A Phase I, Open-Label Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Anti-Tumor Activity of VVD-133214 as Monotherapy and in Combination in Participants With Advanced Solid Tumors Harboring Microsatellite Instability (MSI) and/or Deficient Mismatch Repair (dMMR)
Summary
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.
Arms & interventions
- DrugVVD-133214
VVD-133214 will be administered orally and once daily (QD) in 3-week cycles.
- DrugPembrolizumab
Pembrolizumab will be administered by intravenous (IV) infusion at a fixed dose of 200 mg on Day 1 of each 21-day cycle.
- DrugBevacizumab
Bevacizumab will be administered by intravenous (IV) infusion at a fixed dose of 7.5 mg/kg on Day 1 of each 21-day cycle.
Outcome measures
Primary
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)
Time frame: From first dose of study drug(s) until 30 days after the final dose of VVD-133214 or 90 days after last dose of bevacizumab or pembrolizumab
Incidence of Dose-Limiting Toxicities
Time frame: Cycle 1 (1 cycle is 3 weeks)
Secondary
Maximum Plasma Concentration Observed (Cmax) of VVD-133214
Time frame: At prespecified timepoints in Cycles 1, 2, and 3, and every 2 cycles thereafter (1 cycle is 3 weeks) until last dose of study drug (up to approximately 15 months)
Time of Maximum Plasma Concentration Observed (Tmax) of VVD-133214
Time frame: At prespecified timepoints in Cycles 1, 2, and 3, and every 2 cycles thereafter (1 cycle is 3 weeks) until last dose of study drug (up to approximately 15 months)
Area Under the Plasma Concentration-Time Curve (AUC) of VVD-133214
Time frame: At prespecified timepoints in Cycles 1, 2, and 3, and every 2 cycles thereafter (1 cycle is 3 weeks) until last dose of study drug (up to approximately 15 months)
Apparent Oral Clearance (CL/F) of VVD-133214
Time frame: At prespecified timepoints in Cycles 1, 2, and 3, and every 2 cycles thereafter (1 cycle is 3 weeks) until last dose of study drug (up to approximately 15 months)
Volume of Distribution (V/F) of VVD-133214
Time frame: At prespecified timepoints in Cycles 1, 2, and 3, and every 2 cycles thereafter (1 cycle is 3 weeks) until last dose of study drug (up to approximately 15 months)
Terminal Half-Life (T1/2) of VVD-133214
Time frame: At prespecified timepoints in Cycles 1, 2, and 3, and every 2 cycles thereafter (1 cycle is 3 weeks) until last dose of study drug (up to approximately 15 months)
Objective Response Rate
Time frame: From start of study treatment until end of follow-up (up to approximately 36 months)
Disease Control Rate
Time frame: From start of study treatment until end of follow-up (up to approximately 36 months)
Duration of Response
Time frame: From the time of first occurrence of a documented response until the time of documented disease progression or death from any cause, whichever occurs first (up to approximately 36 months)
Progression-Free Survival, as Assessed by the Investigator
Time frame: From start of study treatment to the first occurrence of documented disease progression or death from any cause, whichever occurs first (up to approximately 36 months)
Overall Survival
Time frame: From start of study treatment to the time of death from any cause (up to approximately 36 months)
Eligibility criteria
Study locations (9)
City of Hope Cancer Center
Duarte, California, 91010
City of Hope at Irvine Lennar
Irvine, California, 91355
Emory University School of Medicine
Atlanta, Georgia, 30322
Norton Cancer Institute - MDC
Louisville, Kentucky, 40202
Rutgers Cancer Institute of New Jersey
New Brunswick, New Jersey, 08901
Duke University
Durham, North Carolina, 27705
Oklahoma University Health Sciences Center
Oklahoma City, Oklahoma, 73170
SCRI Oncology Partners
Nashville, Tennessee, 37203
MD Anderson Cancer Center
Houston, Texas, 77030