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A Study of RGX-202-01 as a Single Agent and as Combination Therapy in Patients With Advanced Gastrointestinal Malignancies

About

Brief Summary

RGX-202-001: 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 Description: This is a Phase 1, first-in-human (FIH), two stage (dose escalation and expansion) study evaluating multiple doses of orally administered RGX-202-01 with or without FOLFIRI (single agent or combination therapy) in patients with advanced gastrointestinal cancer who have had progressive disease (PD) on available standard therapies or for which there are no standard therapies available. There are two treatment regimens for this study: single-agent therapy with RGX-202-01; and RGX-202-01 in combination with “FOLFIRI” standard therapy (irinotecan, folinic acid, and 5-FU [fluorouracil]). The Dose Escalation Stage will enroll 12-24 patients. The starting dose will be 600mg taken twice per day, every day in 28-day cycles. The Dose Escalation Stage will include the two regimens as follows:

  • RGX-202-01 alone in patients with advanced gastrointestinal malignancies, and
  • RGX-202-01 combined with FOLFIRI in patients with advanced gastrointestinal malignancies. For the combination regimen, the RGX-202-01 dose will be one dose level below that at which multiple adverse events are NOT observed. The Dose Expansion Stage will enroll approximately 45 patients. Patients will receive RGX-202-01 at one dose level below the last dose of RGX-202-01 that will have been completed as a single-agent therapy, and that was not considered to be the maximum tolerated dose. The Dose Expansion Stage will include the two regimens as follows:
  • RGX-202-01 alone in patients with advanced gastrointestinal malignancies and express the SLC6a8 biomarker, and
  • RGX-202-01 combined with FOLFIRI in patients with advanced gastric/gastroesophageal or colorectal malignancies. Following consent, patients will undergo screening for no more than 28 days. Patients who are eligible following screening will be enrolled into one of two stages noted above, and then one of two regimens within that assigned stage. Patients who receive RGX-202-01 alone will come to the clinic once during Week 1, Week 3, and Week 4. Patients who receive RGX-202-01 in combination with FOLFIRI will come to the clinic twice during Week 1 and Week 3, and once during Week 4. At the end of treatment, patients will come to the clinic within 21 days after their last dose. Patients will then come to the clinic for a safety follow-up visit approximately 30 days after their dose. Research staff will contact patients approximately every 3 months after their last dose for survival follow-up. This follow-up will continue for 6 months following the patient’s last dose.

Primary Purpose
Treatment
Study Type
Interventional
Phase
Phase I

Eligibility

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

Adult subjects diagnosed with advanced gastrointestinal malignancies. For more information about the eligibility criteria for this trial, refer to the Health Professional version.

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 UGT1A128, UGT1A16, 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

Join this Trial

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Study Stats
Protocol No.
18-001039
Category
Hematology-Oncology
Oncology
Contact
CHRISTOPHER LIM
Location
  • UCLA Santa Monica
For Providers
NCT No.
NCT03597581
For detailed technical eligibility, visit ClinicalTrials.gov.