Advanced or metastatic solid tumors with RAS/MAPK pathway mutations

Primary Objectives: Dose Extension Phase (Part 2): • Evaluate the objective response rate (ORR) of the concomitant therapy in each extended cohort under RP2D using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Secondary Objectives: Dose Extension Phase (Part 2): • Further describe the efficacy characteristics of DCC 3116 as monotherapy, in combination with trametinib, in combination with binimetinib, and in combination with sotorasib in the extended cohorts under RP2D. • Further describe the pharmacokinetic (PK) characteristics of DCC 3116 in combination with trametinib. • Further describe the pharmacokinetic (PK) characteristics of DCC 3116 in combination with binimetinib. • Further describe the pharmacokinetic (PK) characteristics of DCC 3116 in combination with sotorasib. • Evaluate the safety and tolerability of DCC 3116 in combination with trametinib. • Evaluate DCC 3116 in combination with trametinib. Safety and tolerability of DCC 3116 with binimetinib • Evaluation of the safety and tolerability of DCC 3116 with sotorasib

DCC-3116

DCC-3116

Sustained-release tablets

MG

Dose Extension Phase (Part 2): Efficacy: The primary efficacy endpoint for the dose extension phase (Part 2) will be ORR, based on the trial administrator's assessment, defined as the proportion of participants achieving a confirmed complete response (CR) or partial response (PR) according to RECIST v1.1.

Participants must meet all of the following criteria to be eligible for this trial:

1. Male or female participants aged ≥ 18 years

2. Dose extension period (Part 2): Disease progression despite standard treatment, or, in the trial administrator's opinion, ineffective or intolerable conventional therapy.

a. Extension Group 1: Pancreatic Ductal Adenocarcinoma (PDAC) Patients

i. Must be pathologically confirmed PDAC with a documented KRAS mutation. A molecular pathology report documenting the KRAS mutation status is required.

ii. Must have received only one line of systemic therapy for advanced or metastatic cancer, and, in the trial administrator's opinion, have a life expectancy exceeding 3 months.

b. Extension Group 2: Non-Small Cell Lung Cancer (NSCLC) Patients

i. Must be pathologically confirmed NSCLC with a documented KRAS, NRAS, NF1, or BRAF mutation. ii. Must have a molecular pathology report documenting KRAS, NRAS, NF1, or BRAF mutation status

ii. Have received at least two lines (but no more than four lines) of systemic therapy for advanced or metastatic cancer, and have a life expectancy of more than three months as determined by the trial administrator

- Participants documented with BRAF V600E or KRAS G12C mutations must have received approved and known clinically beneficial treatment prior to enrollment in this trial

c. Extended Group 3: Colorectal Carcinoma (CRC) Patients

i. Must have pathologically confirmed CRC and be documented with KRAS, NRAS, NF1, or BRAF mutations. ii. Must have a molecular pathology report documenting KRAS, NRAS, NF1, or BRAF mutation status

ii. Have received at least two lines of systemic therapy for advanced or metastatic cancer and, according to the trial administrator, have a life expectancy of more than 3 months

- If approved targeted therapy is available, participants documented with BRAF V600E or KRAS G12C mutations must have received targeted therapy.

d. Extended Group 4: Melanoma Patients

i. Must have pathologically confirmed melanoma and be documented with NRAS mutations. ii. Must have a molecular pathology report documenting NRAS mutation status

ii. Have received at least one line (but no more than two lines) of systemic therapy for advanced or metastatic cancer, including therapy with T-cell checkpoint inhibitors, and have a life expectancy of more than 3 months as determined by the trial administrator

iii. Must not have previously received MEK inhibitor therapy

e. Extended Group 5: Patients with KRAS G12C-mutant NSCLC

i. Must be pathologically confirmed NSCLC and documented with a KRAS G12C mutation. 1. A molecular pathology report documenting KRAS G12C mutation status is required.

ii. The patient has received at least one line (but no more than three lines) of systemic therapy for advanced or metastatic cancer, and the life expectancy is estimated to be more than three months, as determined by the trial administrator.

iii. The patient must not have previously received sotorasib or other KRAS G12C inhibitor therapy.

3. Fresh tumor biopsies from the primary or metastatic cancer lesion must be provided, which can be collected during the screening period if the trial administrator determines the risk is acceptable, along with stockpiled tumor tissue specimens (if available; preferably collected after the last anticancer therapy). If fresh tumor biopsies are not available, stockpiled tumor tissue specimens must be provided.

4. Must have at least one lesion measurable according to the Responsive Criteria in Solid Tumor Response (RECIST) version 1.1.

5. Performance status at screening by the Eastern Cooperative Oncology Group (ECOG):

• Dose extension period: 0 to 1

6. At screening, adequate organ function and bone marrow reserves must be assessed by the following laboratories (the central laboratory for the dose extension period [Part 2]):

a. Bone marrow function: Absolute neutrophil count (ANC) ≥1,500/μL; heme ≥9 g/dL; platelet count ≥75,000/μL

b. Liver function: Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 × upper limit of normal. ULN); Serum total bilirubin ≤1.5×ULN, except for participants with known Gilbert's syndrome, who are eligible to participate in the group without binimetinib, and whose serum total bilirubin must be <3×ULN (if serum bilirubin is between 1.5 and 3×ULN, then alkaline phosphatase [ALP] must be ≤2.0×ULN).

c. Renal function: Creatinine clearance (CL) ≥50 mL/min, estimated according to the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula.

d. Coagulation function: Prothrombin time (PT), International normalized ratio (INR), Partial thromboplastin time (PTT), or activated PTT (aPTT). ≤1.5×ULN
Note: Participants who have received stable anticoagulant maintenance therapy for at least 30 days prior to using the investigational drug must have a PT/INR measurement of >1.5×ULN. However, the therapy may be discontinued at screening and on day 1 of cycle 2 for tumor biopsy, provided that the trial administrator determines that the participant is suitable for the trial and assesses that the risk is within an acceptable range. Sufficient justification must be provided to the trial client before acceptance of the application.

e. Corrected serum calcium > 8.0 mg/dL, serum sodium > 130 mmol/L, serum albumin > 3 g/dL

7. Must be able to take the medication orally

8. Female participants of childbearing potential must:

a. Have a negative serum beta-human chorionic gonadotropin (β-HCG) pregnancy test at screening, a negative pregnancy test before taking the first dose of the trial drug on day 1 of cycle 1, and

b. Agree to use two methods of contraception, one of which must be highly effective, and continue to use it throughout the trial, and for at least 120 days after the last dose of DCC-3116 monotherapy, in combination with trametinib, in combination with binimetinib, or in combination with sotorasib.

9. Male participants must:

a. Consent to use two methods of contraception, one of which must be highly effective, throughout the trial and for 120 days after the last dose of DCC-3116 monotherapy, in combination with trametinib, in combination with binimetinib, or in combination with sotorasib.

b. Avoid sperm donation for 120 days prior to the first dose of the investigational drug, until the last dose of DCC-3116 monotherapy, in combination with trametinib, in combination with binimetinib, or in combination with sotorasib.

10. Participants must be able to understand and comply with the trial protocol, and participants must sign a Subject Consent Form (ICF); a signed Subject Consent Form (ICF) must be obtained before any trial-specific procedure.
1. The following medications must not be received during the specified period prior to the first dose of the investigational drug:

a. Prior treatment with a known potent or moderate CYP3A4 or P-gp inhibitor or inducer (given for anticancer or other reasons), including certain herbal remedies (e.g., St. John's wort): 14 days or 5 times the drug half-life (whichever is longer).

b. Prior treatment with other anticancer therapies, or any investigational therapy used for the participant's condition with a known safety and pharmacokinetic (PK) record: 14 days or 5 times the drug half-life (whichever is shorter).

c. Investigational therapies with unknown safety and pharmacokinetic (PK) records: 28 days. If sufficient data from the investigational treatment indicate that the risk of drug-drug interactions and late toxicities from prior treatment are low, the trial client's medical monitor may allow a shorter washout period (14 days).

d. Grapefruit or grapefruit juice: 14 days

2. Prior to receiving the first dose of the investigational drug, all toxicities from prior treatment have not resolved to ≤Grade 1 (according to the National Cancer Institute Common Terminology Criteria for Adverse Events, NCI CTCAE version 5.0) or returned to the participant's baseline state (excluding hair loss). Participant baseline status is defined as no change in severity within 28 days prior to signing the participant consent form.

3. Presence or history of central nervous system (CNS) metastases or leptomeningeal disease, except in the following cases:

• If there is a history of brain metastases, they must remain stable for at least 6 months (no new metastatic lesions seen at screening compared to previous scans, and no evidence of known metastatic lesions worsening).

• If there is a history of leptomeningeal disease, it must have cleared for at least 6 months prior to screening.

• If neurological symptoms consistent with CNS disease are present, no new such symptoms or exacerbations should have occurred within at least 6 months prior to screening.

• If there is a history of CNS metastases or leptomeningeal disease, further treatment is no longer necessary.

4. Within 6 months prior to receiving the first dose of the investigational drug, the patient has New York Heart Association Class III or IV heart disease, active ischemia, or any other uncontrolled heart disease, such as angina, clinically significant arrhythmia requiring treatment, uncontrolled hypertension, congestive heart failure, or myocardial infarction.

5. At screening, the patient has a prolonged QT interval after correction according to the Fridericia formula (QTcF), with multiple instances of QTcF > 450 ms (male) or > 470 ms (female), or a history of long QT syndrome.

6. At screening, the patient's left ventricular ejection fraction (LVEF) is < 50%.

7. Within 6 months prior to receiving the first dose of the investigational drug, the patient has experienced a systemic arterial thrombotic or embolic event, such as a cerebrovascular accident (including ischemic attacks) or moderate hemoptysis.

8. 9. Having experienced a systemic venous thrombotic event (e.g., deep vein thrombosis) or a pulmonary event (e.g., pulmonary embolism) within one month prior to starting the investigational drug.

Note: Participants who experienced a thromboembolic event before receiving the first dose of the investigational drug and are currently receiving stable anticoagulation therapy, or who do not require anticoagulation therapy, are eligible.

10. Having malabsorption syndrome, or other conditions deemed by the trial administrator to be sufficient to affect oral absorption.

11. Having a bone disease requiring ongoing treatment or already receiving the required treatment (including radiation, bisphosphonates, and/or denosumab).

12. Having undergone major surgery within four weeks prior to receiving the first dose of the investigational drug. 12. All surgical wounds must be healed and free from infection or dehiscence before receiving the first dose of the investigational drug.

13. Any other significant clinical complication, such as uncontrolled lung disease, active infection, or any other condition deemed by the trial administrator to potentially affect adherence to the trial protocol, interfere with the interpretation of trial results, or expose participants to safety risks.

14. Known allergic or hypersensitivity reactions to any component of DCC-3116, trametinib, binimetinib, or sotorasib, or any of its excipients. For information on trametinib, binimetinib, and sotorasib excipients, please refer to the drug leaflet.

15. For participants receiving DCC-3116 in combination with trametinib or DCC-3116 in combination with binimetinib: those who discontinued treatment with trametinib or binimetinib due to unacceptable adverse events (AEs) identified as being related to trametinib or binimetinib. Exceptions include: Participants who must discontinue previous trametinib treatment due to fever may be considered for inclusion in the DCC-3116 plus binimetinib group.

15. For participants receiving DCC-3116 plus sotorasib in dose escalation part 1: Those who previously received sotorasib treatment but discontinued treatment due to poor tolerability caused by an adverse event identified as sotorasib-related.

16. For participants receiving DCC-3116 plus sotorasib: Those using proton pump inhibitors (PPIs) and H2 receptor antagonists who were unable to discontinue treatment 3 days prior to the start of investigational drug administration.

17. HIV infection is an exclusion criterion, except for those meeting all of the following criteria:

• CD4 count > 350/μL

• Past
17. No opportunistic infection that could be identified as HIV within the past 12 months.

• Continuous use of a stable antiretroviral drug not prohibited by the trial program for at least 4 weeks prior to enrollment, and an HIV viral load below 400 copies/mL.

18. Hepatitis B virus (HBV) infection is an exclusion criterion unless the HBV DNA viral load test is negative and the participant has been on a course of HBV suppression therapy not prohibited by the trial program for at least 4 weeks prior to enrollment.

19. Hepatitis C virus (HCV) infection is an exclusion criterion unless the HCV RNA viral load test is negative and the participant has completed curative HCV treatment before enrollment, or has been on a course of HCV therapy not prohibited by the trial program for at least 4 weeks prior to enrollment.

20. Pregnant or breastfeeding female participants.

21. Currently participating in an interventional trial. If you are participating in a non-invasive trial (including observational trials), you may be eligible for:

22. For participants receiving DCC-3116 and binimetinib in combination: known to have Gilbert's syndrome

Participants meeting any of the following criteria will be excluded from this trial:

1. Participants must not have received the following medications during the specified period prior to their first dose of the investigational drug:

a. Prior treatment with a known potent or moderate CYP3A4 or P-glycoprotein (P-gp) inhibitor or inducer (for anticancer or other reasons) (see Section 9.8.3), including certain herbal remedies (e.g., St. John's wort): 14 days or 5 times the drug's half-life (whichever is longer).

b. Prior treatment with other anticancer therapies, or any investigational therapy used for the participant's condition with a known safety and pharmacokinetic (PK) record: 14 days or 5 times the drug's half-life (whichever is shorter).

c. Investigational therapy with an unknown safety and PK record: 28 days. If sufficient data from the investigational treatment indicate that the risk of drug-drug interactions and late toxicities from prior treatment are low, the trial commissioner's medical monitor may allow a shorter washout period (14 days).

d. Grapefruit or grapefruit juice: 14 days

2. A prior or concurrent history of a malignant tumor requiring treatment, or an active cancer expected to require treatment during this trial. Hormone maintenance therapy is permitted after curative treatment for breast or prostate cancer, provided the medication used is not a prohibited drug. Participants with a history of malignant tumors who have received curative treatment and have undergone at least one follow-up assessment without evidence of disease may be considered.

3. Prior to receiving the first dose of the investigational drug, all toxicities of prior treatment have not resolved to ≤Grade 1 (according to the National Cancer Institute Common Terminology Criteria for Adverse Events, NCI CTCAE version 5.0) or returned to the participant's baseline status (excluding hair loss). Participant baseline status is defined as no change in severity within 28 days prior to signing the participant consent form.

4. Presence or history of central nervous system (CNS) metastases or leptomeningeal disease, except in the following cases:

• If there is a history of brain metastases, they must remain stable for at least 6 months (no new metastatic lesions seen at screening compared to previous scans, and no evidence of known metastatic lesions worsening).

• If there is a history of leptomeningeal disease, it must have cleared for at least 6 months prior to screening.

• If neurological symptoms consistent with CNS disease are present, no new such symptoms or exacerbations should have occurred within at least 6 months prior to screening.

• If there is a history of CNS metastases or leptomeningeal disease, further treatment is no longer necessary.

5. Within 6 months prior to receiving the first dose of the investigational drug, the patient has New York Heart Association Class III or IV heart disease, active ischemia, or any other uncontrolled heart disease, such as angina, clinically significant arrhythmia requiring treatment, uncontrolled hypertension, congestive heart failure, or myocardial infarction.

6. At screening, the patient has a QT interval prolongation (QTcF) corrected according to the Fridericia formula (QTcF) with multiple findings of QTcF > 450 ms (male) or > 470 ms (female), or a history of long QT syndrome in Part 1. Three repeated 12-lead electrocardiograms (ECGs) confirmed a mean QTcF > 450 ms (male) or > 470 ms (female) at screening, or a history of long QT syndrome in Part 2.

7. Left ventricular ejection fraction (LVEF) <50% at screening.

8. A systemic arterial thrombotic or embolic event, such as a cerebrovascular accident (including ischemic attack) or moderate hemoptysis, occurred within 6 months prior to receiving the first dose of the investigational drug.

9. A systemic venous thrombotic event (e.g., deep vein thrombosis) or pulmonary event (e.g., pulmonary embolism) occurred within 1 month prior to starting the investigational drug.

Note: Participants who experienced a thromboembolic event before receiving the first dose of the investigational drug and are currently receiving stable anticoagulation therapy, or who do not require anticoagulation therapy, are eligible.

10. Suffering from malabsorption syndrome, or other conditions deemed by the trial administrator to be sufficient to affect oral absorption.

11. Underwent major surgery within 4 weeks prior to receiving the first dose of the investigational drug. All surgical wounds must be healed and free from infection or dehiscence before receiving the first dose of the investigational drug.

12. Any other significant clinical complication, such as uncontrolled lung disease, active infection, or any other condition deemed by the trial administrator to potentially affect adherence to the trial protocol, interfere with the interpretation of trial results, or expose the participant to safety risks.

13. Known allergic or hypersensitivity reactions to any component of DCC-3116, trametinib, binimetinib, sotorasib, or any of its excipients. Please refer to the current version of IB for a list of excipients used in DCC 3116. For information on the excipients of trametinib, binimetinib, and sotorasib, please refer to the drug leaflet.

14. For participants receiving DCC-3116 in combination with trametinib or DCC-3116 in combination with binimetinib: Those who discontinued treatment with trametinib or binimetinib due to unacceptable adverse events (AEs) identified as being related to trametinib or binimetinib. An exception is given to participants who must discontinue previous trametinib treatment due to fever; these participants may be considered for inclusion in the DCC-3116 in combination with binimetinib group.

15. For participants receiving DCC-3116 in combination with sotorasib in Part 1 of dose escalation: those who discontinued treatment with sotorasib due to poor tolerability caused by a previously identified sotorasib-related adverse event (AE).

16. For participants receiving DCC-3116 in combination with sotorasib: those using proton pump inhibitors (PPIs) and H2 receptor antagonists who were unable to discontinue treatment 3 days prior to the start of investigational drug administration.

17. Known HIV infection is an exclusion criterion, except for those meeting all of the following criteria:

• CD4 count > 350/μL

• No opportunistic infection definitively classified as AIDS within the past 12 months

• Continuous use of a stable antiretroviral drug not prohibited by the trial program (Section 9.8.3) for at least 4 weeks prior to enrollment, and an HIV viral load below 400 copies/mL 18. Known hepatitis B virus (HBV) infection is an exclusion criterion unless the HBV DNA viral load test is negative and the participant has been on a course of HBV suppression therapy not prohibited by the trial program for at least 4 weeks prior to enrollment.

19. Known hepatitis C virus (HCV) infection is an exclusion criterion unless the HCV RNA viral load test is negative and the participant has completed curative HCV treatment or has been on a course of HCV therapy not prohibited by the trial program for at least 4 weeks prior to enrollment.

20. Female participants who are pregnant or breastfeeding.

21. Participants currently enrolled in an invasive trial. This is acceptable if the participant is enrolled in a non-invasive trial (including observational trials).

22. For participants receiving DCC-3116 and binimetinib in combination: Known Gilbert's syndrome.