Phase 1b/2 Study of Oral LRK-4189 Monotherapy and LRK-4189 Combination Therapy with Standard Chemotherapy in Metastatic Colorectal Cancer and Solid Tumors

The primary objective is to identify an appropriate dose of LRK‑4189—either the active dose or the maximum tolerated dose—for initial expansion, to evaluate its preliminary efficacy in patients with metastatic colorectal cancer, and to determine the optimal dose for specific indications, thereby informing dose selection for subsequent studies.

Secondary objectives include:

• Determine the pharmacokinetics of LRK‑4189.
• Further document safety and tolerability of LRK‑4189.
• Document the safety, tolerability, pharmacokinetics and preliminary efficacy of LRK‑4189 in combination with mFOLFOX6 or FOLFIRI.
• Evaluate the mechanism of action through the pharmacodynamics of LRK‑4189.

The trial enrolled 120 adult patients with histologically confirmed metastatic colorectal cancer arising from solid tumors. Eligible participants were ≥18 years of age, of any gender, and had an ECOG performance status of 0 to 1, indicating full activity or limited strenuous activity while ambulatory. All subjects possessed measurable disease per RECIST 1.1 and had progressed after at least one line of standard‑of‑care systemic therapy. Inclusion required adequate organ function, resolution of prior treatment‑related adverse events to Grade 1 or baseline (except alopecia), and provision of a recent formalin‑fixed paraffin‑embedded tumor biopsy. Reproductive safety criteria mandated appropriate contraception for both female and male participants. Exclusion criteria encompassed uncontrolled cardiac QTcF > 480 msec, active infections, and other conditions compromising safety. The cohort comprised both male and female individuals classified as vulnerable, reflecting the advanced disease status of the population.

The study is a Phase 1b/2, open‑label, dose‑escalation, expansion and optimization trial designed to identify the recommended dose of LRK‑4189 alone or in combination with mFOLFOX6 or FOLFIRI in participants with solid tumors. Dose escalation follows a standard 3 + 3 algorithm to determine the maximum tolerated dose or an active dose for subsequent expansion cohorts; no randomization or blinding is employed. The sequence of visits includes a screening visit for informed consent, eligibility assessments, laboratory tests, ECG, and collection of a formalin‑fixed paraffin‑embedded tumor biopsy; a baseline visit on Day 1 of Cycle 1 for administration of the first dose; on‑treatment visits on Day 1 of each subsequent cycle for safety evaluation, pharmacokinetic and pharmacodynamic sampling, and drug administration; imaging assessments every eight weeks using RECIST 1.1 criteria; an end‑of‑treatment visit after the last administered dose; and a safety follow‑up visit approximately 30 days after discontinuation. Participants are expected to remain in the trial for up to twelve treatment cycles (approximately 12 months) plus the follow‑up period, resulting in a total involvement of no more than 15 months. Early termination may occur if a dose‑limiting toxicity is observed, if disease progression is documented, if unacceptable laboratory abnormalities develop, if the participant withdraws consent, or if the investigator deems continuation unsafe.

The investigational product LRK-4189 is supplied as an oral solution. Administration is performed by oral ingestion; the specific dose, dose unit, and frequency are defined in the dose‑escalation protocol and may be adjusted during the escalation and expansion phases to determine the active dose or maximum tolerated dose.

The background chemotherapy regimen mFOLFOX6 consists of oxaliplatin, folinic acid, and fluorouracil administered by intravenous injection or infusion. Oxaliplatin and fluorouracil are given as IV infusions, while folinic acid is delivered by IV injection or infusion according to standard dosing schedules.

The background chemotherapy regimen FOLFIRI comprises irinotecan, folinic acid, and fluorouracil administered by infusion. Irinotecan is given as an IV infusion, and both folinic acid and fluorouracil are administered by IV injection or infusion in accordance with established protocols.

Drug administration is documented in source‑documented dosing logs, and compliance is monitored through pill counts for the oral solution and infusion records for intravenous agents. Pharmacokinetic and pharmacodynamic sampling is performed at predefined time points to assess exposure and target engagement.

Efficacy will be evaluated by radiographic assessment of target lesions according to RECIST 1.1 criteria. Objective response rate (ORR), disease control rate (DCR, defined as ORR plus stable disease on at least two post‑baseline assessments >4 weeks apart), duration of response (DOR), progression‑free survival (PFS), overall survival (OS), and shrinkage of target lesions will be recorded. These parameters constitute the primary efficacy endpoints for Parts 2 and 3 of the study.