A Phase 1/2 Study of Inlexisertib (DCC-3116) in Patients With RAS/MAPK Pathway Mutant Solid Tumors

Inclusion Criteria:

1. Male or female participants ≥18 years of age

2. Dose Escalation Phase (Part 1): Escalation Cohort B combination with trametinib and Cohort C combination withbinimetinib closed on January 8, 2024.

3. Participants must have a pathologically confirmed diagnosis of an advanced ormetastatic solid tumor with a documented RAS, NF1, or RAF mutations. Amolecular pathology report documenting mutational status of RAS, NF1, or RAFmust be available.

4. Progressed despite standard therapies, and received at least 1 prior line ofanticancer therapy.

• Participants with a documented mutation in BRAF V600E or V600K must havereceived approved treatments known to provide clinical benefit prior tostudy entry.

3. Participants enrolled in the inlexisertib and sotorasib cohort (Cohort D) musthave a KRAS G12C mutation.

4. Dose Expansion Phase (Part 2): Expansion Cohorts 1, 2, 3 and 4 combinations will not open for enrollment. Cohort 5: Patients with KRAS G12C mutant NSCLC

• Pathologically confirmed NSCLC with a documented mutation in KRAS G12C.

• Received at least 1 prior line of systemic therapy in the advanced ormetastatic setting.

• Have not received prior sotorasib or other KRAS G12C inhibitor therapy.

4. Must provide a fresh tumor biopsy from a primary or metastatic cancer lesion if itcan be biopsied with acceptable risk as determined by the Investigator.

5. Must have at least 1 measurable lesion according to Response Evaluation Criteria inSolid Tumors (RECIST), v1.1

6. Eastern Cooperative Oncology Group (ECOG) score of 0 to 2 (Dose Escalation) or 0 to 1 (Dose Expansion) at Screening

7. Adequate organ function and bone marrow function.

8. If a female of childbearing potential must have a negative pregnancy test prior toenrollment and agree to follow the contraception requirements.

9. Male participants must agree to follow contraception requirements.

10. Must provide signed consent to participate in the study and is willing to complywith study-specific procedures.

Exclusion Criteria:

1. Must not have received the following within the specified time periods prior to thefirst dose of study drug:

2. Prior therapies (anticancer or therapies given for other reasons) that areknown strong or moderate inhibitors or inducers of CYP3A4 or P-glycoprotein (P-gp) including certain herbal medications (e.g., St. John's Wort): 14 days or 5× the half-life of the medication (whichever is longer)

3. All other prior anticancer therapies or any therapy that is investigational forthe participant's condition with a known safety and PK profile: 14 days or 5×the half-life of the medication (whichever is shorter)

4. Investigational therapies with unknown safety and PK profile: 28 days. If thereis enough data on the investigational therapy to assess the risk for drug-druginteractions and late toxicities of prior therapy as low, the Sponsor's MedicalMonitor may approve a shorter washout of 14 days

5. Grapefruit or grapefruit juice: 14 days

6. Has a prior or concurrent malignancy that requires treatment or is expected torequire treatment for active cancer during this study . Hormonal maintenance aftertreatment is allowed.

7. Have not recovered from all toxicities from prior therapy according to NationalCancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE).

8. Presence or history of central nervous system (CNS) metastases or leptomeningealdisease, with some exceptions

9. New York Heart Association Class III or IV heart disease, active ischemia, or anyother uncontrolled cardiac condition such as angina pectoris, clinically significantcardiac arrhythmia requiring therapy, uncontrolled hypertension, congestive heartfailure, or myocardial infarction within 6 months prior to the first dose of studydrug.

10. Prolongation of the QT interval corrected by Fridericia's formula (QTcF) based onrepeated demonstration of QTcF >450 ms in males or >470 ms in females at screening,or history of long QT syndrome.

11. Left ventricular ejection fraction (LVEF) <50% at Screening

12. Systemic arterial thrombotic or embolic events within 6 months prior to the firstdose of study drug

13. Systemic venous thrombotic events within 1 month prior to the first dose of studydrug

14. Malabsorption syndrome

15. Major surgery within 4 weeks of the first dose of study drug. All surgical woundsmust be healed and free of infection or dehiscence before the first dose of thestudy drug.

16. Any other clinically significant comorbidities.

17. For participants receiving inlexisertib and trametinib combination or inlexisertiband binimetinib combination: previous treatment with trametinib or binimetinib thatresulted in treatment discontinuation due to intolerability as a result of anadverse event (AE) that was considered related to trametinib or binimetinib.

18. For participants receiving inlexisertib and sotorasib combination in Dose EscalationPart 1: previous treatment with sotorasib that resulted in treatment discontinuationdue to intolerability as a result of an adverse event (AE) that was consideredrelated to sotorasib.

19. For participants receiving inlexisertib and sotorasib combination: Use of protonpump inhibitors (PPIs) and H2 receptor antagonists that cannot be discontinued 3days prior to the start of study drug administration.

20. Known allergy or hypersensitivity to any component of the investigational drugproducts.

21. Known human immunodeficiency virus unless the following requirements are met:

22. CD4 count >350/µL

23. No AIDS-defining opportunistic infection in the last 12 months

24. Stable anti-retroviral regimen with medications that are not prohibited by theprotocol for at least 4 weeks with HIV viral load less than 400 copies/mL priorto enrollment.

25. Known active hepatitis B, active hepatitis C infection or if the participant istaking medications that are prohibited per protocol.

26. If female, the participant is pregnant or lactating.

27. Ongoing participation in an interventional study.

28. For participants receiving inlexisertib and binimetinib combination: Known Gilbert'ssyndrome