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

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ClinicalTrials.gov Identifier: NCT03597581
Recruitment Status : Recruiting
First Posted : July 24, 2018
Last Update Posted : October 5, 2023
Sponsor:
Information provided by (Responsible Party):
Inspirna, Inc.

Study Description
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Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Gastrointestinal Cancer Gastrointestinal Neoplasms Colorectal Cancer Colorectal Neoplasms Colorectal Carcinoma Gastric Cancer Gastric Neoplasm KRAS Mutation-Related Tumors CRC Colorectal Cancer Metastatic Drug: RGX-202-01 Drug: FOLFIRI Drug: Bevacizumab Phase 1

Study Design
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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 (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
Actual Study Start Date : June 5, 2018
Estimated Primary Completion Date : December 31, 2023
Estimated Study Completion Date : December 31, 2024

Resource links provided by the National Library of Medicine

Drug Information available for: Bevacizumab

Arms and Interventions
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Arm Intervention/treatment
Experimental: Single agent RGX-202-01 Dose Escalation
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 Dose Escalation

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.

Drug: FOLFIRI
FOLFIRI is a chemotherapy regimen consisting of irinotecan, leucovorin, and 5-fluorouracil. Irinotecan is a topoisomerase inhibitor, which prevents DNA from uncoiling and duplicating.
Experimental: Expansion: 2nd Line Colorectal Cancer (CRC) KRAS (+)

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

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

Drug: Bevacizumab
Bevacizumab is a vascular endothelial growth factor inhibitor.


Outcome Measures
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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 +/- bevacizumab.

  2. RGX-202-01 overall response rate [ Time Frame: 24 months ]
    Overall response rate (ORR) associated with RGX-202-01 treatment in combination with FOLFIRI plus bevacizumab.

  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 +/- bevacizumab.


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.


Eligibility Criteria
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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
Criteria

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
Contacts and Locations
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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 ClinicalTrials.gov identifier (NCT number): NCT03597581


Contacts
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Contact: Steve Kaesshaefer 1-973-715-2917 steve.kaesshaefer@inspirna.com

Locations
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United States, Arizona
Arizona Oncology Associates, PC - HAL Recruiting
Prescott Valley, Arizona, United States, 86314
Contact: Erike Arguello Vargas       Erika.arguellovargas@usoncology.com   
Principal Investigator: Allan Espinosa Morazan         
Arizona Oncology Associates, PC - HOP E Recruiting
Tucson, Arizona, United States, 85704
Contact: Stacey Kimbell       stacey.kimbell@usoncology.com   
Principal Investigator: Suresh Mukkamala         
United States, California
Cedars-Sinai Medical Center Recruiting
Los Angeles, California, United States, 90048
Contact: Abrahm Levi       Abrahm.Levi@cshs.org   
Principal Investigator: Andrew Hendifar, MD         
Sharp HealthCare Completed
San Diego, California, United States, 92123
Sansum Clinic Recruiting
Santa Barbara, California, United States, 93105
Contact: Cherise Lastra       clastra@ridleytreecc.org   
Principal Investigator: Mukul Gupta, MD         
UCLA Department of Medicine Recruiting
Santa Monica, California, United States, 90404
Contact: Rosen, MD    310-633-8400      
Principal Investigator: Lee Rosen, MD         
United States, Delaware
Medical Oncology Hematology Consultants, PA Recruiting
Newark, Delaware, United States, 19713
Contact: Elizabeth Macwade       elizabeth.macwade@usoncology.com   
Principal Investigator: Jamal Misleh         
United States, Nebraska
Oncology Hematology West P.C. dba Nebraska Cancer Specialists Recruiting
Omaha, Nebraska, United States, 68130
Contact: Scott Degenhardt       sdegenhardt@nebraskacancer.com   
Principal Investigator: Joel Michalski         
United States, New Hampshire
Dartmouth Recruiting
Lebanon, New Hampshire, United States, 03756
Contact: Casey O'Quinn       casey.m.o'quinn@hitchcock.org   
Principal Investigator: Kathryn Hourdequin         
United States, New York
Memorial Sloan Kettering Cancer Center Not yet recruiting
New York, New York, United States, 10065
Contact: Andrea Cercek, MD    646-888-4189      
Principal Investigator: Andrea Cercek, MD         
United States, North Carolina
University of North Carolina Chapel Hill Recruiting
Chapel Hill, North Carolina, United States, 27599
Contact: Hayatu Abdullahi       hayatu_abdullahi@med.unc.edu   
Principal Investigator: Hanna Sanoff, MD         
United States, Oregon
Northwest Cancer Specialists, P.C. Recruiting
Portland, Oregon, United States, 97227
Contact: Jennifer Thompson       Jennifer.Thompson@USONCOLOGY.COM   
Principal Investigator: Spencer Shao         
United States, Pennsylvania
Thomas Jefferson Recruiting
Philadelphia, Pennsylvania, United States, 19107
Contact: Betty Lung       Betty.Lung@jefferson.edu   
Contact    267-584-9165      
Principal Investigator: Atrayee BasuMallick         
United States, South Carolina
Prisma Health Cancer Institute Recruiting
Greenville, South Carolina, United States, 29605
Contact: Lisa Johnson       lisa.johnson@prismahealth.org   
Principal Investigator: Ki Chung         
United States, Tennessee
Tennessee Oncology Recruiting
Nashville, Tennessee, United States, 37203
Contact: Cristina Parcescu, MD    615-329-7274    cristina.parcescu@sarahcannon.com   
Principal Investigator: David Spigel, MD         
United States, Texas
Texas Oncology, P.A Recruiting
McAllen, Texas, United States, 78503
Contact: Nereida O Salinas       nereida.salinas@usoncology.com   
Principal Investigator: Suresh Ratnam         
Texas Oncology, P.A Recruiting
Tyler, Texas, United States, 75702
Contact: Shelly Maxfield       Shelly.Maxfield@usoncology.com   
Principal Investigator: Donald Richards         
Sponsors and Collaborators
Inspirna, Inc.
Investigators
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Study Chair: Robert Wasserman, MD CMO
More Information
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Responsible Party: Inspirna, Inc.
ClinicalTrials.gov Identifier: NCT03597581    
Other Study ID Numbers: RGX-202-001
First Posted: July 24, 2018    Key Record Dates
Last Update Posted: October 5, 2023
Last Verified: October 2023

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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 Inspirna, Inc.:
SLC6a8
Creatine transporter
FOLFIRI
Colorectal Cancer
CRC
 KRAS
Colorectal Cancer Metastatic
NRAS
RAS
Additional relevant MeSH terms:
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Neoplasms
Colorectal Neoplasms
Stomach Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Intestinal Neoplasms
Neoplasms by Site
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
 Rectal Diseases
Stomach Diseases
Bevacizumab
Antineoplastic Agents, Immunological
Antineoplastic Agents
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Growth Inhibitors