First Results from the Dose Escalation Part of the Phase 1 Study of KTX1001, an Oral, First-in-Class, Potent Inhibitor of MMSET/NSD2 for Relapsed/Refractory Multiple Myeloma (RRMM)

Background:

Despite recent major advances, multiple myeloma (MM) remains incurable using therapies that are currently available to patients. There are no available/approved targeted therapies for MM that allow for individualized therapeutic approaches to the disease. Fifteen to 20% of newly diagnosed MM patients have a translocation of chromosomes 4 and 14 [t(4;14)]. This translocation puts transcription of the gene encoding Multiple Myeloma SET domain-containing protein (MMSET or NSD2), a histone 3 lysine 36 methyltransferase, under the control of the IgH super enhancer. The super enhancer drives the overexpression of MMSET resulting in an abnormal histone code that promotes myelomagenesis. Presence of t(4;14) is associated with poor clinical prognosis (Caro Am Soc Clin Oncol Educ Book 2021). KTX-1001 is a first-in-class, selective and potent small molecule inhibitor of MMSET, and is the first investigational drug that targets the t(4;14) MM patient population.

Methods:

This Phase 1, first-in-human open-label study (NCT05651932) is designed to assess the safety, tolerability, and initial clinical activity of KTX-1001 in relapsed/refractory MM (RRMM) and has two parts: dose escalation (Part A) and dose expansion (Part B). In Part B, only t(4;14)+ MM patients will be evaluated in single agent and combination expansion cohorts. Patients with RRMM who have received ≥3 prior lines of therapy, including a proteasome inhibitor (PI), immunomodulatory drug (IMiD), and anti-CD38 antibody are eligible for the dose escalation part. The primary objective of the study is to determine a recommended phase 2 dose (RP2D) and schedule of KTX-1001. Secondary and exploratory objectives include pharmacokinetic (PK) and pharmacodynamic (PD) evaluation of KTX-1001, and assessment of preliminary efficacy. KTX-1001 is administered orally until disease progression, unacceptable toxicity, or patient withdrawal from the study. A Safety Review Committee (SRC) reviews all data prior to each dose escalation decision and on a regular basis.

Results:

As of June 14, 2024, 17 patients (pts) have been treated with KTX-1001 in Part A across 6 dose levels (SRC reviewed). Dose Level 7 has been reached with no dose limiting toxicities (DLTs). Ten of these patients are t(4;14) positive. Patients have received a median of 5 prior lines of therapy (range: 3-17), including 7 pts with prior BCMA CAR-T, 6 pts with prior BCMA bispecific and/or ADC, 5 pts with prior non-BCMA bispecific, and 12 pts with prior transplant. Patient demographics include a median age of 68 years (range: 50-83), 10 male/ 7 female, 13 white, 2 black or African American, 2 as other identified race, and 3 Hispanic or Latino pts. Six pts remain on treatment. KTX-1001 shows excellent tolerability to date, with treatment emergent AEs (TEAEs) (CTCAEv5.0) predominantly of grade 1 and 2 severity. Most frequently observed TEAEs suspected to be related to KTX-1001 include fatigue (35%), diarrhea (24%), and constipation (24%), for which no grade 3 or 4 events have been observed. Frequency and/or severity of TEAEs have not increased with escalating doses nor treatment duration, and no patients have discontinued due to an AE. Two heavily pre-treated patients [one known to be t(4;14)+] have demonstrated long-lasting stable disease and clinical benefit at 10 and 7 months respectively. Both patients have been intra-patient dose escalated. For PK and PD data collected to date, drug exposure and steady-state concentration of KTX-1001 (at C1D15, when steady state concentration has been reached) appear to be dose-proportional. PD data indicate a dose-dependent decrease in the H3K36me2 mark on treatment versus baseline across dose levels 1 through 6, suggesting that the RP2D may be reached by year end. Updated results will be presented at the congress.

Conclusions:

Dose escalation of KTX-1001 is ongoing with an excellent tolerability profile to date and demonstration of on-target pharmacodynamics that will inform the determination of the RP2D(s). These PD data support the targeted mechanism of action of KTX-1001 to selectively inhibit MMSET and break the t(4;14) histone code. Given KTX-1001's promising safety profile, single-agent and combination expansion cohorts with standard-of-care MM agents/classes will begin in 2025 to further optimize doses and provide proof of concept in Part B of the Phase 1 study.

Bories:BMS Foundation, Janssen: Research Funding; Kite/Gilead, Novartis: Other: Travel/accommodation expenses ; AbbVie, BMS/Celgene, Kite/Gilead, Novartis, Servier: Honoraria. Gasparetto:Janssen, Amgen, GSK: Membership on an entity's Board of Directors or advisory committees; Connect registry BMS, GSK, Janssen, Pfizer: Membership on an entity's Board of Directors or advisory committees; BMS, Karyopharm, Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Dingli:BMS: Consultancy, Honoraria; Regeneron: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; MSD: Consultancy, Honoraria; K36 Therapeutics: Research Funding; Janssen: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Genentech: Consultancy; Sorrento: Consultancy, Honoraria; Apellis: Consultancy, Honoraria, Research Funding; Alexion: Consultancy, Honoraria. Lonial:Bristol Myers Squibb, Janssen Biotech Inc, Novartis, Takeda: Research Funding; TG Therapeutics Inc (no cancer agents currently): Membership on an entity's Board of Directors or advisory committees; AbbVie Inc, Amgen Inc, Bristol Myers Squibb, Celgene Corporation, Genentech, a member of the Roche Group, GSK, Janssen Biotech Inc, Novartis, Pfizer Inc, Regeneron Pharmaceuticals Inc, Takeda Pharmaceuticals USA Inc: Membership on an entity's Board of Directors or advisory committees. Usmani:Sanofi: Consultancy, Research Funding; Array Biopharma: Research Funding; Bristol-Myers Squibb - Celgene: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Merck: Research Funding; SeaGen: Consultancy, Research Funding; GSK: Consultancy, Research Funding; Genentech: Consultancy; Johnson & Johnson - Janssen: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Gilead: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Oncopeptides: Consultancy; SkylineDX: Consultancy, Research Funding; EdoPharma: Consultancy; TeneoBio: Consultancy; Sanofi: Consultancy, Research Funding; Pharmacyclics: Research Funding; Bristol-Myers Squibb - Celgene:: Consultancy, Research Funding; SecuraBio: Consultancy; Pfizer: Consultancy; Abbvie: Consultancy, Research Funding; Gracell: Consultancy. Berdeja: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, Speakers Bureau; AstraZeneca; BMS; Caribou Biosciences; Galapagos; Janssen; K36 Therapeutics; Kite Pharma; Legend Biotech; Pfizer; Regeneron; Roche; Sanofi-Aventis; Sebia; Takeda: Consultancy. Chung:Merck: Research Funding; Caelum Biosciences: Research Funding; Johnson & Johnson Innovative Medicine: Membership on an entity's Board of Directors or advisory committees, Other: travel reimbursement, Research Funding; K36 Therapeutics: Research Funding; Bristol Myers Squibb: Research Funding; Genentech: Research Funding; Cellectis: Research Funding; CarsGen Therapeutics: Research Funding; Abbvie: Research Funding. Afrough:Karyopharm Therapeutics: Honoraria, Other; Sanofi: Honoraria, Other; Bristol-Myers Squibb: Honoraria, Other; Adaptive Biotech: Research Funding; K36 Therapeutics: Research Funding; Abbvie: Research Funding. Rosiñol:Janssen, BMS, Amgen, Takeda, GSK, Menarini, Sanofi: Honoraria. Yee:Janssen, Amgen, BMS: Research Funding; Sanofi, Janssen, Adaptive Biotechnologies, Regneron, Prothena, GSK, Karyopharm, AbbVie, Amgen, BMS, Sebia: Consultancy. Trudel:GSK, BMS, Roche, Genentech, Pfizer, Janssen, K36 Therapeutics: Research Funding; GSK, BMS, Roche: Consultancy, Honoraria, Research Funding; Princess Margaret Cancer Centre: Current Employment; Sanofi, GSK, Pfizer, BMS, Janssen, AstraZeneca, BMS, Forus: Honoraria. Siegel:Merck: Honoraria; Sanofi: Honoraria; Pfizer: Honoraria; BMS: Honoraria; Envision Pharma: Honoraria; Envision Pharma: Honoraria; Sebia: Honoraria; Prothena: Honoraria; COTA: Current holder of stock options in a privately-held company; K36 Therapeutics: Honoraria; Roche: Honoraria. Rodríguez-Otero:Roche: Consultancy; Sanofi: Membership on an entity's Board of Directors or advisory committees, Other: Honoraria for lectures; Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Honoraria for lectures; GSK: Membership on an entity's Board of Directors or advisory committees, Other: Honoraria for lectures; Amgen: Other: Honoraria for lectures; Johnson & Johnson - Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Honoraria for lectures; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Regeneron: Other: Honoraria for lectures; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Honoraria for lectures; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel grants. Bang:K36 Therapeutics: Current Employment, Current holder of stock options in a privately-held company. Connolly:K36 Therapeutics, Pfizer: Current Employment, Current equity holder in private company, Current equity holder in publicly-traded company, Current holder of stock options in a privately-held company. Lewis:K36 Therapeutics: Current Employment, Current equity holder in private company, Current holder of stock options in a privately-held company. Flynt:K36 Therapeutics, Bristol Myers Squibb, JnJ, Abbvie, Pfizer, Amgen: Current Employment, Current equity holder in private company, Current equity holder in publicly-traded company, Current holder of stock options in a privately-held company, Ended employment in the past 24 months. Vazquez:K36 Therapeutics: Current Employment, Current holder of stock options in a privately-held company. Miskin:K36 Therapeutics, LAVA Therapeutics, TG Therapeutics: Current Employment, Current equity holder in publicly-traded company, Current holder of stock options in a privately-held company, Ended employment in the past 24 months. Winograd:K36 Therapeutics: Current Employment, Current equity holder in private company, Current holder of stock options in a privately-held company. Mateos:Pfizer: 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; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Johnson and Johnson: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Regeneron: Honoraria; Stemline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Honoraria; Salamanca University: Current Employment; Celgene: Honoraria.