The study focuses on Pancreatic Ductal Adenocarcinoma, a rare and aggressive cancer that starts in the pancreas. All participants have tumors that carry the genetic change known as KRAS G12D. The trial is testing an oral medication called INCB161734 to see if it can improve outcomes when used together with standard cancer‑killing drugs.
The purpose of the trial is to compare the effect of adding the new drug to usual treatment versus adding a placebo. Patients receive a combination of chemotherapy that may include irinotecan, oxaliplatin, paclitaxel albumin-bound, gemcitabine, fluorouracil, and calcium folinate hydrate. The oral study medication or the placebo is taken each day, while the chemotherapy drugs are given through an IV infusion on scheduled days.
Participants are randomly assigned to one of the two groups and neither they nor the doctors know which group they are in. Treatment cycles are repeated every few weeks, with regular visits for drug administration, blood tests, and imaging scans to check the tumor. The study continues until the disease progresses, side effects require stopping treatment, or a predefined period of follow‑up is completed.
1randomization and assignment to study medication
after joining the study, the participant is randomly assigned to receive either the oral study drug incb161734 or a matching placebo. the assignment is double‑blind, meaning neither the participant nor the study staff knows which medication is given.
2start of oral study medication
the assigned oral tablet is taken once daily. the dose of incb161734 is 1200 mg per tablet. the placebo is taken in the same manner. the tablet is continued daily for the entire treatment period unless the study medication is stopped because of disease progression or unacceptable side effects.
3first chemotherapy infusion (day 1 of cycle 1)
on the first day of each treatment cycle, an intravenous infusion is given that includes the following drugs at the specified doses:
irinotecan: 150 mg/m2 (milligrams per square meter of body surface area) given by infusion.
oxaliplatin: 85 mg/m2 given by infusion.
abraxane (paclitaxel albumin‑bound): 125 mg/m2 given as a dispersion for infusion.
gemcitabine: 1000 mg/m2 given by infusion.
fluorouracil: 2400 mg/m2 given by infusion.
calcium folinate hydrate: 400 mg/m2 given by infusion.
all drugs are administered on the same day as a series of separate infusions according to the study protocol.
4repetition of chemotherapy cycles
the infusion schedule is repeated every two weeks (the exact interval follows the study protocol) as a new treatment cycle. cycles continue until disease progression, unacceptable toxicity, or completion of the planned number of cycles as determined by the study investigators.
5safety monitoring before each cycle
before each chemotherapy cycle, the participant undergoes a physical examination, vital‑sign measurement, electrocardiogram (ecg) and blood‑sample laboratory tests to check for side effects.
6tumor imaging assessments
computed tomography (ct) scans or other imaging studies are performed approximately every eight weeks to assess tumor size and determine whether the disease is responding, stable, or progressing.
7quality‑of‑life questionnaires
the participant completes standardized questionnaires (eortc qlq‑c30, qlq‑pan26, eq‑5d‑5l) at baseline and at regular intervals during treatment to record health‑related quality of life.
8end of treatment and follow‑up
when treatment stops, the participant enters a follow‑up period during which survival status and any late side effects are recorded at scheduled visits.
Who Can Join the Study?
Be able to understand the study information and sign a written informed consent form agreeing to take part.
Be 18 years old or older at the time of signing the consent.
Have a diagnosis of pancreatic cancer that has spread (called metastatic adenocarcinoma of the pancreas) confirmed by a tissue or cell test; certain other types of pancreatic tumors (squamous, sarcomatoid, neuroendocrine, or acinar) are not allowed.
Have a documented KRAS G12D mutation in the tumor tissue or in a blood sample, identified by an approved genetic test (either PCR or NGS methods).
Have not received any prior systemic therapy (treatment that works throughout the whole body) for the metastatic disease; if you had treatment for earlier‑stage disease, it must have been at least 6 months before joining the study.
Have cancer lesions that can be measured on imaging scans according to the standard RECIST v1.1 criteria, with baseline images available.
Have an ECOG performance status of 0 or 1, meaning you are fully active (0) or able to do light work but not in bed more than 50% of the day (1).
Who Cannot Join the Study?
Had previous chemotherapy, radiation, or surgery for metastatic pancreatic cancer, unless that treatment was for non‑metastatic disease and was given at least six months before the study starts.
If you are a woman who is currently pregnant or breastfeeding.
If you have any other health problem that, in the doctor’s opinion, would make it hard for you to follow the study schedule, could put you at serious risk, or could affect the study results.
If you have another cancer that is getting worse or needs treatment now, or if you have had a different cancer in the past two years, except for certain low‑risk skin cancers and a few other listed cancers.
If you live in France and are considered a vulnerable adult who cannot give consent, is under legal protection, or is not covered by French social security.
If you have untreated or growing brain or central nervous system (CNS) tumors. Treated brain tumors may be allowed only if treatment finished at least two weeks ago, you have no new symptoms, and you are not taking steroids for at least a week.
If you are currently taking another experimental drug, or have taken one within the time it takes the drug to leave your body (about five half‑lives) or within the last 28 days, whichever is shorter.
If you have previously taken any drug that blocks the KRAS protein (a KRAS inhibitor).
If side effects from earlier chemotherapy have not fully gone away (except mild anemia, tiredness, or hair loss), especially nerve problems such as tingling or numbness that are moderate or severe.
If you are receiving any other cancer treatment (such as chemotherapy, radiation, surgery, or immunotherapy) at the same time as the study drugs.
If you have serious uncontrolled medical problems, such as severe liver disease (including drug‑induced injury, alcoholic liver disease, severe fatty liver, bile duct blockage, or uncontrolled fluid buildup in the abdomen), significant heart disease (recent heart attack, unstable chest pain, severe heart failure, uncontrolled high blood pressure, dangerous heart rhythm problems, or long QT syndrome), major gastrointestinal issues that could affect drug absorption (such as stomach or intestinal surgery, bypass, venting tube, recent bowel blockage, or any condition preventing oral medication), or serious lung conditions (interstitial lung disease, pneumonitis, recent lung blood clot, severe asthma, severe COPD, large fluid around the lungs, or autoimmune diseases involving the lungs).
If you have a current or recent infection that needs systemic antibiotics, antifungal, or antiviral medicines within one week before the first dose.
If an electrocardiogram (ECG, a heart rhythm test) shows a clinically important abnormality, especially a prolonged QT interval greater than 470 milliseconds.
If you received a live or live‑attenuated vaccine (such as measles, mumps, rubella, chickenpox, yellow fever, rabies, BCG, typhoid, or the nasal flu spray) within 28 days before the first dose.
If you have any medical reason that makes it unsafe to receive the study drugs, such as poor nutrition, bleeding problems, mouth ulcers, severe diarrhea, or anemia caused by vitamin B12 deficiency.
If you have an acute hepatitis B infection, or if you have chronic hepatitis B with a high level of virus (HBV DNA ≥ 500 IU/mL) at screening. (Lower levels may be allowed if you are already on hepatitis B treatment.)
If you have hepatitis C infection with detectable viral RNA. (You may join if you have completed treatment and the virus is no longer detectable.)
If you have HIV infection with a CD4 + T‑cell count below 350 cells/µL, detectable HIV RNA, or are taking antiretroviral drugs that strongly affect the enzyme CYP3A4/5. (Switching to weaker drugs is allowed if done at least 28 days before the first dose.)
If you have an unexplained fever higher than 38.5 °C (101.3 °F) during screening or on the day the first dose is given, unless the fever is known to be caused by the tumor.
If you have a known severe allergy or previous serious reaction to any ingredient in the study drug INCB161734, or to similar antibody‑based medicines.
If you have a known severe allergy or previous serious reaction to any ingredient in the chemotherapy drugs used in the study (mFOLFIRINOX or GemNabP).
If you are planned to receive the chemotherapy regimen mFOLFIRINOX and you have a complete deficiency of the enzyme DPD (dihydropyrimidine dehydrogenase), which affects how the drug is processed.
INCB161734 is an experimental oral tablet being studied to see if it can improve treatment when added to standard chemotherapy for patients with a specific KRAS gene mutation in pancreatic cancer. In this trial, participants receive this medication along with the usual chemotherapy drugs to test whether it helps slow tumor growth or extend survival compared with chemotherapy alone.
Irinotecan is a chemotherapy drug given through an IV line. It works by interfering with the DNA of cancer cells, which can stop them from dividing and growing. In this study, irinotecan is part of the standard chemotherapy regimen used as a comparison to see if adding INCB161734 provides additional benefit.
Oxaliplatin is another IV chemotherapy medication that damages the DNA of cancer cells, preventing them from multiplying. It is commonly used in combination with other drugs for pancreatic cancer, and in this trial it serves as part of the standard treatment against which the new drug is measured.
Abraxane (paclitaxel albumin‑bound) is a chemotherapy drug delivered by IV infusion. It helps stop cancer cells from dividing by stabilizing their internal structures. In this study, Abraxane is included in the usual chemotherapy regimen to compare outcomes with and without the experimental medication.
Gemcitabine is an IV chemotherapy agent that interferes with the building blocks of DNA, slowing the growth of cancer cells. It is a standard part of treatment for pancreatic cancer and is used in the trial as part of the control chemotherapy regimen.
Fluorouracil is an IV chemotherapy drug that disrupts the synthesis of DNA and RNA in cancer cells, hindering their ability to grow and divide. It is combined with other chemotherapy drugs in the trial to form the standard treatment arm.
Calcium Folinate (also known as leucovorin) is given by IV to enhance the effectiveness of fluorouracil. It helps the chemotherapy work better against cancer cells and is included in the standard chemotherapy combination used for comparison in the study.
Pancreatic ductal adenocarcinoma – Pancreatic ductal adenocarcinoma is a cancer that begins in the cells lining the pancreatic ducts. It usually starts as a small growth that can enlarge and invade nearby tissues. Over time the tumor may spread to surrounding organs such as the duodenum, liver, or lymph nodes. The growth can block the flow of digestive enzymes and cause swelling of the pancreas. As it expands, it may involve nearby blood vessels and nerves. This progression often leads to changes in digestion and abdominal discomfort.
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