Advanced Solid Tumors, Colorectal Cancer
Conditions
Keywords
Deficient mismatch repair, dMMR, Microsatellite instability, MSI
Brief 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.
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.
Sponsors
Vividion Therapeutics, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
This is an open label study. Participants will be assigned to dose cohorts in the order in which they are enrolled. However, if two or more cohorts in the same part of the study are open for enrollment at the same time, participants will be randomized into these cohorts.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* 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 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; For the combination with pembrolizumab only: Histologically confirmed locally advanced, or metastatic CRC with no prior systemic treatment for metastatic disease and not amenable to surgery * Have received and then progressed following, or are intolerant to, standard therapy in the advanced setting * Presence of measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 * Life expectancy of at least (≥)12 weeks * Availability of formaldehyde-fixed paraffin-embedded (FFPE) archival tumor tissue for submission to Sponsor/central laboratory for retrospective central testing; for participants without archival tissue, a biopsy from either primary or metastatic tumor lesion, deemed medically feasible, must be taken * Adequate hematologic, end-organ, and cardiovascular function, as defined in the protocol
Exclusion criteria
* 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 * Known active or uncontrolled bacterial, viral, fungal, mycobacterial (including but not limited to tuberculosis and atypical mycobacterial disease), parasitic, or other infection (excluding fungal infections of nail beds), or any major episode of infection requiring treatment with intravenous antibiotics or hospitalization within 2 weeks prior to the start of drug administration (related to the completion of the course of antibiotics, except if for tumor fever) or 6 months for any intracranial abscess * Has a positive test at screening for hepatitis B virus, hepatitis C virus, or for human immodeficiency virus (HIV), per local diagnostic standard and in accordance with local laws and regulations * Uncontrolled diabetes or symptomatic hyperglycemia (i.e., well controlled defined as a screening hemoglobin A1c \<8% and no urinary ketoacidosis) * Significant cardiovascular/cerebrovascular disease within 6 months prior to Day 1 of study drug administration * Alcohol or drug dependence or abuse * Patients with known Werner (WRN) syndrome * Prior treatment with any WRN helicase inhibitor * Treatment with moderate or strong CYP3A4 inducers within 14 days prior to initiation of study treatment * Treatment with moderate or strong CYP3A4 or P-glycoprotein inhibitors within 14 days prior to initiation of study treatment * Pregnancy, breastfeeding, or intention of becoming pregnant during the study Additional
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| 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) | 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 | Cycle 1 (1 cycle is 3 weeks) |
Secondary
| Measure | Time frame |
|---|---|
| Duration of Response | 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) |
| Maximum Plasma Concentration Observed (Cmax) of VVD-133214 | 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 | 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 | 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 | 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 | 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 | 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 | From start of study treatment until end of follow-up (up to approximately 36 months) |
| Progression-Free Survival, as Assessed by the Investigator | 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) |
| Disease Control Rate | From start of study treatment until end of follow-up (up to approximately 36 months) |
| Overall Survival | From start of study treatment to the time of death from any cause (up to approximately 36 months) |
Countries
Australia, Belgium, Canada, China, Denmark, France, Malaysia, South Korea, Spain, United Kingdom, United States
Contacts
CONTACTVividion Clinical Trial Call Center
STUDY_DIRECTORClinical Trials
Vividion Therapeutics
Outcome results
None listed