Phase 3 Randomized Study of INCB161734 Plus Combination Chemotherapy Versus Placebo Plus Chemotherapy in KRAS G12D‑Mutated Metastatic Pancreatic Ductal Adenocarcinoma

The primary objective is to compare the efficacy of INCB161734 combined with standard chemotherapy versus placebo combined with chemotherapy in patients with previously untreated metastatic pancreatic ductal adenocarcinoma harboring the KRAS G12D mutation, addressing a critical need for targeted therapeutic improvement in this molecular subset. Secondary objectives include:

• Further assessment of the combination’s efficacy relative to placebo in the same patient population.
• Evaluation of safety and tolerability of INCB161734 plus chemotherapy versus placebo plus chemotherapy.
• Assessment of changes in health‑related quality of life.
• Characterization of the pharmacokinetic profile of INCB161734 when administered with chemotherapy.
• Investigation of predictive biomarkers of pharmacologic activity and their correlation with clinical safety or efficacy.
• Collection of health‑economic data relevant to treatment of pancreatic ductal adenocarcinoma.

349 participants with histologically confirmed metastatic pancreatic ductal adenocarcinoma were enrolled. Eligible individuals were adults (≥18 years) of both sexes, with an ECOG performance status of 0 or 1, indicating full activity or restricted strenuous activity but ambulatory. All participants demonstrated a documented KRAS G12D mutation in tumor tissue or circulating DNA, and had radiographically measurable disease per RECIST v1.1. Enrollment required no prior systemic therapy for metastatic disease, although patients who had received treatment for earlier‑stage disease were permitted if a six‑month treatment‑free interval preceded randomization. Selection was based on histologic confirmation, mutation status, performance status, and measurable disease criteria; no specific dietary, physical‑activity, or other lifestyle restrictions were stipulated. The trial population comprised vulnerable patients as defined by regulatory criteria, encompassing both male and female subjects.

The study is a Phase 3, randomized, double-blind, placebo‑controlled trial evaluating INCB161734 in combination with standard chemotherapy versus placebo plus the same chemotherapy in adults with previously untreated, KRAS G12D–mutated pancreatic ductal adenocarcinoma. Participants undergo a screening visit to verify histologic diagnosis, KRAS G12D mutation status, measurable disease per RECIST v1.1, and ECOG performance status of 0‑1. Eligible subjects are then randomized 1:1 to receive oral INCB161734 1200 mg daily or a matching placebo, both administered with a chemotherapy backbone that includes intravenous irinotecan 150 mg/m², oxaliplatin 85 mg/m², fluorouracil 2400 mg/m², calcium folinate 400 mg/m², gemcitabine 1000 mg/m², and paclitaxel albumin‑bound 125 mg/m². Treatment cycles are repeated every two weeks. Follow‑up visits occur at the start of each cycle for safety monitoring, dose adjustments, and laboratory tests, while tumor imaging is performed every eight weeks to assess response. The trial continues until disease progression, death, withdrawal of consent, or a safety event that mandates discontinuation, after which an end‑of‑study visit is conducted for final assessments. The recruitment period extends from April 2026 to May 2029, and individual participant involvement is expected to last up to 24 months or until an early termination criterion is met. The primary efficacy endpoints are overall survival and blinded independent central review of progression‑free survival, with secondary endpoints including objective response, duration of response, safety, health‑related quality of life, pharmacokinetics, and exploratory biomarker analyses.

The investigational product, INCB161734 hydrochloride dihydrate, is supplied as a 1200 mg oral tablet and is administered once daily by the oral route throughout each treatment cycle. Participants assigned to the control arm receive a matching oral placebo tablet administered with the same frequency and schedule.

All participants receive a standard chemotherapy backbone consisting of intravenous agents administered according to body‑surface‑area dosing: irinotecan 150 mg/m², oxaliplatin 85 mg/m², paclitaxel albumin‑bound (Abraxane) 125 mg/m² as a dispersion for infusion, gemcitabine 1000 mg/m², fluorouracil 2400 mg/m², and calcium folinate hydrate 400 mg/m². Each drug is prepared in the appropriate pharmaceutical form and delivered via intravenous infusion on the schedule defined in the protocol.

Dosing is performed on specified days of each treatment cycle, with dose adjustments permitted for toxicity as outlined in the study guidelines. Compliance with oral study medication is monitored through patient diaries, pill counts, and periodic verification of plasma drug concentrations. Intravenous chemotherapy administration is recorded in the electronic case report form, and infusion‑related parameters are documented to ensure adherence to the prescribed regimen.

The primary efficacy assessment includes Overall Survival, defined as the interval from randomization to death from any cause; Progression‑Free Survival evaluated by blinded independent central review using RECIST v1.1, defined as the time from randomization to the first documented disease progression or death; and Objective Response Rate, determined by the best overall response of complete or partial response as assessed by the central review per RECIST v1.1.

Secondary efficacy parameters comprise Duration of Response, measured from the date of first documented response to disease progression or death; Disease Control Rate, defined as the proportion of patients achieving complete response, partial response, or stable disease; Progression‑Free Survival assessed by investigator assessment using RECIST v1.1; investigator‑determined Objective Response Rate and Duration of Response; and health‑related outcomes evaluated through changes from baseline in Health‑Related Quality of Life instruments, specifically the EORTC QLQ‑C30, QLQ‑PAN26, and EQ‑5D‑5L questionnaires. Additional exploratory measures include quantification of plasma concentration of INCB161734 and analysis of blood and tumor specimens for genomic, transcriptomic, proteomic, and metabolomic biomarkers that may correlate with clinical response or resistance. Resource utilization associated with unplanned medical encounters is also recorded. All efficacy endpoints are analyzed according to predefined statistical plans, with central imaging reviews conducted per RECIST v1.1 criteria and patient‑reported outcomes processed using validated scoring algorithms.