Pembrolizumab before and after Surgery in Treating Patients with Stage IB-IIIA Non-small Cell Lung Cancer
This phase II trial studies how well pembrolizumab before and after surgery works in treating patients with stage IB-IIIA non-small cell lung cancer. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread.
- Histologically cytologically confirmed NSCLC
- Clinical stage IB (>= 3 cm per computed tomography [CT]), stage IIA/IIB, or stage IIIA (N0-2) amenable to surgical resection
- Primary tumor >= 3 cm (for all stages entered) to increase the likelihood that excess tumor will be available after resection
- Patient must be deemed a surgical candidate as documented by surgeon within their respective institutional standards
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
- NO prior chemotherapy, radiation therapy or biologic/targeted therapy for current diagnosis of lung cancer
- No active invasive malignancy in the past 2 years other than non-melanoma skin cancer; cancers that are in-situ are not considered invasive
- Signed written informed consent including Health Insurance Portability and Accountability Act (HIPAA) according to institutional guidelines
- Absolute neutrophil count (ANC) or atypical glandular cell (AGC) >= 1500 per uL
- Platelets >= 100,000 per uL
- Hemoglobin >= 9 g/dL or >= 5.6 mmol/L without transfusion or erythropoietin (EPO) dependency (within 7 days of assessment)
- 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 subject with creatinine levels > 1.5 X institutional ULN * Creatinine clearance should be calculated per institutional standard
- Serum total bilirubin =< 1.5 X ULN OR direct bilirubin =< ULN for subjects with total bilirubin levels > 1.5 ULN
- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X ULN
- Albumin >= 2.5 mg/dL
- International normalized ratio (INR) or prothrombin time (PT) =< 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants
- Activated partial thromboplastin time (aPTT) =< 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants
- Females of child-bearing potential (not surgically sterilized or postmenopausal [a woman who is >= 45 years of age and has not had menses for greater than 1 year]) must test negative for pregnancy within 48 hours prior to any initial study procedure based on a serum pregnancy test; both sexually active males and females of reproductive potential must agree to use a reliable method of birth control, as determined by the patient and their health care team, during the study and for 120 days following the last dose of study drug; if subject uses appropriate contraceptive methods (the use of two forms at the same time) from the time of the initial serum pregnancy test, then the subsequent pregnancy test can be done within 72 hours of receiving study drug administration; if appropriate; contraceptive measures are not begun immediately with the first serum pregnancy test, then subsequent serum pregnancy tests must be done within 48 hours prior to the study drug administration
- Patients must agree to research blood sampling to participate in study
- Have measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
- Forced expiratory volume in 1 second (FEV1) and carbon monoxide diffusing capability test (DLCO) >= 40% predicted (or per institutional standard)
- Treatment within the last 30 days with a drug that has not received regulatory approval for any indication at the time of study entry or used an investigational device within 4 weeks of the first dose of treatment
- Has a known history of active TB (Bacillus tuberculosis)
- Hypersensitivity to pembrolizumab or any of its excipients
- Concurrent administration of any other anti-tumor therapy
- Has received prior therapy with an anti-PD-1, anti-PD-L-1, or anti-PD-L2 agent
- Has known active hepatitis B (e.g., hepatitis B virus surface antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative])
- Inability to comply with protocol or study procedures
- Active infection requiring antibiotics, antifungal or antiviral agents, that in the opinion of the investigator would compromise the patient’s ability to tolerate therapy
- Has known history of, or any evidence of active, non-infectious pneumonitis that required steroids (steroid treatment of chronic obstructive pulmonary disease [COPD] or asthma allowed)
- Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)
- Has 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 (e.g. thyroxine, insulin or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency etc.) is not considered a form of system treatment; patients with a history of inflammatory bowel disease, including ulcerative colitis and Crohn’s disease, are excluded from this study, as are patients with a history of symptomatic disease (e.g., rheumatoid arthritis, systemic progressive sclerosis [scleroderma], systemic lupus erythematosus, autoimmune vasculitis [e.g., Wegener’s granulomatosis]); motor neuropathy considered of autoimmune origin (e.g. Guillain-Barre syndrome and myasthenia gravis)
- Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment
- Has a known additional invasive malignancy that is progressing or requires active treatment; exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer
- Is 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 120 days after the last dose of trial treatment
- Has had major surgery (other than definitive lung cancer surgery) within two weeks of study or other serious concomitant disorders that in the opinion of the investigator would compromise the safety of the patient or compromise the patient’s ability to complete the study
- Has received any non-oncology vaccine therapy used for prevention of infectious diseases (for up to 30 days before or after any dose of pembrolizumab); 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
- Has history of myocardial infarction having occurred less than 6 months before inclusion, any known uncontrolled arrhythmia, symptomatic angina pectoris, active ischemia, or cardiac failure not controlled by medications; patients with coronary artery disease (CAD) recently treated with surgery and/or stent, if stable without symptomatic angina pectoris, active ischemia are eligible
- Has evidence or a history of interstitial lung disease
- Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
- Prisoners or subjects who are compulsorily detained involuntarily incarcerated) for treatment of either psychiatric or physical (e.g., infectious) illness
Locations & Contacts
Contact: Dennis A. Wigle
Contact: Konstantin Hristov Dragnev
Contact: Neal E. Ready
Trial Objectives and Outline
I. To determine whether the surgery feasibility rate of neoadjuvant pembrolizumab is not significantly worse than the historical surgical feasibility rate of neoadjuvant chemotherapy.
I. Estimate the rate of objective response rate for the protocol treatment.
II. Evaluate disease-free survival and patterns of metastases after protocol treatment.
III. Blood-based biomarkers will be evaluated for changes before and after protocol treatment.
IV. Determine the percentage of patients with “detectable” (percentage of >= 0.05% with each value also being at least twice that of the background unstimulated control value) tumor infiltrating lymphocytes (TILs) after protocol treatment.
V. Evaluate whether presence, quantity or quality of detectable TILs is associated with pathologic response to neoadjuvant therapy.
VI. Treatment-related adverse evaluate will be summarized by type and grade.
VII. The proportion of patients with detectable circulating T cells specific against tumor associated antigens (TAA) after the protocol treatment will be estimated and its confidence interval will be provided.
VIII. Estimate the rate of pathologic response rate for neoadjuvant pembrolizumab in early stage non-small cell lung cancer (NSCLC).
IX. Determine if the immunomodulatory effects of neoadjuvant chemotherapy plus pembrolizumab impact the suppressive mechanisms, restoring functional reactivity to important anti-tumor effector cell populations.
X. Explore an alternative definition for detectability suitable for expression values generated using Boolean gating, and determine the percentage of patients with circulating T cells meeting this definition.
XI. Perform gene expression analysis on tumor to elucidate genes associated with function and modulation of the PD-1/PD-L1 axis.
Patients receive pembrolizumab intravenously (IV) over 30 minutes on days 1 and 22. Patients then undergo surgery between days 29-56 followed by standard of care chemotherapy and radiation therapy. After completion of adjuvant therapy, patients receive pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unexpected toxicity.
After completion of study treatment, patients are followed up every 3-4 months for 2 years after surgery and then every 6 months for up to 5 years.
Trial Phase & Type
Duke University Medical Center
Neal E. Ready
Secondary IDs NCI-2017-00093
Clinicaltrials.gov ID NCT02818920