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1012 Results from the Completed Dose Escalation Portion of the Phase 1 Study of HPN217, a Half-Life Extended Tri-Specific T Cell Activating Construct (TriTAC®) Targeting B Cell Maturation Antigen (BCMA) for Relapsed/Refractory Multiple Myeloma (MM)

Program: Oral and Poster Abstracts
Type: Oral
Session: 653. Multiple Myeloma: Prospective Therapeutic Trials: Relapsed and Refractory Myeloma
Hematology Disease Topics & Pathways:
Biological therapies, Antibody Therapy, Research, clinical trials, Chimeric Antigen Receptor (CAR)-T Cell Therapies, Clinical Research, Plasma Cell Disorders, drug development, Diseases, Therapies, Immunotherapy, Infusion, Lymphoid Malignancies
Monday, December 11, 2023: 5:15 PM

Sumit Madan, MD1, Caitlin L. Costello, MD2, Brea Lipe, MD3, Andrew J. Cowan, MD4,5,6,7,8,9, Eva Medvedova, MD10*, Jens Hillengass, MD, PhD11, P. Leif Bergsagel, MD12, Xavier Leleu, MD13, Cyrille Touzeau, MD, PhD14*, Daniel Morillo, MD15*, Albert Oriol16*, Raya Mawad, MD17, Henning Schade, MD18*, Salomon Manier, MD, PhD19, Yifah Yaron, MD, PhD20*, Banmeet Anand, PhD20* and Al-Ola Abdallah, MD21

1Banner MD Anderson Cancer Center, Gilbert, AZ
2Moores Cancer Center at University of California San Diego, San Diego, CA
3University of Rochester Medical Center, Rochester, NY
4Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA
5Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA
6Division of Medical Oncology, Department of Medicine, University of Washington, Seattle, WA
7University of Washington/Fred Hutchinson Cancer Center, Seattle, WA
8University of Washington, Seattle, WA
9Division of Medical Oncology, Fred Hutchinson Cancer Research Center, Seattle, WA
10Knight Cancer Institute, Oregon Health & Science University, Portland, OR
11Roswell Park, Buffalo, NY
12Division of Hematology/Oncology, Department of Internal Medicine, Mayo Clinic, Scottsdale, AZ
13Service D'Hématologie Et Thérapie Cellulaire, Poitiers, France
14Centre Hospitalier Universitaire de Nantes, Nantes, France
15Hematology Department, Hospital Universitario Fundación Jiménez Díaz, Madrid, Spain
16Hematology Department, Institut Català d’Oncologia and Institut Josep Carreras, Hospital Germans Trias I Pujol, Barcelona, Spain
17Fred Hutchinson Cancer Center, Seattle, WA
18Colorado Blood Cancer Institute, Denver, CO
19CHU Lille, Université de Lille, Lille, France
20Harpoon Therapeutics, South San Francisco, CA
21University of Kansas Medical Center, Kansas City, KS


HPN217 is a B Cell Maturation Antigen (BCMA)-targeting tri-specific T cell engager (TCE). HPN217 contains three binding domains including anti-BCMA for MM cell binding, anti-albumin for half-life extension, and anti-CD3 for T cell engagement and activation. HPN217 is a small (~50 kDa) globular protein, designed to increase the therapeutic window by minimizing off-target toxicities and cytokine release syndrome (CRS). HPN217 is under investigation in patients (pts) with heavily pretreated relapsed/refractory MM (RRMM).


This study is designed to assess the safety, pharmacology and early clinical activity of HPN217 using fixed and step-dose (prime dose followed by target doses) regimens in dose escalation cohorts along with expansion of selected regimens for further evaluation. Pts with RRMM who have received at least 3 prior therapies including a proteasome inhibitor, an immunomodulatory drug, and CD38-targeted therapy are eligible. Prior exposure to a BCMA-targeting agent is permitted. Primary objectives include evaluation of safety, tolerability, pharmacokinetics (PK), and determination of the Recommended Phase 2 Dose(s) (RP2D). Secondary objectives include preliminary efficacy. HPN217 is administered IV once weekly or once every 2 weeks. Adverse events (AEs) are graded by CTCAE 5.0, and ASTCT for cytokine release syndrome (CRS) and ICANS. Clinical activity is assessed per IMWG Response Criteria.


Dose escalation has been completed. 97 pts were enrolled across 15 dose escalation cohorts and expansion of 3 regimens with the highest target dose levels from dose escalation (12mg weekly; 24mg every 2 weeks; 24mg weekly for 1 cycle followed by 24mg every 2 weeks). As of 26 June 2023, across all cohorts, 94 pts were treated and had received a median (range) of 6 (2-19) prior lines of treatment (62% penta-exposed, 17% BCMA-targeted therapy, 68% prior transplantation). Median age was 70 (38-85) years. 36 pts (38%) remain on treatment. The most common (≥25%) treatment‑emergent adverse events (TEAEs) across all cohorts and in the 12mg and 24mg cohorts are summarized in Table 1. Dose limiting toxicities (DLTs) of reversible transaminitis (Gr 3, n=1; Gr 4, n=1) in 2 pts at 2.86 mg fixed dose during dose escalation informed the choice of 2.15 mg as priming dose in the highest step dose cohorts; a maximum tolerated dose (MTD) has not been reached in step dose cohorts.

All CRS events were grade 1-2 except one event of grade 3 CRS at 24 mg. Grade 1 ICANS was reported in 2 pts. Responses were observed at doses ≥ 2.15 mg. Among the 12mg and 24mg cohorts, 55% (22/40) of efficacy-evaluable pts currently have had a confirmed response (PR or better) including 2 pts with prior BCMA directed CAR-T cell therapy; disease assessments for recently enrolled patients are pending. Among pts with a response, 73% (16/22) have had a confirmed response of VGPR or better. Across all dose levels, the median time on treatment for pts with a confirmed response was 40 weeks (range 8.3-114 weeks), including 9 patients on treatment for over 12 months, with data maturing to include longer follow-up on patients recently enrolled. HPN217 exhibited linear and dose proportional PK across all dose groups with a median half-life of 68 hours (range 26-197 hours). Transient cytokine increases were higher with the initial/priming dose compared to subsequent/target doses.


Dose escalation of HPN217, a novel half-life extended BCMA-targeting T-cell engager, has been completed; the MTD was not reached in step dose cohorts. The 12mg and 24mg target doses are well tolerated with manageable adverse event profiles similar to those at lower dose levels and are associated with robust and durable clinical responses. Additional follow up of recently enrolled pts in 12 mg and 24 mg cohorts will inform the choice of the RP2D(s), and complete data on all pts enrolled will be presented. NCT04184050

Disclosures: Madan: Janssen: Consultancy, Speakers Bureau; BMS: Speakers Bureau; Karyopharm: Consultancy; GSK: Honoraria; Oncopeptides: Honoraria; Pfizer: Honoraria. Costello: Takeda: Consultancy, Research Funding; Regeneron: Honoraria; Poseida, Ionis, Harpoon Therapeutics: Research Funding; Pfizer: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Lipe: Janssen, GSK, BMS, ABBVIE, Sanofi: Consultancy. Cowan: BMS: Consultancy, Research Funding; EUSA: Consultancy; GSK: Consultancy; Harpoon: Research Funding; Janssen: Consultancy, Research Funding; Nektar: Research Funding; Sanofi: Research Funding; Secura Bio: Consultancy; Allogene: Consultancy; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Research Funding. Hillengass: Prothena: Consultancy; Sanofi: Consultancy; Axxess Network: Consultancy; OncLive: Consultancy; Janssen: Consultancy, Other: DSMB; Skyline: Consultancy; Oncopeptides: Consultancy; Amgen: Other: Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events; Beigene: Other: Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events; ESMO Florida: Other: Other: Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events; Targeted Oncology: Other: Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events; Angitia: Consultancy; Sebia: Consultancy; GSK: Consultancy, Research Funding. Bergsagel: Aptitude Health: Honoraria; Omeros: Consultancy; CellCentric: Consultancy; Novartis: Patents & Royalties: Royalty for hCRBN mice; Mayo Clinic: Patents & Royalties: Royalty for hCRBN and Vk*MYC mice; Pfizer: Research Funding; Radmetrix: Consultancy; Janssen: Consultancy; Salarius: Consultancy. Leleu: Takeda: Honoraria; AbbVie: Honoraria; Janssen: Honoraria; Sanofi: Honoraria; Novartis: Honoraria; Amgen: Honoraria; Merck: Honoraria; GSK: Honoraria; Harpoon Therapeutics: Honoraria; BMS/Celgene: Honoraria. Touzeau: Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees. Morillo: ABBVIE: Honoraria; GSK: Honoraria. Oriol: GSK: Consultancy, Honoraria, Speakers Bureau; BMS/Celgene: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Other: Consulting fees. Manier: Pfizer: Consultancy; Abbvie: Consultancy; Amgen: Consultancy; BMS: Consultancy; Janssen: Consultancy; Regeneron: Consultancy; Roche: Consultancy; Sanofi: Consultancy. Yaron: Harpoon Therapeutics: Current Employment. Anand: Harpoon Therapeutics: Current Employment.

*signifies non-member of ASH