A Study to Investigate Ompenaclid Combined With FOLFIRI Plus Bevacizumab in Advanced/Metastatic Colorectal Cancer

Inclusion Criteria

1. Advanced disease, defined as cancer that is either metastatic or locally advancedand unresectable and for which additional radiation therapy or other locoregionaltherapies are not considered feasible.

2. Progression of disease after receiving only 1 prior regimen considered standard ofcare for CRC in the advanced/metastatic setting, and it must have been anoxaliplatin containing regimen. Patients who have mismatch repair deficiency/ highmicrosatellite instability (dMMR/MSI-H) CRC must have also received prior treatmentwith pembrolizumab or a Food and Drug Administration (FDA)/European Union (EU)-approved programmed cell death protein 1 (PD-1)/ programmed death-ligand 1 (PD-L1) inhibitor. Patients may have received prior treatment with bevacizumab or anEuropean Medicines Agency (EMA) approved biosimilar. Patients who developedmetastatic CRC within 12 months of completion of adjuvant oxaliplatin and 5-FU basedtherapy are also eligible.

3. Histologic or cytologic evidence of a malignant colorectal tumor of adenocarcinomaor poorly differentiated histology that is laboratory-confirmed to be RAS mutant.Confirmation of RAS mutant status by liquid biopsy is acceptable only if the tumorsample is not available and the liquid biopsy was performed before initiation of thepatient's prior treatment regimen. Patients who convert to RAS mutant status afterinitially having documented wild-type histology are not eligible.

4. Disease that is measurable by standard imaging techniques by Response EvaluationCriteria in Solid Tumors (RECIST) version 1.1. For patients with prior radiationtherapy, measurable lesions must be outside of any prior radiation field(s), unlessdisease progression has been documented at that disease site subsequent toradiation.

5. At least 18 years old.

6. ECOG performance score ≤ 1.

7. Adequate baseline organ function, as demonstrated by the following:

8. Calculated creatinine clearance > 60 mL/min per institutional standard.

9. Serum albumin ≥ 2.5 g/dL.

10. Bilirubin ≤ 1.5 x institutional upper limit of normal range (ULN).

11. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 xinstitutional ULN; patients with hepatic metastases may have AST and ALT ≤ 5 xinstitutional ULN.

12. Absolute neutrophil count (ANC) ≥1.5x109/L.

13. Hemoglobin ≥ 8 g/dL and no red blood cell (RBC) transfusions during the prior 14 days.

14. Platelet count ≥ 100 x 109/L and no platelet transfusions during the prior 14days.

15. If not taking warfarin (or similar vitamin K inhibitor) the following values arerequired: international normalized ratio (INR) ≤ 1.5 or prothrombin time (PT) ≤ 1.5x ULN and either partial thromboplastin time or activated partial thromboplastintime (PTT or aPTT) ≤ 1.5 x ULN. Patients on warfarin (or similar vitamin Kinhibitor) may be included if on a stable dose with a therapeutic INR < 3.5.

16. Left ventricular ejection fraction (LVEF) x 45% as determined by eitherechocardiography (ECHO) or multigated acquisition (MUGA) scanning.

17. Woman of childbearing potential (WOCBP) must have a negative serum or urinepregnancy test within 2 weeks prior to treatment.

18. Men and WOCBP must agree to use acceptable contraceptive methods for the duration oftime on the study and continue to use acceptable contraceptive methods for at least 6 months from the last dose of bevacizumab or 2 months after the last dose ofompenaclid, whichever is longer.

19. Provides signed informed consent prior to initiation of any study-specificprocedures or treatment.

20. Able to adhere to the study visit schedule and other protocol requirements,including follow-up for survival assessment

Exclusion Criteria:

1. Persistent clinically significant toxicities (Grade ≥ 2) from previous anticancertherapy. Excluded are Grade 2 chemotherapy-related neuropathy and alopecia which arepermitted and Grade 2 laboratory abnormalities if they are not associated withsymptoms, are not considered clinically significant by the Investigator, or can bemanaged with available medical therapies.

2. CRC with histology (or component of histology) consistent with small cell,neuroendocrine, or squamous carcinoma, or lymphoma.

3. Received treatment with chemotherapy, external-beam radiation, or other systemicanticancer therapy within 14 days prior to study therapy administration (42 days forprior nitrosourea or mitomycin-C).

4. Received treatment with an investigational systemic anticancer agent within 5 halflives of the investigational systemic therapy or within 28 days, whichever isshorter prior to Study Drug administration.

5. Has an additional active malignancy that may confound the assessment of the studyendpoints. Patients with a past cancer history with substantial potential forrecurrence must be discussed with the Medical Monitor before study entry. Patientswith the following concomitant neoplastic diagnoses are eligible: non-melanoma skincancer, carcinoma in situ (including transitional cell carcinoma, cervicalintraepithelial neoplasia, and melanoma in situ), organ-confined prostate cancerwith no evidence of progressive disease.