BrUOG 397: NEO Rad (LOW): Neoadjuvant Low Dose Stereotactic Body Radiotherapy, Ipilimumab and Nivolumab

Inclusion Criteria:

1. Pathologically confirmed NSCLC

2. Age > 18

3. ECOG Performance Status 0-1.

4. Pulmonary function capacity capable of tolerating the proposed lung resection. FEV1at least 2 L. If less than 2 L, the predicted postoperative forced expiratory volumein 1 second (FEV1) must be > 0.8 L or be > 35% of the predicted value. Postoperativepredicted DLCO ≥ 35% is required.

5. Resectable stage IB-IIIB (T2-3N0, T1-T3N1-2) NSCLC (per the 8th Edition AmericanJoint Committee on Cancer (AJCC) classification) who are candidates for surgery withintent of R0 resection. Invasive T3 disease (eg, phrenic nerve, pericardium, chestwall other than Pancoast superior sulcus) may be included if the surgeon and studyteam deem it to be resectable.

6. N2 nodes must be discrete (ie, not invading surrounding structures). If patientshave N2 disease, as suspected by CT or PET, histologic proof of N2 status isrecommended.

7. Patients must be evaluated by a Thoracic Surgeon prior to registration. Operabilityis defined as having adequate pulmonary, cardiac, renal, nutritional,musculoskeletal, neurologic, and cognitive capacity to undergo major pulmonaryresection with acceptable morbidity and mortality. Absence of major associatedcomorbidities that increase the surgery risk to an unacceptable level.

8. No prior history of thoracic radiation.

9. Adequate Organ and marrow function as defined below

• leukocytes ≥2,000/mcL,

• absolute neutrophil count ≥1,000/mcL,

• platelets ≥100,000/mcL,

• Hemoglobin >8.0 g/dL

• Total bilirubin within normal institutional limits

• AST(SGOT)/ALT(SGPT) ≤2.5 × institutional upper limit of normal

• creatinine within normal institutional limits OR creatinine clearance ≥50mL/min/1.73 m2 for participants with creatinine levels above institutionalnormal.

10. Patients are capable of giving informed consent and/or have an acceptable surrogatecapable of giving consent on the subject's behalf.

11. Nonpregnant and non-nursing. The effect of ipilimumab and nivolumab on the fetus isunknown.

12. Women of childbearing potential (WOCBP) must be willing to use 2 methods of birthcontrol or be surgically sterile, or abstain from heterosexual activity for thecourse of the study through 5 months after the last dose of study medication.Patients of childbearing potential are those who have not been surgically sterilizedor have not been free of menses >1 year.

13. Evidence of postmenopausal status or negative urinary or serum pregnancy test forfemale premenopausal patients. Women will be considered postmenopausal if they havebeen amenorrheic for 12 months without an alternative medical cause. The followingage-specific requirements apply:

14. Women <50 years of age would be considered postmenopausal if they have beenamenorrheic for 12 months or more following cessation of exogenous hormonaltreatments and if they have luteinizing hormone and follicle-stimulating hormonelevels in the postmenopausal range for the institution or underwent surgicalsterilization (bilateral oophorectomy or hysterectomy).

15. Women ≥50 years of age would be considered postmenopausal if they have beenamenorrheic for 12 months or more following cessation of all exogenous hormonaltreatments, had radiation-induced menopause with last menses >1 year ago, hadchemotherapy-induced menopause with last menses >1 year ago, or underwent surgicalsterilization (bilateral oophorectomy, bilateral salpingectomy, or hysterectomy).

16. Patient is willing and able to comply with the protocol for the duration of thestudy including undergoing treatment and scheduled visits and examinations includingfollow up.

17. Male patients must agree to use an adequate method of contraception starting withthe first dose of study therapy through 7 months after the last dose of studytherapy.

Exclusion Criteria:

1. Pathologically confirmed NSCLC *

2. Age > 18 *

3. ECOG Performance Status 0-1.

4. Pulmonary function capacity capable of tolerating the proposed lung resection. FEV1at least 2 L. If less than 2 L, the predicted postoperative forced expiratory volumein 1 second (FEV1) must be > 0.8 L or be > 35% of the predicted value. Postoperativepredicted DLCO ≥ 35% is required.

5. Resectable stage IB-IIIB (T2-3N0, T1-T3N1-2) NSCLC (per the 8th Edition AmericanJoint Committee on Cancer (AJCC) classification) who are candidates for surgery withintent of R0 resection. Invasive T3 disease (eg, phrenic nerve, pericardium, chestwall other than Pancoast superior sulcus) may be included if the surgeon and studyteam deem it to be resectable.

6. N2 nodes must be discrete (ie, not invading surrounding structures). If patientshave N2 disease, as suspected by CT or PET, histologic proof of N2 status isrecommended.

7. Patients must be evaluated by a Thoracic Surgeon prior to registration. Operabilityis defined as having adequate pulmonary, cardiac, renal, nutritional,musculoskeletal, neurologic, and cognitive capacity to undergo major pulmonaryresection with acceptable morbidity and mortality. Absence of major associatedcomorbidities that increase the surgery risk to an unacceptable level. *

8. No prior history of thoracic radiation.

9. Adequate Organ and marrow function as defined below

• leukocytes ≥2,000/mcL,

• absolute neutrophil count ≥1,000/mcL,

• platelets ≥100,000/mcL,

• Hemoglobin >8.0 g/dL

• Total bilirubin within normal institutional limits

• AST(SGOT)/ALT(SGPT) ≤2.5 × institutional upper limit of normal

• creatinine within normal institutional limits OR creatinine clearance ≥50mL/min/1.73 m2 for participants with creatinine levels above institutionalnormal.

10. Patients are capable of giving informed consent and/or have an acceptable surrogatecapable of giving consent on the subject's behalf.

11. Nonpregnant and non-nursing. The effect of ipilimumab and nivolumab on the fetus isunknown.

12. Women of childbearing potential (WOCBP) must be willing to use 2 methods of birthcontrol or be surgically sterile, or abstain from heterosexual activity for thecourse of the study through 5 months after the last dose of study medication.Patients of childbearing potential are those who have not been surgically sterilizedor have not been free of menses >1 year.

13. Evidence of postmenopausal status or negative urinary or serum pregnancy test forfemale premenopausal patients. Women will be considered postmenopausal if they havebeen amenorrheic for 12 months without an alternative medical cause. The followingage-specific requirements apply:

14. Women <50 years of age would be considered postmenopausal if they have beenamenorrheic for 12 months or more following cessation of exogenous hormonaltreatments and if they have luteinizing hormone and follicle-stimulating hormonelevels in the postmenopausal range for the institution or underwent surgicalsterilization (bilateral oophorectomy or hysterectomy).

15. Women ≥50 years of age would be considered postmenopausal if they have beenamenorrheic for 12 months or more following cessation of all exogenous hormonaltreatments, had radiation-induced menopause with last menses >1 year ago, hadchemotherapy-induced menopause with last menses >1 year ago, or underwent surgicalsterilization (bilateral oophorectomy, bilateral salpingectomy, or hysterectomy).

16. Patient is willing and able to comply with the protocol for the duration of thestudy including undergoing treatment and scheduled visits and examinations includingfollow up.

17. Male patients must agree to use an adequate method of contraception starting withthe first dose of study therapy through 7 months after the last dose of studytherapy.