Colorectal Cancer, Colorectal Cancer Metastatic, Colorectal Carcinoma, Colorectal Neoplasms, CRC, Gastric Cancer, Gastric Neoplasm, Gastrointestinal Cancer, Gastrointestinal Neoplasms, KRAS Mutation-Related Tumors
Conditions
Keywords
SLC6a8, Creatine transporter, FOLFIRI, Colorectal Cancer, CRC, KRAS, Colorectal Cancer Metastatic, NRAS, RAS, FOLFOX
Brief summary
This is a Phase 1 study currently evaluating PO administered ompenaclid in combination with FOLFIRI and bevacizumab in patients with advanced (i.e., locally advanced and unresectable, or metastatic) previously treated colorectal adenocarcinoma. The single agent ompenaclid dose escalation stage and the ompenaclid in combination with FOLFIRI and bevacizumab dose escalation stage of the study has been completed; the expansion stage of ompenaclid in combination with FOLFIRI and bevacizumab is ongoing. In April-24 a protocol amendment added a new dose escalation and expansion stage which will evaluate ompenaclid in combination with FOLFOX and bevacizumab in patients with metastatic CRC. It is anticipated that a total of 30 patients will be enrolled in this new dose escalation and expansion stage of the study.
Detailed description
Expansion Stage: Ompenaclid in Combination with FOLFIRI and Bevacizumab Eligible patients must have had PD after receiving only one prior regimen considered standard of care for CRC in the advanced/metastatic setting, which must have been an oxaliplatin-containing regimen. However, if the patient has mismatch repair deficient (dMMR)/ microsatellite instability-high (MSI-H) CRC, they must have also received prior treatment with pembrolizumab or a US Food and Drug Administration (FDA) approved PD-1/PD-L1 inhibitor. Patients who developed recurrent metastatic CRC within 12 months of completion of adjuvant oxaliplatin and 5-FU based therapy are also eligible as long as they did not receive an additional first-line regimen in the advanced/metastatic setting. All patients will receive ompenaclid at a dose of 2400 mg or 3000 mg administered PO BID on a continuous daily schedule. The FOLFIRI dose and schedule will be irinotecan 180 mg/m2 IV over 90 minutes concurrently with leucovorin 400 mg/m2 IV over 2 hours, followed by 5-FU 2400 mg/m2 IV infusion over 46 hours, on Days 1 and 15 of each 28-day cycle, and the bevacizumab dose will be 5 mg/kg on Days 1 and 15 of each 28-day cycle. The goal of the expansion stage will be to provide further characterization of the efficacy, safety and tolerability of combination therapy, and PK and pharmacodynamics of ompenaclid when combined with FOLFIRI and bevacizumab, at two different dose levels of ompenaclid. The dose of ompenaclid in combination with FOLFIRI and bevacizumab in the expansion stage will be 2400 or 3000 mg PO BID. The 3000 mg BID dose represents the last dose of ompenaclid that has been evaluated in combination with FOLFIRI and bevacizumab in the dose escalation stage and which was not considered to be the MTD. Approximately 52 patients will be treated with ompenaclid in combination with FOLFIRI and bevacizumab, all of whom had/will have CRC. Dose Escalation and Expansion Stages: Ompenaclid in Combination with FOLFOX and Bevacizumab Based on experience from the completed single agent and combination therapy dose escalation parts of this study where an MTD was not reached and no DLTs were observed, the dose escalation of ompenaclid in combination with FOLFOX and bevacizumab will evaluate 3 escalating doses of ompenaclid (1800 mg \[Cohort 1\], 2400 mg \[Cohort 2\], and 3000 mg \[Cohort 3\] administered BID PO) on Days 1-28 of a 28-day cycle, in combination with FOLFOX and bevacizumab dosing. Dose escalation will follow a standard 3+3 design. All safety data from all patients enrolled in each cohort will be reviewed by a Safety Review Committee (SRC) to confirm any DLTs that were experienced and to make a determination regarding enrollment in the next cohort. A patient must have received at least 70% of their total planned ompenaclid doses and both the courses of FOLFOX and bevacizumab planned during the 28-day DLT assessment period with follow-up through the end of this period to be eligible for DLT assessment. If a DLT necessitates enrollment of additional patients into a cohort, all of the safety data for that cohort will be reviewed by the SRC after those additional patients have completed the DLT assessment period. The goal of the expansion stage will be to provide further characterization of safety and tolerability of combination therapy, and PK and pharmacodynamics of ompenaclid when combined with FOLFOX and bevacizumab at two different dose levels of ompenaclid: the MTD/maximum tested dose as determined in the dose escalation stage, and one dose level below the MTD/maximum tested dose. A total of approximately 30 patients will be treated with ompenaclid in combination with FOLFOX plus bevacizumab to provide characterization of the safety and tolerability of combination therapy, and PK and pharmacodynamics of ompenaclid when combined with FOLFOX plus bevacizumab. This total includes approximately 10 patients treated at each of the two ompenaclid dose levels during the expansion stage.
Interventions
DRUGompenaclid
RGX-202-01 (ompenaclid) is a small molecule inhibitor of the creatine transporter, SLC6a8.
DRUGFOLFIRI
FOLFIRI is a chemotherapy regimen consisting of irinotecan, leucovorin, and 5-fluorouracil. Irinotecan is a topoisomerase inhibitor, which prevents DNA from uncoiling and duplicating.
DRUGBevacizumab
Bevacizumab is a vascular endothelial growth factor inhibitor.
DRUGFOLFOX regimen
The FOLFOX regimen used for this protocol consists of oxaliplatin given at 85 mg/m2 IV together with leucovorin at 400 mg/m2 IV (substitution with levo-leucovorin 200 mg/m2 IV is allowed) (duration per institutional policy), followed by a 5-FU bolus of 400 mg/m2 (over 2-5 minutes), and then continuous infusional 5-FU given at a dose of 2400 mg/m2 over 46-48 hours (1200 mg/m2/day), given on Days 1 and 15 of each 28-day cycle. A minimum of 8 FOLFOX cycles should be received if tolerated per standard of care guidelines
Sponsors
Inspirna, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
for RGX-202-01 plus FOLFIRI and bevacizumab expansion stages: * 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| RGX-202-01 maximum tolerated dose | 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. |
| RGX-202-01 overall response rate | 24 months | Overall response rate (ORR) associated with RGX-202-01 treatment in combination with FOLFIRI plus bevacizumab. |
| RGX-202-01 treatment-emergent adverse events | 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
| Measure | Time frame | Description |
|---|---|---|
| RGX-202-01 maximum plasma concentration | 24 months | Pharmacokinetics: Maximum plasma concentration (Cmax) of RGX-202-01. |
| RGX-202-01 area under the curve | 24 months | Pharmacokinetics: Area under the curve (AUC) of RGX-202-01. |
Countries
United States
Outcome results
None listed