Background and Significance:

lsatuximab (Isa) is an anti-CD38 monoclonal antibody that induces myeloma cell death through multiple mechanisms. Intravenous (IV) Isa is currently approved to treat relapsed and/or refractory multiple myeloma (RRMM) in combination with pomalidomide and dexamethasone (Isa-Pd) or carfilzomib and dexamethasone (Isa-Kd).

In most countries, the approved Isa IV regimen comprises a 250-mL fixed-volume infusion administered over 75 minutes from the third infusion onwards. Subcutaneous (SC) Isa administration offers shorter duration (median ~10 mins) and a smaller fixed administration volume (10 mL). Device-mediated SC administration may offer further benefits over manual SC administration, including hands-free treatment delivery, a smaller and hidden needle, and controlled flow rate. Such improvements in route and duration of administration can ultimately improve patients' quality of life and reduce healthcare resource utilization (Anderson KC et al. Future Oncol 2019;15:3267-81).

Therefore, there is a need to confirm efficacy and safety of SC Isa in the combinations that have been approved for IV Isa. In a Phase 1b study (NCT04045795) in patients with RRMM, efficacy and safety of SC Isa administered by an investigational on-body delivery system (OBDS) plus Pd were comparable to IV Isa-Pd, with no infusion reactions (IRs) (Quach H et al. Clin Lymphoma Myeloma Leuk 2023;23(Suppl. 2):S206-7).

Here, we describe the design of a Phase 2 trial to assess the efficacy and safety of SC Isa, administered by OBDS, in combination with weekly carfilzomib and dexamethasone, in patients with RRMM.

Study Design and Methods:

SubQSA (NCT06356571) is a single-arm, open-label, Phase 2 study of patients receiving SC Isa via OBDS in combination with weekly carfilzomib and dexamethasone at 30-40 sites in the USA. Eligible patients will be aged ≥18 years with documented diagnosis of RRMM and measurable disease, having received 1-3 prior lines of therapy. Exclusion criteria will include diagnosis of primary refractory MM, prior treatment with carfilzomib, prior anti-CD38 received <6 months before the first Isa dose, and intolerance to previously received anti-CD38.

Isa (10 mL) will be administered by OBDS, at the recommended SC Phase 2 dose of 1400 mg, on Days (D) 1, 8, 15 and 22 for Cycle (C) 1 and then on D1 and 15 for subsequent cycles. The Isa OBDS (Enable Injections, Inc., Cincinnati, OH, USA), is a sterile, single-use, disposable, elastomeric, user filled, wearable bolus injector applied to a single injection site in the periumbilical region that is rotated at each administration. Carfilzomib will be administered at 20 mg/m² on C1D1 and then escalated to 70 mg/m² on D8 and 15 of C1, followed by D1, 8 and 15 of subsequent cycles. Once-weekly dosing of carfilzomib was chosen for this study because it most accurately represents real-world US practice. Dexamethasone will be administered at 20 mg on D1, 8, 15, and 22 of C1 and then on D1, 8 and 15 of subsequent cycles; administration will be IV on C1D1, and subsequently either IV or oral. Duration of each cycle will be 28 days. In addition to dexamethasone, patients will receive premedication for IRs with montelukast (C1 only), acetaminophen, and diphenhydramine. Patients can continue therapy until disease progression, unacceptable adverse events (AEs), patient request to discontinue treatment, or any other reason. After 12 months of study treatment, patients can switch to post-trial access.

The primary endpoint will be overall response rate (ORR), defined according to International Myeloma Working Group criteria. Secondary endpoints will include safety (incidences of IRs, treatment-emergent AEs, serious AEs, laboratory abnormalities), tolerability (injection site reactions), efficacy (rate of complete response or better, very good partial response or better, duration of response, time to first response, time to best response), patient satisfaction, immunogenicity, and pharmacokinetic (PK) exposure parameters. AE severity will be graded according to NCI CTCAE v5.0.

Estimated enrollment will be 64 patients, of whom 15 will participate in immunogenicity/PK analyses. Cutoff date for primary analysis will be 6 months after last participant in (LPI); final analysis will be performed 12 months after LPI. ORR will be summarized with a two-sided 95% confidence interval by the Clopper-Pearson method.

This study is not yet recruiting.

Funding: Sanofi.

Disclosures

Buck:Sanofi, Jansen, BMS: Honoraria. Geils:AbbVie: Other: Investigator on trial. Philipovskiy:Immuneering: Research Funding; Arvinas: Research Funding; AbbVie: Research Funding; Valerio: Research Funding; Frontier Med: Research Funding; Monte Rosa Therapeutics: Research Funding; Florida Cancer Specialists and Research Institute: Current Employment. Barnes:Sanofi: Current Employment. Brill:Sanofi: Current Employment. Fukao:Sanofi: Current Employment. Leroy-Carita:Sanofi: Current Employment. Berdeja:AstraZeneca; BMS; Caribou Biosciences; Galapagos; Janssen; K36 Therapeutics; Kite Pharma; Legend Biotech; Pfizer; Roche; Sanofi-Aventis; and Takeda: Consultancy; 2 Seventy Bio; Abbvie; Amgen; BMS; C4 Therapeutics; Caribou Biosciences; CARsgen; Cartesian Therapeutics; Celularity; CRISPR Therapeutics; Fate Therapeutics; Genentech; GSK; Ichnos Sciences; Incyte; Janssen; Juno Therapeutics; K36 Therapeutics; Karyopharm: Research Funding; Janssen: Honoraria.

Off Label Disclosure:

Isatuximab is currently approved in various countries for intravenous administration in patients with relapsed/refractory multiple myeloma (RRMM). The present study investigates subcutaneous administration of isatuximab in patients with RRMM.

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2024
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