Phase I/II trial of LAVA-1207, a novel bispecific gamma-delta T-cell engager alone, or with low dose IL-2 or pembrolizumab, in metastatic castration resistant prostate cancer (mCRPC).

Niven Mehra Radboud University Medical Center, Nijmegen, Netherlands info_outline Niven Mehra, Jens Voortman, David R Wise, Emiliano Calvo, Josep M. Piulats, Enrique Gonzalez-Billalabeitia, Ignacio Ortego, Umang Swami, Joel Picus, Meghan Karlik, Teeru Bihani, Jurjen Ruben, Sonia Macia, Hans J. van der Vliet, Marya F. Chaney, Debbie Robbrecht

Authors Niven Mehra Radboud University Medical Center, Nijmegen, Netherlands info_outline Niven Mehra, Jens Voortman, David R Wise, Emiliano Calvo, Josep M. Piulats, Enrique Gonzalez-Billalabeitia, Ignacio Ortego, Umang Swami, Joel Picus, Meghan Karlik, Teeru Bihani, Jurjen Ruben, Sonia Macia, Hans J. van der Vliet, Marya F. Chaney, Debbie Robbrecht Organizations Radboud University Medical Center, Nijmegen, Netherlands, Department of Medical Oncology, Amsterdam UMC, location VUMC, Amsterdam, Netherlands, Perlmutter Cancer Center, NYU Langone Health, New York, NY, START Madrid-CIOCC, Centro Integral Oncológico Clara Campal, Madrid, Spain, Medical Oncology Department, Catalan Institute of Cancer (ICO). Cancer Immunotherapy Group (CIT), Bellvitge Biomedical Research Institute (IDIBELL) —OncoBell, L'hospitalet De Llobregat, Barcelona, Spain, Hospital Universitario 12 de Octubre, Madrid, Spain, Early Phase Drug Development Program START Madrid-CIOCC, Centro Integral Oncológico Clara Campal, Madrid, Spain, Huntsman Cancer Institute at the University of Utah, Salt Lake City, UT, Washington University in St. Louis, St. Louis, MO, LAVA Therapeutics, Utrecht, Netherlands, LAVA Therapeutics N.V., Utrecht, Netherlands, Merck & Co, Inc., Rahway, NJ, Erasmus MC Kankerinstituut, Rotterdam, Netherlands Abstract Disclosures Research Funding LAVA Therapeutics Background: LAVA-1207 is a humanized bispecific antibody that binds with high affinity to the Vδ2 chain of Vγ9Vδ2-T cells and to prostate-specific membrane antigen (PSMA). It comprises a heterodimer of two fusion proteins, each consisting of a VHH linked to a human IgG1 Fc domain. Preclinical evidence demonstrates that, upon binding both targets, LAVA-1207 leads to potent Vγ9Vδ2-T cell degranulation and cytolytic activity against PSMA-expressing prostate cancer cells. IL-2 is an immune modulator which has been shown to support expansion of activated Vγ9Vδ2-T cells. PD-1 is an inhibitory immune checkpoint receptor that can dampen (Vγ9Vδ2-) T cell reactivity, suggesting that pembrolizumab could potentiate the effect of LAVA-1207. Methods: This trial is a phase 1/2a open label study with a 3+3 design in patients with refractory mCRPC to assess the safety of LAVA-1207 alone or with low dose IL-2 or with pembrolizumab, and to determine the recommended Phase 2a dose (RP2D). Secondary objectives include evaluation of pharmacokinetics, pharmacodynamics, immunogenicity, and preliminary antitumor activity. Exploratory endpoints include evaluation of the effect of study treatment on circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA). LAVA-1207 is administered IV every two weeks. Two parallel cohorts assessing LAVA-1207 with low dose subcutaneous IL-2 have been implemented: (1) single IL-2 administration and (2) three IL-2 administrations on consecutive days per cycle for up to four cycles. An additional dose escalation arm evaluates LAVA-1207 in combination with pembrolizumab, 400mg Q6W, IV. Patients with mCRPC that have failed at least one prior AR therapy and taxane-based chemotherapy (unless deemed medically unsuitable to receive a taxane) will be enrolled on the study. Patients should have progressive disease either by PSA or by RECIST 1.1 or appearance of 2 or more bone metastases. Patients must have ECOG performance status of 0-1. PSMA-PET is performed at baseline. Paired biopsies are requested to further assess LAVA-1207 activity. Dose escalation is ongoing. Expansion arm(s) will be included based on available data from part 1 of the study and may include one or more of LAVA-1207, LAVA-1207 with low dose IL-2, or LAVA-1207 in combination with pembrolizumab. Clinical trial information: NCT05369000.