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3233 Initial Results of Dose Escalation of ISB 1342, a Novel CD3xCD38 Bispecific Antibody, in Patients with Relapsed / Refractory Multiple Myeloma (RRMM)

Program: Oral and Poster Abstracts
Session: 653. Myeloma and Plasma Cell Dyscrasias: Prospective Therapeutic Trials: Poster II
Hematology Disease Topics & Pathways:
Research, clinical trials, Clinical Research, Plasma Cell Disorders, Diseases, Lymphoid Malignancies
Sunday, December 11, 2022, 6:00 PM-8:00 PM

Sanjay R Mohan, MD, MSCI1, Cristiana Costa Chase, MD2, Jesus G Berdeja, MD3, Lionel Karlin4*, Karim Belhadj, MD5*, Aurore Perrot, MD, PhD6*, Philippe Moreau, MD7*, Cyrille Touzeau8*, Thomas Chalopin9*, Alexander M Lesokhin, MD10, Carol Ann Huff, MD11, David H. Vesole, MD, PhD12, Joshua Richter, MD13, Jeffrey V. Matous, MD14, Igor Proscurshim, MD15*, Eileen Wolff15*, Girish Gudi, PhD15*, Andrew Garton16*, Vinu Menon, PhD17*, Sunitha Gn, PhD18*, Yacine Salhi16*, Eric J. Feldman, MD16* and Mohamad Mohty, MD PhD19

1Department of Medicine, Division of Hematology-Oncology, Vanderbilt-Ingram Cancer Center, Nashville, TN
2Duke University, Durham, NC
3Department of Hematology, Tennessee Oncology and Sarah Cannon Research Institute, Nashville, TN
4Department of Hematology, Hospices Civils de Lyon, Lyon Sud University Hospital, Pierre-Bénite, France
5Centre Hospitalier et Universitaire Henri Mondor, Creteil, France
6Hematology Department, University Hospital, Vandoeuvre Les Nancy, France
7Hematology Department, University Hospital Hôtel-Dieu, Nantes, France
8University Hospital Hôtel Dieu, Nantes Cedex 1, FRA
9Department of Hematology and Cellular Therapy, Tours University Hospital, UMR CNRS, François Rabelais University, Tours, France
10Memorial Sloan Kettering Cancer Center, New York, NY
11Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD
12Myeloma Division, John Theurer Cancer Center at Hackensack Meridian Health, Hackensack, NJ
13Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY
14Colorado Blood Cancer Institute, Denver, CO
15Ichnos Sciences, New York, NY
16Ichnos Sciences, New York
17Glenmark Pharmaceuticals, Mumbai, India
18Glenmark Pharmaceuticals Limited, Mahape, India
19EBMT Paris study office / CEREST-TC, Paris, France, Department of Hematology, Saint Antoine Hospital, Paris, France, INSERM UMR 938, Sorbonne University, Paris, France

Introduction: ISB 1342 is a heterodimer based on the Ichnos proprietary Bispecific Engagement by Antibodies based on the TCR (BEAT®) platform and is a humanized CD3xCD38 bispecific antibody designed to simultaneously engage the CD3 molecule on T cells and the CD38 antigen on multiple myeloma (MM) cells. By co-engaging CD3ε on T cells and CD38 on tumor cells, ISB 1342 redirects T cells to kill CD38-expressing tumor cells. This mechanism of action is differentiated from existing monospecific CD38 targeting therapies and was designed to overcome resistance to daratumumab in MM. We report here, findings from the dose-escalation portion of an ongoing, multi-center, open-label, single-agent phase 1 study (NCT03309111) of ISB 1342 in patients with RRMM.

Methods: Adult patients (≥18 years of age) with RRMM that relapsed after or were considered refractory to prior therapies, including a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 antibody; received escalating, intravenous (IV) doses of ISB 1342 every two weeks (Q2W) or weekly (QW) with a priming dose administered on the first day. The focus of this report will be on patients enrolled in the QW schedule. Patients had measurable disease per the International Myeloma Working Group (IMWG) updated criteria 2016. Dose escalation began with 0.001mg/kg (prime) / 0.003 mg/kg in the Q2W schedule with single patient accelerated titration for the first four cohorts then a “3 + 3” design; dose escalation in the QW schedule began at 0.2/0.3 mg/kg and followed a “3 + 3” design. The primary study objectives are to determine the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of ISB 1342. Secondary objectives included evaluation of anti-myeloma activity, pharmacokinetics (PK) and pharmacodynamics, and immunogenicity of ISB 1342.

Results: As of July 7, 2022, 24 patients had received a once weekly, IV infusion of ISB 1342 in 6 dose-escalation groups from 0.2/0.3 mg/kg dose level to 1.0 / 4.0 mg/kg dose level. The majority were males (63%) and white (67%); 21% were black or African American. The median age was 67 years (range, 54-76) and the median disease duration since onset was 6.7 years (range, 2.8-22.2). The median number of prior anti-myeloma lines of therapy was 6 (range 1-10); 8 (33%) patients had received prior B cell maturation antigen (BCMA)-targeted therapy including bi-specifics, antibody drug conjugates (ADCs) and/or cell therapies. Twenty-one (88%) patients were considered to be triple-refractory and 18 (75%) were considered to be penta-refractory. Twenty-two (92%) patients experienced treatment-related adverse events (TRAEs) of any grade. Most TRAEs were grade 1-2, including infusion related reactions (42%), anemia (21%), cytokine release syndrome (CRS, 17%), thrombocytopenia (17%), and diarrhoea (13%). Nine (38%) patients had grade 3 or higher TRAEs with only infusion related reactions occurring in more than 5% of patients (17%, all grade 3 events). No grade 5 TRAE was observed. One dose limiting toxicity (DLT), a Grade 3 delirium was observed in a 73-year-old patient treated at 0.3/0.55 dose level after the third dose of ISB 1342, and who also presented with Grade 4 pneumonia; three additional patients were enrolled at that dose level, no other DLT was observed, and dose escalation continued. The median duration of treatment was 2 months (range, 1-5). The ISB 1342 serum concentration-time profiles showed Cmax near the end of infusion, followed by a biphasic decline. The serum exposures showed a dose-dependent increase following both Q2W and Q1W regimens. With the Q1W regimen, the serum Ctrough was higher than that with the Q2W regimen at similar dose levels. Transient increases in serum cytokine levels were observed within 24 hours following ISB 1342 administration, including IFNg, TNFa, IL-2, IL-6 and IL-10.

Conclusions: Treatment with ISB 1342 was well tolerated at the dose levels evaluated. The observed CRS events were moderate. Dose escalation continues with additional dose cohorts accruing. The updated clinical, biomarker and PK data will be presented for this ongoing study.

Disclosures: Mohan: Astex: Research Funding; Incyte: Research Funding. Berdeja: My institution, Sarah Cannon Research Institute, receives research funds in my name for the following: 2Seventy bio, AbbVie, Acetylon, Amgen, Bluebird bio, BMS, C4 Therapeutics, CARsgen, Cartesian Therapeutics, Celgene, Celularity, CRISPR Therapeutics,: Research Funding; My institution, Sarah Cannon Research Institute, received consultancy payments for the following: Bluebird bio, BMS, Celgene, CRISPR Therapeutics, Janssen, Kite Pharma, Legend Biotech, SecuraBio, Takeda: Consultancy. Karlin: GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Financial Support travel & scientific meetings; Abbvie: Membership on an entity's Board of Directors or advisory committees; Celgene-BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Financial Support travel & scientific meetings. Belhadj: BMS, JANSSEN, SANOFI, AMGEN, ABBVIE: Consultancy, Honoraria, Other: Travel for ASH, ASCO and EHA Annual Meeting. Perrot: Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees. Moreau: AbbVie, Amgen, Celgene, Janssen, Oncopeptides, Sanofi: Honoraria. Lesokhin: Sanofi: Research Funding; BMS: Honoraria; Amgen: Honoraria; Pfizer, Genmab, Sanofi, Iteos, BMS, Janssen: Consultancy; Janssen, Pfizer, BMS, Genentech/Roche: Research Funding; Janssen, Pfizer, Iteos, Sanofi, Genmab: Honoraria; Trillium Therapeutics: Consultancy, Research Funding; Serametrix, inc: Patents & Royalties; Memorial Sloan Kettering Cancer Center: Current Employment. Huff: Prothena: Current equity holder in publicly-traded company; Glaxo Smith Kline: Research Funding; Oncopeptides: Research Funding; Janssen: Research Funding; Sanofi: Research Funding. Vesole: Jassen: Speakers Bureau; Amgen: Speakers Bureau; Karyopharm: Speakers Bureau; GSK: Speakers Bureau; BMS: Speakers Bureau; Takeda: Speakers Bureau. Richter: BMS/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Oncopeptides: Consultancy, Honoraria; Secura Bio: Consultancy, Honoraria; Takeda: Consultancy. Matous: BeiGene: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees. Proscurshim: Ichnos Sciences: Current Employment, Current holder of stock options in a privately-held company. Wolff: Ichnos Sciences: Current Employment. Gudi: Ichnos Sciences: Current Employment, Current holder of stock options in a privately-held company, Patents & Royalties. Garton: Ichnos Sciences: Current Employment. Menon: Glenmark Pharmaceuticals Ltd.: Current Employment. Gn: Glenmark Pharmaceuticals Limited: Current Employment. Salhi: Ichnos Sciences: Current Employment, Current holder of stock options in a privately-held company. Feldman: Ichnos Sciences: Current Employment, Current holder of stock options in a privately-held company. Mohty: GSK: Honoraria; Gilead: Honoraria; Oncopeptides: Honoraria; Pfizer,: Honoraria; Adaptive Biotechnologies: Honoraria; Astellas: Honoraria; Novartis: Honoraria; Amgen: Honoraria; Jazz Pharmaceuticals: Honoraria, Research Funding; Celgene: Honoraria; Bristol Myers Squibb: Honoraria; Takeda: Honoraria; Sanofi: Honoraria, Research Funding; Janssen: Honoraria, Research Funding.

*signifies non-member of ASH