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A Study of RGX-202-01 as a Single Agent and as Combination Therapy 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.
 
ClinicalTrials.gov Identifier: NCT03597581
Recruitment Status : Recruiting
First Posted : July 24, 2018
Last Update Posted : September 11, 2020
Sponsor:
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 +/- 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 of the study, additional patients with colorectal cancer (CRC) selected by expression of the creatine kinase B (CKB) biomarker 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 in combination with FOLFIRI plus bevacizumab.


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 Drug: Bevacizumab 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, 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 : March 31, 2021
Estimated Study Completion Date : May 31, 2022

Resource links provided by the National Library of Medicine

Drug Information available for: Bevacizumab

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.

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: RGX-202-01 in combination with FOLFIRI plus bevacizumab

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.

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.




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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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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:

  • Written informed consent
  • 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
  • Woman of child-bearing potential must have a negative serum or urine pregnancy test within 2 weeks prior to treatment
  • Men and women of child-bearing potential agree to use acceptable contraceptive methods while on the study and continue to use acceptable contraceptive methods for 1 month after the last dose of study therapy
  • Able to adhere to study visit schedule, protocol requirements and survival assessments during follow up period
  • Patients with diabetes mellitus should be on stable regimen of oral hypoglycemic therapy and/or insulin before beginning study treatment and serum glucose values should consistently be grade 2 or less.

Inclusion Criteria for RGX-202-01 plus FOLFIRI and bevacizumab dose escalation and expansion stages:

  • Must have received only one prior standard of care oxaliplatin-containing regimen for locally advanced/metastatic colorectal cancer
  • 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.
  • Expansion stage participants should also meet the additional inclusion criterion of centrally determined CKB expression by an immunohistochemistry (IHC) method

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

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: Michael Szarek, PhD 646-856-9261 trials@rgenix.com

Locations
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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.
ClinicalTrials.gov Identifier: NCT03597581    
Other Study ID Numbers: RGX-202-001
First Posted: July 24, 2018    Key Record Dates
Last Update Posted: September 11, 2020
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.:
SLC6a8
Creatine transporter
FOLFIRI
Additional relevant MeSH terms:
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Neoplasms
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
Bevacizumab
Antineoplastic Agents, Immunological
Antineoplastic Agents
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Growth Inhibitors