Ipilimumab and Nivolumab in Combination With Radiation Therapy in Treating Patients With Stage 2-3 Non-small Lung Cancer
Ipilimumab and Nivolumab in Combination With Radiation Therapy in Treating Patients With Stage 2-3 Non-small Lung Cancer
This phase I trial studies the side effects of ipilimumab and nivolumab in combination with
 radiation therapy, and to see how well they work in treating patients with stage II-III
 non-small cell lung cancer. 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. Radiation therapy uses high energy rays to kill
 tumor cells and shrink tumors. Ipilimumab and nivolumab may also help radiation therapy work
 better by making tumor cells more sensitive to the radiation therapy. Giving ipilimumab and
 nivolumab in combination with radiation therapy may work better in treating patients with
 stage II-III non-small cell lung cancer compared to standard chemotherapy in combination with
 radiation therapy.
PRIMARY OBJECTIVES:

 I. To determine safety and feasibility of ipilimumab-nivolumab (Bristol-Meyers-Squibb,
 Opdivo), a cytotoxic T-lymphocyte-associated protein 4 (CTLA4) and programmed death 1 (PD-1)
 inhibitor in the treatment of local-regionally advanced non-small cell lung cancer (NSCLC).

 SECONDARY OBJECTIVES:

 I. To evaluate the clinical outcomes of treatment with ipilimumab-nivolumab concurrent with
 radiation therapy in patients with local-regionally advanced NSCLC.

 II. To observe and record anti-tumor activity. III. To identify potential predictive and
 prognostic biomarkers for early recurrence using circulating cell-free deoxyribonucleic acid
 (DNA) (cfDNA).

 IV. To identify potential predictive and prognostic biomarkers for early recurrence using
 tumor tissue PD-L1 immunohistochemistry (IHC).

 V. To identify potential predictive and prognostic biomarkers for early recurrence using
 tumor tissue tumor mutational burden (TMB).

 VI. To identify potential resistance mechanisms using immune biomarker and genetic analysis
 in post-progression biopsies.

 EXPLORATORY OBJECTIVES:

 I. Tumor tissue/blood biomarkers will be assessed for tumor mutation burden (TMB) and PD-L1
 immunohistochemistry.

 II. Patient microbiomes will be evaluated with stool specimen collection kits.

 OUTLINE:

 CONCURRENT THERAPY: Patients receive nivolumab intravenously (IV) over 30 minutes on day 1
 and ipilimumab IV over 30 minutes on day 1. Treatment with nivolumab repeats every 21 days
 for up to 8 cycles, and treatment with ipilimumab repeats every 42 days for up to 4 cycles in
 the absence of disease progression or unacceptable toxicity. Within 1 day of starting
 nivolumab and ipilimumab, patients also undergo radiation therapy 5 days a week
 (Monday-Friday) over 6-7 weeks in the absence of disease progression or unacceptable
 toxicity.

 MAINTENANCE THERAPY: Patients then receive nivolumab IV over 30 minutes on day 1. Treatment
 repeats every 28 days for up to 8 cycles in the absence of disease progression or
 unacceptable toxicity.

 After completion of study treatment, patients are followed up every 3 months for 2 years.
Inclusion Criteria:

 -  Patients must have histologically or cytologically confirmed NSCLC (any histology)

 -  Patients must have stage II or III local-regionally advanced NSCLC that is deemed to
 be best treated by systemic and concurrent radiotherapy. Eligible patients with stage
 II disease must be unresectable or refuse surgical resection

 -  No prior therapy for the current stage II or stage III NSCLC disease

 -  ECOG (Eastern Cooperative Oncology Group) performance status =< 2 (Karnofsky >= 60%)

 -  Leukocytes >= 2,000/mcL

 -  Absolute neutrophil count >= 1,000/mcL

 -  Platelets >= 75,000/mcL

 -  Total bilirubin =< 1.5 x institutional upper limit of normal (ULN)

 -  Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
 [SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =<
 3 x institutional ULN

 -  Creatinine =< 1.5 x institutional ULN

 -  Glomerular filtration rate (GFR) >= 50 mL/min/1.73 m^2 for patients with creatinine
 levels above institutional normal

 -  No prior history of autoimmune disease, including but not limited to systemic lupus
 erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis
 associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjogren's
 syndrome, Bell's palsy, Guillain-Barre syndrome, multiple sclerosis, autoimmune
 vasculitis, or glomerulonephritis

 -  Patients with a history of autoimmune hypothyroidism on a stable dose of thyroid
 replacement hormone may be eligible

 -  Patients with controlled type 1 diabetes mellitus on a stable insulin regimen may
 be eligible

 -  Patients with eczema, psoriasis, lichen simplex chronicus of vitiligo with
 dermatologic manifestations only (e.g., patients with psoriatic arthritis would
 be excluded) are permitted provided that they meet the following conditions:

 -  Patients with psoriasis must have a baseline ophthalmologic exam to rule out
 ocular manifestations

 -  Rash must cover less than 10% of body surface area (BSA)

 -  Disease is well controlled at baseline and only requiring low potency
 topical steroids (e.g., hydrocortisone 2.5%, hydrocortisone butyrate 0.1%,
 fluocinolone 0.01%, desonide 0.05%, alclometasone dipropionate 0.05%)

 -  No acute exacerbations of underlying condition within the last 12 months
 (not requiring PUVA [psoralen plus ultraviolet A radiation], methotrexate,
 retinoids, biologic agents, oral calcineurin inhibitors, high potency or
 oral steroids)

 -  No prior history of idiopathic pulmonary fibrosis, pneumonitis (including drug
 induced), organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing
 pneumonia, etc.), or evidence of active pneumonitis on screening chest computerized
 tomography (CT) scan

 -  No active pregnancy. The effects of ipilimumab-nivolumab on the developing human fetus
 are unknown. For this reason and because radiation and possibly immunotherapies used
 in this trial are known or possibly known to be teratogenic, women of child-bearing
 potential and men must agree to use adequate contraception (hormonal or barrier method
 of birth control; abstinence) prior to study entry and for the duration of study
 participation. Should a woman become pregnant or suspect she is pregnant while she or
 her partner is participating in this study, she should inform her treating physician
 immediately. Men treated or enrolled on this protocol must also agree to use adequate
 contraception prior to the study, for the duration of study participation, and 7
 months after completion of ipilimumab-nivolumab administration

 -  Ability to understand and the willingness to sign a written informed consent document

 -  Patients with known epidermal growth factor receptor (EGFR) mutation or anaplastic
 lymphoma kinase (ALK) rearrangement are eligible

 Exclusion Criteria:

 -  Prior systemic therapy for the current active local-regionally advanced NSCLC

 -  Patients who are receiving any other investigational agents

 -  History of allergic reactions attributed to compounds of similar chemical or biologic
 composition to nivolumab

 -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
 infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
 arrhythmia, or psychiatric illness/social situations that would limit compliance with
 study requirements

 -  Pregnant women are excluded from this study because nivolumab is an immunotherapy
 agent with the potential for teratogenic or abortifacient effects. Because there is an
 unknown but potential risk for adverse events in nursing infants secondary to
 treatment of the mother with nivolumab, breastfeeding should be discontinued if the
 mother is treated with nivolumab. These potential risks may also apply to radiation
 therapy used in this study

 -  Known human immunodeficiency virus (HIV) positivity

 -  Active chronic treatment (that is still required) with systemic immunosuppressive
 medications (including but not limited to prednisone, cyclophosphamide, azathioprine,
 methotrexate, thalidomide, and anti-tumor necrosis factor [TNF] agents)

 -  Patients who have received acute, low dose, systemic immunosuppressant medications
 (e.g., a one-time dose of dexamethasone for nausea) may be enrolled. The use of
 inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone) for patients
 with orthostatic hypotension or adrenocortical insufficiency is allowed

 -  History of severe allergic, anaphylactic, or other hypersensitivity reactions to
 chimeric or humanized antibodies or fusion proteins

 -  Patients with prior allogeneic bone marrow transplantation or prior solid organ
 transplantation

 -  Active untreated hepatitis. Patients with known past or resolved hepatitis B infection
 (defined as having a negative hepatitis B surface antigen [HBsAg] test and a positive
 anti-HBc [antibody to hepatitis B core antigen] antibody test) are eligible. Patients
 positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain
 reaction (PCR) is negative for HCV RNA (ribonucleic acid). Hepatitis B virus (HBV) and
 HCV viral loads must also be undetectable

 -  Known active untreated tuberculosis

 -  Administration of a live, attenuated vaccine within 4 weeks before treatment start or
 anticipation that such a live attenuated vaccine will be required during the study.
 Influenza vaccination should be given during influenza season only (approximately
 October to March). Patients must not receive live, attenuated influenza vaccine (e.g.,
 FluMist) within 4 weeks prior to treatment start or at any time during the study

 -  Malignancies within 3 years prior to treatment start, with the exception of those with
 a negligible risk of metastasis or death and with expected curative outcome (such as
 adequately treated stage I-II cancers, carcinoma in situ of the cervix, basal or
 squamous cell skin cancer, localized prostate cancer treated surgically with curative
 intent, or ductal carcinoma in situ treated surgically with curative intent) or
 undergoing active surveillance per standard-of-care management (e.g., CLL [chronic
 lymphocytic leukemia] Rai stage 0, prostate cancer with Gleason score =< 6, and
 prostate-specific antigen [PSA] =< 10 mg/mL, etc.)