Session: 626. Aggressive Lymphomas: Prospective Therapeutic Trials: Poster II
Hematology Disease Topics & Pathways:
Therapies
In preclinical studies, IKS03 demonstrated significant in vivo efficacy with complete tumor regressions in CD19-positive diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and mantle cell lymphoma (MCL) xenograft models at single doses of 0.1 to 1 mg/kg. IKS03 demonstrated greater activity than the clinical benchmark ADC loncastuximab tesirine. IKS03 is also highly effective in patient-derived xenograft models that contain some of the genetic alterations commonly found in relapsed/refractory NHL patients. Results from toxicology studies in cynomologus monkey suggest a manageable safety profile at single doses, well above those required for in vivo activity. Pharmacokinetics are favorable with a mean total ADC half-life of 8 days and undetectable levels of the active PBD payload in circulation confirming targeted delivery of the payload.
Study Design and Methods: This Phase 1 multicenter, open label, non-randomized study of IKS03 will consist of two parts: dose-escalation (Part I) and dose-expansion (Part II) together enrolling approximately 140 adult patients with relapsed or refractory B-cell NHL after at least two prior lines of systemic therapy. Patients will receive repeat doses of study drug by IV infusion on Day 1 of each 21-day cycle, until disease progression, unacceptable toxicity, or another withdrawal criterion is met. Key exclusion criteria include: active central nervous system involvement with NHL; clinically significant cardiovascular, pulmonary or hepatic disease; or receipt of other CD19-directed therapy within 3 months.
Part I dose escalation will enroll patients with confirmed CD19-positive, measurable or non-measurable advanced B-cell NHL. Eligible subtypes include DLBCL, MCL, FL, high-grade B-cell, and marginal zone lymphoma as per WHO 2016 classification. Patients with Burkitt’s lymphoma, Waldenström macroglobulinemia, and chronic lymphocytic leukemia are excluded. In Part 1, the primary objective is establishment of the recommended Phase 2 dose (RP2D) by evaluation of safety, tolerability and the maximum tolerated dose (MTD) of IKS03. Dose escalation will follow a 3+3 design. A two cycle Dose-Limiting Toxicity (DLT) assessment period will be observed, and dose-escalation decisions will be guided by a study safety committee. Dose escalation increments will be adjusted based on occurrence of protocol-specified DLTs as well as overall tolerability. Secondary objectives include characterization of immunogenicity and pharmacokinetic (PK) profile of IKS03. Exploratory objectives include preliminary antineoplastic activity per Lugano criteria (Cheson et al, JCO 2014) and evaluation of pharmacodynamic markers.
Part II will further evaluate the antineoplastic activity of IKS03 at the RP2D in expansion cohorts of patients with selected NHL subtypes and with measurable disease. Sample size will be determined for each subtype using a Simon Two-Stage design. Secondary objectives include further evaluation of safety, tolerability, immunogenicity and PK profile of IKS03 as well as confirmation of the RP2D. Clinical trial information: NCT05365659.
Disclosures: Assouline: BeiGene: Consultancy; Novartis Canada: Research Funding; AbbVie: Honoraria; Janssen: Honoraria; Roche-Genentech: Honoraria; Ipsen: Consultancy; AstraZeneca: Honoraria; Gilead: Honoraria; Palladin: Honoraria. Lewis: Janssen: Honoraria; Loxo/Lilly: Other: Travel, Accommodations, Expenses and Trial Steering Committee; Merck/MSD: Other: Advisory Board participant; Roche: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria. Harrup: F. Hoffmann-La Roche Ltd, Takeda: Current equity holder in publicly-traded company; F. Hoffmann-La Roche Ltd, Beigene: Research Funding; FibroGen: Research Funding. Lutz: Iksuda Therapeutics Ltd: Consultancy. Thirlway: Iksuda Therapeutics Ltd: Current Employment. Deckert: Iksuda Therapeutics Ltd: Consultancy. Browning: Iksuda Therapeutics Ltd: Consultancy. Wood: Iksuda Therapeutics Ltd: Consultancy. Nadler: Iksuda Therapeutics Ltd: Consultancy.
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