A Randomized, Double-Blind, Phase 3 Study of Chemotherapy With or Without INCB161734 in Previously Untreated, KRAS G12D–Mutated Metastatic Pancreatic Ductal Adenocarcinoma (DAWN-303)

Prior treatment

• Receipt of prior systemic or local (eg, surgery, radiotherapy) treatment of metastatic PDAC with the exception of treatment for nonmetastatic disease administered ≥ 6 months prior to Cycle 1 Day 1. Note 1: Prior placement of a biliary stent/tube is permitted if performed ≥ 7 days prior to randomization. Note 2: Receipt of prior palliative radiotherapy is permitted. A 1-week washout is required for prior palliative radiation.
• Untreated and/or progressing CNS metastases (eg, evidence of new or enlarging brain metastasis or new neurological symptoms attributable to brain or CNS metastases). Note: Participants with previously treated and clinically stable brain or CNS metastases are eligible if all of the following apply: a. Central nervous system metastasis treatment has been completed at least 2 weeks prior to screening CNS imaging. b. Any neurologic symptoms have returned to baseline. c. There is no evidence of new or enlarging CNS metastasis or leptomeningeal disease or clinically significant CNS edema or hemorrhage. d. Corticosteroids have not been required for symptoms of CNS metastases or toxicities of CNS metastasis treatment for at least 7 days before the first dose of study treatment.
• Current treatment with another investigational medication or treated with an investigational medication other than the study treatment within 5 half-lives or 28 days (whichever is shorter) before the first dose of study treatment.
• Prior treatment with any KRAS inhibitor.
• Toxicity from prior systemic therapy that has not recovered to ≤ Grade 1 or baseline (with the exceptions of anemia not requiring transfusion support, fatigue, and any grade of alopecia). Paresthesia and/or peripheral sensory neuropathy of Grade 2 or higher due to prior chemotherapy (eg, oxaliplatin) is exclusionary.
• Concurrent anticancer therapy (eg, chemotherapy, radiation therapy, surgery, ablation, immunotherapy, biologic therapy, investigational therapy, or tumor embolization) other than the therapies being tested in this study.
• Chronic or current active infectious disease requiring systemic antibiotic, antifungal, or antiviral treatment within 1 week before the first dose of study drug.
• Received a live or live-attenuated vaccine within 28 days before the first dose of study treatment. Note: Examples of live vaccines include but are not limited to the following: measles, mumps, rubella, chickenpox/zoster, yellow fever, rabies, BCG, and typhoid. Seasonal influenza vaccines for injection are generally killed-virus vaccines and are allowed; however, intranasal influenza vaccines are live, attenuated vaccines and are not allowed.
• Any medical contraindication to receiving any component of study treatment based on local labeling (e.g., SmPC) including poor nutritional state, bleeding, stomatitis, ulcers in the mouth and gastrointestinal tract, severe diarrhoea or anemia caused by vitamin B12 deficiency.
• Known acute HBV infection. In participants with chronic HBV infection, HBV DNA ≥ 500 IU/mL during screening is exclusionary. Note: Participants with chronic HBV and HBV DNA < 500 IU/mL may participate if they have received anti-HBV treatment (per local practice) for a minimum of 14 days before the first dose of study treatment, and they are willing to continue on anti-HBV treatment during the study. Note: Participants with cleared prior HBV infection are eligible.
• For participants receiving mFOLFIRINOX chemotherapy: Known complete DPD as reported in the participant's medical record. Apply local guidelines and regulations for DPD activity testing and dose adjustments in case of partial deficiency or UGT1A1 homozygous deficiency.

Other illness

• Any condition that would, in the investigator's judgment, interfere with full participation in the study, including administration of study treatment and attending required study visits; pose a significant risk to the participant; or interfere with interpretation of study data.
• Known additional malignancy that is progressing or requires active treatment, or history of other malignancy within 2 years before the first dose of study treatment. Exceptions include: Cured basal cell or squamous cell carcinoma of the skin, prostate intraepithelial neoplasm, Bowen's disease or prostate cancer with a Gleason score ≤ 6, superficial bladder cancer, carcinoma in situ of the cervix, or other non-invasive or indolent malignancy, or cancers from which the participant has been disease-free for > 1 year after treatment with curative intent.
• Known history of HCV infection with detectable HCV RNA. Note: Participants who have completed treatment for HCV and are HCV RNA negative are eligible.
• Known hypersensitivity or severe reaction to any component of the INCB161734 formulation (refer to the IB) or a history of severe allergic reaction and/or anaphylaxis to a chimeric or humanized antibody or fusion protein.
• Known hypersensitivity or severe reaction to any formulation component of the selected chemotherapy (mFOLFIRINOX or GemNabP).

Lab values

• Significant concurrent, uncontrolled medical condition including but not limited to the following: a. Hepatic − Known history of DILI; alcoholic liver disease; metabolic dysfunction-associated steatohepatitis; primary biliary cirrhosis; ongoing extrahepatic obstruction caused by stones, cirrhosis of the liver, or portal hypertension; or uncontrolled ascites (defined as > 2 paracentesis within 28 days prior to randomization). b. Cardiovascular − History of clinically significant or uncontrolled cardiac disease, including recent (within the last 12 months) unstable angina pectoris or acute myocardial infarction, or New York Heart Association Class III or IV heart failure, including pre-existing clinically significant ventricular arrhythmia, cardiomyopathy not controlled by medication, history of long QT syndrome, or other clinically significant heart disease (ie, ≥ uncontrolled Grade 3 hypertension). Note: Participants with a pacemaker and well-controlled rhythm for at least 1 month before the first dose of study drug will be allowed. c. Gastrointestinal − Significant GI disorder that could interfere with absorption, metabolism, or excretion of study drug, including gastrectomy, gastric or intestinal bypass surgery, or presence of a venting gastric tube that may interfere with absorption of the study drug. Note: Prior Whipple procedure is allowed. − Recent (≤ 3 months) history or ongoing partial or complete bowel obstruction, unless corrected by surgery. − Any concomitant condition of the upper GI tract that precludes administration of oral medications. d. Pulmonary − Evidence of interstitial lung disease or active, noninfectious pneumonitis. - - History of radiation pneumonitis or drug-induced pneumonitis. - - Lung-specific intercurrent clinically significant illnesses including, but not limited to, any underlying pulmonary disorder (eg, pulmonary emboli within 1 month of study randomization, severe asthma, severe COPD, restrictive lung disease, large pleural effusion, etc). - - Any autoimmune, connective tissue or inflammatory disorders (eg, rheumatoid arthritis, Sjogren's syndrome, sarcoidosis etc) where there is documented pulmonary involvement at the time of screening.
• Known history of HIV infection and any of the following: − CD4 + T-cell count < 350 cells/µL − Detectable HIV RNA − On an ART regimen containing drugs that are strong CYP3A4/5 inhibitors or inducers Note: Switching to an alternative ART regimen with drugs that are weak or intermediate CYP3A4/5 inhibitors or inducers is allowed but must be taken for at least 28 days before the first dose of study treatment.

Other

• Women who are pregnant or breastfeeding.
• The following participants are excluded in France: vulnerable populations according to article L.1121-6 of the French Public Health Code and adults under legal protection, or who are unable to express their consent per article L.1121-8 of the French Public Health Code, not affiliated to a social security per article L.1121-8-1 of the French Public Health Code.
• History or presence of an ECG abnormality that, in the investigator's opinion, is clinically meaningful. − Screening QTcF interval > 470 milliseconds is excluded; in the event that a single QTcF is > 470 milliseconds, the participant may enroll if the average QTcF for the 3 ECGs is < 470 milliseconds.
• Unexplained fever > 38.5°C during screening visits or on the first scheduled day of dose administration that in the investigator's opinion might compromise participation in the study or affect the study outcome. Note: At the discretion of the investigator, participants with tumor fever may be enrolled.

• Ability to comprehend and willingness to sign a written ICF for the study.
• Aged 18 years or older at the time of signing the ICF.
• Histologically or cytologically confirmed metastatic adenocarcinoma of the pancreas (as per American Joint Committee on Cancer 8th Edition. Note 1: Prescreening for participants with suspected PDAC is allowed. Note 2: Squamous, sarcomatoid, neuroendocrine (carcinoid, islet cell), and acinar pancreatic carcinoma are excluded.
• Documented KRAS G12D mutation in tumor tissue or blood (eg, ctDNA genetic testing). The following are acceptable: a. Presence of KRAS G12D mutation documented in participant medical record as detected in tumor tissue or blood (eg, ctDNA genetic testing) based on a sponsor-approved assay (PCR- or NGS-based only). b. Presence of KRAS G12D mutation determined prior to screening by local laboratory assay or sponsor-approved assay (PCR- or NGS-based only) qualified per national country regulations and performed on tumor tissue or blood using sponsor-permitted methods and laboratories.
• No prior systemic treatment for metastatic PDAC. Note: Participants who previously received therapy for nonmetastatic disease may enroll if no systemic treatment was administered within 6 months before randomization into the study.
• Radiographically measurable disease (based on local site investigator/radiology evaluation) per RECIST v1.1 criteria, evidenced by available baseline imaging. Note 1: Target lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions. Note 2: Tumor lesions that have been biopsied should not be selected as target lesions unless postbiopsy imaging confirms that they still qualify as RECIST-defined measurable lesions.
• ECOG performance status of 0 or 1.