This is a first-in-human, Phase I, open-label, multicenter, dose-escalation and dose expansion study to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary anti-tumor activity of VVD-133214 monotherapy, and in combination with bevacizumab or pembrolizumab, in participants with microsatellite instability (MSI) and/or deficient mismatch repair (dMMR) advanced solid tumors. VVD-133214 is an oral drug that acts on a protein called Werner (WRN), which may promote the growth of cancers that are MSI and/or dMMR. By acting on WRN, VVD-133214 may be able to block the growth of these types of cancer.
Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1
Have a microsatellite instability (MSI) and/or deficient mismatch repair (dMMR), histologically or cytologically documented advanced (unresectable and/or metastatic) solid tumor
For monotherapy only (solid tumor): Have received and then progressed following or are intolerant to at least 2 standard treatment regimens in the advanced setting including standard chemotherapy or checkpoint inhibitors according to tumor type.
For the combination with bevacizumab only: Advanced, or metastatic colorectal adenocarcinoma (CRC) treated with at least 2 but no more than 3 prior lines of systemic therapy for the treatment of advanced CRC and demonstrated progressive disease or intolerance to the last regimen. Prior treatment regimens must have included (unless not eligible for or intolerant to any of these agents): An immune checkpoint inhibitor (if available as standard of care), Fluoropyrimidine, Irinotecan and/or oxaliplatin, +/- an anti-VEGF monoclonal antibody, Participants with RAS WT tumors may have received anti-epidermal growth factor receptor (EGFR) monoclonal antibody based on Investigator discretion. Treatment with adjuvant/neoadjuvant chemotherapy and/or immunotherapy will count as a line of therapy for advanced disease if progression occurred during or within 12 months of completing the treatment.
Inability or unwillingness to swallow pills
Malabsorption syndrome or other condition that would interfere with enteral absorption
Known hypersensitivity or intolerance to ingredients from the study drug formulation including patients with rare genetic disorders such as galactosaemia, glucose-galactose intolerance or congenital lactase deficiency
Known uncontrolled central nervous system (CNS) metastases (progressing or requiring anticonvulsants or corticosteroids for symptomatic control) and/or carcinomatous meningitis
Sequential
VVD-133214
DrugVVD-133214 will be administered orally and once daily (QD) in 3-week cycles.
Pembrolizumab
DrugPembrolizumab will be administered by intravenous (IV) infusion at a fixed dose of 200 mg on Day 1 of each 21-day cycle.
Bevacizumab
DrugBevacizumab will be administered by intravenous (IV) infusion at a fixed dose of 7.5 mg/kg on Day 1 of each 21-day cycle.
Incidence of Adverse Events, with Severity Graded According to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0 (NCI CTCAE v5.0)
Incidence of Dose-Limiting Toxicities
Maximum Plasma Concentration Observed (Cmax) of VVD-133214
Time of Maximum Plasma Concentration Observed (Tmax) of VVD-133214
Area Under the Plasma Concentration-Time Curve (AUC) of VVD-133214
Apparent Oral Clearance (CL/F) of VVD-133214
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