A Phase II Study of PD-1 Blockade With or Without LAG-3 Inhibition in Combination With Infliximab for the Treatment of Metastatic Melanoma and Prevention of Adverse Events
Overview
- Phase
- Phase 2
- Intervention
- Pembrolizumab
- Conditions
- Metastatic Melanoma
- Sponsor
- Massachusetts General Hospital
- Enrollment
- 36
- Locations
- 1
- Primary Endpoint
- Incidence of immune-related adverse events (irAE) in patients treated with anti-PD-1 plus infliximab compared to pembrolizumab plus placebo
- Status
- Active, not recruiting
- Last Updated
- 3 months ago
Overview
Brief Summary
The purpose of this research is to test the safety and effectiveness of the investigational combination of anti-Programmed Death (PD)-1 antibody therapy with or without LAG-3 inhibition (pembrolizumab or nivolumab+relatlimab) and infliximab in treating metastatic melanoma.
Detailed Description
This is a randomized, double-blind, phase 2 clinical trial that combines anti-Programmed Death (PD)-1 antibody therapy with or without LAG-3 inhibition (pembrolizumab or nivolumab+relatlimab) with the anti-Tumor Necrosis Factor (TNF)-α antibody infliximab as first line treatment for the management of patients with metastatic or recurrent melanoma. The U.S. Food and Drug Administration (FDA) has not approved infliximab for metastatic melanoma but it has been approved for other uses. The FDA has approved pembrolizumab as a treatment option for metastatic melanoma. The FDA has approved nivolumab+relatlimab as a treatment option for metastatic melanoma. Pembrolizumab is a blocking antibody (a protein used in the immune system to identity and neutralize bacteria, viruses, and other foreign pathogens) that binds to PD-1 (a protein that helps regulate the immune system's response in the body) and blocks the interaction with PD-L1 and PD-L2 (proteins that inhibits the body's immune response). By blocking this interaction, it might lead to an anti-tumor immune response that may decrease tumor growth. Relatlimab is believed to work by attaching to and blocking a molecule called Lymphocyte Activation Gene-3 (LAG-3). LAG-3 is a protein that is present on different types of cells in the immune system and controls parts of the immune system by shutting it down. Scientists believe that one way cancers escape the immune system is by shutting it down. Antibodies that block LAG-3 can potentially prevent LAG-3 from shutting down the immune system, thus allowing it to recognize and help the body destroy the cancer cells. Nivolumab is believed to work by attaching to and blocking a molecule called PD-1. PD-1 is a protein that is present on different types of cells in the immune system and controls parts of the immune system by shutting it down. Antibodies that block PD-1 can potentially prevent PD-1 from shutting down the immune system, thus allowing it to recognize and help the body destroy the cancer cells. Infliximab is an anti-TNFα agent (an antibody that blocks certain inflammatory hormones) that may interact with irEC (immune related (entero)colitis - inflammation that occurs in the digestive tract) which can develop among people with advanced melanoma. Anti- TNFα agents have shown to lead to rapid symptomatic improvement. By combining anti-PD-1 antibody therapy (pembrolizumab or nivolumab+relatlimab) and infliximab we believe it may lead to reduced immune related side effects while increasing effective anti-tumor immune response. The research study procedures include screening for eligibility and study treatment including evaluations and follow up visits. Participants will be randomized to receive either a) anti-PD-1 antibody therapy (pembrolizumab or nivolumab+relatlimab) plus infliximab or b) anti-PD-1 antibody therapy (pembrolizumab or nivolumab+relatlimab) plus placebo (an intravenous solution without medication). Participants will receive study treatment for as long as their disease does not worsen, they do not experience any unacceptable side effects, or they have completed the two years of anti-PD-1 antibody therapy. Participants will then be followed until the study doctor determines follow-up is no longer needed or until participant withdrawal. It is expected that about 36 people will take part in this research study A research grant, The Bridge Project, is supporting this research study by providing funding for the study.
Investigators
Ryan J Sullivan
Principal Investigator
Massachusetts General Hospital
Eligibility Criteria
Inclusion Criteria
- •Age greater than or equal to 18 years
- •Participants must have histologically confirmed Stage III unresectable or Stage IV metastatic melanoma
- •Patients should be treatment naïve and eligible for treatment with anti-PD-1 or anti-PD-1/LAG3 as a first line therapy (as selected by their treating physician)
- •Patients previously treated for melanoma with surgical resection alone who present with recurrent Stage III unresectable or Stage IV metastatic melanoma are eligible for enrollment
- •Patients who were previously treated with systemic neo-adjuvant or adjuvant anti-PD-1 therapy more than 6 months prior to study enrollment will be eligible. There are no restrictions to the use of prior BRAF targeted therapy.
- •Participants must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as \> 20 mm with conventional techniques or as \> 10 mm with spiral CT scan
- •Diagnostic imaging studies such as MRIs and CT scans must be performed within 30 days of the date of registration
- •Participants must have normal organ and marrow function as defined below:
- •Leukocytes (WBC) \> 3,000/uL
- •Absolute neutrophil count \> 1,500uL
Exclusion Criteria
- •Patients with ocular or mucosal melanoma
- •Participants previously treated with anti-PD1/PDL1/CTLA-4 monoclonal antibodies for metastatic or unresectable disease
- •Patients who are receiving other anti-neoplastic agents
- •Symptomatic or untreated leptomeningeal disease
- •Patients carrying a diagnosis of immunodeficiency or receiving systemic steroid therapy (prednisone or equivalent \> 10 mg/day) or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment. Corticosteroids to prevent contrast reactions is allowable
- •Patients with active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment
- •Prior history of inflammatory bowel disease, microscopic colitis or segmental colitis associated with diverticulosis
- •Breastfeeding and pregnant women are excluded from this study since all anti-PD-1 drugs are class D agents with the potential for teratogenic or abortifacient effects.
- •Uncontrolled intercurrent illness including, but not limited to:
- •A. Ongoing or active infection
Arms & Interventions
Anti-PD-1 therapy + Infliximab
Participants will be randomly assigned to receive physician's choice of anti-PD-1 therapy (pembrolizumab or nivolumab+relatlimab) and infliximab. * Pembrolizumab will be administered every 3 weeks for up to 2 years * Nivolumab+relatlimab will be administered every 4 weeks for up to 2 years * Infliximab will be administered on weeks 0, 2, and 6 (+/- 3 days) for a total of 3 doses
Intervention: Pembrolizumab
Anti-PD-1 therapy + Infliximab
Participants will be randomly assigned to receive physician's choice of anti-PD-1 therapy (pembrolizumab or nivolumab+relatlimab) and infliximab. * Pembrolizumab will be administered every 3 weeks for up to 2 years * Nivolumab+relatlimab will be administered every 4 weeks for up to 2 years * Infliximab will be administered on weeks 0, 2, and 6 (+/- 3 days) for a total of 3 doses
Intervention: Infliximab
Anti-PD-1 therapy + Infliximab
Participants will be randomly assigned to receive physician's choice of anti-PD-1 therapy (pembrolizumab or nivolumab+relatlimab) and infliximab. * Pembrolizumab will be administered every 3 weeks for up to 2 years * Nivolumab+relatlimab will be administered every 4 weeks for up to 2 years * Infliximab will be administered on weeks 0, 2, and 6 (+/- 3 days) for a total of 3 doses
Intervention: Relatlimab
Anti-PD-1 therapy + Infliximab
Participants will be randomly assigned to receive physician's choice of anti-PD-1 therapy (pembrolizumab or nivolumab+relatlimab) and infliximab. * Pembrolizumab will be administered every 3 weeks for up to 2 years * Nivolumab+relatlimab will be administered every 4 weeks for up to 2 years * Infliximab will be administered on weeks 0, 2, and 6 (+/- 3 days) for a total of 3 doses
Intervention: Nivolumab
Anti-PD-1 therapy + Placebo
Participants will be randomly assigned to receive physician's choice of anti-PD-1 therapy (pembrolizumab or nivolumab+relatlimab) and placebo. * Pembrolizumab will be administered every 3 weeks for up to 2 years * Nivolumab+relatlimab will be administered every 4 weeks for up to 2 years * Placebo. will be administered on weeks 0, 2, and 6 (+/- 3 days) for a total of 3 doses
Intervention: Pembrolizumab
Anti-PD-1 therapy + Placebo
Participants will be randomly assigned to receive physician's choice of anti-PD-1 therapy (pembrolizumab or nivolumab+relatlimab) and placebo. * Pembrolizumab will be administered every 3 weeks for up to 2 years * Nivolumab+relatlimab will be administered every 4 weeks for up to 2 years * Placebo. will be administered on weeks 0, 2, and 6 (+/- 3 days) for a total of 3 doses
Intervention: Placebo
Anti-PD-1 therapy + Placebo
Participants will be randomly assigned to receive physician's choice of anti-PD-1 therapy (pembrolizumab or nivolumab+relatlimab) and placebo. * Pembrolizumab will be administered every 3 weeks for up to 2 years * Nivolumab+relatlimab will be administered every 4 weeks for up to 2 years * Placebo. will be administered on weeks 0, 2, and 6 (+/- 3 days) for a total of 3 doses
Intervention: Relatlimab
Anti-PD-1 therapy + Placebo
Participants will be randomly assigned to receive physician's choice of anti-PD-1 therapy (pembrolizumab or nivolumab+relatlimab) and placebo. * Pembrolizumab will be administered every 3 weeks for up to 2 years * Nivolumab+relatlimab will be administered every 4 weeks for up to 2 years * Placebo. will be administered on weeks 0, 2, and 6 (+/- 3 days) for a total of 3 doses
Intervention: Nivolumab
Outcomes
Primary Outcomes
Incidence of immune-related adverse events (irAE) in patients treated with anti-PD-1 plus infliximab compared to pembrolizumab plus placebo
Time Frame: 12 weeks
Assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 5.0
Secondary Outcomes
- Incidence of anti-PD-1 antibody cessation due to immune-related adverse events (irAEs)(12 weeks up to 2 years)
- Response rate of patients receiving combination anti-PD-1 antibody/infliximab compared with anti-PD-1 antibody/placebo(Time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented up to 2 years)
- Cumulative steroid exposure (dose x duration) used for management of irAEs for anti-PD-1 antibody/infliximab compared to anti-PD-1 antibody/placebo patients(12 weeks up to 2 years)
- Incidence of colitis in patients treated with anti-PD-1 antibody plus infliximab compared to anti-PD-1 antibody plus placebo(12 weeks up to 2 years)
- Incidence of severe immune-related adverse events (irAEs) (grade 3-5) in patients treated with anti-PD-1 antibody plus infliximab compared to anti-PD-1 antibody plus placebo(12 weeks up to 2 years)
- Incidence of clinically apparent infections in patients treated with anti-PD-1 antibody plus infliximab compared to anti-PD-1 antibody plus placebo(12 weeks up to 2 years)
- Progression free survival rate of patients receiving combination anti-PD-1 antibody /infliximab compared with anti-PD-1 antibody/placebo(Time from randomization (or registration) to the earlier of progression or death due to any cause up to 2 years.)
- Incidence of diarrhea in patients treated with anti-PD-1 antibody plus infliximab compared to anti-PD-1 antibody plus placebo(12 weeks up to 2 years)
- Overall survival rate of patients receiving combination anti-PD-1 antibody/infliximab compared with anti-PD-1 antibody/placebo(Time from randomization (or registration) to death due to any cause, or censored at date last known alive up to 2 years)