Nivolumab with or without Ipilimumab after Chemotherapy and Radiation Therapy in Treating Patients with Stage III Non-small Cell Lung Cancer That Cannot Be Removed by Surgery
This randomized phase II trial studies how well nivolumab with or without ipilimumab after chemotherapy and radiation therapy work in treating patients with stage III non-small cell lung cancer that cannot be removed by surgery. Immunotherapy with monoclonal antibodies, such as nivolumab and ipilimumab, may help the body’s immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread.
- Written informed consent and Health Insurance Portability and Accountability Act (HIPAA) authorization for release of personal health information; NOTE: HIPAA authorization may be included in the informed consent or obtained separately
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 within 14 days prior to registration
- Histological or cytological confirmation of NSCLC; a pathology report confirming the diagnosis of NSCLC must be obtained and reviewed by the treating physician prior to registration to study
- Must have unresectable or inoperable stage IIIA or IIIB disease; subjects must be considered unresectable or inoperable based on the judgment of the treating physician
- Subjects must have completed concurrent chemoradiation with a platinum doublet and a dose of radiation ranging from 59.4-66.6 Gy; subjects must have stable disease or disease response as evidenced on computed tomography (CT) or positron emission tomography (PET) scan evaluation; for those eligible, protocol therapy should begin a minimum of 28 days and a maximum 56 days following the completion of chemoradiation OR Subjects must have completed up to 2 cycles of consolidation therapy started within 28-56 days of completion of radiation; after completion of consolidation chemotherapy, subjects must have stable disease or disease response as evidenced by CT or PET scan evaluation; for those eligible, protocol therapy should begin 28-56 days after the last cycle of chemotherapy
- Prior cancer treatment must be completed at least 28 days prior to registration and the subject must have recovered from all reversible acute toxic effects of the regimen (other than alopecia) to =< grade 1 or baseline
- Absolute neutrophil count (ANC) >= 1.5 K/mm^3 (obtained within 14 days prior to registration)
- Hemoglobin (Hgb) >= 9 g/dL; transfusion is allowed (obtained within 14 days prior to registration)
- Platelets >= 100,000/mcl (obtained within 14 days prior to registration)
- Serum creatinine =< 1.5 x upper limit of normal (ULN) OR measured or calculated creatinine clearance (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) >= 60 mL/min for subjects with creatinine levels > 1.5 x institutional ULN (obtained within 14 days prior to registration)
- Bilirubin =< 1.5 x ULN OR direct bilirubin of =< ULN for subjects with total bilirubin levels of > 1.5 x ULN (obtained within 14 days prior to registration)
- Aspartate aminotransferase (AST) =< 2.5 x ULN (obtained within 14 days prior to registration)
- Alanine aminotransferase (ALT) =< 2.5 x ULN (obtained within 14 days prior to registration)
- International normalized ratio (INR) or prothrombin time (PT) =< 1.5 x ULN unless subject is receiving anticoagulant therapy as long as PT/INR/ partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants (obtained within 14 days prior to registration)
- Activated partial thromboplastin time (aPTT) =< 1.5 x ULN unless subject is receiving anticoagulant therapy as long as PT/INR/PTT is within therapeutic range of intended use of anticoagulants (obtained within 14 days prior to registration)
- Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [hCG]) within 7 days prior to registration; NOTE: women are considered of childbearing potential unless they are surgically sterile (have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or are postmenopausal; menopause is defined clinically as 12 months of amenorrhea in a woman over age 45 in the absence of other biological or physiological causes. In addition, women under the age of 62 must have a documented serum follicle stimulating hormone (FSH) level greater than 40 mIU/mL
- Women of childbearing potential must be willing to abstain from heterosexual activity or use an effective method of contraception from the time of informed consent until 23 weeks after treatment discontinuation
- Men who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1% per year; men receiving study drug and who are sexually active with WOCBP will be instructed to adhere to contraception for a period of 31 weeks after the last dose of investigational product
- As determined by the enrolling physician or protocol designee, ability of the subject to understand and comply with study procedures for the entire length of the study
- Pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 23 weeks (female) or 31 weeks (male) after the last dose of trial treatment
- Active central nervous system (CNS) metastases; if symptomatic or without prior brain imaging, subjects must undergo a head computed tomography (CT) scan or brain magnetic resonance imaging (MRI) within 28 days prior to registration for protocol therapy to exclude brain metastases
- Treatment with any investigational agent within 28 days prior to registration for protocol therapy
- Prior chemotherapy, adjuvant therapy, or radiotherapy for lung cancer other than standard concurrent chemoradiation or up to 2 cycles of consolidation as described above
- Prior therapy with a PD-1, PD-L1, PD-L2 or CTLA-4 inhibitor or a lung cancer-specific vaccine therapy
- Previously received a solid organ transplant or allogeneic progenitor/stem cell transplant
- Presence of metastatic disease (stage IV NSCLC) is not allowed; subjects must be evaluated with a CT or PET scan prior to registration for protocol therapy to exclude metastatic disease
- Active second cancers
- Evidence of active autoimmune disease requiring systemic treatment within the past 90 days or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents; subjects with vitiligo or resolved childhood asthma/atopy would be an exception to this rule; subjects that require intermittent use of bronchodilators or local steroid injections would not be excluded from the study; subjects with hypothyroidism stable on hormone replacement or Sjogren’s syndrome will not be excluded from the study
- Interstitial lung disease or history of pneumonitis requiring treatment with corticosteroids
- Diagnosis of immunodeficiency or is receiving chronic systemic corticosteroid therapy or other immunosuppressive therapy (excludes inhaled corticosteroids) within 7 days of first dose of study drug
- History of psychiatric illness or social situations that would limit compliance with study requirements
- Clinically significant acute infection requiring systemic antibacterial, antifungal, or antiviral therapy including: * Tuberculosis (clinical evaluation that includes clinical history, physical examination, and radiographic findings, and tuberculosis [TB] testing in line with local practice), * Hepatitis B (known positive hepatitis B virus [HBV] surface antigen (HBsAg) result), * Hepatitis C, or * Human immunodeficiency virus (positive HIV 1/2 antibodies) * NOTES: Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible; patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for hepatitis C virus (HCV) ribonucleic acid (RNA); subjects with HIV/acquired immunodeficiency syndrome (AIDS) with adequate antiviral therapy to control viral load would be allowed if they are stable and have been on treatment for >= 4 weeks prior to first dose of study drug(s); subjects with viral hepatitis with controlled viral load would be allowed while on suppressive antiviral therapy; testing not required
- Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject’s participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the site investigator
- Hypersensitivity to nivolumab, ipilimumab, or any of their excipients
- Has received a live vaccine within 30 days prior to planned start of study therapy; NOTE: seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however, intranasal influenza vaccines (e.g., Flu-Mist) are live attenuated vaccines, and are not allowed
Locations & Contacts
Contact: Greg Durm
Contact: Peggy Heires
Contact: Karen Estok
Contact: Hilary Hernan
Trial Objectives and Outline
I. To determine if consolidation therapy with nivolumab alone following concurrent chemoradiation improves 18-month progression free survival (PFS) relative to a historical control of chemoradiation alone, in subjects with inoperable or unresectable stage IIIA or IIIB non-small cell lung cancer (NSCLC) (Arm 1).
II. To determine if consolidation therapy with nivolumab and ipilimumab following concurrent chemoradiation improves 18-month PFS relative to a historical control of chemoradiation followed by single agent checkpoint inhibitor, in subjects with inoperable or unresectable stage IIIA or IIIB NSCLC (Arm 2).
I. To determine if consolidation therapy with nivolumab alone following concurrent chemoradiation improves time to metastatic disease and overall survival (OS) relative to a historical control of chemoradiation alone in subjects with inoperable or unresectable stage IIIA or IIIB NSCLC (Arm 1).
II. To determine if consolidation therapy with nivolumab and ipilimumab following concurrent chemoradiation improves time to metastatic disease and overall survival (OS) relative to a historical control of chemoradiation followed by single agent checkpoint inhibitor in subjects with inoperable or unresectable stage IIIA or IIIB NSCLC (Arm 2).
III. To assess toxicity and tolerability of consolidation therapy with nivolumab plus ipilimumab or nivolumab alone following concurrent chemoradiation in subjects with inoperable or unresectable stage IIIA or IIIB NSCLC.
I. To assess PD-L1, CD4, CD8, expression levels in the tumor samples of subjects with inoperable or unresectable stage IIIA or IIIB NSCLC and correlate with PFS, OS, time to metastatic disease, and treatment toxicity.
II. To assess associations between deoxyribonucleic acid (DNA), ribonucleic acid (RNA), microRNA, DNA methylation, protein expression, lipidomic profiling, immune markers, protein biomarker panels, and other markers and efficacy and toxicity of treatment.
III. To explore whether clinical characteristics may be associated with the development of pneumonitis and correlate with PFS, OS, time to metastatic disease, and treatment toxicity.
IV. To explore whether radiation treatment plan deviation or lung dosimetric factors may be associated with the development of pneumonitis and correlate with PFS, OS, time to metastatic disease, and treatment toxicity.
V. To examine characteristics of BAL samples (e.g. cytokines and chemokines) in patients who develop pneumonitis.
OUTLINE: Patients are randomized into 1 of 2 arms.
ARM I: Patients receive nivolumab intravenously (IV) over 30 minutes on day 1. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.
ARM II: Patients receive nivolumab IV over 30 minutes on days 1, 15, and 29 and ipilimumab IV over 30 minutes on day 1. Treatment repeats every 42 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up for 100 days, then every 3 months for years up to 2 years.
Trial Phase & Type
Indiana University / Melvin and Bren Simon Cancer Center
Secondary IDs NCI-2017-01945
Clinicaltrials.gov ID NCT03285321