Study of Combined Ionizing Radiation and Ipilimumab in Metastatic Non-small Cell Lung Cancer (NSCLC)

Phase II Study of Combined Ionizing Radiation and Ipilimumab in Metastatic Non-small Cell Lung Cancer (NSCLC)

The purpose of this study is to investigate how effective and how safe the combination of radiation therapy and an investigational medication targeting the immune system known as Ipilimumab in the treatment of metastatic non-small cell lung cancer (NSCLC).

The investigators would like to see if this combination of radiation and Ipilimumab can stimulate the body's immune system to stop the growth of tumors that are outside the field of radiation. The investigators would like see if using this combination of radiation therapy with Ipilimumab could help the body reject the patient's own tumor or at least help their immune system to maintain the disease stable and/or slow its growth.

Radiation therapy (RT) is currently a standard procedure for treatment of NSCLC. Ipilimumab is considered an investigational medication because it is not approved by the Food and Drug Administration (FDA) for the treatment of NSCLC. Ipilimumab has been approved by the FDA for the treatment of metastatic melanoma.

Research Hypothesis:

1. Through a combination of local RT and ipilimumab an anti-tumor immune response is elicited at the irradiated site, as an in vivo, individualized immunization that is systemically effective, as reflected by objective responses outside the RT field (abscopal effect).
2. The immune response can be prospectively monitored among the treated patients.

Objective 1: Evaluate the safety and therapeutic efficacy of anti-cytotoxic T-lymphocyte-associated protein -4 mono clonal Antibody (anti-CTLA-4 mAb) and concurrent local RT in NSCLC patients with metastatic disease.

An open label phase II trial will evaluate the preliminary efficacy of the combination of Ipi and RT, applied to a single metastatic site. Efficacy is measured with respect to systemic tumor responses (abscopal response, outside the field of therapy) defined by immune-related Response Criteria (irRC) in all non-irradiated measurable lesions, as a demonstration of an effective anti-tumor immune response. Secondary endpoints include local response in the RT treated tumor, progression free survival, and overall survival.

Objective 2: Determine the effects of RT and anti-CTLA-4 mAb on development of anti-tumor immunity.

The investigators hypothesize that RT will convert the irradiated tumor into an in situ vaccine and elicit an endogenous tumor-specific cellular and humoral immune response, which in the presence of cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) blockade will promote immune-mediated destruction of the irradiated and abscopal metastases. Pre- and post-treatment tumor biopsies will be examined for changes in immune contexture, and blood for evidence of emerging anti-tumor immune responses. Associations with clinical response will be explored.

Inclusion Criteria:

1. Ability to understand and the willingness to sign a written informed consent document;

2. Histologic diagnosis of metastatic NSCLC;

3. Any Kras or EGFR status is permitted;

4. Patients must have at least two distinct measurable metastatic sites, with one of at least 1 cm or larger in its largest diameter. Patients may have additional non-measurable metastatic lesions (e.g., bone metastases);

5. Patients must have prior treatment with at least one line of therapy for metastatic NSCLC. Any prior therapy is permitted except prior therapy with ipilimumab;

6. An interval of 2 weeks from last previous therapy is required;

7. Patients must have adequate organ and marrow function as defined by initial laboratory tests:

   • WBC ≥ 2000/uL
   • ANC ≥ 1000/uL
   • Platelets ≥ 50 x 103/uL
   • Hemoglobin ≥ 8 g/dL
   • Creatinine ≤ 3.0 x ULN
   • AST/ALT ≤ 2.5 x ULN, or ≤ 5 x ULN if liver metastases are present.
   • Bilirubin ≤ 3.0 x ULN (except patients with Gilbert's Syndrome, who must have a total bilirubin ≤ 3.0 mg/dL);

8. Performance status ECOG 0-1;

9. Men and women, ages > 18 years of age;

10. Life expectancy > 3 months;

11. Patients may have brain metastases if these are stable for at least 4 weeks, or greater than 2 weeks post gamma knife therapy and patients are not steroid dependent;

12. Brain Scan (CT/MRI) prior to enrollment

13. Women of childbearing potential (WOCBP) must be using an adequate method of contraception to avoid pregnancy throughout the study and for up to 8 weeks after the last dose of Ipi.

Exclusion Criteria:

1. Patients having no lesions outside the field of radiation thus nullifying the ability to measure an abscopal effect;
2. Autoimmune disease: Patients with a history of inflammatory bowel disease are excluded from this study as are patients with a history of symptomatic disease (e.g., rheumatoid arthritis, progressive systemic sclerosis [scleroderma]), systemic lupus erythematosus, autoimmune vasculitis [e.g., Wegener's granulomatosis];
3. Any underlying medical or psychiatric condition, which in the opinion of the Investigator, will make the administration of study drug hazardous or obscure the interpretation of adverse events (AEs), such as a condition associated with frequent diarrhea;
4. Concomitant therapy with any of the following: Interleukin-2 (IL-2), interferon or other non-study immunotherapy regimens; cytotoxic chemotherapy; immunosuppressive agents; other investigation therapies; or chronic use of systemic corticosteroids;
5. Prior therapy with ipilimumab or another anti-CTLA-4 antagonist;
6. Women who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period and for at least 8 weeks after cessation of study drug, or have a positive pregnancy test at baseline, or are pregnant or breastfeeding;
7. Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) for treatment of either a psychiatric or physical (e.g., infectious) illness.