Study Groups:
If participant is found to be eligible to take part in this study, participant will be
randomly assigned (as in the flip of a coin) to receive either SABR alone (Group 1) or SABR
and nivolumab (Group 2). This is done because no one knows if one study group is better, the
same, or worse than the other group.
Participant will have an equal chance (50/50) of being assigned to either group. Both
participant and the doctor will know which treatment participant is receiving.
Study Drug Administration:
Participant will receive SABR as part of participant's standard care. The study doctor will
discuss with participant how SABR will be administered and how often participant will
receive it.
If participant is in Group 2, participant will also receive nivolumab by vein over about 30
minutes within 24 hours before or after participant's SABR treatment and then every 2 weeks
after that for a total of 7 doses (about 3 months).
Length of Study Participation:
Participant will receive SABR over about 1-2 weeks. If participant is in Group 2,
participant may receive nivolumab for up to 7 doses. Participant will no longer be able to
take the study drug if the disease gets worse, if intolerable side effects occur, or if
participant is unable to follow study directions.
Participation in this study will be over after 5 years.
Follow-Up:
After participant completes SABR therapy, participant will be followed every 3 months for 2
years, then every 6 months for up to 3 years, and then 1 time every year after that. At each
follow-up visit:
- Participant will have a physical exam
- Participant will have a CT scan.
- At Month 9, participant may have a PET-CT scan. The doctor will tell participant if
participant will have this scan.
This is an investigational study. SABR is delivered using FDA approved and commercially
available methods. Nivolumab is FDA approved and commercially available for the treatment of
NSCLC. It is considered investigational to use it in combination with SABR to treat NSCLC.
Up to 140 participants will be take part in this study. All will be enrolled at MD Anderson.
Inclusion Criteria:
1. Histological confirmation of NSCLC by either biopsy or cytology will be is required
for the primary diagnosis and is recommended for recurrent disease. The following
primary cancer types are eligible: squamous cell carcinoma, adenocarcinoma (with or
without bronchioloalveolar carcinoma features), large cell carcinoma (with or without
neuroendocrine features), neuroendocrine carcinoma (either NSCLC with neuroendocrine
features or atypical carcinoids, but not small cell lung carcinoma),
bronchioloalveolar cell carcinoma, or non-small cell carcinoma not otherwise
specified.
2. Stage I or selected stage IIa according to the 7th version of the IASLC system: stage
I (T1 or T2a [tumor size </=5 cm] N0M0) stage IIa (T2 [tumor size >5 cm but </= 7 cm]
N0M0).
3. Patients with multiple primary lung tumors (defined below) are eligible: a)
synchronous tumors (diagnosed within 6 months [mo]), *different histology, *same
histology, *second tumor in different lobed or lung; b) metachronous tumors
(diagnosed >6 mo apart), *different histology, *same histology, **second tumor in
different lobe or lung, **tumor-free interval of at least 4 years (y).
4. Patients with isolated lung parenchymal recurrent/persistent NSCLC (histology as
defined in eligibility criterion 1) after prior definitive surgery or
radiotherapy/chemotherapy, when the lesion or lesions are suitable for SABR, are also
eligible. Patients with a single metastatic focus in the lung parenchyma with no
lesions are also eligible, because this presentation is challenging to distinguish
from recurrent disease. Recurrent disease can be in the same lobe or a different lobe
but should not abut critical structures (esophagus, brachial plexus, major vessels,
heart, spinal cord); should not involve any lymph node; and should not include any
other suspicious lesions in the lung or any other locations. Any prior therapy
(surgery, radiotherapy, or systemic) must have been completed at least 12 weeks
before administration of the study drug.
5. cont'd from inclusion #4: Tumors should be </=7 cm (measured by computed tomography
(CT) imaging in the lung window setting) with N0M0; positron emission tomography
(PET) imaging is required for restaging (per eligibility criterion 5 below) and any
lymph node suspected of harboring tumor should be confirmed by biopsy (per
eligibility criterion 6 below).
6. A PET/CT scan is required within 12 weeks from enrollment. Any lymph node suspected
of harboring disease based on its shape, size, or PET SUV should be discussed by
treating physician and diagnostic radiologist.
7. Patients with medically inoperable stage I disease (T1 or T2a [tumor size </=5 cm]
N0M0) or selected stage IIa disease (T2 [tumor size >5 cm but </=7 cm] N0M0) who have
poor lung function or other significant cardiovascular or other comorbidity such as
diabetes are eligible. Patients with operable disease who choose to have SABR are
also eligible. The standard justification for medical inoperability is based on
pulmonary function and can include any of the following: baseline FEV1 <50% of
predicted value; diffusion capacity <50% of predicted value; baseline hypoxemia or
hypercapnia; exercise oxygen consumption <50% of predicted value; severe pulmonary
hypertension; severe cerebral, cardiac, or peripheral vascular disease; and severe
chronic heart disease.
8. Patients must be >/= 18 years of age.
9. Patients must have a Zubrod performance status score of 0-2 (2 is included here
because such patients are typically >70 years old and cannot tolerate surgery).
10. All patients must sign a study-specific consent form
11. All patients (men & women) of childbearing potential should use a method of birth
control that is effective for them throughout their participation in this study.
Women of childbearing potential should use an adequate contraceptive method to avoid
pregnancy for 5 months (30 days plus the time required for nivolumab to undergo five
half-lives) after the last dose of investigational drug; must have a negative serum
or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human
chorionic gonadotropin [HCG]) within 24 hours before the start of nivolumab; and must
not be breastfeeding. Men who are sexually active with women of childbearing
potential must use a contraceptive method with a failure rate of less than 1% per
year; men receiving nivolumab will be instructed to use contraception for 7 months
after the last dose of nivolumab. Women who are not of childbearing potential (i.e
are postmenopausal or surgically sterile) & azoospermic men do not require
contraception.
12. All patients must have adequate organ function as defined below. All screening lab
tests should be done within 30 days before study registration and the first dose of
study drug. WBC >=2000/uL; Neuts >=1500/uL; PLT >=100x10^3/uL; HGB >9.0g/dL; Serum
creatinine <=1.5xULN or creatinine clearance (calculated with the Cockcroft-Gault
formula below) ≥40 mL/min: Men: ([l40-age in years] × weight in kg) / (72 × serum
creatinine in mg/dL) Women: ([l40-age in years] × weight in kg) / (72 × serum
creatinine in mg/dL) × 0.85; AST/ALT <=3xULN; Bili T <=1.5xULN (although patients
with Gilbert syndrome can have total bilirubin <3.0 mg/dL)
13. All patients must sign a study-specific consent form.
14. All patients (men & women) of childbearing potential should use method of birth
control that is effective for them throughout their participation in this study.
Women of childbearing potential should use an adequate contraceptive method to avoid
pregnancy for 5 months (30 days plus the time required for nivolumab to undergo five
half-lives) after last dose of investigational drug; must have a negative serum or
urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human
chorionic gonadotropin [HCG]) within 24 hours before the start of nivolumab; and must
not be breastfeeding. Men who are sexually active with women of childbearing
potential must use a contraceptive method with a failure rate of less than 1% per
year; men receiving nivolumab will be instructed to use contraception for 7 months
after the last dose of nivolumab. Women who are not of childbearing potential (i.e.,
are postmenopausal or surgically sterile) and azoospermic men do not require
contraception.
15. All patients must have adequate organ function as defined below. All screening lab
tests should be done within 30 days before study registration and the first dose of
study drug. *WBC >/= 2000/uL; * Neutrophils >/= 1500/uL; *Platelets >/= 100 x10^3/uL;
*Hemoglobin > 9.0 g/dL; *Serum creatinine </= 1.5 x ULN or creatinine clearance
(calculated with the Cockcroft-Gault formula below) >/= 40 mL/min: Men ([140 - age in
years] x weight in kg)/ (72 x serum creatinine in mg/dL) *Women: ([140 - age in
years] x weight in kg) / (72 x serum creatinine in mg/dL) x 0.85 *AST/ALT </=3 x ULN;
*Total Bilirubin </= 1.5 x ULN (although patients with Gilbert syndrome can have
total bilirubin <3.0 mg/dL)
Exclusion Criteria:
1. Patients with tumors >7 cm or tumors involving the main bronchus or associated
vessels or tumors that abut any critical structures (such as esophagus, brachial
plexus, heart, mediastinal major vessels) are not suitable for SABR.
2. Patients with direct evidence of regional or distant metastases after appropriate
staging studies, or with synchronous non-lung primary or prior non-lung malignancy
(other than nonmelanomatous skin cancer or in situ cancer) diagnosed within the past
3 years are not eligible. Patients with a history of curable non-lung cancer up to 3
years before registration and have been cancer-free for 2 years are eligible.
3. Patients who have received previous immunotherapy with PD1 or CTLA4 antibodies are
not eligible.
4. Patients with plans to receive other concomitant local therapy (including standard
fractionated radiotherapy and surgery) or other systemic therapy (including
chemotherapy, target therapy and other type of immunotherapy or investigative agents)
while on this protocol, except at disease progression, are not eligible.
5. Female patients who are pregnant or lactating are not eligible (because treatment
involves unforeseeable risks to the embryo or fetus).
6. Patients for whom SABR plans cannot meet the minimum requirement of target coverage
and dose-volume constraints of critical structures (see SABR treatment planning
section) are not eligible.
7. Patients who have active, known, or suspected autoimmune disease are not eligible.
However, patients with vitiligo, type I diabetes mellitus, residual hypothyroidism
due to an autoimmune condition that requires only hormone replacement, psoriasis not
requiring systemic treatment, or conditions not expected to recur in the absence of
an external trigger are permitted to enroll.
8. Patients with a known history of antibodies to human immunodeficiency virus (HIV) -1
or -2 are not eligible. Patients with live vaccines.
9. Patients with a positive test for hepatitis B virus surface antigen (HBV sAg) or
hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic
infection are not eligible.
10. Patients who have a condition requiring systemic treatment with corticosteroids (>10
mg daily prednisone equivalents) or other immunosuppressive medications within 14
days of study drug administration are not eligible. However, inhaled or topical
steroids, adrenal replacement doses, and >10 mg daily prednisone equivalents are
permitted in the absence of active autoimmune disease.
11. Patients with allergies or adverse drug reactions to the following are not eligible:
*History of allergy to study drug components; *History of severe hypersensitivity
reaction to any monoclonal antibody.
12. Patients who have had prior treatment with an anti-PD1, anti-PDL1, anti-PDL2,
anti-CTLA4 antibody, or any other antibody or drug specifically targeting T-cell
costimulation or immune checkpoint pathways are not eligible.
