A Study of RGX-202-01 (Ompenaclid) as Combination Therapy in 2nd Line RAS Mutant Advanced Colorectal Cancer

Open to people ages 18 years and up

• The patient must have histologic or cytologic evidence of a RAS colorectal cancer of adenocarcinoma or poorly differentiated histology and must have disease that is resistant to or relapsed following available standard systemic therapy or for which there is no standard systemic therapy or reasonable therapy likely to result in clinical benefit or if such therapy has been refused by the patient.
• The patient must have 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).
• Pathologically documented adenocarcinoma or poorly differentiated locally advanced/metastatic colorectal cancer
• Have at least 1 measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 as assessed by the Investigator
• Adults ≥18 years
• Eastern Cooperative Oncology Group performance status (ECOG PS) 0 to 1
• Adequate cardiac function, as defined by left ventricular ejection fraction (LVEF) ≥45%
• Adequate organ function
• Prothrombin time ≤1.5 x ULN or international normalized ratio within ≤1.5; and either partial thromboplastin time or activated partial thromboplastin time ≤1.5 x ULN. Patients on warfarin may be included if on a stable dose with a therapeutic INR <3.5

Inclusion Criteria for RGX-202-01 plus FOLFIRI and bevacizumab expansion stages:

For the expansion stage only, patients must have a tumor that is laboratory-confirmed to be RAS mutant.

• Must have received only one prior standard of care oxaliplatin-containing regimen for locally advanced/metastatic colorectal cancer (CRC)
• Must have received prior treatment with pembrolizumab or an FDA approved PD-1/L1 inhibitor as well, if the patient has dMMR/MSI-H colorectal cancer
• May have received prior treatment with bevacizumab, cetuximab, or panitumumab, or an FDA approved biosimilar.

• Unresolved Grade > 2 toxicities from prior anticancer therapy; excluding Grade 2 chemotherapy-related neuropathy, alopecia; and excluding Grade 2-3 asymptomatic laboratory abnormalities if considered clinically insignificant by the Investigator, or can be managed with available medical therapies
• Has malignancy of small cell, neuroendocrine, or squamous histology
• Unable to meet the requirement of an adequate treatment washout period before enrollment
• Has additional malignancy that may confound the assessment of study endpoints. Participants with 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 are not excluded
• Has clinically significant cardiovascular disease (New York Heart Association Class III or IV congestive heart failure, history of myocardial infarction, uncontrolled angina, unstable angina or stroke within 6 months before enrollment, uncontrolled hypertension or clinically significant arrhythmias not controlled by medication
• Has clinically active brain or leptomeningeal metastases
• Has 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
• Pregnant or breast feeding
• Has an ongoing chronic hepatopathy of any origin
• Has an evidence of muscular dystrophies or ongoing muscle pathology
• Has oxygen-support requirements
• Has corrected QT interval (QTc) prolongation to >470 ms (females) or >450 ms (males)
• Has a physical abnormality or medical condition that limits swallowing multiple pills or has a history of non-adherence to oral therapies
• Has a malabsorption condition, such as short bowel syndrome, impaired GI function or GI disease that may significantly alter absorption, or a high likelihood of impending bowel obstruction, such as strictures
• Has clinically significant ascites (i.e. requiring paracentesis within the preceding 28 days or treatment with pain medication)
• Has a medical condition which, in the opinion of the Investigator, places the patient at an unacceptably high risk for toxicities

Exclusion Criteria for RGX-202-01 plus FOLFIRI and bevacizumab dose escalation and expansion stages:

• Has 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 treatment
• Has known homozygous or heterozygous for UGT1A1*28, UGT1A1*6, UGT1A9*1 or ABCG2 allele
• Require treatment with strong CYP3A4 inhibitors or strong UGT1A1 inhibitors
• Previously treated with FOLFIRI or other irinotecan containing regimens
• Has proteinuria ≥ 2gm/24 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 - except if such an event occurred only around the time of diagnosis - or chronic inflammatory bowel disease or chronic diarrhea
• History of severe, non-healing wounds, ulcers or bone fractures
• History of arterial thromboemboli or severe hemorrhage within 6 months of prior FOLFIRI treatment with an exception of tumor bleeding before tumor resection surgery
• History of hemorrhagic diathesis or tendency towards thrombosis