Trial in Progress: A Phase 1b/2 Study of GB5121, a Brain-Penetrant, Potent, Highly Selective, and Irreversible BTK Inhibitor for Relapsed/Refractory Primary/Secondary CNS Lymphoma and Primary Vitreoretinal Lymphoma

Background: Bruton's tyrosine kinase (BTK) plays an important role in B cell receptor and Toll-like receptor signaling pathways, which are constitutively active in the majority of primary CNS lymphomas, and hence represents an excellent therapeutic target. Ibrutinib, a first-generation BTK inhibitor (BTKi), has been evaluated in two phase 1/2 trials for relapsed/refractory primary/secondary CNS lymphoma (R/R PCNSL, SCNSL) and primary vitreoretinal lymphoma (PVRL) showing limited survival benefit. Improved BTKis may achieve better therapeutic outcomes. GB5121 is an oral, brain-penetrant, potent, highly selective, irreversible, small molecule BTKi in development for hematologic malignancies with CNS involvement. Preclinical studies demonstrated that GB5121 exhibited several characteristics differentiating it from other BTKis, including rapid equilibrium into the brain, increased brain target occupancy, and fast inactivation rate. These characteristics combined with GB5121's kinase selectivity and activity in DLBCL models in vitro and in vivo support its clinical investigation in BTK-driven CNS lymphomas. To that end, a phase 1b/2 open-label, international study of GB5121 in adult subjects with R/R PCNSL, R/R isolated SCNSL, or PVRL has been initiated (STAR CNS; NCT05242146).

Objectives: The objective of the phase 1b dose-escalation portion of the study will be to evaluate safety, tolerability, pharmacokinetic/pharmacodynamic profile, dose-limiting toxicity (DLT), maximum tolerated dose, and therapeutic activity to determine the optimal biological dose that will inform the recommended phase 2 dose (RP2D). The phase 1b expansion study will further explore the therapeutic activity and characterize the safety and tolerability of GB5121 at the RP2D. The efficacy, safety, and tolerability of GB5121 at the RP2D established in the phase 1b dose escalation study will be investigated in phase 2.

Methods: The study will be conducted in three parts: phase 1b dose-escalation, phase 1b expansion, and phase 2. Eligibility criteria for phase 1b dose-escalation and expansion (N ≈ 30 for each part) include ≥ 18 years of age, ECOG ≤ 2, R/R PCNSL, R/R SCNSL with CNS-only relapse, or R/R PVRL. Patients with newly diagnosed PCNSL who cannot tolerate standard high-dose methotrexate-based therapies are also eligible. Subjects who had prior allogeneic stem cell transplant are excluded. A Bayesian optimal interval design will be employed to perform dose escalation with the primary objective of determining the recommended phase 2 dose. In the absence of DLT, subsequent dose levels will increase sequentially according to a modified Fibonacci approach. The phase 2 portion of the study will initiate following the determination of the RP2D based on phase 1 results and is a single-arm, open-label study of GB5121 in subjects with R/R PCNSL. Adverse events will be graded per Common Terminology Criteria for Adverse Events (CTCAE v5.0) to establish a toxicity profile. Therapeutic response (overall response rate, complete response, partial response) will be determined according to the criteria of the International Primary CNS Lymphoma Collaborative Group. Progression-free survival and overall survival will be evaluated. This clinical trial started enrollment in May 2022.

Results: N/A (trial in progress)

Conclusions: N/A (trial in progress)

Soussain:Gossamer Bio: Other: travel funding ; AstraZeneca: Research Funding; Hangzhou Henzen Pharmaceuticals: Research Funding. Lewis:AstraZeneca: Consultancy, Honoraria; Janssen: Honoraria, Patents & Royalties: conference attendance; Novartis: Patents & Royalties: conference attendance; Roche: Consultancy, Honoraria; Loxo/Lilly: Other: Trial Steering Committee; IQVIA: Membership on an entity's Board of Directors or advisory committees. Grommes:Scripps Conference Services & CME: Other: provision of services; Ono Pharma: Other: provision of services; Kite Pharmaceuticals: Other: provision of services; BTG International: Other: provision of services; Ampressa Therapeutics, Inc: Other: provision of services. Fox:CPRIT: Consultancy; Amphivena Therapeutics: Patents & Royalties; Viracta Therapeutics, Inc.: Consultancy, Current equity holder in publicly-traded company; Triursus: Consultancy; Sunesis Pharmaceuticals: Current equity holder in publicly-traded company, Ended employment in the past 24 months; Gossamer Bio, Inc.: Consultancy, Current equity holder in publicly-traded company. Ward:Gossamer Bio: Consultancy; Loxo Oncology at Lilly: Consultancy; InClin: Consultancy; CTI Biopharma: Consultancy. Peterson:Gossamer Bio, Inc.: Current Employment, Current equity holder in publicly-traded company. Cravets:Gossamer Bio, Inc.: Current Employment, Current equity holder in publicly-traded company. Mathias:Gossamer Bio, Inc.: Current Employment, Current equity holder in publicly-traded company. Sosa:Gossamer Bio, Inc.: Current Employment, Current equity holder in publicly-traded company. Kirby:Gossamer Bio, Inc.: Current Employment, Current equity holder in publicly-traded company. Ding:Gossamer Bio, Inc.: Current Employment, Current equity holder in publicly-traded company. Yusuf:Gossamer Bio, Inc.: Current Employment, Current equity holder in publicly-traded company. Rose:Gossamer Bio, Inc.: Current Employment, Current equity holder in publicly-traded company. Steinberg:Gossamer Bio, Inc.: Current Employment, Current equity holder in publicly-traded company. Tun:Gossamer Bio, Inc.: Consultancy, Research Funding.