Abstract
3081 Background: Zotatifin (eFT226) is a first in class, potent and sequence selective inhibitor of RNA helicase eIF4A1 that promotes stable mRNA:eIF4A:drug ternary complex at specific polypurine motifs within the 5’-UTR, preventing ribosome docking and thus, efficient translation of select transcripts. In preclinical models zotatifin treatment simultaneously down-regulated translation of numerous oncogenes with complex 5’ mRNA structures, including ERBB2, FGFR1/2, EGFR, KRAS, and CCND1. Methods: Patients (pts) with select advanced solid tumors harboring mutations/amplification of ERBB2, FGFR1, FGFR2, EGFR, or KRAS or with pancreatic cancer were enrolled into 3+3 dose escalation portion of the protocol (Part 1), and indication specific expansions continue to enroll at recommended phase 2 dose (RP2D; Part 2). The primary endpoints of Part 1 include determination of safety, tolerability, and maximum tolerated dose (MTD)/RP2D; additional endpoints include characterization of pharmacokinetic, pharmacodynamic (including from blood-based assay during escalation and from pre- and on-treatment biopsy at/near MTD with reverse phase protein array (RPPA)), and initial efficacy. Results: As of cut-off date Jan 13, 2022, Dose escalation phase (Part 1) included 37 patients treated with zotatifin at dose levels: 0.005, 0.01, 0.02, 0.035 mg/Kg IV weekly, and 0.035, 0.05, 0.07, 0.1 mg/kg IV 2 weeks-on and 1 week-off. DLTs were observed in 3 patients: Gr 2 thrombocytopenia (0.035 mg/kg weekly), Gr 3 anemia (0.1 mg/kg) and Gr 3 gastrointestinal bleed resulting in anemia (0.1 mg/kg). MTD/RP2D is 0.07 mg/Kg IV 2 weeks-on and 1 week-off. The most common treatment emergent adverse events (TEAEs) in Part 1 include: fatigue, anemia, diarrhea and dyspnea. The most common AEs at RP2D (n = 16 pts; Part 1 and Part 2) include: anemia (25% all gr 1 or 2), fatigue (25% all gr 1 or 2) and dyspnea (19%; 13% Gr 3) diarrhea (13%, all Gr 1 or 2). Pharmacokinetics were generally linear and dose proportional and exposures at MTD/RP2D are consistent with target pharmacologic levels in preclinical models. Blood based biomarkers showed dose- and time- dependent evidence of target engagement. Pre- and on-treatment biopsy data in expansion patients showed decreased expression of target proteins. No patient in dose escalation experienced an objective tumor response; initial efficacy data from Part 2 and at RP2D will be presented. Conclusions: eIF4A inhibitor zotatifin achieves pharmacologically relevant exposures with on-target AEs that are manageable at the MTD, with evidence of target knockdown from on-treatment biopsies. Part 2 indication-specific expansions (including in ER+ FGFR-amplified MBC as single agent, ER+ MBC in combination with fulvestrant and abemaciclib, and KRAS NSCLC in combination with sotorasib) are on-going. Clinical trial information: NCT04092673.
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have