Clinical Trials /

A Study of RGX-202-01 With or Without FOLFIRI in Patients With Advanced Gastrointestinal Malignancies

NCT03597581

Description:

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 creatine kinase B (CKB) 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 CKB biomarker) and in combination with FOLFIRI (gastric/gastroesophageal cancer and CRC).

Related Conditions:
  • Adenocarcinoma of the Gastroesophageal Junction
  • Bile Duct Adenocarcinoma
  • Colorectal Adenocarcinoma
  • Gallbladder Adenocarcinoma
  • Gastric Adenocarcinoma
  • Pancreatic Adenocarcinoma
  • Small Intestinal Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: A Study of RGX-202-01 With or Without FOLFIRI in Patients With Advanced Gastrointestinal Malignancies
  • Official Title: A Phase 1 Study of RGX-202-01, a Small Molecule Inhibitor of the Creatine Transporter SLC6a8, With or Without FOLFIRI, in Patients With Advanced Gastrointestinal Malignancies With Select Expansion Cohorts

Clinical Trial IDs

  • ORG STUDY ID: RGX-202-001
  • NCT ID: NCT03597581

Conditions

  • Gastrointestinal Cancer
  • Gastrointestinal Neoplasms
  • Colorectal Cancer
  • Colorectal Neoplasms
  • Colorectal Carcinoma
  • Gastric Cancer
  • Gastric Neoplasm
  • Pancreatic Cancer
  • Pancreatic Neoplasm

Interventions

DrugSynonymsArms
RGX-202-01Single agent RGX-202-01
FOLFIRIRGX-202-01 in combination with FOLFIRI

Purpose

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).

Trial Arms

NameTypeDescriptionInterventions
Single agent RGX-202-01ExperimentalRGX-201-01 is administered orally twice daily on days 1-28 of each 28-day cycle. The dose regimen is dependent on the cohort in which the patient is enrolled.
  • RGX-202-01
RGX-202-01 in combination with FOLFIRIExperimentalRGX-201-01 is administered orally twice 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.
  • RGX-202-01
  • FOLFIRI

Eligibility Criteria

        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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:RGX-202-01 maximum tolerated dose
Time Frame:6 months
Safety Issue:
Description: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.

Secondary Outcome Measures

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

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Rgenix, Inc.

Trial Keywords

  • SLC6a8
  • Creatine transporter
  • FOLFIRI

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