A Phase Ib Clinical Trial to Evaluate Early Immunologic Pharmacodynamic Parameters Following Neoadjuvant Anti-PD-1 (Nivolumab), or the Combination of Anti-PD-1 Plus Anti-CTLA-4 (Nivolumab Plus Ipilimumab) in Patients With Surgically Accessible Glioblastoma
Overview
- Phase
- Phase 1
- Intervention
- Nivolumab
- Conditions
- Glioblastoma
- Sponsor
- Patrick Wen, MD
- Enrollment
- 63
- Locations
- 4
- Primary Endpoint
- Tumor Infiltrating T Lymphocyte (TIL) Density
- Status
- Active, Not Recruiting
- Last Updated
- 2 months ago
Overview
Brief Summary
This research trial is studying the safety and effectiveness of nivolumab in combination with ipilimumab and surgery when used in the treatment of recurrent glioblastoma.
The names of the study drugs involved in this study are:
- Nivolumab
- Ipilimumab
- Placebo (IV solution with no medicine)
- Zr-89 Crefmirlimab berdoxam (optional sub-study)
Detailed Description
The research study procedures include screening for eligibility and study treatment including evaluations and follow up visits. It is expected that about 60 people will take part in this research study. There are 3 study groups participating in this study and each group receives different study drugs. After screening, participants will be randomized into one of three study groups. Participants will receive one of the following study treatments prior to undergoing surgery for tumor removal: * Group A receives nivolumab plus ipilimumab * Group B receives nivolumab plus placebo-ipilimumab * Group C receives two placebo infusions, placebo-nivolumab plus placebo-ipilimumab Neither the participant nor the research doctor will know which study drugs the participant will receive prior to surgery. After recovering from surgery, participants will receive the following doses of study medication: \-- Nivolumab plus ipilimumab every 3 weeks for 3 doses followed by nivolumab every 4 weeks This research study is a Phase Ib clinical trial, which tests the safety and effectiveness of an investigational drug to learn whether the drug works in treating a specific disease. "Investigational" means the drug is being studied. The U.S. Food and Drug Administration (FDA) has not approved the use of nivolumab or ipilimumab for your specific disease, but it has been approved for other uses. Both nivolumab and ipilimumab are antibodies (types of human protein) that work to stop tumor cells from growing and multiplying by immunotherapy. Immunotherapy is trying to have the body's own immune system work against tumor cells. Nivolumab and ipilimumab have been used in other research studies, and information from those other research studies suggest these drugs may help to stop glioblastoma cells from growing. Subjects also have the option of undergoing Zr-89 Crefmirlimab berdoxam PET scans. This consists of one infusion with Zr-89 Crefmirlimab berdoxam followed by a PET scan prior to starting study treatment and another infusion with PET scan about 3 days prior to surgery. The U.S. Food and Drug Administration (FDA) has not approved Zr-89 Crefmirlimab berdoxam as a treatment for any disease.
Investigators
Patrick Wen, MD
Sponsor Investigator
Dana-Farber Cancer Institute
Eligibility Criteria
Inclusion Criteria
- •Have histologically confirmed World Health Organization Grade IV IDH wildtype glioblastoma or variants including gliosarcoma or IDH wildtype glioma with molecularly features of glioblastoma.
- •Previous first line therapy with at least radiotherapy.
- •Patients must be undergoing surgery that is clinically indicated as determined by their care providers.
- •Be at first or second relapse. Note: Relapse is defined as progression following initial therapy (i.e., radiation ± chemotherapy).
- •Participants must have shown unequivocal evidence for tumor progression by MRI per RANO criteria.
- •Participants must have confirmation of availability of sufficient tissue from prior surgery revealing glioblastoma or variants for submission following registration. The following amount of tissue is required:
- •1 formalin-fixed paraffin-embedded (FFPE) tumor tissue block (preferred) OR
- •10 FFPE unstained slides (5 μm thick)
- •An interval of at least 12 weeks from the completion of radiation therapy to registration unless there is unequivocal histologic confirmation of tumor progression.
- •Participants must have recovered to grade 0 or 1 or pre-treatment baseline from clinically significant toxic effects of prior therapy (including but not limited to exceptions of alopecia, laboratory values listed per inclusion criteria, and lymphopenia (which is common after therapy with temozolomide).
Exclusion Criteria
- •IDH mutation by immunohistochemistry.
- •Current or planned participation in a study of an investigational agent or using an investigational device.
- •Has a diagnosis of immunodeficiency.
- •Has tumor primarily localized to the brainstem or spinal cord.
- •Has presence of diffuse leptomeningeal disease or extracranial disease.
- •Has received systemic immunosuppressive treatments, aside from systemic corticosteroids (such as methotrexate, chloroquine, azathioprine, etc.) within six months of registration.
- •Has received bevacizumab or aflibercept. VEGFR inhibitors are allowed.
- •Requires treatment with high dose systemic corticosteroids defined as dexamethasone \> 2 mg/day or bioequivalent at the time of registration.
- •Has received prior interstitial brachytherapy, implanted chemotherapy, stereotactic radiosurgery or therapeutics delivered by local injection or convection enhanced delivery.
- •Has history of known coagulopathy that increases risk of bleeding or a history of clinically significant hemorrhage within 12 months of registration.
Arms & Interventions
Nivolumab and Ipilimumab Before and After Surgery
One dose of nivolumab plus ipilimumab will be administered 14(±5) days before surgery. After surgery, participants receive nivolumab in combination with ipilimumab every 3 weeks for 9 weeks and then nivolumab alone every 4 weeks.
Intervention: Nivolumab
Nivolumab and Ipilimumab Before and After Surgery
One dose of nivolumab plus ipilimumab will be administered 14(±5) days before surgery. After surgery, participants receive nivolumab in combination with ipilimumab every 3 weeks for 9 weeks and then nivolumab alone every 4 weeks.
Intervention: Ipilimumab
Nivolumab and Ipilimumab Before and After Surgery
One dose of nivolumab plus ipilimumab will be administered 14(±5) days before surgery. After surgery, participants receive nivolumab in combination with ipilimumab every 3 weeks for 9 weeks and then nivolumab alone every 4 weeks.
Intervention: Surgery
Nivolumab and Placebo-Ipilimumab Before Surgery, Nivolumab After Surgery
One dose of nivolumab plus placebo-ipilimumab will be administered 14(±5) days before surgery. After surgery, participants receive nivolumab in combination with ipilimumab every 3 weeks for 9 weeks and then nivolumab alone every 4 weeks.
Intervention: Nivolumab
Nivolumab and Placebo-Ipilimumab Before Surgery, Nivolumab After Surgery
One dose of nivolumab plus placebo-ipilimumab will be administered 14(±5) days before surgery. After surgery, participants receive nivolumab in combination with ipilimumab every 3 weeks for 9 weeks and then nivolumab alone every 4 weeks.
Intervention: Ipilimumab-Placebo
Nivolumab and Placebo-Ipilimumab Before Surgery, Nivolumab After Surgery
One dose of nivolumab plus placebo-ipilimumab will be administered 14(±5) days before surgery. After surgery, participants receive nivolumab in combination with ipilimumab every 3 weeks for 9 weeks and then nivolumab alone every 4 weeks.
Intervention: Surgery
Placebo-Nivolumab and Placebo-Ipilimumab Before Surgery, Nivolumab and Ipilimumab After Surgery
One dose of placebo-nivolumab plus placebo-ipilimumab will be administered 14(±5) days before surgery. After surgery, participants receive nivolumab in combination with ipilimumab every 3 weeks for 9 weeks and then nivolumab alone every 4 weeks
Intervention: Nivolumab-Placebo
Placebo-Nivolumab and Placebo-Ipilimumab Before Surgery, Nivolumab and Ipilimumab After Surgery
One dose of placebo-nivolumab plus placebo-ipilimumab will be administered 14(±5) days before surgery. After surgery, participants receive nivolumab in combination with ipilimumab every 3 weeks for 9 weeks and then nivolumab alone every 4 weeks
Intervention: Nivolumab
Placebo-Nivolumab and Placebo-Ipilimumab Before Surgery, Nivolumab and Ipilimumab After Surgery
One dose of placebo-nivolumab plus placebo-ipilimumab will be administered 14(±5) days before surgery. After surgery, participants receive nivolumab in combination with ipilimumab every 3 weeks for 9 weeks and then nivolumab alone every 4 weeks
Intervention: Ipilimumab-Placebo
Placebo-Nivolumab and Placebo-Ipilimumab Before Surgery, Nivolumab and Ipilimumab After Surgery
One dose of placebo-nivolumab plus placebo-ipilimumab will be administered 14(±5) days before surgery. After surgery, participants receive nivolumab in combination with ipilimumab every 3 weeks for 9 weeks and then nivolumab alone every 4 weeks
Intervention: Ipilimumab
Placebo-Nivolumab and Placebo-Ipilimumab Before Surgery, Nivolumab and Ipilimumab After Surgery
One dose of placebo-nivolumab plus placebo-ipilimumab will be administered 14(±5) days before surgery. After surgery, participants receive nivolumab in combination with ipilimumab every 3 weeks for 9 weeks and then nivolumab alone every 4 weeks
Intervention: Surgery
Outcomes
Primary Outcomes
Tumor Infiltrating T Lymphocyte (TIL) Density
Time Frame: 24 Months
TIL density will be assessed and compared between the three arms using the Two-sample t-Test.
Safety of Study Drug Therapy
Time Frame: 24 Months
Adverse events will be graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Safety will be assessed by quantifying the toxicities and grades experienced by participants who have received at least one dose of study treatment.
Secondary Outcomes
- Percentage of Progression Free Survival (PFS-6)(24 months)
- Cell Cycle-Related Genetic Signature within the Tumor Microenvironment(24 months)