Participant is eligible for participation in the study if all of the following apply:

1. IRB/ IEC approved written informed consent and privacy language as per national regulations (eg, HIPAA authorization for US study sites) must be obtained from the participant prior to any study-related procedures (including withdrawal of prohibited medication, if applicable).

2. Participant is considered an adult according to local regulations at the time of signing the ICF.

3. Participants last dose of prior antineoplastic therapy, including any immunotherapy, was 21 days or 5 half-lives, whichever is shorter, prior to study drug dosing.

4. Participants can be enrolled based upon definitively diagnosed locally advanced unresectable or metastatic solid tumor with KRAS G12C mutation with pathology report available as source documentation. Archival tissue block (or slides) or fresh tissue samples must be sent to the central laboratory for retrospective testing.

5. Phase 1A (Dose Escalation/Backfill)/Phase 1B (Dose Expansion): Participant has progressed after at least 1 available approved standard therapy or for whom standard therapy has proven to be ineffective or intolerable or is considered inappropriate; or for whom a clinical trial of an investigational agent is a recognized standard of care.

6. Phase 2 (Expansion Cohorts):

• Cohort A: NSCLC Participants: At least 2 prior lines of therapy which included both an anti-PD1/L1 and platinum-based chemotherapy, either concurrently or sequentially, unless contraindicated and who have progressed or were intolerant to a prior KRAS G12C (OFF) inhibitor.

• Cohort B: NSCLC Participants: At least 1 prior line of therapy which included both an anti-PD1/L1 and platinum-based chemotherapy either concurrently or sequentially, unless contraindicated and who are KRAS G12C inhibitor naïve.

• Cohort C: CRC Participants: At least 1 prior line of systemic therapy containing a fluoropyrimidine- and oxaliplatin- or irinotecan-based chemotherapy. Participants with MSI-H/dMMR tumors should have received treatment with an anti-PD-1 monoclonal antibody. Participants must have received prior KRAS G12C (OFF) inhibitor.

• Cohort D: CRC Participants: At least 1 prior line of systemic therapy containing a fluoropyrimidine- and oxaliplatin- or irinotecan-based chemotherapy. Participants with MSI-H/dMMR tumors should have received treatment with an anti-PD-1 monoclonal antibody. Participants must be KRAS G12C inhibitor naïve.

• Cohort E: Other solid tumors (excluding NSCLC and CRC): At least 1 prior line of therapy or for whom SOC therapy has been proven ineffective or intolerable or is considered inappropriate; or for whom a clinical trial of an investigational agent is recognized as SOC.

7. Participants must have at least 1 measurable lesion per RECIST v1.1

8. ECOG performance status: • Phase 1A/B – ECOG 0-1 • Phase 2 – ECOG 0-2

9. Participants with stable treated brain metastases, not requiring steroids (> 10 mg of daily prednisone or its equivalent), may be acceptable (consultation with the Medical Monitor required).

10. Participant has predicted life expectancy > 12 weeks in the opinion of the investigator.

11. Adequate hematological, renal, and hepatic function performed within 14 days prior to first dose of study drug: • Absolute neutrophil count (ANC) > 1000/mm3 (≥ 1.0 x 109 /L) • Platelet count ≥ 75,000/mm3 (≥ 75 x 109 /L) • Hemoglobin ≥ 9.0 g/dL (90 g/L) • ALT ≤ 3 x ULN (if liver metastases are present, ≤ 5.0 x ULN) • AST ≤ 3 x ULN (if liver metastases are present, ≤ 5.0 x ULN) • Total bilirubin ≤ 1.5 x ULN (if associated with liver metastases or Gilbert’s Syndrome, ≤ 3 x ULN provided the direct bilirubin is ≤ 1.5 mg/dL) • Serum creatinine ≤ 1.5 x ULN or creatinine clearance ≥ 60 mL/min calculated per by Cockcroft-Gault Method

12. Has a negative serum pregnancy test (for women of child-bearing potential) at Screening prior to the first dose of study treatment.

13. Female participants must either:

• Be of nonchildbearing potential which includes postmenopausal (defined as at least 1 year without any menses for which there is no other obvious pathological or physiological cause) prior to screening or documented surgically sterile (eg, hysterectomy, bilateral salpingectomy, bilateral oophorectomy) NOTE: those who are amenorrheic due to an alternative medical cause are not considered postmenopausal and must follow the criteria for childbearing potential participants.

• Or, if of childbearing potential, agree not to try to become pregnant during the study and for at least 3 months after the final study drug administration; have a negative urine or serum pregnancy test within 7 days prior to Day 1; and if heterosexually active, agree to consistently use 1 form of highly effective birth control* starting at screening an throughout the study including for at least 3 months after the final study drug administration. • Must not be breastfeeding or lactating at screening and throughout the Treatment Period and for 3 months after last dose of FMC-376. • Must not donate ova starting with the first dose of FMC-376, throughout the Treatment Period and for 3 months after the last dose of FMC-376.

14. Men of child-producing potential agree to use highly effective contraceptive methods and avoid sperm donation or preservation during the study treatment and for at least 3 months after the last dose of study drug. A man is considered of child-producing potential unless he has had a bilateral vasectomy with documented aspermia or a bilateral orchiectomy.

15. Participants who have received radiotherapy (normal and palliative) must have completed this therapy at least 2 weeks prior to study drug administration, C1D1 (excluding stereotactic radiation).

16. Radiation for stereotactic radiosurgery for CNS mets must be completed at least 4 weeks prior to C1D1 and the participant must have an MRI of the brain and/or spinal cord completed at least 4 weeks following the completion of radiation which does not demonstrate any new mets or symptomatic cerebral edema. The participant must also not require steroids that equal or exceed 10 mg of daily prednisone or its equivalent. The participant must have recovered from any side effects of stereotactic radiosurgery.

17. Participant agrees not to participate in another interventional study while receiving study intervention in the present study.

Participant will be excluded from participation in the study if any of the following apply:

1. Participant has received investigational therapy within 21 days or 5 half-lives, whichever is shorter, prior to the first dose of study drug.

2. Phase 1A (Backfill only), Phase 1B and Phase 2: More than 2 prior KRAS G12C (OFF) inhibitors

3. Phase 1A (Backfill only), Phase 1B and Phase 2: Prior treatment with KRAS G12C (ON) inhibitor

4. Leptomeningeal disease or carcinomatous meningitis

5. Participant has clinically significant toxicity resulting from prior cancer therapies that have not returned to baseline or ≤ Grade 1 based on NCI CTCAE (v. 5.0) except for alopecia or neuropathy which must be ≤ Grade 2.

6. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures biweekly or more frequently. • Indwelling pleural or abdominal catheters may be allowed, provided the patient has adequately recovered from the procedure, is hemodynamically stable and symptomatically improved, and after discussion with the Medical Monitor. 

7. Participant has had a major surgical procedure, based upon investigator assessment, within 28 days prior to the first dose of study drug, or a major surgical procedure is planned during the study.

8. Participant has history of stroke, transient ischemic attack or myocardial infarction within 6 months prior to first dose of study drug, symptomatic congestive heart failure (New York Heart Association > class II), uncontrolled cardiac arrhythmia or history of or active ventricular arrhythmia requiring medication, coronary artery disease or unstable angina.

9. Corrected QT interval using the Fridericia's formula (QTcF) > 470 msec during Screening period.

10. Participant has a known or suspected hypersensitivity to FMC-376 or any components of the formulation.

11. Serious infections requiring IV antibiotics within 7 days of first dose of study drug.

12. Clinically significant history of liver disease, including viral or other hepatitis, current alcohol abuse, or cirrhosis.

13. Known HIV infection

14. Acute or chronic uncontrolled renal disease, pancreatitis, or liver disease (with exception of participants with Gilbert’s Syndrome, asymptomatic gallstones, liver metastases, or stable chronic liver disease) per Investigator assessment.

15. Participant has a prior malignancy, requiring treatment or intervention, within the previous 2 years of study drug dosing, except for appropriately treated local malignancies that have been apparently cured, such as basal or squamous cell skin cancer, prostatic intraepithelial neoplasm without evidence of prostate cancer, superficial bladder cancer or carcinoma in situ of the cervix or breast, which are allowed.

16. Malabsorption syndrome or other condition that would interfere with enteral absorption (eg, Crohn’s disease, ulcerative colitis).

17. Pregnant or breastfeeding. Participants with elevated HCG due to underlying malignancy may be eligible if confirmed not to be pregnant.

18. Any serious illness, uncontrolled inter-current illness, psychiatric illness, or other medical history, including laboratory results which in the opinion of the Investigator or Medical Monitor would be likely to impact safety or compliance with study requirements or confounds the ability to interpret data.

19. Have received a live vaccine within 28 days prior to the first dose of study drug. If participants plan to receive other (eg, inactivated) vaccines, it is recommended to complete this at least 14 days prior to dosing, if possible.