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

The purpose of this study is to measure tumor response to treatment with ompenaclid (RGX-202-01) in patients with previously treated RAS mutant advanced or metastatic CRC. All patients will receive treatment with FOLFIRI and bevacizumab. In addition, patients will be randomized to receive either ompenaclid 3000 mg BID or matching placebo (herein referred to as Study Drug). Each treatment cycle is 28 days in duration.

This is a Phase 2, randomized, double-blind placebo-controlled study of ompenaclid or matching placebo (Study Drug) in combination with standard-of-care FOLFIRI plus bevacizumab as background therapy in patients with previously treated RAS mutant advanced or metastatic CRC. Randomization will be stratified by whether or not the patient received prior treatment with bevacizumab or an EMA-approved biosimilar. Written informed consent must be obtained prior to initiating any screening activities, except where patients have agreed to the use of previously available tests completed within 28 days of the planned first dose of Study Drug, e.g., computed tomography (CT)/magnetic resonance imaging (MRI) scans. Screening for study eligibility must be completed within 28 days prior to first dose of Study Drug. Patients who are determined to be eligible, based on Screening assessments, will be randomized in the study, and receive their first dose of Study Drug on Cycle 1, Day 1. A treatment cycle is 28 days in duration. Patients will be randomized in a 1:1 ratio to receive oral administration of the five 600-mg tablets BID of ompenaclid or matching placebo (Study Drug). The intravenous FOLFIRI dose and schedule for all patients will be irinotecan 180 mg/m2 over 90 minutes concurrently with folinic acid 400 mg/m2 over 2 hours,followed by 5-FU 2400 mg/m2 over 46 hours, on Days 1 and 15 of each 28-day cycle. The bevacizumab dose of 5 mg/kg will be administered intravenously on Days 1 and 15 of each 28-day cycle. During treatment, patients will attend study center visits and have study evaluations performed as detailed in the Schedule of Events (Table 1-1). All routine study visits are to be conducted on an outpatient basis. Patients may continue to receive Study Drug until the development of PD, or another discontinuation criterion is met, including unacceptable toxicity, voluntary withdrawal from treatment, or closure of the study by the Sponsor; no maximum duration of therapy has been set. After discontinuation of the Study Drug, patients will complete an End of Treatment (EOT) visit within 21 days after their last dose of Study Drug. Safety follow-up is to be conducted by telephone 30 days (+/- 3 days) after their last dose of Study Drug and longer if drug-related AEs have not resolved at that time. Patients and/or their health care providers will also be contacted by telephone approximately every 90 days for information on evidence of PD in settings in which discontinuation of Study Drug was for reasons other than PD, such as an adverse event (AE) or investigator discretion, and/or for assessment of survival status (tumor measurements as specified in the protocol are not required after the EOT visit). This extended follow-up for disease status and survival after discontinuation of the Study Drug may continue until the target number of disease progression events have been observed or for 12 months after the patient's EOT visit, whichever is later. The End of Study for a given patient is defined as the date of the last extended follow-up disease/survival status, or until death, withdrawal of consent, loss to follow-up, or study closure, whichever occurs first.

Eligibility Criteria:
Inclusion Criteria

1. 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.
2. 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.
3. 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.
4. 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.
5. At least 18 years old.
6. ECOG performance score ≤ 1.
7. Adequate baseline organ function, as demonstrated by the following:

   1. Calculated creatinine clearance \> 60 mL/min per institutional standard.
   2. Serum albumin ≥ 2.5 g/dL.
   3. Bilirubin ≤ 1.5 x institutional upper limit of normal range (ULN).
   4. 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.
   5. Absolute neutrophil count (ANC) ≥1.5x109/L.
   6. Hemoglobin ≥ 8 g/dL and no red blood cell (RBC) transfusions during the prior 14 days.
   7. Platelet count ≥ 100 x 109/L and no platelet transfusions during the prior 14 days.
8. 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.
9. Left ventricular ejection fraction (LVEF) x 45% as determined by either echocardiography (ECHO) or multigated acquisition (MUGA) scanning.
10. Woman of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test within 2 weeks prior to treatment.
11. 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.
12. Provides signed informed consent prior to initiation of any study-specific procedures or treatment.
13. 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 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.
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 systemic anticancer therapy within 14 days prior to study therapy administration (42 days for prior nitrosourea or mitomycin-C).
4. 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.
5. 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.