RGX-202-001 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. 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 (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 of the study, additional patients with advanced gastrointestinal malignancies selected by expression of the SLC6a8 biomarker, gastric/gastroesophageal cancer, or colorectal cancer (CRC) will be treated at the MTD (or maximum tested dose if no MTD is identified, or dose below the MTD if there is evidence suggesting a more favorable risk/benefit profile). This stage will provide further characterization of the safety, efficacy, PK, and pharmacodynamics of RGX-202-01 as a single agent (selected by expression of the SLC6a8 biomarker) and in combination with FOLFIRI (gastric/gastroesophageal cancer and CRC).

Inclusion Criteria:

1. The patient must have histologic or cytologic evidence of a malignant gastrointestinal tumor (gastric or gastroesophageal junction, pancreatic, biliary, small intestine, or colorectal) 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. Documentation of the reason must be provided for patients who have not received a standard therapy likely to result in clinical benefit.
2. 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).
3. The patient must have disease that is measurable by standard imaging techniques by 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.
4. The patient is ≥18 years old.
5. The patient has an ECOG PS of ≤1.
6. The patient has adequate baseline organ function, as demonstrated by the following:
   1. Serum creatinine ≤1.5 times institutional upper limit of normal (ULN) and calculated creatinine clearance >50 mL/min;
   2. Serum albumin ≥2.5 g/dl;
   3. Bilirubin ≤1.5 × institutional ULN;
   4. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 × institutional ULN; patients with hepatic metastases may have AST and ALT ≤ 5 × institutional ULN;
   5. Absolute neutrophil count (ANC) ≥1.5×109/L;
   6. Hemoglobin ≥8 g/dL and no red blood cell (RBC) transfusions during the prior 14 days;
   7. Platelet count ≥100×109/L and no platelet transfusions during the prior 14 days.
7. For patients not taking warfarin: international normalized ratio (INR) ≤1.5 or prothrombin time (PT) ≤1.5 × ULN; and either partial thromboplastin time or activated partial thromboplastin time (PTT or aPTT) ≤1.5 × ULN. Patients on warfarin may be included if on a stable dose with a therapeutic INR <3.5.
8. The patient has a value of CPK-MM ≤ 1.5 x ULN and normal CPK-MB and CPK-BB fractions.
9. The patient has a left ventricular ejection fraction (LVEF) ≥ 45% as determined by either echocardiography (ECHO) or multigated acquisition (MUGA) scanning.
10. If the patient is a woman of child bearing potential (WOCBP), she has had a negative serum or urine pregnancy test within 2 weeks prior to treatment.
11. The patient (men and WOCBP) agrees to use acceptable contraceptive methods for the duration of time on the study and continues to use acceptable contraceptive methods for 1 month after the last dose of study therapy.
12. The patient has signed informed consent prior to initiation of any study-specific procedures or treatment.
13. The patient is able to adhere to the study visit schedule and other protocol requirements, including follow-up for survival assessment.
14. Patients with diabetes mellitus should be on a stable regimen of oral hypoglycemic therapy and/or insulin before beginning study therapy with RGX-202-01 and serum glucose values should consistently be grade 2 or less.
15. Tumor tissue (a minimum of 5 and up to 15 unstained slides, from a fresh tumor biopsy prior to starting study therapy must be available prior to the first dose of study therapy. This biopsy should be obtained within 28 days prior to starting RGX-202-01. A biopsy obtained earlier than 28 days prior to start of RGX-202-01 may be considered acceptable, especially if obtained within 3 months and if no systemic anti-cancer therapy has been administered since the date of the biopsy. If a biopsy is deemed by the investigator to not be feasible and/or in the patient's best interest, prior approval must be obtained from the Medical Monitor to waive this requirement. In this case, archived tumor tissue must be made available prior to commencing study treatment.

Additional Inclusion Criteria for Expansion Stages:

1. For the single agent therapy expansion cohort, patients must have a gastrointestinal malignancy expressing the SLC6a8 biomarker and must have received only one prior regimen for advance/metastatic disease. Patients treated with more than one prior regimen must be approved by the Medical Monitor. Only patients exhibiting positive expression of SLC6a8 in tumor cells detected by an immunohistochemistry (IHC) method will be enrolled.
2. For the combination therapy expansion cohort, patients with gastroesophageal junction or gastric cancer must have received only one prior systemic regimen in the metastatic setting. Prior therapy with a checkpoint inhibitor (PD-1/PD-L1 inhibitor) is allowed.
3. For the combination therapy expansion cohort, patients with colorectal cancer must have received at least one irinotecan-containing and one oxaliplatin-containing regimen in the metastatic setting or have refused such therapy. Patients with KRAS wild-type colorectal cancer must have received prior therapy with cetuximab or panitumumab. Patients may have received up to two prior systemic regimens in the metastatic setting. Patients with a Microsatellite Instability-High (MSI-High) tumor must have received a checkpoint inhibitor (PD-1/PD-L1 inhibitor) and may have received up to three prior systemic regimens in the metastatic setting. Patients may have received prior treatment with bevacizumab.

Exclusion Criteria:

1. The patient has persistent clinically significant toxicities (Grade ≥2) from previous anticancer therapy (excluding Grade 2 chemotherapy-related neuropathy and alopecia which are permitted and excluding Grade 2-3 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. The patient has a gastrointestinal malignancy of small cell, neuroendocrine, or squamous histology.
3. The patient has 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. The patient has received treatment with an investigational systemic anticancer agent within 5 half-lives of the investigational systemic therapy prior to study therapy administration.
5. The patient 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.
6. The patient has clinically significant cardiovascular disease (e.g., uncontrolled or any New York Heart Association Class 3 or 4 congestive heart failure (see Appendix 1), uncontrolled angina, history of myocardial infarction, unstable angina or stroke within 6 months prior to study entry, uncontrolled hypertension or clinically significant arrhythmias not controlled by medication).
7. The patient has 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.
8. The patient 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.
9. The patient is pregnant or breast feeding.
10. The patient has an ongoing chronic hepatopathy of any origin.
11. The patient has evidence of muscular dystrophies or ongoing muscle pathology.
12. The patient has oxygen-support requirements.
13. QTcF >450 msec (males) or >470 msec (females).
14. The patient has a physical abnormality or medical condition that limits swallowing multiple pills or has a history of non-adherence to oral therapies.
15. The patient 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.
16. The patient has clinically significant ascites (i.e. requiring periodic paracentesis or treatment with pain medication).
17. The patient has any medical condition which, in the opinion of the Investigator, places the patient at an unacceptably high risk for toxicities.

    The following exclusion criteria are relevant for patients who will be treated with RGX-202-01 plus FOLFIRI, per protocol, on both Dose Escalation and Dose Expansion Cohorts:

18. The patient 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 FOLFIRI treatment.
19. The patient has a known prior history of severe myelosuppression, diarrhea, or mucocutaneous toxicity with a 5FU- or irinotecan-containing regimen, or the patient is known to be homozygous or heterozygous for the UGT1A1*28, UGT1A1*6, UGT1A9*1 or ABCG2 allele.
20. The patient requires treatment with strong CYP3A4 inhibitors or strong UGT1A1 inhibitors.
21. The patient has gastric/gastroesophageal junction, biliary, pancreatic, small bowel or colorectal cancer and has previously received the FOLFIRI regimen at any point in the past with evidence of disease progression within 8 weeks.