A Phase 1/2, First in Human Study of DCC-3116 as Monotherapy and in Combination with RAS/MAPK Pathway Inhibitors in Patients with Advanced or Metastatic Solid Tumors with RAS/MAPK Pathway Mutations

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 with

binimetinib closed on January 8, 2024.

1. Participants must have a pathologically confirmed diagnosis of an advanced or

metastatic solid tumor with a documented RAS, NF1, or RAF mutations. A

molecular pathology report documenting mutational status of RAS, NF1, or RAF

must be available.

2. Progressed despite standard therapies, and received at least 1 prior line of

anticancer therapy.

- Participants with a documented mutation in BRAF V600E or V600K must have

received approved treatments known to provide clinical benefit prior to

study entry.

3. Participants enrolled in the DCC-3116 and sotorasib cohort (Cohort D) must have

a KRAS G12C mutation.

3. 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 but no more than 3 prior lines of systemic

therapy in the advanced or metastatic 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 that

can be biopsied with acceptable risk as determined by the Investigator, and archival

tumor tissue sample, if available. If a fresh tumor biopsy is not possible, then an

archival tumor tissue sample must be provided.

5. Eastern Cooperative Oncology Group (ECOG) score of 0 to 2 (Dose Escalation) or 0 to

1 (Dose Expansion) at Screening

6. Adequate organ function and bone marrow function.

7. If a female of childbearing potential must have a negative pregnancy test prior to

enrollment and agree to follow the contraception requirements.

8. Male participants must agree to follow contraception requirements.

9. Must provide signed consent to participate in the study and is willing to comply

with study-specific procedures.

Exclusion Criteria

1. Must not have received the following within the specified time periods prior to the

first dose of study drug:

1. Prior therapies (anticancer or therapies given for other reasons) that are

known strong or moderate inhibitors or inducers of CYP3A4 or 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)

2. All other prior anticancer therapies or any therapy that is investigational for

the participant's condition with a known safety and PK profile: 14 days or 5×

the half-life of the medication (whichever is shorter)

3. Investigational therapies with unknown safety and PK profile: 28 days. If there

is enough data on the investigational therapy to assess the risk for drug-drug

interactions and late toxicities of prior therapy as low, the Sponsor's Medical

Monitor may approve a shorter washout of 14 days

4. Grapefruit or grapefruit juice: 14 days

2. Have not recovered from all toxicities from prior therapy according to National

Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE).

3. Presence or history of central nervous system (CNS) metastases or leptomeningeal

disease, with some exceptions

4. New York Heart Association Class III or IV heart disease, active ischemia, or any

other uncontrolled cardiac condition such as angina pectoris, clinically significant

cardiac arrhythmia requiring therapy, uncontrolled hypertension, congestive heart

failure, or myocardial infarction within 6 months prior to the first dose of study

drug.

5. Prolongation of the QT interval corrected by Fridericia's formula (QTcF) based on

repeated demonstration of QTcF >450 ms in males or >470 ms in females at screening,

or history of long QT syndrome.

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

7. Systemic arterial thrombotic or embolic events within 6 months prior to the first

dose of study drug

8. Systemic venous thrombotic events within 1 month prior to the first dose of study

drug

9. Malabsorption syndrome

10. Bone disease that requires ongoing treatment or has required treatment.

11. Major surgery within 4 weeks of the first dose of study drug. All surgical wounds

must be healed and free of infection or dehiscence before the first dose of the

study drug.

12. Any other clinically significant comorbidities.

13. For participants receiving DCC-3116 and trametinib combination or DCC-3116 and

binimetinib combination: previous treatment with trametinib or binimetinib that

resulted in treatment discontinuation due to intolerability as a result of an

adverse event (AE) that was considered related to trametinib or binimetinib.

14. For participants receiving DCC-3116 and sotorasib combination in Dose Escalation

Part 1: previous treatment with sotorasib that resulted in treatment discontinuation

due to intolerability as a result of an adverse event (AE) that was considered

related to sotorasib.

15. For participants receiving DCC-3116 and sotorasib combination: Use of proton pump

inhibitors (PPIs) and H2 receptor antagonists that cannot be discontinued 3 days

prior to the start of study drug administration.

16. Known allergy or hypersensitivity to any component of the investigational drug

products.

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

1. CD4 count >350/µL

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

3. Stable anti-retroviral regimen with medications that are not prohibited by the

protocol for at least 4 weeks with HIV viral load less than 400 copies/mL prior

to enrollment.

18. Known active hepatitis B, active hepatitis C infection or if the participant is

taking medications that are prohibited per protocol.

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

20. Ongoing participation in an interventional study.

21. For participants receiving DCC-3116 and binimetinib combination: Known Gilbert's

syndrome