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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT03597581
Recruitment Status : Recruiting
First Posted : July 24, 2018
Last Update Posted : September 10, 2019
Information provided by (Responsible Party):
Rgenix, Inc.

Brief Summary:

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).

Condition or disease Intervention/treatment Phase
Gastrointestinal Cancer Gastrointestinal Neoplasms Colorectal Cancer Colorectal Neoplasms Colorectal Carcinoma Gastric Cancer Gastric Neoplasm Pancreatic Cancer Pancreatic Neoplasm Drug: RGX-202-01 Drug: FOLFIRI Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 60 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : June 5, 2018
Estimated Primary Completion Date : July 31, 2020
Estimated Study Completion Date : April 30, 2021

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
Experimental: Single agent RGX-202-01
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
RGX-202-01 is a small molecule inhibitor of the creatine transporter, SLC6a8.

Experimental: RGX-202-01 in combination with FOLFIRI

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
RGX-202-01 is a small molecule inhibitor of the creatine transporter, SLC6a8.

FOLFIRI is a chemotherapy regimen consisting of irinotecan, leucovorin, and 5-fluorouracil. Irinotecan is a topoisomerase inhibitor, which prevents DNA from uncoiling and duplicating.

Primary Outcome Measures :
  1. RGX-202-01 maximum tolerated dose [ Time Frame: 6 months ]
    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.

  2. RGX-202-01 overall response rate [ Time Frame: 24 months ]
    Overall response rate (ORR) associated with RGX-202-01 treatment as a single agent, and separately, in combination with FOLFIRI.

  3. RGX-202-01 treatment-emergent adverse events [ Time Frame: 24 months ]
    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.

Secondary Outcome Measures :
  1. RGX-202-01 maximum plasma concentration [ Time Frame: 24 months ]
    Pharmacokinetics: Maximum plasma concentration (Cmax) of RGX-202-01.

  2. RGX-202-01 area under the curve [ Time Frame: 24 months ]
    Pharmacokinetics: Area under the curve (AUC) of RGX-202-01.

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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 left ventricular ejection fraction (LVEF) ≥ 45% as determined by either echocardiography (ECHO) or multigated acquisition (MUGA) scanning.
  9. 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.
  10. 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.
  11. The patient has signed informed consent prior to initiation of any study-specific procedures or treatment.
  12. The patient is able to adhere to the study visit schedule and other protocol requirements, including follow-up for survival assessment.
  13. 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.
  14. 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 CKB 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 CKB 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 and patients may have received up to two prior regimens in the metastatic setting.
  3. For the combination therapy expansion cohort, patients with colorectal cancer must have have a tumor expressing the CKB biomarker by an immunohistochemistry (IHC) method. Patients 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 paracentesis within the preceding 28 days 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 of starting FOLFIRI.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT03597581

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Contact: Michael Szarek, PhD 646-856-9261

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United States, California
City of Hope Recruiting
Duarte, California, United States, 91010
Contact: Marwan Fakih, MD    626-256-4673      
Cedars-Sinai Medical Center Recruiting
Los Angeles, California, United States, 90048
Contact: Andrew Hendifar, MD    310-423-2217      
UCLA Department of Medicine Recruiting
Santa Monica, California, United States, 90404
Contact: Lee Rosen, MD    310-633-8400      
United States, New York
Memorial Sloan Kettering Cancer Center Recruiting
New York, New York, United States, 10065
Contact: Andrea Cercek, MD    646-888-4189      
United States, North Carolina
University of North Carolina Chapel Hill Recruiting
Chapel Hill, North Carolina, United States, 27599
Contact: Autumn McRee, MD    919-843-6286      
United States, Tennessee
Tennessee Oncology Recruiting
Nashville, Tennessee, United States, 37203
Contact: Johanna Bendell, MD    615-320-5090      
United States, Texas
Mary Crowley Cancer Research Recruiting
Dallas, Texas, United States, 75230
Contact: James Strauss, MD    972-566-3000      
Sponsors and Collaborators
Rgenix, Inc.

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Responsible Party: Rgenix, Inc. Identifier: NCT03597581     History of Changes
Other Study ID Numbers: RGX-202-001
First Posted: July 24, 2018    Key Record Dates
Last Update Posted: September 10, 2019
Last Verified: September 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Rgenix, Inc.:
Creatine transporter
Additional relevant MeSH terms:
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Colorectal Neoplasms
Pancreatic Neoplasms
Stomach Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Intestinal Neoplasms
Neoplasms by Site
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Endocrine Gland Neoplasms
Pancreatic Diseases
Endocrine System Diseases
Stomach Diseases