Abstract Background: Cancer cells maintain fitness by developing survival adaptations that foster escape from intrinsic and extrinsic cell death under stress. Phosphatidylinositol 5-phosphate 4-kinase, type II, gamma (PIP4K2C) is a lipid kinase associated with poor outcomes in several cancers including colorectal (CRC), breast, and pancreatic cancer. PIP4K2C regulates its partners through a catalytic-independent mechanism and is co-opted by cancer cells to evade immune surveillance and adapt to stress. LRK-4189 is a first-in-class, oral heterobifunctional cereblon (CRBN) -dependent PIP4K2C degrader. LRK-4189 treatment reduced tumor growth and improved survival in multiple CRC mouse models and in ex vivo primary human CRC spheroids. Proof of mechanism is measured by PIP4K2C degradation and cytokines from peripheral blood. This supports the initial evaluation of LRK-4189 initial in healthy volunteers before advancing to cancer patients at a confirmed active dose. Methods: This randomized, double-blind, placebo-controlled phase 1 study assesses the preliminary safety, tolerability, PK and PD of single ascending doses of LRK-4189 in healthy adults. The sequential design includes five cohorts of eight subjects (total n=40), with six receiving LRK-4189 and two placebo. In each cohort, two sentinel subjects (one placebo, one active) are treated and observed for 48 hours before dosing the remaining subjects. Volunteers are screened and consented prior to admission on Day -1, dosed on Day 1, and discharged on Day 3. Outpatient follow-ups occur on Days 5, 7, and 15. Target engagement is measured by flow cytometry of PIP4K2C in peripheral blood mononuclear cells (PBMCs), and efficacy biomarkers by ex vivo blood stimulation followed by cytokine ELISA. Results: Enrollment is ongoing. The first two dosing cohorts are complete. No related adverse events were reported. One volunteer in cohort 1 reported a mild dry cough due to the environmental factors on Day 1, resolving within 10 days without treatment. In cohort 2, two volunteers reported mild events - one backache on Day 2 resolving by Day 3, and one of muscle/shoulder pain from exercise on Day 11. Neither required treatment. No clinically significant laboratory findings, ECGs, nor vital sign changes were seen in the first two cohorts. The data review committee approved the maximal three-fold dose escalation to dose levels 2 and 3. PK data are above detection limits from the first dose level. The exposure is within protocol-defined safety limits, allowing continued escalation. Data suggest LRK-4189 behaves well from a PK standpoint. Preliminary target engagement analysis provides suitable data for PD response assessment. Cytokine data will be presented. Conclusions: The study will be completed and reported fully at the conference. The data to date support the ongoing trial and preparation for a Phase 1-2 trial in CRC patients Clinical Trial Registration IRAS number: 1012766 Citation Format: Krista Goodman, Eva d'Hennezel, Morgan O'Shea, Melvyn Chow, Julie Arnold, Sujen Lai, Catherine Sabatos-Peyton, Amber Morgan, Phillipa Graham, Alice Bexon, Sharan Sidhu, Eric Van Cutsem. Proof of mechanism from a phase 1, single ascending dose (SAD) study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of LRK-4189 in healthy subjects abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (8Suppl): Abstract nr CT052.
Goodman et al. (Fri,) studied this question.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: