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3339 Dose Escalation of ISB 1342, a Novel CD38xCD3 Bispecific Antibody, in Patients with Relapsed / Refractory Multiple Myeloma (RRMM)

Program: Oral and Poster Abstracts
Session: 652. Multiple Myeloma: Clinical and Epidemiological: Poster II
Hematology Disease Topics & Pathways:
Research, clinical trials, Clinical Research
Sunday, December 10, 2023, 6:00 PM-8:00 PM

Prashant Kapoor, MD1, Don A. Stevens, MD2*, Xavier Leleu, MD3, Karim Belhadj Merzoug4*, Lionel Karlin5*, Salomon Manier, MD, PhD6, Thomas Chalopin, MD7*, Cyrille Hulin, MD8*, Aurore Perrot, MD, PhD9, Jésus G Berdeja, MD10, Cristiana Costa Chase, MD11, Cyrille Touzeau, MD, PhD12*, Philippe Moreau, MD, PhD13*, Sanjay Mohan, MD, MSCI14, Alexander Lesokhin, MD15, Carol Huff, MD16, David H. Vesole, MD, PhD17, Joshua Richter, MD18, Jeffrey V Matous, MD19, Eileen Wolff20*, Tejas Shah20*, Jeppe Seestern Koch-Olsen21*, Andrew Garton, PhD20*, Vinu Menon22*, Sunitha Gn23*, Mario Perro, PhD24*, Eugene Zhukovsky25*, Cyril Konto, MD22, Lida Pacaud, MD22* and Mohamad Mohty, MD, PhD26

1Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN
2Norton Cancer Institute Brownsboro Hospital, Louisville, KY
3Service D'Hématologie Et Thérapie Cellulaire, Poitiers, France
4Hopital Henri Mondor, Creteil, FRA
5Hôpital Lyon Sud, Hospices Civils de Lyon, Pierre-Bénite, France
6CHRU Lille, Lille, France
7Centre hospitalier universitaire de Tours, Hospital, Tours, FRA
8CHU Hopitaux de Bordeaux, Hôpital Haut-Lévêque, Bordeux, France
9Service Hematologie, CHU de Toulouse, IUCT-O, Université de Toulouse, UPS, Service d’Hématologie, Toulouse, France
10Sarah Cannon Center For Blood Cancers, Nashville, TN
11Duke Cancer Institute, Durham, NC
12Centre Hospitalier Universitaire de Nantes, Nantes, France
13Hematology Clinic, University Hospital Hotel-Dieu, Nantes, France
14Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN
15Division of Hematology and Oncology, Memorial Sloan Kettering Cancer Center, New York, NY
16Johns Hopkins University, Baltimore, MD
17Multiple Myeloma Division, John Theurer Cancer Center, Hackensack Meridian Health, Hackensack, NJ
18Department of Medicine, Hematology and Medical Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY
19Sarah Cannon Research Institute, Colorado Blood Cancer Institute, Denver, CO
20Ichnos Sciences Inc., New York
21Ichnos Sciences, New York
22Ichnos Sciences, New York, NY
23Glenmark Pharmaceuticals Limited, Mumbai, India, Mumbai, India
24Ichnos Sciences Biotherapeutics SA, Epalinges, Switzerland
25Ichnos Sciences Biotherapeutics SA, Lausanne, Switzerland
26Saint-Antoine Hospital, Sorbonne University, Paris, France

Introduction: ISB 1342 is a humanized CD38xCD3 bispecific T-cell engager using Ichnos proprietary Bispecific Engagement by Antibodies based on the T cell receptor (BEAT®) platform, designed to simultaneously bind CD38 on multiple myeloma (MM) cells and CD3ε on T cells, to induce tumor killing. This mechanism of action is different from existing monospecific CD38 targeting therapies and was designed to overcome resistance to daratumumab in MM. ISB 1342 exhibits potent killing of the primary MM cells and MM cell lines with low sensitivity to daratumumab (Pouleau B. et al., Blood 2023; 142 (3): 260–273). We report here, the updated findings from the weekly dose-escalations of intravenous (IV) and subcutaneous (SC) injections of an ongoing, single-agent phase 1 study (NCT03309111) of ISB 1342 in patients with RRMM.

Methods: Adult patients with RRMM that relapsed after or were refractory to prior therapies, including a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 antibody; received ISB 1342 on a weekly (QW) schedule by IV or SC injection with a priming dose on the first day in 2 parallel dose-escalation schemas. Patients had measurable disease per the International Myeloma Working Group (IMWG) criteria (2016). Dose escalation in the QW schedule began at 0.2/0.3 mg/kg priming/treatment dose and followed a “3 + 3” design. The primary study objectives are to determine the maximum tolerated dose (MTD) and select a recommended phase 2 dose (RP2D) of ISB 1342. Secondary objectives includ evaluation of anti-myeloma activity, pharmacokinetics (PK), pharmacodynamics, and immunogenicity of ISB 1342.

Results: As of July 18, 2023, based on ongoing clinical database, 39 subjects had received weekly IV infusions of ISB 1342 in 8 dose-escalation groups from 0.2/0.3 mg/kg to 4.0/16.0 mg/kg as priming/treatment dose; and 7 additional subjects had received weekly SC injections at 2.0/8.0 mg/kg. Two different formulations have been tested in SC group. Median number of cycles administered was 2. The majority were male (57%) and white (74%); 13% were Black or African American. The median age was 69 years (range, 54-76) and the median time since diagnosis was 6.6 years (range, 2.8-22.2). The median number of prior anti-myeloma lines of therapy was 6 (range 1-12). Twenty-one (67%) subjects were considered to be triple-class refractory and 18 (48%) penta-drug refractory.

Forty-one (89%) subjects experienced treatment-related adverse events (TRAEs) of any grade. Most TRAEs were grade 1-2, including infusion related reactions (37%), cytokine release syndrome (CRS, 34%, all grade 1or 2), anemia (24%), neutropenia (24%), and thrombocytopenia (17%). Five subjects in SC group (71% of SC) had injection site reaction, all grade 1 or 2. Grade 3 or higher TRAEs occurring in more than 5% of subjects were infusion related reaction (no grade 4), anemia (no grade 4), neutropenia, leukopenia. No Grade 5 TRAE was observed.

After QW IV infusion, ISB 1342 serum concentration peaked at the end of infusion and then showed bi-exponential decline. ISB 1342 serum exposures increased in a dose linear fashion across the tested IV infusion dose range. The limited PK data after SC injection suggest slow presentation of ISB 1342 into the systemic circulation leading to lower Cmax and delayed Tmax relative to IV. Transient increases in serum cytokines were observed within 24 hours after ISB 1342 dosing, including IFNg, TNFa, IL-2, IL-6 and IL-10. Transient increases in T-cell activation were observed by flow cytometry at 24-48 hours after ISB 1342 dosing at 1.0 / 4.0 μg/kg and above, based on increased expression of CD69 on peripheral blood CD4+ and CD8+ T-cell populations (Figure 1). Comparison of the available data from subjects treated at 2 / 8 μg/kg (Cohort 109) indicated reduced T-cell activation following SC compared to IV administration of ISB 1342. The efficacy signals observed in Cohorts 108 and 109 are consistent with the estimates of the lower boundary of the predicted efficacious dose range using a quantitative systems pharmacology (QSP) model based on preclinical data. Updated clinical data, including response rates and safety data, will be present at the meeting.

Conclusions: Treatment with ISB 1342 was well tolerated at higher dose levels evaluated. Observed CRS events were moderate. No increased risk of infection has been observed . Updated safety, efficacy, biomarker and PK data will be presented.

Disclosures: Leleu: Novartis: Honoraria; Takeda: Honoraria; Janssen: Honoraria; BMS/Celgene: Honoraria; GSK: Honoraria; Sanofi: Honoraria; Harpoon Therapeutics: Honoraria; AbbVie: Honoraria; Merck: Honoraria; Amgen: Honoraria. Karlin: AbbVie, Amgen, Celgene, Janssen, Sanofi, Takeda: Honoraria; Amgen, Celgene, GSK, Janssen, Takeda: Consultancy. Manier: Pfizer: Consultancy; Janssen: Consultancy; Amgen: Consultancy; BMS: Consultancy; Abbvie: Consultancy; Regeneron: Consultancy; Roche: Consultancy; Sanofi: Consultancy. Hulin: Pfizer: Honoraria; AbbVie: Honoraria; Sanofi: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Bristol Myers Squibb: Honoraria. Perrot: Abbvie, Adaptive, Amgen, BMS, Janssen, Pfizer, Sanofi, Takeda: Honoraria. Berdeja: Celularity: Research Funding; Cartesian: Research Funding; CRISPR Therapeutics: Consultancy, Research Funding; 2seventy bio: Consultancy, Research Funding; Acetylon: Research Funding; Takeda: Consultancy, Research Funding; Sanofi: Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Janssen: Consultancy, Research Funding, Speakers Bureau; Genentech: Research Funding; GSK: Research Funding; Ichnos Sciences: Research Funding; AbbVie: Research Funding; Karyopharm: Research Funding; Legend Biotech: Consultancy; Lilly: Research Funding; Kite Pharma: Consultancy; Incyte: Research Funding; EMD Serono: Research Funding; Fate Therapeutics: Research Funding; CARsgen: Research Funding; C4 Therapeutics: Research Funding; Amgen: Research Funding; Celgene: Consultancy, Research Funding; Novartis: Research Funding; Teva: Research Funding; Roche: Consultancy; Poseida: Research Funding. Touzeau: Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees. Moreau: GSK: Honoraria, Other: Advisory Board; janssen, celgene BMS, abbvie, sanofi, amgen, takeda, pfizer: Honoraria, Other: advisory boards. Mohan: Karyopharm, Astex, Incyte, Kartos, Ichnos, NCCN: Research Funding. Lesokhin: BMS: Research Funding; Genentech: Research Funding; Janssen: Research Funding; Iteos: Consultancy; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Arcellx: Membership on an entity's Board of Directors or advisory committees; Serametrix (now Caprion): Patents & Royalties. Huff: Ichnos Sciences: Research Funding; Prothena: Research Funding; Sanofi: Honoraria. Richter: Astra Zeneca: Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Bristol-Meyers-Squibb: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Matous: BeiGene and Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Other: WM advisory Boards for both companies; Janssen: Other: consultancy and education talks to staff. Wolff: Ichnos Sciences Inc.: Current Employment. Shah: Ichnos Sciences: Current Employment. Koch-Olsen: Ichnos Sciences Inc.: Current Employment. Garton: Ichnos Sciences: Current Employment. Menon: Ichnos Sciences: Current Employment. Perro: Ichnos Sciences Biotherapeutics SA: 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. Mohty: JAZZ PHARMACEUTICALS: Honoraria, Research Funding.

*signifies non-member of ASH