-Author name in bold denotes the presenting author
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4707 Initial Dose Escalation of ISB 1442, a Novel CD38 Biparatopic x CD47 Bispecific Antibody, in Patients with Relapsed / Refractory Multiple Myeloma (RRMM)

Program: Oral and Poster Abstracts
Session: 652. Multiple Myeloma: Clinical and Epidemiological: Poster III
Hematology Disease Topics & Pathways:
clinical trials, Research, Clinical Research
Monday, December 11, 2023, 6:00 PM-8:00 PM

Dickran Kazandjian, MD1, Hang Quach, MD, FRACP, FRCPA, MBBS2, Hanlon Sia3*, Phoebe Joy Ho, MBBS, FRACP, FRCPA4, Andrew Spencer, MBBS, MD, FRACP, FRCPA5*, Mark A. Schroeder, MD6, Binod Dhakal, MBBS7, Tara Cochrane, MBBS, FRCPA, FRACP8, Jeffrey A. Zonder, MD9, Nancy Yi10*, Dominique Duchesne11*, Tejas Shah11*, Andrew Garton, PhD11*, Vinu Menon12*, Sunitha Gn13*, Stefano Sammicheli14*, Eugene Zhukovsky14*, Cyril Konto, MD12, Lida Pacaud, MD12* and Peter Tan15*

1Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL
2St Vincent's Hospital - University of Melbourne, Melbourne, Australia
3Pindara Private Hospital, Benowa, QLD, AUS
4Institute of Haematology Royal Prince Alfred Hospital, University of Sydney, Sydney, AUS
5The Alfred Hospital, Melbourne, VIC, AUS
6Department of Internal Medicine, Division of Oncology, School of Medicine, Washington University, Saint Louis, MO
7BMT and Cellular Therapy Program, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI
8Department of Haematology, Gold Coast University Hospital, Southport, Australia
9Karmanos Cancer Institute, Detroit, MI
10Ichnos Sciences Inc., New York, NY
11Ichnos Sciences Inc., New York
12Ichnos Sciences, New York, NY
13Glenmark Pharmaceuticals Limited, Mumbai, India, Mumbai, India
14Ichnos Sciences Biotherapeutics SA, Lausanne, Switzerland
15One Clinical Research, Nedlands, Australia

Introduction: ISB 1442 is a fully human bispecific, biparatopic antibody that targets CD38 and CD47, generated using Ichnos’ Bispecific Engagement by Antibodies based on the T cell receptor (BEAT®) platform. ISB 1442 is designed to kill CD38-expressing tumor cells through multiple mechanisms of action including blocking CD47-signal regulatory protein alpha (SIRPα) axis to increase several antibody effector functions: antibody-dependent cellular phagocytosis (ADCP), antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) through optimized architecture, affinity to targets, and Fc engineering. ISB 1442 has 2 Fab domains binding to distinct CD38 epitopes that do not compete functionally with daratumumab. ISB 1442 is expected to have optimized tolerability with low potential for adverse effects on red blood cells (RBC) such as hemagglutination, platelet aggregation and RBC depletion (Sammicheli at al., ASH 2021, Blood (2021) 138 (Supplement 1): 73). We report here initial findings from the early dose-escalation portion of an ongoing, multi-center, open-label, single-agent phase 1/2 study (NCT05427812) of ISB 1442 in patients with RRMM.

Methods: Adult patients with relapsed refractory multiple myeloma (RRMM) to prior therapies, including a proteasome inhibitors (PIs), an immunomodulatory drugs (IMiDs), and an anti-CD38 antibodies received subcutaneous (SC) doses of ISB 1442 weekly (QW) in 28-day cycles. Patients had measurable disease per the International Myeloma Working Group (IMWG) criteria (2016). Dose escalation began at 6 mg dose with single patient accelerated titration phase for the first 3 cohorts, followed by a standard titration phase with a “3 + 3” design. The primary study objective for phase 1 is to assess the safety and tolerability to determine the maximum tolerated dose (MTD) and select the recommended phase 2 dose (RP2D) of ISB 1442. For phase 2 the primary study objective is to evaluate efficacy of ISB 1442. Secondary objectives include evaluation of pharmacokinetics (PK) and immunogenicity of ISB 1442. Exploratory objectives include assessment of minimal residual disease (MRD), assessment of cellular biomarkers in blood and bone marrow, and soluble factors in blood, and their correlation with efficacy, safety and other clinical endpoints of interest.

Results: As of July 18, 2023, based on preliminary data from ongoing clinical database, 10 subjects had received once weekly SC injections of ISB 1442 in 4 dose-escalation groups from 6 mg to 150 mg. The majority were male (60%) and white (90%). The median age was 67 years (range 57-79). The median number of prior anti-myeloma lines of therapy was 6 (range 3-7); 70% were exposed to 5 drugs (2PIs, 2IMiDs, and CD38). The median number of ISB 1442 cycles was 1(range 1-2). Eight subjects (80%) experienced treatment-related adverse events (TRAEs), all were grade 1 or 2: cytokine release syndrome (CRS) (50%), injection site reactions (injection site erythema 20%, injection site bruising 10%), anemia (10%, 1 subject, grade 2) (Table 1). No grade 5 TRAE was observed. Following QW SC injection, ISB 1442 was slowly absorbed into the systemic circulation with Tmax generally occurring on day 2 of dosing. The ISB 1442 serum concentrations generally remained quantifiable over the entire dosing duration from 20 mg and above. The available PK data suggest an approximately dose-linear increase in serum concentration up to DL 3 (60 mg), followed by a supra-proportional increase in serum levels in subjects treated at DL 4 (150 mg). To date, 5 subjects treated at DL4 (150 mg) have experienced clinical symptoms of CRS (Grade 1-2) following the first dose of ISB 1442. Assessment of a panel of 63 soluble factors (including multiple cytokines, chemokines and growth factors) in the peripheral blood revealed that several subjects at DL3-4 exhibited transient increases (>10-fold) in macrophage inflammatory protein-1b (MIP-1b/CCL4) within 24h after treatment with ISB 1442, consistent with a macrophage-associated mechanism of action.

Conclusions: Treatment with ISB 1442 was well tolerated at the dose levels evaluated. The observed clinical CRS events were moderate and potentially related to macrophage activation following ISB 1442 administration. Updated clinical, biomarker and PK data will be presented for this ongoing study.

Disclosures: Kazandjian: Bridger Consulting Group: Consultancy, Honoraria; Aptitude Health: Consultancy, Honoraria; Aperture Medical Technology, LLC: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Arcellx: Consultancy, Current Employment, Honoraria; Bristol Myer Squibb: Consultancy, Honoraria; MMRF: Ended employment in the past 24 months, Honoraria; MJH Life Sciences: Current Employment, Honoraria; Karyopharm Therapeutics: Current Employment, Speakers Bureau; Plexus Communications: Ended employment in the past 24 months, Honoraria; Curio Science: Ended employment in the past 24 months, Honoraria; Alphasights: Consultancy, Honoraria. Quach: Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: receipt of study materials, Research Funding; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: receipt of study materials; Leadership or fiduciary role, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Leadership or fiduciary role, Research Funding; Sanofi: Consultancy, Honoraria, Other: receipt of study materials, Research Funding; Janssen: Consultancy; Abbvie: Consultancy; Antengene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Research Funding. Schroeder: Incyte: Honoraria; GSK: Consultancy; Novo nordisk: Consultancy; Sorrento therapeutics: Membership on an entity's Board of Directors or advisory committees; Kura: Membership on an entity's Board of Directors or advisory committees; Marker Therapeutics: Membership on an entity's Board of Directors or advisory committees. Dhakal: Janssen, Karyopharm, GSK, Arcellx, GSK, Sanofi, Genentech, Pfizer: Consultancy, Honoraria, Speakers Bureau. Cochrane: Beigene: Research Funding; Imago BioSciences, Inc., a subsidiary of Merck & Co., Inc., Rahway, NJ, USA: Research Funding; Janssen-Cilag: Speakers Bureau. Zonder: Janssen, Prothena, Regeneron: Consultancy; Takeda, Telios: Other: Consultancy which has ended within the past 24 months; Bristol-Myers Squibb/Celgene: Research Funding. Yi: Ichnos Sciences Inc.: Current Employment. Duchesne: Ichnos Sciences: Current Employment. Shah: Ichnos Sciences: Current Employment. Garton: Ichnos Sciences: Current Employment. Menon: Ichnos Sciences: Current Employment. Sammicheli: Ichnos Sciences: Current Employment. Zhukovsky: Ichnos Sciences Biotherapeutics SA: Current Employment. Konto: Ichnos Sciences: Current Employment. Pacaud: Ichnos Sciences Inc.: Current Employment, Current holder of stock options in a privately-held company. Tan: Gilead: Research Funding; Constellation Pharmaceuticals, Inc: Research Funding; Genor Biopharma Co. Ltd: Research Funding; Qilu Pharmaceuticals Co. Ltd: Research Funding; Loxo Oncology at Lilly: Research Funding; Kartos Therapeutics: Research Funding; Shanghai EpimAb Biotherapeutics: Research Funding; Bristol-Myers Squibb: Research Funding; Janssen: Research Funding; Abbvie: Research Funding; Beigene: Research Funding; Ellipses Pharma: Research Funding; Novartis: Research Funding; Protagonist Therapeutics, Inc: Research Funding; Ichnos Sciences SA: Research Funding.

*signifies non-member of ASH