A First-in-Human Phase 1 Dose Escalation and Expansion Study of the Oral CARD11-BCL10-MALT1 Signaling Pathway Inhibitor XL114 in Patients with Non-Hodgkin's Lymphoma

Background

Non-Hodgkin's lymphoma (NHL) represents a heterogeneous group of lymphoid neoplasms with an unmet medical need for patients who are refractory or resistant to current treatments. XL114 is an orally bioavailable inhibitor of the CARD11-BCL10-MALT1 (CBM) signaling pathway. Constitutive activation of the CBM pathway plays a role in various B-cell and T-cell malignancies, including tumor development, proliferation, and/or treatment resistance (Juilland M and Thome M. Curr Opin Hematol. 2016). XL114 exhibited antiproliferative activity in NHL cell lines with constitutively active CBM signaling, including activated B-cell‒like diffuse large B-cell lymphoma (ABC-DLBCL), mantle cell lymphoma (MCL), and follicular lymphoma cell lines. Dose-dependent tumor growth inhibition (TGI) with XL114 was demonstrated in two OCI-LY10 (human ABC-DLBCL cell line) murine xenograft models (Chikkanna D, et al. AACR 2021. Abstract 1266). Here we present the study design of an ongoing phase 1 trial in patients with NHL.

Study Design and Methods

This first-in-human, open-label, phase 1 trial (NCT05144347) consists of dose-escalation and cohort-expansion stages. In the dose-escalation stage (interval 3+3 design), a maximum tolerated dose (MTD) and/or recommended dose (RD) of XL114 will be determined in patients (~36) with various advanced B- and T-cell NHLs (Figure 1). Patients enrolled in the dose-escalation stage must have histologically diagnosed NHL (per World Health Organization classification) that has progressed and for which available therapies are intolerable, ineffective, or do not exist. The starting dose will be 100 mg orally once daily. Upon determining the MTD and/or RD, the expansion stage will enroll patients with NHL into tumor-specific cohorts (~23 patients per cohort): ABC-DLBCL, MCL, and chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) (Figure 2). Enrollment will be according to Simon's two-stage design, assuming a power of 80% and one-sided α of 10%. Patients enrolled in the expansion stages must be aged ≥18 years, have clinical or radiographic evidence of progressive disease that requires treatment in the opinion of the investigator, an Eastern Cooperative Oncology Group Performance Status of 0-1, and must have received 2-6 prior lines of systemic anticancer treatment. Additional patients (~12 ABC-DLBCL, MCL, or SLL) may be enrolled into a biomarker cohort to evaluate XL114 effects on tumor tissue and mechanisms of resistance. The primary endpoint of the expansion stage is to assess the objective response rate (ORR) of XL114 per the investigator based on tumor-specific response criteria. Additional endpoints are: safety and tolerability; pharmacokinetics; overall survival; duration of response (DOR) and progression-free survival (PFS) per the investigator; as well as ORR, DOR, and PFS per blinded independent radiology committee for selected cohorts. Exploratory endpoints include the relationship between pharmacokinetics, pharmacodynamics, tumor and blood biomarkers, efficacy, and safety. The study has started screening patients, with total enrollment estimated to be up to 144 patients.

Solis:Exelixis, Inc.: Current Employment, Current equity holder in private company. Vidal-Cardenas:Exelixis, Inc.: Current Employment, Current equity holder in private company. Uttamsingh:Exelixis, Inc.: Current Employment, Current equity holder in private company.