphoma (DLBCL)
Presenter: Lela Creutz Session: Phase I and Phase II Clinical Trials in Progress Time: 4/21/2026 2:00:00 PM → 4/21/2026 5:00:00 PM
Authors
Martin Hutchings 1 , Andrew Zelenetz 2 , Jacob H. Christensen 3 , Almudena Cascales Hernandez 4 , Sarit Assouline 5 , Luis E. Malpica Castillo 6 , Shalin Kothari 7 , Dipenkumar Modi 8 , Miguel A. Canales Albendea 9 , Damian Cubillas 10 , Alejandro M. Garcia-Sancho 11 , Catherine M. Diefenbach 12 , John Kuruvilla 13 , Paolo F. Caimi 14 , Krish Patel 15 , Sean Landrette 16 , Eric Zhi 16 , Yuanyuan Zhang 16 , Roland Meier 16 , Mathew J. Matasar 17 1 Rigshospitalet and University of Copenhagen, Copenhagen, Denmark, 2 Memorial Sloan Kettering Cancer Center, New York, NY, 3 Odense University Hospital, Odense, Denmark, 4 Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain, 5 McGill University, Montreal, QC, Canada, 6 The University of Texas MD Anderson Cancer Center, Houston, TX, 7 Yale School of Medicine and Yale Cancer Center, New Haven, CT, 8 Karmanos Cancer Institute/Wayne State University, Detroit, MI, 9 Clínica Universidad de Navarra, Pamplona, Spain, 10 START Center for Cancer Research, Madrid, Spain, 11 Hospital Universitario de Salamanca, Salamanca, Spain, 12 Laura and Isaac Perlmutter Cancer Center, New York University Grossman School of Medicine, New York, NY, 13 Princess Margaret Cancer Centre, Toronto, ON, Canada, 14 Cleveland Clinic, Cleveland, OH, 15 Sarah Cannon Research Institute, Nashville, TN, 16 Arvinas Operations, Inc., New Haven, CT, 17 Rutgers Cancer Institute of New Jersey, New Brunswick, NJ
Abstract
Background: Despite recent advancements in NHL therapies, many patients experience disease progression or relapse. Agents with novel mechanisms of action and combination strategies are needed to improve clinical outcomes. B-cell lymphoma 6 (BCL6) is a master transcriptional regulator of immune cells, particularly of germinal center B cells, and an established oncogenic driver in NHL. ARV-393 is an oral PROteolysis TArgeting Chimera (PROTAC) BCL6 degrader that binds an E3 ubiquitin ligase and BCL6 to induce ubiquitination of BCL6 and its subsequent proteasomal degradation. ARV-393 monotherapy potently inhibited tumor growth and induced tumor regressions across NHL cell-derived xenograft (CDX) and patient-derived xenograft models, including models of DLBCL, transformed follicular lymphoma, and nodal T-follicular helper cell lymphoma (nTFHL). Furthermore, administration of ARV-393 with a CD20×CD3 bispecific antibody, glofitamab, demonstrated combinatorial antitumor activity in a humanized high-grade B-cell lymphoma CDX model, inducing deeper tumor growth inhibition and increased tumor regressions vs either monotherapy. These preclinical findings demonstrated single-agent ARV-393 antitumor activity across NHL subtypes and suggested mechanistic synergy with glofitamab, supporting clinical investigation of monotherapy in NHL and this chemotherapy-free combination in patients with DLBCL. Methods: This global, multicenter, open-label, first-in-human, phase 1 dose escalation and optimization/expansion study (NCT06393738) is evaluating the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of ARV-393 as monotherapy in relapsed or refractory (R/R) NHL or in combination with glofitamab in R/R DLBCL, with a primary objective of determining provisional doses for further exploration. Patients eligible for ARV-393 monotherapy are adults with confirmed R/R B-cell NHL who previously received ≥2 lines of systemic therapy (including rituximab), or nTFHL who previously received standard of care therapy. Patients eligible for ARV-393 in combination with glofitamab are adults with pathologically confirmed R/R DLBCL, DLBCL not otherwise specified, or large B-cell lymphoma arising from follicular lymphoma who were treated with ≥2 prior lines of systemic therapy. ARV-393 will be administered orally once daily in 28-day cycles alone or in combination with intravenous glofitamab during 21-day cycles. Approximately 255 patients will be enrolled across study cohorts. As of January 2026, enrollment is ongoing.
Disclosure
M. Hutchings, AbbVie ). AstraZeneca ). Bristol Myers Squibb ). Celgene ). Genentech ). Genmab ). Incyte ). Johnson & Johnson ). Merck ). Novartis ). Roche ). Pfizer ). Seattle Genetics ). Takeda ). A. Zelenetz, BeOne Independent Contractor, ). Curio Science Independent Contractor. Genentech/Roche Independent Contractor, ). BMS Independent Contractor. AstraZeneca Independent Contractor, ). Arvinas Independent Contractor, ). Adaptive Biotechnologies Independent Contractor. Gilead Independent Contractor. Lilly ). International Lymphoma Radiation Oncology Group (ILROG) Travel. J. H. Christensen, Takeda ), Travel. Johnson & Johnson ). Beigene Travel. A. Cascales Hernandez, None. S. Assouline, Novartis ), Other, Consultancy/Advisory board; Speaker. AstraZeneca Other, Consultancy/Advisory board. AbbVie Other, Consultancy/Advisory board. BeOne Other, Consultancy/Advisory board. Roche Other, Consultancy/Advisory board. L. E. Malpica Castillo, Dizal Pharma Employment, ). S. Kothari, Eli Lilly Independent Contractor. ADC Therapeutics Independent Contractor. AbbVie Independent Contractor. Genentech Independent Contractor. Foresight Diangostics Independent Contractor. Incyte Independent Contractor. Bristol Myers Squibb ). D. Modi, Genentech ), Other, Consulting/advisory role (spouse). Karyopharm ). Regeneron ), Other, Honorarium. Genmab ), Consulting/advisory role. AstraZeneca ), Other, Consulting advisory role (spouse); Expert testimony. ADC therapeutics; Incyte; BMS; Daichi Sankyo (spouse) Other, Consulting/advisory role. M. A. Canales Albendea, None.. D. Cubillas, None. A. M. Garcia-Sancho, Gilead/Kite ), Travel, Other, Honoraria, Consulting fees. AbbVie; BMS; Janssen; Roche Travel, Other, Honoraria, Consulting fees. AstraZeneca, Ideogen, Lilly, Roche, Sobi Other, Honoraria, Consulting fees. BeOne, Incyte, Kyowa Kirin, Takeda Other, Honoraria. C. M. Diefenbach, None. J. Kuruvilla, AbbVie Independent Contractor, Other, Honoraria. AstraZeneca Independent Contractor, ), Other, Honoraria. BeOne Independent Contractor, ), Other, Honoraria. BMS Independent Contractor, Other, Honoraria. Kite/Gilead Independent Contractor, Other, Honoraria. Merck Independent Contractor, ), Other, Honoraria. Roche Independent Contractor, ), Other, Honoraria. OmniaBio Independent Contractor. Amgen Other, Honoraria. Arvinas Other, Honoraria. Genmab Other, Honoraria. Incyte Other, Honoraria. Janssen Other, Honoraria. Lilly Other, Honoraria. Novartis Other, honoraria. Pfizer Other, Honoraria. P. F. Caimi, ADC Therapeutics ). ContaX Stock. Genentech ). Genmab ). Novartis Independent Contractor. Recordati ). Abcon Stock Option. BMS Independent Contractor. K. Patel, AbbVie ), Other, Consulting (institution and self). Adaptive Biotechnologies ), Other, Consulting (institution and self). Adicet ). AstraZeneca ), Other, Consulting (institution and self). Bristol-Myers Squibb Other, Consulting (institution and self) Speakers Bureau (self). CRISPR Therapeutics ). Fate Therapeutics ). Genentech/Roche Other, Consulting (institution and self). Kite Other, Consulting and speakers bureau (self). Indapta Therapeutics ). Janssen ), Other, Consulting (paid to institution). Lilly ), Other, Consulting (paid to institution and self). Loxo Oncology ). MEI Pharma ). Merck ), Consulting (institution and self). Nurix; Pharmacyclics; Sana Biotechnology; Xencor ). Pfizer ), Consulting (paid to self). Arcus Biosciences; Avencell Therapeutics; BeOne Medicine; Century Therapeutics; Foresight Diagnostics; Genmab; Legend Biotech; Lyell Immunopharma; Sanofi Other, Consulting (paid to institution). Caribou Biosciences Other, Consulting (paid to institution and self). S. Landrette, Arvinas Employment, Stock, Stock Option. Orphai Therapeutics Stock, Patent. Yale University Patent. E. Zhi, Arvinas Employment, Stock. Y. Zhang, Arvinas Employment, Stock, Stock Option. R. Meier, Arvinas Independent Contractor. M. J. Matasar, AbbVie Independent Contractor, Other, Advisory/Consultancy. ADC Therapeutics Independent Contractor. AstraZeneca Independent Contractor. Epizyme Independent Contractor. Johnson & Johnson Independent Contractor. Kite Independent Contractor. Regeneron Independent Contractor. Roche Independent Contractor, ), Other, Advisory/Consultancy. Pfizer Independent Contractor, Other, Advisory/Consultancy. Hutch-Med Independent Contractor. Merck Stock Option. Bayer ). GM Biosciences ). Immunovaccine Technologies ). Janssen ). Genentech ). Pharmacyclics ). Seattle Genetics ). Recursion Pharmaceuticals, Arnold & Porter Other, Expert Testimony. Allogene; Arvinas; Genmab; Genentech; Incyte Corporation; Merck; Novartis; Visionaries Other, Advisory/Consultancy.
Cited in
Control: 9605 · Presentation Id: 12198 · Meeting 21436