This trial will evaluate the safety, tolerability, and preliminary efficacy of tegavivint as monotherapy (single) and in combination with standard therapies in patients with metastatic colorectal carcinoma (mCRC).
Signed informed consent form (ICF)
Male or female, 18 years of age or older
Histologically and/or cytologically documented metastatic colorectal adenocarcinoma (all other histological types are excluded)
Disease progression or intolerance to ≥ 2 lines of systemic therapy for advanced/metastatic disease, including the following prior therapies unless contraindicated: fluoropyrimidine-, oxaliplatin- and irinotecan-based regimens, an anti-vascular endothelial growth factor (VEGF) therapy, and if RAS wild-type, an anti-epidermal growth factor receptor (EGFR) therapy.
Patients receiving therapy with other anti-neoplastic or experimental agents.
Patients receiving concomitant strong or moderate inhibitors of CYP3A4/5 that cannot be discontinued 7 days or 5 half-lives (whichever is longer) prior to Cycle 1 Day 1.
Patients receiving concomitant strong or moderate inducers of CYP3A4/5 that cannot be discontinued at least 14 days prior to Cycle 1 Day 1.
Patients with known history of Gilbert's syndrome or other genetic conditions affecting UGT1A1 function.
Sequential
Tegavivint
DrugTegavivint is a first-in-class chemical inhibitor that interferes with the binding of Transducin beta-like protein 1 (TBL1) to beta-catenin.
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Treatment groupsSee each treatment group below.
Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]
To establish the safety of tegavivint monotherapy treatment related toxicities as per National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 (NCI-CTC AE V5.0)
Maximum Tolerated Dose (MTD)/Administered Dose
To determine the MTD and/or Recommended Phase 2 dose (RP2D) of tegavivint monotherapy. The dose escalation/de-escalation decisions will be made based on isotonic regression of dose-limiting toxicity (DLT) rates across all dose levels. The MTD will be selected as the dose with an estimated DLT probability closest to the target of 30% among the doses tested.
Response Rates
To evaluate the preliminary efficacy of tegavivint as monotherapy and in combination with standard of care treatment in patients with mCRC, response rates will be measured radiologically according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
Maximum Observed Concentration (Cmax) of Tegavivint [Pharmacokinetics (PK)]
To characterize the pharmacokinetics (PK) of tegavivint alone and in combination, the maximum observed concentration (Cmax) of tegavivint will be measured in mg/L. Cmax represents the peak concentration of tegavivint in the blood.
Time to Maximum Observed Concentration (Tmax) of Tegavivint [Pharmacokinetics (PK)]
To characterize the pharmacokinetics (PK) of tegavivint alone and in combination, the time to maximum observed concentration (Tmax) of tegavivint will be measured in hours. Tmax represents the time it takes to reach the peak concentration of tegavivint in the blood.
Elimination Half-Life (t1/2) of Tegavivint [Pharmacokinetics (PK)]
To characterize the pharmacokinetics (PK) of tegavivint alone and in combination, the elimination half-life (t1/2) of tegavivint will be measured in hours. t1/2 represents the time required for the blood concentration of tegavivint to decrease by 50%.
Expression Level of β-catenin [Pharmacodynamics (PD)]
To assess pharmacodynamics (PD) and impacts of tegavivint on the Wnt/β-catenin pathway, the expression level of β-catenin will be measured.
Levels of Circulating Tumor DNA (ctDNA) [Pharmacodynamics (PD)]
To assess pharmacodynamics (PD) of tegavivint, the level of circulating tumor DNA (ctDNA) burden will be measured.
Expression Levels of Wnt-Responsive Proteins in Serum [Pharmacodynamics (PD)]
To assess pharmacodynamics (PD) of tegavivint, the expression levels of Wnt-responsive proteins in serum will be measured.
Number of Predictive Genetic Mutations
Patients will be evaluated for their total number of potential predictive genetic mutations, including rat sarcoma virus (RAS), B-raf (BRAF), and microsatellite instability (MSI)/mismatch repair deficiency (dMMR) status.
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HonorHealth Research Institute
Lead sponsor
Iterion Therapeutics
Collaborator
