Clinical Trials

Inclusion Criteria: 

• Ability to comprehend and willingness to sign a written ICF for the study.
• Age 18 years or older at the time of signing the ICF.
• Willing and able to conform to and comply with all Protocol requirements, including all scheduled visits and Protocol procedures.
• Life expectancy greater than 12 weeks.
• ECOG performance status score of 0 or 1.
• Locally advanced or metastatic solid tumor with KRAS G12D mutation:
  • Participants will be required to have a documented KRAS G12D alteration from tumor tissue or cfDNA as determined by a locally qualified laboratory employing a molecular assay having a relevant mark of conformity for analytical performance (eg, CLIA [US] or UKCA, CE, CE UKNI, or others) to be eligible.
• Disease progression on prior standard treatment, intolerance to or ineligibility for standard treatment, or no standard available treatment to improve the disease outcome.
• Cohort-specific requirements as follows:
  • Part 1a: histologically or cytologically confirmed malignant solid tumor of any tissue origin;
  • Part 1b
    • Disease Group 1: diagnosis of PDAC;
    • Disease Group 2: diagnosis of CRC;
    • Disease Group 3: diagnosis of NSCLC;
    • Disease Group 4: diagnosis of other (not part of Disease Groups 1, 2, and 3) advanced solid tumors.
  • Parts 2a and 2b:
    • Combination Group 1 (INCB161734 in combination with cetuximab):
      • Diagnosis of PDAC or CRC.
    • Combination Group 2 (INCB161734 in combination with retifanlimab):
      • Diagnoses of PDAC, CRC, or NSCLC;
      • Prior systemic therapy may have included an anti–PD-1 inhibitor.
• Measurable lesions by CT or MRI based on RECIST v1.1 criteria that are considered nonamenable to surgery or other curative treatments or procedures. Locally advanced disease must not be amenable to resection with curative intent or other curative treatments or procedures. Tumor lesions that are located in a previously irradiated area or in an area subjected to other locoregional therapy should only be selected as target lesions if progression has been demonstrated in such lesions.
• Availability of a baseline archival tumor specimen or willingness to undergo a pretreatment biopsy (core or excisional) to obtain the specimen:
• Parts 1a, 1b, 2a, and 2b: fresh pretreatment biopsy (within the screening period) or archival tissue (collected within < 24 months prior to C1D1):
  • Part 1c: fresh pretreatment biopsy (within the screening period) or archival tissue (collected within < 2 months prior to C1D1) and willingness to undergo an on-treatment tumor biopsy (core or excisional). Note: Tumor lesions selected as target lesions should not be selected for biopsy.
• Ability to swallow and retain oral medication.
• Willingness to avoid pregnancy or fathering children based on the criteria below:
  • Male participants with reproductive potential must agree to take appropriate precautions to avoid fathering children from screening through 180 days after the last dose of study drug and must refrain from donating sperm during this period. Permitted methods (see Appendix A) in preventing pregnancy should be communicated to the participants and their understanding confirmed;
  • Female participants who are WOCBP must have a negative serum pregnancy test at screening and a negative urine pregnancy test before the first dose on Day 1 and must agree to take appropriate precautions to avoid pregnancy from screening through 180 days after the last dose of study drug and must refrain from donating oocytes during this period. Permitted methods in preventing pregnancy (see Appendix A) should be communicated to the participants and their understanding confirmed;
  • Female participants not considered to be of childbearing potential as defined in Appendix A are eligible.

Exclusion Criteria:

Cancer History

• Known additional invasive malignancy within 1 year of the first dose of study drug:
  • Note: The following are allowed:
    • Prior additional malignancy from which the participant has been disease-free for > 1 year after treatment with curative intent;
    • Noninvasive or indolent malignancy;
    • Definitively treated early-stage basal cell or squamous cell carcinoma of the skin, superficial bladder cancer, in situ cervical cancer, early-stage endometrial cancer, Gleason 6/7 prostate cancer, ductal carcinoma in situ, or lobular carcinoma in situ of the breast.
• Untreated brain or CNS metastases or brain/CNS metastases that have progressed (eg, evidence of new or enlarging brain metastasis, new neurological symptoms attributable to brain or CNS metastases, new associated edema):
  • Note: Participants (except those in Part 1c) with previously treated and clinically stable brain or CNS metastases are eligible if all of the following apply:
    • There is no evidence of progression by imaging obtained after at least 2 weeks post-treatment;
    • Any neurologic symptoms have returned to baseline;
    • Use of corticosteroids for treatment of brain metastases has not been required for at least 7 days before the first dose of study drug.

Prior Cancer Therapy

• History of organ transplant, including allogeneic stem cell transplantation.
• Treatment with anticancer therapies (including curative radiation to the thorax or systemic anticancer therapies) within 5 half-lives or 28 days (whichever is shorter) or participation in another interventional clinical study within 28 days before the first administration of study drug.
• Prior treatment with any KRAS G12D inhibitor.
• Any prior radiation therapy within 28 days before the first dose of study drug. Note: Palliative radiation therapy to single sites or small fields may be allowed based on the investigator's judgment but not within 1 week of the first dose of study drug. Note: Participants must have recovered from all radiation-related toxicities, not require corticosteroids for this purpose, and not have had radiation pneumonitis.
• Has not recovered to ≤ Grade 1 from toxic effects of prior therapy and/or complications from prior surgical intervention before starting study drug. Note: Participants with stable chronic conditions (≤ Grade 2) not expected to resolve (such as anemia not requiring transfusion support, neuropathy, hypothyroidism, and alopecia) are exceptions and may enroll.
• For participants in Parts 2a and 2b who will be receiving retifanlimab as part of this study: immune-related toxicity during prior immune therapy for which permanent discontinuation of therapy was recommended (per product label or consensus guidelines) or any immune-related toxicity requiring intensive or prolonged immunosuppression to manage (with the exception of endocrinopathy that is well controlled on HRT).

Medical History

• Significant concurrent, uncontrolled medical condition, including but not limited to the following:
  • Hepatic:
    • Known history of DILI; alcoholic liver disease; nonalcoholic steatohepatitis; primary biliary cirrhosis; ongoing extrahepatic obstruction caused by stones, cirrhosis of the liver, or portal hypertension.
  • 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 cardiac disease, including preexisting clinically significant ventricular arrhythmia, congestive heart failure, cardiomyopathy not controlled by medication, history of long QT syndrome, or other clinically significant heart disease (ie, ≥ uncontrolled Grade 3 hypertension). Participants with a pacemaker and well-controlled rhythm for at least 1 month before the first dose of study drug will be allowed.  
  • Gastrointestinal:
    • Significant gastrointestinal disorder that could interfere with absorption, metabolism, or excretion of study drug, including gastrectomy, partial gastrectomy, or presence of a venting gastric tube that may interfere with absorption of the study drug;
    • Recent (≤ 3 months) history or ongoing partial or complete bowel obstruction, unless corrected by surgery;
    • Any concomitant condition of the upper gastrointestinal tract that precludes administration of oral medications.
  • Pulmonary (only participants in Parts 2a and 2b):
    • Evidence of interstitial lung disease or active, noninfectious pneumonitis;
    • History of interstitial lung disease.
• History or presence of an ECG abnormality that, in the investigator's opinion, is clinically meaningful:
  • Screening QTcF interval > 450 milliseconds is excluded; in the event that a single QTc is > 450 milliseconds, the participant may enroll if the average QTc for the 3 ECGs is < 450 milliseconds:
  • For participants with an intraventricular conduction delay (QRS interval > 120 milliseconds), screening QTcF interval > 470 milliseconds is excluded. In the event that a single QTc is > 470 milliseconds, the participant may enroll if the average QTc for the 3 ECGs is < 470 milliseconds. Participants with left bundle branch block are excluded.
• Chronic or current active infectious disease requiring systemic antibiotic, antifungal, or antiviral treatment (within 14 days before first dose of study drug). Note: If a participant has a positive screening test result for SARS-CoV-2 infection, they should be excluded until test normalization and clinical recovery.
• For participants in Parts 2a and 2b who will be receiving retifanlimab as part of this study: active autoimmune disease requiring systemic immunosuppression in excess of physiologic maintenance doses of corticosteroids (> 10 mg/day of prednisone or equivalent):
  • Physiologic corticosteroid replacement therapy at doses ≤ 10 mg/day of prednisone or equivalent for adrenal or pituitary insufficiency and in the absence of active autoimmune disease is permitted;
  • Participants with asthma that requires intermittent use of bronchodilators, inhaled corticosteroids, or local corticosteroid injections may participate;
  • Participants using topical, ocular, intra-articular, or intranasal corticosteroids (with minimal systemic absorption) may participate;
  • Brief courses of corticosteroids for prophylaxis (eg, contrast dye allergy) or study treatment–related standard premedications are permitted.
• Active HBV (or at risk of reactivation), defined as follows: positive HBsAg result (laboratory test required at screening), and/or positive total anti-HBc result (laboratory test required at screening), and/or quantitative HBV DNA test result greater than the lower limits of detection of the assay (if known, can be done as part of screening if available locally):
  • Note: Participants with no prior history of HBV infection who have been vaccinated against HBV and who have a positive anti-HBs result as the only evidence of prior exposure may participate in the study.
• Active HCV, defined as follows: positive anti-HCV result (laboratory test required at screening) and quantitative HCV RNA test result greater than the lower limits of detection of the assay (laboratory test only required if anti-HCV–positive, can be done as part of screening if available locally):
  • Note: Anti-HCV–positive participants who received and completed treatment for HCV that was intended to eradicate the virus may participate if HCV RNA levels are undetectable at least 12 weeks after the last dose of therapy. Anti-HCV–positive participants with no available confirmatory negative HCV RNA test results will be excluded.
• Known HIV infection (positive for HIV 1/2 antibodies).

Medications

• Treatment with prohibited medication as described in Section 6.7.3 within 5 half-lives or 28 days (whichever is shorter) before the first dose of study drug.
• For participants in Parts 2a and 2b who will be receiving retifanlimab as part of this study: has received a live vaccine within 28 days before first administration of study drug:
  • Note: Examples of live vaccines include but are not limited to measles, mumps, rubella, varicella-zoster (chickenpox), yellow fever, rabies, Bacille Calmette-Guérin, and typhoid vaccines. 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.
• Known hypersensitivity or severe reaction to any component of study drug(s) or formulation components.

Organ Function

• Laboratory values at screening as defined in Table 7.

Other Exclusions

• Any major surgery within 28 days before the first dose of study drug.
• Women who are pregnant or breastfeeding or expecting to conceive or men who are expecting to father children within the projected duration of the study, starting with the screening visit through 180 days after the last dose of study drug treatment. For Japan, women who are pregnant (including women who may possibly be pregnant based on medical interview by investigators in Japan) or are breastfeeding and wish to enroll must discontinue breastfeeding at least 90 days before receiving study drug. They must also refrain from breastfeeding during the course of study and for 90 days after the last dose of study drug.
• Any condition that would, in the investigator's judgment, interfere with full participation in the study, including administration of study drug and attending required study visits; pose a significant risk to the participant; or interfere with interpretation of study data.
• 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.

Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Eligibility last updated 10/6/23. Questions regarding updates should be directed to the study team contact.