Ipilimumab, Nivolumab, and Stereotactic Body Radiation Therapy in Treating Patients with Stage IV Non-small Cell Lung Cancer
This randomized phase I / II trial studies the side effects and best dose of stereotactic body radiation therapy when given before or with ipilimumab and nivolumab in treating patients with stage IV non-small cell lung cancer. Stereotactic body radiation therapy uses special equipment to position a patient and deliver radiation to tumors with high precision. This method can kill tumor cells with fewer doses over a shorter period and cause less damage to normal tissue. Immunotherapy with monoclonal antibodies, such as ipilimumab and nivolumab, may help the body’s immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving stereotactic body radiation therapy, ipilimumab, and nivolumab may work better in treating patients with non-small cell lung cancer.
- Have a histologic diagnosis of stage IV NSCLC
- Be willing and able to provide written informed consent/assent for the trial
- Have measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 including at least two metastatic lesions that meet criteria for SBRT radiation * 0.25 cc to 65 cc of viable tumor (i.e. primary disease or metastases) approximately 5 cm in maximal dimension; tumors larger than 65 cc can be partially treated
- For biopsy identified patients: be willing to undergo repeat biopsy of a target lesion before treatment and after radiation; subjects for whom newly-obtained samples cannot be provided (e.g. inaccessible or subject safety concern) may be exempted from this requirement after consultation with the principal investigator
- Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) performance scale
- Absolute neutrophil count (ANC) >= 1,500 /mcL (performed within 10 days of treatment initiation)
- Platelets >= 100,000 / mcL (performed within 10 days of treatment initiation)
- Hemoglobin >= 9 g/dL or >= 5.6 mmol/L without transfusion or erythropoietin (EPO) dependency (within 7 days of assessment) (performed within 10 days of treatment initiation)
- Serum creatinine =< 1.5 X upper limit of normal (ULN) OR measured or calculated (creatinine clearance should be calculated per institutional standard) creatinine clearance >= 50 mL/min for subject with creatinine levels > 1.5 X institutional ULN (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) (performed within 10 days of treatment initiation)
- Serum total bilirubin =< 1.5 X ULN OR direct bilirubin =< ULN for subjects with total bilirubin levels > 1.5 ULN (performed within 10 days of treatment initiation)
- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X ULN OR =< 5 X ULN for subjects with liver metastases (performed within 10 days of treatment initiation)
- Albumin >= 3.0 mg/dL (performed within 10 days of treatment initiation)
- Female subject of childbearing potential should have a negative urine or serum pregnancy within 24 hours prior to receiving the first dose of study medication; if the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
- Female subjects of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication; subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year
- Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy
- Have an investigator determined life expectancy of at least 6 months
- Patients whose tumors known to harbor an exon 19 deletion or exon 21 L858R EGFR mutation must have progressed on or had intolerance to an EGFR TKI; patients whose tumors are known to harbor an ALK translocation must have progressed on or had intolerance to an ALK inhibitor
- Has received prior chemotherapy for NSCLC with the exception of neoadjuvant or adjuvant platinum-based chemotherapy for NSCLC completed > 6 months prior to enrollment
- Has prior exposure to anti-PD1/PD-L1 or anti-CTLA4 therapy
- Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment
- Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy at a dose of > 10 mg prednisone daily or equivalent at time of first dose of trial treatment
- Has a known history of active TB (Bacillus tuberculosis)
- Hypersensitivity to nivolumab, ipilimumab, or any of its excipients
- Has received radiation therapy within 2 weeks of study drug administration
- Has a known additional 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
- Patients with uncontrolled brain metastases; patients with controlled brain metastases will be allowed on protocol; controlled brain metastases will be defined as treated brain metastases; brain metastases will be considered “treated” on the day of surgical resection or the first day of radiation therapy (stereotactic radiosurgery [SRS] or whole body radiation therapy [WBRT]) depending on the treatment method; if patients require radiation therapy after surgery, they will still be considered “treated” on the day of surgery; however, all treatment for brain metastases must be completed prior to the initiation of protocol therapy; no follow up imaging is required prior to the start of protocol therapy
- 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 systemic treatment
- Has known history of non-infectious pneumonitis that required steroids or active pneumonitis
- Has evidence of interstitial lung disease
- Has an active infection requiring systemic therapy
- 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 treating investigator
- Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
- Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 120 days after the last dose of trial treatment
- If known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected) then patient is not eligible for cohorts including SBRT to liver lesions
- Has received a live vaccine within 30 days of 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
- Has had prior radiation therapy (defined as > 10% of prior prescription dose) to the area planning to be treated with SBRT
Locations & Contacts
Contact: Jyoti D. Patel
Trial Objectives and Outline
I. To determine the recommended stereotactic body radiation therapy (SBRT) dose to various metastatic locations in patients with stage IV non-small cell lung cancer (NSCLC) when delivered prior to or concurrently with nivolumab and ipilimumab.
I. To estimate and compare rates of >= grade 3-4 adverse events, by organ system, by Common Terminology Criteria for Adverse Events (CTCAE) version (v)4.0 that occur within 3 months from the start of SBRT when given prior to or concurrently with nivolumab/ipilimumab.
II. To estimate and compare the rates of long-term adverse events (after 3 months) from the end of SBRT when given prior to or concurrently with nivolumab/ipilimumab.
III. To summarize and compare the response rate and progression-free survival at 6 months with SBRT given either prior to or concurrently with nivolumab/ipilimumab.
IV. To determine and compare the control of the SBRT treated lesion and non-treated lesion(s) when given either prior to or concurrently with nivolumab/ipilimumab.
V. To evaluate and compare changes in the tumor microenvironment induced by radiation when given prior to or concurrently with nivolumab/ipilimumab.
VI. To evaluate whether response to therapy correlates with PD-L1 expression levels among patients treated with nivolumab/ipilimumab either concurrently or sequential to SBRT.
VII. To explore whole peripheral blood mononuclear cell (PBMC) and peripheral blood cell T cell subset interferon (IFN) gamma Enzyme-Linked ImmunoSpot (ELISPOT) levels throughout the study course and correlate with response to treatment.
VIII. To explore peripheral blood T cell receptor deep sequencing quantification of T cell receptor (TCR) repertoire changes throughout the study course and how TCR repertoire may correlate with progression free survival and overall survival.
IX. To correlate local response to SBRT on positron emission tomography (PET) scan compared to computed tomography (CT) imaging pre- and post-radiation.
X. To determine if pulmonary function test (PFT) post-protocol therapy is similar to that predicted using normal tissue complication probability of SBRT alone.
OUTLINE: This is a dose de-escalation study of stereotactic body radiation therapy. Patients are randomized to 1 of 2 arms.
ARM I: Patients undergo SBRT over 1-2 weeks for a total of 3-5 fractions. Beginning 1-7 days after completion of SBRT, patients receive nivolumab intravenously (IV) over 30 minutes on days 1, 15, and 29 and ipilimumab IV over 30 minutes on day 1. Courses repeat every 6 weeks for up to 24 months 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. Courses repeat every 6 weeks for up to 24 months in the absence of disease progression or unacceptable toxicity. Within 2 weeks of first dose of nivolumab, patients also undergo SBRT over 1-2 weeks for a total of 3-5 fractions.
After completion of study treatment, patients are followed up at 30 and 100 days, then every 12 weeks.
Trial Phase & Type
University of Chicago Comprehensive Cancer Center
Jyoti D. Patel
Secondary IDs NCI-2017-01737
Clinicaltrials.gov ID NCT03223155