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

Study Overview
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Brief Summary
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RGX-202-01 (ompenaclid) is a Phase 1, first-in-human, dose escalation and expansion study of RGX-202-01 as a single agent and in combination with FOLFIRI +/- bevacizumab. RGX-202-01 is a small molecule inhibitor of the creatine transporter SLC6a8, a novel metabolic target that drives gastrointestinal cancer progression. During the dose escalation stage, multiple doses of orally administered RGX-202-01 with or without FOLFIRI +/- bevacizumab (single agent or combination therapy) will be evaluated in patients with advanced gastrointestinal tumors (i.e., locally advanced and unresectable, or metastatic) who have had PD on available standard systemic therapies or for which there are no standard systemic therapies of relevant clinical impact. In the expansion stage: Patients with colorectal cancer (CRC) RAS Mutant will be treated at the optimal dose.

Official Title
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A Phase 1 Study of RGX-202-01 (Ompenaclid) , a Small Molecule Inhibitor of the Creatine Transporter SLC6a8, as a Single Agent and as Combination Therapy in Patients With Advanced Gastrointestinal Malignancies With Select Expansion Cohorts

Conditions
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CRC, Gastrointestinal Cancer, Gastrointestinal Neoplasms, Colorectal Cancer, Colorectal Neoplasms, Colorectal Carcinoma, Gastric Cancer, Gastric Neoplasm, KRAS Mutation-Related Tumors, Colorectal Cancer Metastatic

Intervention / Treatment
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* Drug: RGX-202-01
* Drug: FOLFIRI
* Drug: Bevacizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. Exclusion Criteria: 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single agent RGX-202-01 Dose Escalation<br>RGX-201-01 is administered orally twice or three times daily on days 1-28 of each 28-day cycle. The dose regimen is dependent on the cohort in which the patient is enrolled. | Drug: RGX-202-01<br>* RGX-202-01 is a small molecule inhibitor of the creatine transporter, SLC6a8.<br>|
| Experimental: RGX-202-01 in combination with FOLFIRI Dose Escalation<br>RGX-201-01 is administered orally twice or three times daily on days 1-28 of each 28-day cycle. The dose regimen is dependent on the cohort in which the patient is enrolled. FOLFIRI is administered as follows: irinotecan 180 mg/m2 intravenously over 90 minutes concurrently with folinic acid (leucovorin) 400 mg/m2 intravenously over 2 hours, followed by 5-FU 400 mg/m2 intravenous bolus and then 5-FU 2400 mg/m2 intravenous infusion over 46 hours, on Days 1 and 15 of each 28-day cycle. | Drug: RGX-202-01<br>* RGX-202-01 is a small molecule inhibitor of the creatine transporter, SLC6a8.<br>Drug: FOLFIRI<br>* FOLFIRI is a chemotherapy regimen consisting of irinotecan, leucovorin, and 5-fluorouracil. Irinotecan is a topoisomerase inhibitor, which prevents DNA from uncoiling and duplicating.<br>|
| Experimental: Expansion: 2nd Line Colorectal Cancer (CRC) KRAS (+)<br>2nd Line CRC RAS (+) RGX-201-01 is administered orally twice on days 1-28 of each 28-day cycle. FOLFIRI is administered as follows: irinotecan 180 mg/m2 intravenously over 90 minutes concurrently with folinic acid (leucovorin) 400 mg/m2 intravenously over 2 hours, followed by 5-FU 400 mg/m2 intravenous bolus and then 5-FU 2400 mg/m2 intravenous infusion over 46 hours, on Days 1 and 15 of each 28-day cycle. Bevacizumab is administered as follows: 5 mg/kg on Days 1 and 15 of each 28-day cycle. | Drug: RGX-202-01<br>* RGX-202-01 is a small molecule inhibitor of the creatine transporter, SLC6a8.<br>Drug: FOLFIRI<br>* FOLFIRI is a chemotherapy regimen consisting of irinotecan, leucovorin, and 5-fluorouracil. Irinotecan is a topoisomerase inhibitor, which prevents DNA from uncoiling and duplicating.<br>Drug: Bevacizumab<br>* Bevacizumab is a vascular endothelial growth factor inhibitor.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| RGX-202-01 maximum tolerated dose | Maximum tolerated dose (MTD), or the maximum tested dose at which multiple dose-limiting toxicities (DLTs) are not observed, of RGX-202-01 as a single agent, and separately, in combination with FOLFIRI +/- bevacizumab. | 6 months | 
| RGX-202-01 overall response rate | Overall response rate (ORR) associated with RGX-202-01 treatment in combination with FOLFIRI plus bevacizumab. | 24 months | 
| RGX-202-01 treatment-emergent adverse events | Number of participants with treatment-emergent adverse events (TEAEs) with severity as determined by CTCAE v5 associated with RGX-202-01 treatment as a single agent, and separately, in combination with FOLFIRI +/- bevacizumab. | 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| RGX-202-01 maximum plasma concentration | Pharmacokinetics: Maximum plasma concentration (Cmax) of RGX-202-01. | 24 months | 
| RGX-202-01 area under the curve | Pharmacokinetics: Area under the curve (AUC) of RGX-202-01. | 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CRC, SLC6a8, Creatine transporter, FOLFIRI, Colorectal Cancer, KRAS, Colorectal Cancer Metastatic, NRAS, RAS