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)
Study Identifier:
BP44474
CT.gov Identifier:
EudraCT Identifier:
EU Trial (CTIS) Number:
Study Contact Information:
Recruiting
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Study 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 RO7589831 monotherapy in participants with microsatellite instability (MSI) and/or deficient mismatch repair (dMMR) advanced solid tumors. RO7589831 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, RO7589831 may be able to block the growth of these types of cancer. To evaluate VVD-214 as a monotherapy and in combination with pembrolizumab as a treatment option for patients with solid tumors that display high MSI or deficient mismatch repair (dMMR) including but not limited to colorectal, endometrial, ovarian and gastric cancers
To evaluate VVD-214 in patients with previously treated MSI-high or dMMR colorectal cancer
To evaluate VVD-214 in combination with bevacizumab in patients with microsatellite instability-high (MSI-high) or deficient mismatch repair (dMMR) colorectal cancer whose disease has progressed following prior lines of therapy.
Medical Condition
The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.
Solid Tumor
Bowel (Colorectal)
Phase
The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
Phase I
Sex
Female & Male
Age
18+ years
Study Drug
Drug: Experimental Drugs
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Drug: Common Chinese name: VVD-133214 Common English name: VVD-133214 Product Name: NA: Dosage form: tablets Specification: 25mg Dosage and administration: 150mg or 600mg BID Medication duration: 21 days per cycle, until disease progression.
Drug: Common Chinese name: VVD-133214 Common English name: VVD-133214 Product Name: NA: Dosage form: tablets Specification: 150mg Dosage and administration: 150mg or 600mg BID Medication duration: 21 days per cycle, until disease progression.
Drug: Common Chinese name: VVD-133214 Common English name: VVD-133214 Product Name: NA: Dosage form: tablets Specification: 200mg Dosage and administration: 150mg or 600mg BID Medication duration: 21 days per cycle, until disease progression.
Drug: Chinese generic name: bevacizumab injection Common English name: bevacizumab injection Product Name: Pobevcy: Dosage form: Injection Specification: 100mg Dosage and administration: 7.5 mg/kg Q3W Medication duration: 21 days per cycle, until disease progression.
Drug: Chinese generic name: bevacizumab injection Common English name: bevacizumab injection Product Name: Pobevcy: Dosage form: Injection Specification: 400mg Dosage and administration: 7.5 mg/kg Q3W Medication duration: 21 days per cycle, until disease progression.
Drug: Control Drugs
Drug: :
Study Status
Indicates the current recruitment status or the expanded access status
Recruiting
Requirements information
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
- Willing and able to provide written informed consent for the trial.
- The Age be at least 18 years old when signing the informed consent form.
- Life expectancy ≥ 12 weeks
- An Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1 indicates a fitness status score of 0 or 1.
- For patients with MSI and/or dMMR and histologically or cytologically confirmed advanced (unresectable and/or metastatic) tumors: For Part 2 Cohort 2A (CRC): Patients must have previously received at least 2 but no more than 3 lines of systemic therapy for advanced colorectal cancer and have disease progression or intolerance after the last treatment.
- Archived tumor tissue that has undergone formaldehyde-fixed paraffin embedding (FFPE) is required for submission to the sponsor/central laboratory.
- Measurable lesions meeting RECIST v1.1 criteria
- Good hematological, end-organ and cardiovascular function
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 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
- Unable or unwilling to swallow pills.
- Suffering from malabsorption syndrome or other diseases that may interfere with intestinal absorption.
- Patients with known hypersensitivity or intolerance to the components of the investigational drug formulation, including those with rare genetic disorders such as galactosemia, glucose-galactose intolerance, or congenital lactase deficiency.
- Known uncontrolled central nervous system (CNS) metastases (progressing or requiring anticonvulsants or corticosteroids to control symptoms) and/or carcinomatous meningitis.
- Known active or uncontrolled bacterial, viral, fungal, mycobacterial (including but not limited to Mycobacterium tuberculosis and atypical mycobacterial diseases), parasitic or other infections (excluding nail bed fungal infections), or any major infection outbreak within 2 weeks prior to the start of administration (based on completion of the course of antibiotics, excluding tumor fever) or within 6 months prior to the start of administration that requires systemic antibiotic treatment or hospitalization for any intracranial abscess.
- A positive result for hepatitis B virus (HBV; defined as positive for hepatitis B surface antigen and/or hepatitis B core antibody) or hepatitis C virus (HCV; defined as positive for HCV antibody or HCV RNA) tests, based on local diagnostic criteria and local laws and regulations, indicates acute or chronic infection. Participants with positive hepatitis C antibodies may be eligible to participate in the study if they have received a complete course of curative antiviral therapy and have had at least two negative HCV PCR tests prior to participation in the trial.
- Individuals who test positive for hepatitis B virus, hepatitis C virus, or human immunodeficiency virus (HIV) during screening, in accordance with local diagnostic criteria and local laws and regulations.
- The patient has uncontrolled diabetes or symptomatic hyperglycemia (well controlled is defined as hemoglobin A1c <8% and no urinary ketoacidosis during the screening period).
- The patient had severe cardiovascular or cerebrovascular disease within 6 months prior to day 1 administration of the study drug.
- Alcohol or drug dependence or abuse
- Patients with known WRN syndrome
- Previous treatment with any WRN helicase inhibitor
- Received intermediate or high-potency CYP3A4 inducer treatment within 14 days prior to the start of study treatment.
- Patients who received intermediate- or high-potency CYP3A4 or P-gp inhibitors within 14 days prior to the start of the study treatment.
- Additional Exclusion criteria for participants who are pregnant, breastfeeding, or planning to become pregnant during the study period (only applicable to participants in cohort 2A (in combination with bevacizumab )).
- History of allergic or hypersensitivity reactions to bevacizumab or any of its excipients
- History of hypersensitivity reactions to Chinese hamster ovary cell products or other recombinant human or humanized antibodies
- Deep vein thrombosis (DVT) or pulmonary embolism (PE) occurred within 12 weeks prior to day 1 administration of the study drug. Participants with a history of DVT or PE must be receiving a stable dose of anticoagulation therapy or have discontinued anticoagulation therapy at the time of screening.
- Known to have a coagulation disorder that may increase the risk or tendency to bleed.
- Grade 2+ proteinuria. Patients with grade 2+ proteinuria are eligible for inclusion if their 24-hour urinary protein level is less than 1.0 g/24 hours.
Clinical Study Information for Healthcare Providers
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Study Locations
Location
Investigator
Status
Condition(s) Treated at Site
Location
START Madrid, Spain (CIOCC)
Madrid, Spain, 28050
Investigator
Emiliano Calvo
Status
Recruitment on Hold
Condition(s) Treated at Site
Solid Tumor
Bowel (Colorectal)