Biomarkers of Response to Ipilimumab and Nivolumab in First-line NSCLC

Biomarkers of Response to Ipilimumab and Nivolumab as First-line Therapy for Metastatic Non-small Cell Lung Cancer (NSCLC): an Open-label, Single Arm Phase 2 Study

This research study is studying two immunotherapy drugs as a possible treatment for advanced non-small cell lung cancer (NSCLC).

The drugs involved in this study are:

• Ipilimumab
• Nivolumab

This research study is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of investigational drugs to learn whether the drugs work in treating a specific disease. "Investigational" means that the drugs are being studied.

The FDA (the U.S. Food and Drug Administration) has not approved ipilimumab for this specific disease but it has been approved for other uses, including for patients with advanced melanoma.

The FDA (the U.S. Food and Drug Administration) has approved nivolumab as a treatment option for this disease. However, nivolumab it is not approved in combination with ipilimumab to treat NSCLC.

Nivolumab and ipilimumab are both types of immunotherapy. Immunotherapy works by stimulating the body's own immune system to attack cancer cells. The combination of ipilimumab with nivolumab may or may not increase anti-cancer activity by further boosting the immune system.

In this research study, the investigators are investigating if the combination of ipilimumab and nivolumab is effective in treating advanced NSCLC. The investigators are also investigating whether there are certain DNA or protein markers in the blood or tumor tissue that may indicate whether the combination will work in future patients.

Inclusion Criteria:

• Histologically confirmed stage IV NSCLC, with no prior systemic anti-cancer therapy of any kind (including EGFR and ALK inhibitors). Prior definitive chemoradiation for locally advanced disease is permitted as long as the last administration of chemotherapy or radiation (whichever was given last) occurred at least 6 months prior to enrollment. Prior adjuvant or neoadjuvant chemotherapy for early stage lung cancer is permitted if completed at least 6 months prior to initiating study treatment.

• Participants must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as ≥20 mm with conventional techniques or as ≥10 mm with spiral CT scan, MRI, or calipers by clinical exam. See Section 11 for the evaluation of measurable disease.

• Age ≥ 18 years.

• ECOG performance status ≤ 1 (see Appendix A)

• Participants must have normal organ and marrow function as defined below:

  • Absolute neutrophil count ≥ 1,500/mcL
  • Platelets ≥ 100,000/mcL
  • Total bilirubin ≤ 1.5 × institutional upper limit of normal (ULN)
  • AST(SGOT)/ALT(SGPT) ≤ 2.5 × institutional ULN, OR
  • AST(SGOT)/ALT(SGPT) ≤ 5 × institutional ULN if liver metastases are present
  • Serum creatinine ≤ 1.5 × institutional ULN, OR
  • Creatinine clearance ≥ 60 mL/min/1.73 m2 for participants with serum creatinine levels above 1.5 × institutional ULN.

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

• Participants must have a tumor tissue sample available (formalin-fixed paraffin embedded [FFPE] tissue block or unstained slides); may be newly obtained or obtained within 6 months prior to enrollment (without systemic therapy given after the sample was obtained). Participants without sufficient archival tissue may be enrolled following successful completion of the pre-treatment tumor tissue biopsy. Tissue must be a core needle biopsy, excisional, or incisional biopsy. Fine needle aspirates (FNA) or malignant effusions are not adequate. Bone biopsies without a soft tissue component are not adequate.

• The effects of nivolumab and ipilimumab on the developing human fetus are unknown. For this reason, women of childbearing potential (WOCBP) must agree to follow instructions for acceptable contraception from the time of signing consent, and for 23 weeks after their last dose of protocol-indicated treatment. 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 who are not azoospermic who are sexually active with WOCBP must agree to follow instructions for acceptable contraception from the time of signing consent, and for 31 weeks after their last dose of protocol-indicated treatment.

• Participants must be able and willing to undergo a pre-treatment tumor tissue biopsy. Participants must also be willing to undergo an on-treatment tumor tissue biopsy if clinically feasible.

Exclusion Criteria:

• Participants with known EGFR mutations or ALK rearrangements. All subjects must have been tested for EGFR mutation and ALK rearrangement prior to study entry, unless they are known to have a KRAS mutation.
• Participants who have had prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways.
• Participants who received prior non-CNS directed palliative radiation therapy within 7 days of the date of study entry.
• Participants who are receiving any other investigational agents.
• Participants with known untreated brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. Subjects are eligible if CNS metastases are adequately treated and subjects are neurologically returned to baseline (except for residual signs or symptoms related to the CNS treatment) for at least 2 weeks prior to study entry. Subjects must be either off corticosteroids, or on a stable or decreasing dose of ≤10 mg daily prednisone (or equivalent) for at least 2 weeks prior to first study treatment.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to ipilimumab or nivolumab.
• Participants with previous malignancies are excluded unless a complete remission was achieved at least 2 years prior to first treatment and no additional therapy is required or anticipated to be required during the study period as judged by the treating investigator. Exceptions include non-melanoma skin cancers, and in situ cancers of any type (e.g. bladder, gastric, colon, cervical/dysplasia, melanoma, or breast carcinoma in situ).
• Participants with any other active malignancy requiring concurrent intervention.
• Participants with an active, known, or suspected autoimmune disease. Subjects with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.
• Participants with a condition requiring systemic treatment with corticosteroids of > 10 mg daily prednisone (or equivalent), or subjects requiring other immunosuppressive medications within 14 days of first treatment. Inhaled, topical, ophthalmologic, local steroid injections, and adrenal replacement steroid > 10 mg daily prednisone or equivalent are permitted in the absence of active autoimmune disease.
• Participants with interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity in the opinion of the treating investigator.
• Participants with a known history of testing positive for human immunodeficiency virus (HIV), or known acquired immunodeficiency syndrome (AIDS).
• Participants with known positive test for hepatitis B or C indicating acute or chronic infection.
• Participants with ≥ Grade 2 peripheral neuropathy.
• 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 ipilimumab and nivolumab are both agents 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 ipilimumab or nivolumab, breastfeeding should be discontinued if the mother is treated with ipilimumab or nivolumab. A negative serum pregnancy test is required prior to study entry.