A study to investigate response to ompenaclid combined with FOLFIRI plus bevacizumab in patients with advanced or metastatic colorectal cancer

Prior treatment

• Requires treatment with strong CYP3A4 inhibitors or strong UGT1A1 inhibitors.
• Previously received FOLFIRI or other irinotecan containing treatment regimens.
• History of hemodynamically significant pulmonary embolism within 6 months prior to inclusion in the study.
• Received treatment with an investigational systemic anticancer agent within 5 half-lives of the investigational systemic therapy or within 28 days, whichever is shorter prior to Study Drug administration.
• Clinically significant ascites (i.e., requiring paracentesis within the preceding 28 days or treatment with pain medication).
• Received treatment with chemotherapy, external-beam radiation, or other systemic anticancer therapy within 14 days prior to study therapy administration (42 days for prior nitrosourea or mitomycin-C).
• Has an additional active malignancy that may confound the assessment of the study endpoints. Patients with a past cancer history with substantial potential for recurrence must be discussed with the Medical Monitor before study entry. Patients with the following concomitant neoplastic diagnoses are eligible: non-melanoma skin cancer, carcinoma in situ (including transitional cell carcinoma, cervical intraepithelial neoplasia, and melanoma in situ), organ-confined prostate cancer with no evidence of progressive disease.
• Clinically significant cardiovascular disease: e.g., uncontrolled or any New York Heart Association Class 3 or 4 congestive heart failure, uncontrolled angina, history of myocardial infarction, unstable angina or stroke within 6 months prior to study entry, uncontrolled hypertension (defined as systolic blood pressure [SBP]>160 or diastolic blood pressure [DBP]>90), or clinically significant arrhythmias not controlled by medication.
• Known active or suspected brain or leptomeningeal metastases. Central nervous system (CNS) imaging is not required prior to study entry unless there is a clinical suspicion of CNS involvement.
• Known dihydropyrimidine dehydrogenase (DPD) deficiency or is on treatment with DPD inhibitors, including sorivudine or its chemically related analogues such as brivudine, within 4 weeks prior to the start of FOLFIRI treatment.

Other illness

• Marked proteinuria (≥ 2 g/24 hours) and/or nephrotic syndrome. Patients with a proteinuria 2+ or greater urine dipstick reading should undergo further assessment, e.g., a 24-hour urine collection.
• History of acute or subacute intestinal occlusion, unless such an event occurred only around the time of initial diagnosis, or development of metastatic disease, or from chronic inflammatory bowel disease or chronic diarrhea.
• History of hemorrhagic diathesis or tendency towards thrombosis that is not optimally managed, with the exception of tumor bleeding before tumor resection surgery.
• Physical abnormality or medical condition that limits swallowing multiple pills or has a history of non-adherence to oral therapies.
• A gastrointestinal (GI) condition that may significantly alter absorption.
• Uncontrolled intercurrent illness including, but not limited to, uncontrolled infection, disseminated intravascular coagulation, or psychiatric illness/social situations that would limit compliance with study requirements.
• Any medical condition which, in the opinion of the Investigator, places the patient at an unacceptably high risk for toxicities.

Lab values

• Persistent clinically significant toxicities (Grade ≥2) from previous anticancer therapy. Excluded are Grade 2 chemotherapy-related neuropathy and alopecia which are permitted and Grade 2 laboratory abnormalities if they are not associated with symptoms, are not considered clinically significant by the Investigator, or can be managed with available medical therapies.
• QTc >470 msec.

Other

• Evidence of muscular dystrophies or ongoing muscle pathology.
• Severe, non-healing wounds, ulcers, or bone fractures.
• Oxygen-support requirements.
• CRC with histology (or component of histology) consistent with small cell, neuroendocrine, or squamous carcinoma, or lymphoma.
• Pregnant or breast feeding.

• Advanced disease, defined as cancer that is either metastatic or locally advanced and unresectable and for which additional radiation therapy or other locoregional therapies are not considered feasible.
• Woman of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test within 2 weeks prior to treatment.
• Men and WOCBP must agree to use acceptable contraceptive methods for the duration of time 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 of ompenaclid, whichever is longer.
• Provides signed informed consent prior to initiation of any study-specific procedures or treatment.
• Able to adhere to the study visit schedule and other protocol requirements, including follow-up for survival assessment.
• Progression of disease after receiving only 1 prior regimen considered standard of care for CRC in the advanced/metastatic setting, and it must have been an oxaliplatin-containing regimen. Patients who have mismatch repair deficiency/ high microsatellite instability (dMMR/MSI-H) CRC must have also received prior treatment with 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 an European Medicines Agency (EMA-)-approved biosimilar. Patients who developed metastatic CRC within 12 months of completion of adjuvant oxaliplatin and 5-FU based therapy are also eligible.
• Histologic or cytologic evidence of a malignant colorectal tumor of adenocarcinoma or poorly differentiated histology that is laboratory-confirmed to be RAS mutant. Confirmation of RAS mutant status by liquid biopsy is acceptable only if the tumor sample is not available and the liquid biopsy was performed before initiation of the patient’s prior treatment regimen. Patients who convert to RAS mutant status after initially having documented wild-type histology are not eligible.
• Disease that is measurable by standard imaging techniques by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. For patients with prior radiation therapy, measurable lesions must be outside of any prior radiation field(s), unless disease progression has been documented at that disease site subsequent to radiation.
• At least 18 years old.
• ECOG performance score ≤1.
• Adequate baseline organ function, as demonstrated by the following: a. Calculated creatinine clearance >60 mL/min per institutional standard b. Serum albumin ≥2.5 g/dL c. Bilirubin ≤1.5 x institutional upper limit of normal range (ULN) d. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x institutional ULN; patients with hepatic metastases may have AST and ALT ≤ 5 x institutional ULN e. Absolute neutrophil count (ANC) ≥1.5x10^9/L f. Hemoglobin ≥8 g/dL and no red blood cell (RBC) transfusions during the prior 14 days g. Platelet count ≥100x10^9/L and no platelet transfusions during the prior 14 days
• If not taking warfarin (or similar vitamin K inhibitor) the following values are required: international normalized ratio (INR) ≤1.5 or prothrombin time (PT) ≤1.5 x ULN and either partial thromboplastin time or activated partial thromboplastin time (PTT or aPTT) ≤1.5 x ULN. Patients on warfarin (or similar vitamin K inhibitor) may be included if on a stable dose with a therapeutic INR <3.5.
• Left ventricular ejection fraction (LVEF) ≥ 45% as determined by either echocardiography (ECHO) or multigated acquisition (MUGA) scanning.