A Study to Evaluate the Safety, Pharmacokinetics, and Anti-Tumor Activity of VVD-133214 as Monotherapy and in Combination in Participants With Advanced Solid Tumors

Официальное название

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)

Обзор

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.

Вмешательства

• Препарат VVD-133214
  VVD-133214 will be administered orally and once daily (QD) in 3-week cycles.
• Препарат Pembrolizumab
  Pembrolizumab will be administered by intravenous (IV) infusion at a fixed dose of 200 mg on Day 1 of each 21-day cycle.
• Препарат Bevacizumab
  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.

Первичные конечные точки

• 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) [Срок оценки: 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 [Срок оценки: Cycle 1 (1 cycle is 3 weeks)]

Вторичные конечные точки (11)

• Maximum Plasma Concentration Observed (Cmax) of VVD-133214 [Срок оценки: 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 [Срок оценки: 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 [Срок оценки: 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 [Срок оценки: 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 [Срок оценки: 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 [Срок оценки: 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 [Срок оценки: From start of study treatment until end of follow-up (up to approximately 36 months)]
• Disease Control Rate [Срок оценки: From start of study treatment until end of follow-up (up to approximately 36 months)]
• Duration of Response [Срок оценки: 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 [Срок оценки: 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 [Срок оценки: From start of study treatment to the time of death from any cause (up to approximately 36 months)]

Критерии участия

Критерии включения

• 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

Критерии исключения

• 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 Exclusion Criteria for the Combination with Bevacizumab Only:

• Had major surgery within 4 weeks prior to study drug administration
• Deep venous thrombosis (DVT) or pulmonary embolism (PE) within 12 weeks prior to study drug administration
• Known coagulopathy that increases the risk of bleeding
• Patients with Grade 2+ proteinuria (exception: if 24-hour urinary protein is less than 1.0 gm/24 hours)

Additional Exclusion Criteria for the Combination with Pembrolizumab Only:

• Active or history of autoimmune disease or immune deficiency with some exceptions
• History of interstitial lung disease or pneumonitis
• Treatment with systemic immunosuppressive medication (such as corticosteroids) within 2 weeks prior to initiation of study treatment with some exceptions
• Treatment with organ transplant/graft tissue

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Нерандомизированное

Модель

Последовательный дизайн

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

США · 14 центров

• City of Hope Cancer Center — Duarte
• City of Hope at Irvine Lennar — Irvine
• START Los Angeles — Los Angeles
• Emory University School of Medicine — Atlanta
• Norton Cancer Institute - MDC — Louisville
• University of Michigan — Ann Arbor
• START Midwest — Grand Rapids
• Rutgers Cancer Institute of New Jersey — New Brunswick
• … и ещё 6 центров

South Korea · 7 центров

• Kyungpook National University Chilgok Hospital — Daegu
• National Cancer Center — Gyeonggi-do
• Seoul National University Bundang Hospital — Seongnam-si
• Seoul National University Hospital — Seoul
• Asan Medical Center — Seoul
• Samsung Medical Center — Seoul
• Severance Hospital — Seoul

Испания · 5 центров

• Vall d'Hebron Institute of Oncology (VHIO), Barcelona — Barcelona
• Clinica Universidad de Navarra Madrid — Madrid
• START Madrid. Centro Integral Oncologico Clara Campal — Madrid
• Clinica Universitaria de Navarra — Pamplona
• Hospital Clinico Universitario de Valencia — Valencia

Великобритания · 3 центра

• Sarah Cannon Research Institute — London
• The Christie — Manchester
• Royal Marsden Hospital (Sutton) — Sutton

Австралия · 2 центра

• St Vincents Sydney — Darlinghurst
• Alfred Hospital — Melbourne

Канада · 2 центра

• BCCA-Vancouver Cancer Centre — Vancouver
• Princess Margaret Cancer Center — Toronto

Франция · 2 центра

• CLCC Leon Berard Lyon — Lyon
• Gustave Roussy — Villejuif

Бельгия · 1 центр

• UZ Leuven Gasthuisberg — Leuven

Дания · 1 центр

• Rigshospitalet — København Ø

Малайзия · 1 центр

• Sarawak Public Hospital — Kuching

Идентификаторы

NCT: NCT06004245 · VVD-133214-01 · 2023-503170-20-01

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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