Ipilimumab and Nivolumab in Patients With Anti-PD-1-axis Therapy-resistant Advanced Non-small Cell Lung Cancer.
- Conditions
- Carcinoma, Non-Small-Cell Lung
- Interventions
- Biological: combination nivolumab and ipilimumab
- Registration Number
- NCT03262779
- Lead Sponsor
- Yale University
- Brief Summary
The investigators propose a trial to evaluate if the addition of ipilimumab to nivolumab after primary or acquired resistance to anti- programmed death 1 (PD-1) axis therapy can lead to objective radiographic tumor regression.
- Detailed Description
Approximately 20 percent of unselected patients with advanced non-small cell lung cancer (NSCLC) and progression during or after standard first line chemotherapy will experience tumor response to nivolumab. Treatment options for patients who are not responsive to programmed death 1 (PD-1) axis inhibitor therapy are limited, and the mechanisms of primary resistance are poorly understood.
The combination of nivolumab and ipilimumab is currently FDA approved for the treatment of advanced melanoma based on superiority to either agent alone5. The results of a phase I study evaluating combination therapy with nivolumab and ipilimumab in patients with advanced NSCLC (NCT01454102) were presented at the annual American Society of Clinical Oncology (ASCO) meeting in 20166. Dosing of nivolumab 3 mg/kg every 2 weeks and ipilimumab 1 mg/kg every 6 weeks yielded an objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 of 39%, with one-year survival rate of 69% and grade 3-4 treatment-related adverse event rate of 33%. These results prompted an ongoing phase III study comparing this regimen to standard first line chemotherapy, nivolumab monotherapy or combination therapy with chemotherapy and nivolumab for patients with advanced NSCLC (NCT02477826).
The investigators propose a trial to evaluate if the addition of ipilimumab to nivolumab after primary resistance to anti-PD-1 axis therapy can lead to objective radiographic tumor regression. It is hypothesized that ipilimumab will enable more effective immune priming in some patients, resulting in the trafficking of tumor-specific cytotoxic T cells to the tumor, as well as depletion of tumor-permissive T regulatory cells. With concurrent nivolumab, PD-1 inhibition in the tumor will enable effective anti-tumor attack by tumor-specific T cells. Serial tumor biopsies and blood collections will allow interrogation of changes in the tumor microenvironment (and periphery) that support this hypothesis.
The investigators will primarily enroll patients who have experienced progression of NSCLC after anti-PD-1- axis therapy without initial response to such therapy ('primary resistance'). A smaller cohort of patients with acquired resistance to anti-PD-1 axis therapy (i.e. progression after initial response) will additionally be accrued.
The study record was updated to add individual arms for those with primary resistance and acquired resistance. The intent of the study is not to compare these treatment arms.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 20
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description combination nivolumab and ipilimumab - acquired combination nivolumab and ipilimumab Combination therapy with nivolumab 3 mg/kg administered intravenously (IV) every 2 weeks, and ipilimumab 1 mg/kg administered IV every 6 weeks in patients with acquired resistance. combination nivolumab and ipilimumab - primary combination nivolumab and ipilimumab Combination therapy with nivolumab 3 mg/kg administered intravenously (IV) every 2 weeks, and ipilimumab 1 mg/kg administered IV every 6 weeks in patients with primary resistance.
- Primary Outcome Measures
Name Time Method Objective Response Rate Using RECIST v1.1 to Nivolumab and Ipilimumab When Administered in Combination to Patients With Pre-treated Advanced NSCLC Who Have Experienced Primary Resistance to Anti-PD-1 Axis Therapy as Their Last Line of Systemic Therapy. Tumor response assessment will occur every 9 weeks after initiating trial therapy for the first 24 weeks, and thereafter every 12 weeks until disease progression or up to 4 years. Objective response is defined as a complete or partial response, as determined by investigator assessment using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 confirmed by repeat assessment ≥4 weeks after initial documentation. The categories are: complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD).
- Secondary Outcome Measures
Name Time Method Objective Response Rate in in Advanced Non-small Cell Lung Cancer (NSCLC) With ACQUIRED Resistance to Anti-programmed Death (PD)-1 Axis Therapy as Their Last Line of Systemic Therapy. Tumor response assessment will occur every 9 weeks after initiating trial therapy for the first 24 weeks, and thereafter every 12 weeks, up to four years. Objective response is defined as a complete or partial response, as determined by investigator assessment using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and confirmed by repeat assessment ≥4 weeks after initial documentation. The categories are: complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD). This outcome is only presented for those with advanced non-small cell lung cancer (NSCLC) with ACQUIRED resistance to anti-programmed death (PD)-1 axis therapy as their last line of systemic therapy.
Progression-free Survival With Nivolumab and Ipilimumab When Administered in Combination to Patients With Pre- Treated Advanced NSCLC Who Have Experienced Primary Resistance to Anti-PD-1 Axis Therapy as Their Last Line of Systemic Therapy Until disease progression, unacceptable toxicity, or study termination, up to four years. Progression free survival is defined as the time from the first day of nivolumab treatment until progression of disease using RECIST v1.1. This outcome is only presented for those pre-treated with advanced NSCLC who have experienced primary resistance to anti-PD-1 axis therapy as their last line of systemic therapy.
Progression Free Survival by RECIST v1.1 With Nivolumab and Ipilimumab in Patients With Pre-treated Advanced NSCLC Who Have Experienced Acquired Resistance to Anti-PD-1 Axis Therapy as Their Last Line of Systemic Therapy. Until disease progression, unacceptable toxicity, or study termination, up to four years from enrollment. Progression free survival is defined as the time from the first day of nivolumab treatment until progression of disease using RECIST v1.1 and immune related Response Criteria. This is in those that have experienced acquired resistance to anti-PD-1 axis therapy as their last line of systemic therapy.
Overall Survival (OS) With Nivolumab and Ipilimumab When Administered in Combination to Patients With Pre- Treated Advanced NSCLC Who Have Experienced PRIMARY Resistance to Anti-PD-1 Axis Therapy as Their Last Line of Systemic Therapy. Until death or day of last follow-up, up to four years from enrollment. Overall survival is defined as the time from the first day of treatment until death from any cause. If a patient has not experienced death, OS will be censored at the day of last follow-up. This is in patients that have experienced PRIMARY resistance to anti-PD-1 axis therapy as their last line of systemic therapy.
Overall Survival With Nivolumab and Ipilimumab in Patients With Pre-treated Advanced NSCLC Who Have Experienced ACQUIRED Resistance to Anti-PD-1 Axis Therapy as Their Last Line of Systemic Therapy. Until death or day of last follow-up (up to four years from study enrollment). Overall survival is defined as the time from the first day of treatment until death from any cause. If a patient has not experienced death, OS will be censored at the day of last follow-up.
Objective Response Rate Using irRC to Nivolumab and Ipilimumab When Administered in Combination to Patients With Pre-treated Advanced NSCLC Who Have Experienced PRIMARY or ACQUIRED Resistance to Anti-PD-1 Axis Therapy as Last Line of Systemic Therapy. Tumor response assessment will occur every 9 weeks after initiating trial therapy for the first 24 weeks, and thereafter every 12 weeks, up to four years. Objective response is defined as a complete or partial response, as determined by investigator assessment using irRC and confirmed by repeat assessment ≥4 weeks after initial documentation.
Safety of Nivolumab and Ipilimumab When Administered in Combination in Patients With Pre-treated Advanced NSCLC Who Have Experienced PRIMARY or ACQUIRED Resistance to Anti-PD-1 Axis Therapy as Their Last Line of Systemic Therapy. Up to 4 years Determined based on adverse events which will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events v4.0. Presented are a count of those that experienced at least 1 Serious Adverse Event related to study drug.
Feasibility of Sequential Biopsies in Patients With Pre-treated Advanced NSCLC Who Have Experienced PRIMARY or ACQUIRED Resistance to Anti-PD-1 Axis Therapy as Their Last Line of Systemic Therapy. Tumor biopsies performed at 9 to 10 weeks after receiving first dose of trial therapy. Feasibility of sequential biopsies (performed or not performed) in patients with pre-treated advanced NSCLC who have experienced PRIMARY or ACQUIRED resistance to anti-PD-1 axis therapy as their last line of systemic therapy. Presented are a count of those that had biopsies performed or not performed.
Trial Locations
- Locations (1)
Yale Cancer Center
🇺🇸New Haven, Connecticut, United States