Evaluation of Circulating T Cells and Tumor Infiltrating Lymphocytes (TILs) During / After Pre-Surgery Chemotherapy in Non-Small Cell Lung Cancer (NSCLC)

Phase 2

Completed

Conditions: Non Small Cell Lung Cancer

Interventions: Drug: Ipilimumab
Drug: Paclitaxel, Cisplatin, Carboplatin

Registration Number: NCT01820754

Lead Sponsor: Duke University

Brief Summary: The purpose of this study is to evaluate whether the combination of neoadjuvant chemotherapy (chemotherapy before surgery) plus ipilimumab for lung cancer increases the number of patients with detectable circulating T cells with specificities against tumor associated antigens (TAA) from zero percent (0%) of patients prior to therapy to 20% of patients after neoadjuvant chemotherapy plus ipilimumab.

This is an open label Phase 2 trial. Patients with clinical stage 1B (\>4 cm), 2, (N0-2) or 3 non-small cell lung cancer (NSCLC) and no prior therapy for the current diagnosis of lung cancer will be eligible for the study. Subjects will receive 3 cycles of neoadjuvant chemotherapy (paclitaxel + cisplatin/carboplatin). Ipilimumab will be administered during Cycles 2 and 3 of standard chemotherapy and for up to 4 cycles alone after surgery. Subjects will undergo standard clinically indicated surgical resection of their lung cancer as deemed appropriate by their surgeon.

Standard diagnostic and staging work up will be performed including: pathologic/histologic diagnosis of NSCLC, Positron Emission Tomography (PET)/Computed Tomography (CT) scan, brain imaging, and mediastinoscopy. Three cycles of neoadjuvant chemotherapy will be given. Ipilimumab will be added to neoadjuvant chemotherapy for cycles 2 and 3. Standard surgical evaluation and therapy will be performed following completion of neoadjuvant therapy. Two cycles of single agent ipilimumab will be given after surgery (adjuvantly), followed by 2 cycles of maintenance therapy.

Detailed Description: The investigators propose studying the cell mediated effects of ipilimumab in combination with chemotherapy in the neoadjuvant setting for NSCLC. The overall immune assessment strategy for the proposed ipilimumab neoadjuvant trial will be based on the hypothesis that 1) T cells with specificities against tumor associated antigens expressed by the patient's progressing NSCLC are present, but functionally impaired, at baseline, and 2) that the immunomodulatory effects of chemotherapy plus ipilimumab will impact the suppressive mechanisms, restoring functional reactivity to important anti-tumor effector cell populations.

An important potential biomarker for anti-tumor immune response is the proliferation and stimulation of circulating T cells with specificities against tumor associated antigens (TAA). At baseline few patients with cancer have populations of circulating T cells with specificities against TAA above the detectable level of 0.05% CD8 lymphocytes. The primary endpoint of this clinical trial will be to determine if the addition of ipilimumab to neoadjuvant chemotherapy for non-small cell lung cancer increases the percentage of patients with circulating T cells with specificities against TAA. We will also measure tumor infiltrating lymphocytes in resected tumors.

Study Interventions:

The investigational agent, ipilimumab, will be added to neoadjuvant chemotherapy for cycles 2 and 3. Standard surgical evaluation and therapy will be performed following completion of neoadjuvant therapy. Two cycles of single agent ipilimumab will be given after surgery (adjuvantly), followed by 2 cycles of maintenance therapy.

Neoadjuvant:

Cycle 1: Paclitaxel 175 mg/m2 IV over 3 hours followed by cisplatin 75 mg/m2 over 60 minutes or carboplatin Area Under Curve (AUC) 6 (capped at 900 mg)over 30-60 minutes on day 1 (every 21 days x 1 cycle) Cycles 2 and 3: Ipilimumab 10mg/kg IV over 90 minutes, Paclitaxel 175 mg/m2 over 3 hours followed by cisplatin 75 mg/m2 or carboplatin AUC 6 (capped at 900 mg)IV over 30-60 minutes (every 21 days x 2 cycles) Surgery: Standard surgical evaluation will occur at least 21 days after the last dose (Cycle 3) of chemotherapy followed by surgical therapy.

Post-surgical Therapy: (Total of 4 doses of ipilimumab will be given post-operatively):

Adjuvant: Ipilimumab 10 mg/kg IV every 3 weeks x 2 doses, beginning 4 weeks postoperative (up to 10 weeks if needed for recovery) Maintenance: Ipilimumab 10 mg/kg IV every 12 weeks x 2 doses

Correlative Science Measures: Study specific research blood and tissue test(s) will be conducted:

Blood Specimens:

•Peripheral blood mononuclear cells (PBMC) isolated from freshly drawn anti-coagulated blood will be analyzed for circulating T cells with specificities against tumor-associated antigens (TAA) at 4 time points, namely 1) Baseline prior to treatment, 2) cycle 2, prior to ipilimumab therapy, 3) 21-36 days after completion of cycle 3 chemotherapy prior to surgery, and 4) 3-6 weeks after adjuvant ipilimumab dose #2. Additionally, PBMC from each of the time points will be analyzed for the presence of circulating populations of regulatory T cells, myeloid-derived suppressor cells (MDSC), as well as activated and exhausted T cells.

Tissue Specimens:

•Tumor infiltrating lymphocytes (TILs) will be isolated from the patient's resected tumor and analyzed for infiltrating T cells with specificities against tumor-associated antigens. Additionally, TIL will be analyzed for the presence of infiltrating populations of regulatory T cells, myeloid-derived suppressor cells (MDSC), as well as activated and exhausted T cells.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 24

Inclusion Criteria

Patients are eligible to be in the study if they meet all of the following criteria:

Histologically or cytologically documented non-small cell lung cancer (NSCLC)
Clinical stage 1B (≥4cm per CT), Stage 2A/2B, or Stage 3 (N0-2) amenable to surgical resection
Patients must be deemed a surgical candidate
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
No prior chemotherapy for current diagnosis of lung cancer
Age is ≥ (greater than or equal to) 18 years
No active invasive malignancy in the past 2 years other than non-melanoma skin cancer. Cancers that are in-situ are not considered invasive
Signed written informed consent including Health Insurance Portability and Accountability Act (HIPAA) authorization according to institutional guidelines
Adequate Organ Function:
- Absolute neutrophil count (ANC) or absolute granulocyte count (AGC) ≥1500 per microliter (uL)
- Platelets ≥ 100,000 per uL
- Total bilirubin ≤(less than or equal to)1.5 milligram per deciliter (mg/dL)
- Creatinine clearance ≥ 45 milliliter per minute (mL / min); (Creatinine < 2mg / dL to receive cisplatin)
- Serum glutamic-oxaloacetic transaminase / Serum glutamic pyruvic transaminase (SGOT/SGPT) ≤ 2.5x institutional upper limit normal (ULN)
Females of child-bearing potential (not surgically sterilized and between menarche and 1 year post menopause) must test negative for pregnancy within 48 hours prior to any initial study procedure based on a serum pregnancy test. Both sexually active males and females of reproductive potential must agree to use a reliable method of birth control, as determined by the patient and their health care team, during the study and for 3 months following the last dose of study drug. If subject uses appropriate contraceptive methods (the use of two forms at the same time) from the time of the initial serum pregnancy test, then the subsequent pregnancy test can be done within 72 hours of receiving study drug administration. If appropriate contraceptive measures are not begun immediately with the first serum pregnancy test, then subsequent serum pregnancy tests must be done within 48 hours prior to the study drug administration
Patients must agree to research blood sampling to participate in study

Exclusion Criteria

Patients will be excluded from the study if they meet any of the following criteria:

Have had treatment within the last 30 days with a drug that has not received regulatory (Food and Drug Administration (FDA)) approval for any indication at the time of study entry
Concurrent administration of any other anti-tumor therapy
Inability to comply with protocol or study procedures
Active infection requiring intravenous (IV) antibiotics, antifungal or antiviral agents, that in the opinion of the investigator would compromise the patient's ability to tolerate therapy
Major surgery (other than definitive lung cancer surgery) within two weeks of study or other serious concomitant systemic disorders that, in the opinion of the investigator, would compromise the safety of the patient or compromise the patient's ability to complete the study
Myocardial infarction (MI) having occurred less than 6 months before inclusion, any known uncontrolled arrhythmia, symptomatic angina pectoris, active ischemia, or cardiac failure not controlled by medications
Contraindication to corticosteroids
Unwillingness to stop taking herbal supplements while on study
Female patients who are pregnant or breast-feeding
Autoimmune disease. Patients with a history of inflammatory bowel disease, including ulcerative colitis and Crohn's Disease, are excluded from this study, as are patients with a history of symptomatic disease (e.g., rheumatoid arthritis, systemic progressive sclerosis [scleroderma], systemic lupus erythematosus, autoimmune vasculitis [eg, Wegener's Granulomatosis]); motor neuropathy considered of autoimmune origin (e.g. Guillain-Barre Syndrome and Myasthenia Gravis)
Any non-oncology vaccine therapy used for prevention of infectious diseases (for up to 1 month before or after any dose of ipilimumab)
A history of prior treatment with ipilimumab or prior CD137 agonist or cytotoxic T-lymphocyte-associated protein (CTLA 4) inhibitor or agonist
Prisoners or patients who are compulsorily detained (involuntarily incarcerated) for treatment of either a psychiatric or physical (e.g., infectious) illness

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Ipilimumab	Paclitaxel, Cisplatin, Carboplatin	Neoadjuvant (Pre-Surgery): Cycles 2 and 3: Ipilimumab 10 mg/kg IV over 90 minutes Adjuvant (Post-Surgery): Ipilimumab 10 mg/kg IV every 3 weeks times 2 doses beginning 4 weeks postoperative ( up to 10 weeks if needed for recovery) Maintenance: Ipilimumab 10 mg/kg/IV every 12 weeks times 2 doses
Ipilimumab	Ipilimumab	Neoadjuvant (Pre-Surgery): Cycles 2 and 3: Ipilimumab 10 mg/kg IV over 90 minutes Adjuvant (Post-Surgery): Ipilimumab 10 mg/kg IV every 3 weeks times 2 doses beginning 4 weeks postoperative ( up to 10 weeks if needed for recovery) Maintenance: Ipilimumab 10 mg/kg/IV every 12 weeks times 2 doses

Primary Outcome Measures

Name	Time	Method
Percentage of Subjects With Detectable Circulating T Cells After Treatment	3 months	The primary objective of this trial is to determine the percentage of early stage lung cancer patients with detectable circulating T cells specific against tumor-associated antigen (TAA) after receiving platinum based neoadjuvant chemotherapy plus ipilimumab before surgery. Based on Duke intracellular cytokine staining (ICS) assessments over the past 8 years, "detectable" circulating T cells with specificity against TAA are defined as a CD8, CD4, and double positive (DP) (CD4+CD8+) lymphocyte percentage of ≥ 0.05% with each value also being at least twice that of the background unstimulated control value.

Secondary Outcome Measures

Name	Time	Method
Feasibility and Tolerability of Neoadjuvant Chemotherapy Plus Ipilimumab and Surgery	6 months	Number of subjects experiencing any of the criteria listed below: * Number of subjects receiving 3 doses of preoperative therapy * Number of subjects undergoing surgical exploration within 42 days of day 1 of the last cycle of neoadjuvant chemotherapy * Number of subjects undergoing lobectomy having surgery-related mortality * Number of subjects experiencing dose-limiting toxicity (DLT) during neoadjuvant therapy. DLT will be defined as treatment-related: ≥ Grade 4 hematologic toxicity (excluding neutropenia without fever or infection) or ≥ Grade 3 non-hematologic toxicity (excluding fatigue, nausea, vomiting, peripheral neuropathy, chemotherapy infusion reaction to carboplatin or paclitaxel)
Median Disease-Free Survival	5 years	Disease-free survival (DFS) is defined as the time from surgical resection to disease recurrence (first disease recurrence or death, whichever comes first) after surgery. Patients alive who had not recurred as of the last follow-up had DFS censored at the last follow-up date. The Kaplan-Meier estimator will be used to estimate median DFS and its 95% confidence interval.
Patterns of Pathologic Response and Response Evaluation Criteria in Solid Tumor (RECIST) Response	3 months	Within each category of RECIST response \[partial response (PR), stable disease (SD), progressive disease (PD)\], the number of subjects experiencing a pathologic complete response, pathologic partial response, and no pathologic response. RECIST evaluation will be conducted after completion of neoadjuvant therapy. Pathologic response will be evaluated in the resected tumor as follows: * No Pathologic Response: No evidence of cell death or tumor necrosis * Pathologic Partial Response: ≥30% tumor necrosis or cell death * Pathologic Complete Response: No evidence of viable tumor in surgical specimen (includes lung tissue and dissected lymph nodes)
Number of Subjects Experiencing a Metastasis by Site of Metastasis	3 months	Number of patients experiencing a metastasis between baseline and cycle 3