Abstract CT164: Phase 1a/1b clinical trial of LP-284, a highly potent TP53 mutation agnostic DNA damaging agent, in patients with refractory or relapsed lymphomas and solid tumors (NCT06132503)

Abstract Background: Patients (pts) with relapsed or refractory (R/R) aggressive non-Hodgkin lymphoma (NHL) typically experience poor prognosis. In addition, despite advances in NHL therapies, TP53 mutations and double rearrangements of MYC and BCL2 have been associated with adverse clinical outcomes. LP-284, a DNA damaging agent with nanomolar potency in NHL cells, is agnostic of TP53 mutation status. In a TP53-mutated mantle cell lymphoma (MCL) xenograft model, LP-284 inhibited tumor growth at least 3-fold more than ibrutinib and bortezomib. Furthermore, LP-284 resulted in near complete tumor regression in a MCL model that is refractory to ibrutinib and bortezomib. In a high-grade B-cell lymphoma with MYC and BCL2 rearrangement xenograft model, LP-284 led to 99% tumor growth inhibition when used as a single agent and showed synergistic effect with rituximab. The above data strongly suggests that LP-284 is a promising therapy for aggressive R/R NHL, especially subgroups with TP53 mutation and/or MYC/BCL2 rearrangements. LP-284 also showed promise in the setting of solid tumors, as evidenced by strong anti-tumor potency in a spectrum of solid tumor cell lines and sarcoma xenograft models. Methods: This Phase 1, first-in-human, open-label, dose escalation study assesses the safety, tolerability, pharmacokinetics (PK) and clinical activity of LP-284 in adult pts with R/R lymphomas and solid tumors. Up to 30 adult pts will be enrolled in the Phase 1a dose escalation study. After completion of Phase 1a, up to 40 pts with R/R diffuse large B-cell lymphoma (DLBCL) and MCL, each, will be enrolled for a dose expansion Phase 1b study. The primary objectives of the Phase 1a study are to evaluate the safety and tolerability of escalating doses of LP-284 and to determine the MTD and RP2D. Participants will receive LP-284 via i. v. infusion on days 1, 8, and 15 of 28-day cycles. A Bayesian Optimal Interval (BOIN) design is being used to determine the MTD. Dose escalation involves single patient cohorts for the first 2 dose levels and at least 3 pts/cohort for subsequent dose levels. The secondary objectives are to characterize the PK and to assess the clinical activity of LP-284. The exploratory objectives are to evaluate the association between tumor response and changes in ctDNA and importantly to identify potential genomic features associated with LP-284 response, particularly those related to DNA damage response pathways. The primary objectives of Phase 1b are to obtain preliminary estimates of clinical activity in adult patients with R/R DLBCL and MCL, and to determine the dose of LP-284 for further development based on exposure-response/safety relationships derived from the totality of the data obtained from both Phase 1a and 1b. Trial (NCT06132503) is open to accrual. Citation Format: Jianli Zhou, Reginald Ewesuedo, Giulia Agnello, Aditya Kulkarni, Kishor Bhatia. Phase 1a/1b clinical trial of LP-284, a highly potent TP53 mutation agnostic DNA damaging agent, in patients with refractory or relapsed lymphomas and solid tumors (NCT06132503) abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (7Suppl): Abstract nr CT164.