P624: PHASE 1 STUDY OF JNJ-67856633, A FIRST-IN-HUMAN HIGHLY SELECTIVE MALT1 INHIBITOR, IN RELAPSED/REFRACTORY (R/R) B-CELL NON-HODGKIN LYMPHOMA (B-NHL) AND CHRONIC LYMPHOCYTIC LEUKEMIA (CLL)

Background: MALT1 (mucosa-associated lymphoid tissue lymphoma translocation protein 1) is a key component of the CARD11-BCL10-MALT1 (CBM) complex, which activates the classical NF-κB pathway. JNJ-67856633, a highly selective protease inhibitor of CBM-mediated NF-κB signaling, has demonstrated potent anti-lymphoma activity preclinically in vitro and in vivo. Aims: To present results from a phase 1, first-in-human dose escalation study (NCT03900598) of JNJ-67856633 in patients (pts) with R/R B-NHL and CLL. Methods: Eligible pts were those aged ≥18 years with R/R B-NHL or CLL (per WHO/iwCLL criteria), Eastern Cooperative Oncology Group performance status (ECOG PS) ≤1, and with ≥1 or 2 lines of therapy (LOT). Dose escalation was supported by a modified continual reassessment method to identify recommended phase 2 dose (RP2D). Pts in dose-finding cohorts received JNJ-67856633 orally at doses between 50 mg and 600 mg once daily. Loading doses (LD) were explored to accelerate steady-state exposure of JNJ-67856633: 2 LD using capsules at 400 mg once daily for 14 days followed by 300 mg once daily, and 300 mg twice daily for 7 days followed by 300 mg once daily. Similar LD were used for the tablet formulation. Results: At a clinical cutoff of January 22, 2023, 109 pts with R/R B-NHL or CLL received JNJ-67856633 (n=89, capsules; n=20, tablets). Median age was 70.0 years (range 20-89) and 64% were male. Over half the pts had ≥4 prior LOT. Median duration of treatment was 10.3 weeks (range 0.57-176.29). The most common histology was diffuse large B-cell lymphoma (DLBCL) (n=65; [59.6%]). Treatment-emergent AEs were reported in 97.2% of pts (Table). Hyperbilirubinemia was observed in 44.0% of pts and was taken into consideration when selecting the RP2D. Dose limiting toxicities were reported in 5 pts (400 mg, Grade 3 [G3] hyponatremia; 600 mg, G2 bradycardia; 300 mg, G3 febrile neutropenia; 400 mg LD, G3 renal failure; 300 mg LD, G3 acute renal failure); 4 pts continued with same dosing and 1 pt had dose reduction. Maximum-administered dose was 600 mg once daily and maximum-tolerated dose was not reached. Based on the toxicity profile, RP2D was 300 mg once daily and LD 300 mg. No new safety signals were observed with both formulations at different LD. Preliminary pharmacokinetic (PK) data showed that JNJ-67856633 is rapidly absorbed, with a median Tmax (time to reach maximum drug concentration) ranging from 2-5 hours, and slowly eliminated at doses of 50 mg to 600 mg. JNJ-67856633 accumulated approximately 8-fold upon multiple dosing. When administering the 50 mg capsule, steady-state exposure increased in an approximately dose proportional manner as the dose increased from 50 mg to 400 mg. Exposures were comparable between tablet doses of 200 mg or 240 mg and a capsule dose of 300 mg. Overall response rate (ORR) at the RP2D (n=36) was 27.8% (complete response, n=4 [11.1%]; partial response, n=6 [16.7%]). Responses were observed across indolent and aggressive histologic subtypes. Summary/Conclusion: Preliminary data from this first-in-human MALT1 inhibitor (JNJ-67856633) phase 1 dose escalation study indicates that it has a manageable hematological and non-hematological safety profile. JNJ-67856633 has demonstrated clinical activity in indolent and aggressive lymphomas. LD may be associated with a higher ORR and is further explored in expansion cohorts. The safety and efficacy results from this dose escalation study supported targeting MALT1 in pts with R/R B-NHL and CLL, and further evaluation of JNJ-67856633 in expansion cohorts.Keywords: Phase I, Non-Hodgkin’s lymphoma, relapsed/refractory, Chronic lymphocytic leukemia