Evaluation of Circulating T Cells and Tumor Infiltrating Lymphocytes With Specificities Against Tumor Associated Antigens During and After Neoadjuvant Chemotherapy and Phased Ipilimumab in Non-Small Cell Lung Cancer
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
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.
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.
Cycle 1: Paclitaxel 175 mg/m2 IV over 3 hours followed by cisplatin 75 mg/m2 over 60
minutes or carboplatin AUC (Area Under Curve) 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
Correlative Science Measures: Study specific research blood and tissue test(s) will be
•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.
•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.
Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Percentage of subjects with detectable circulating T cells after treatment
The primary objective of the phase I trial is to determine the percentage of early stage lung cancer patients with detectable circulating T cells specific against TAA (tumor associated antigen) 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.
Frank R Dunphy, MD
Duke University Medical Center / Thoracic Oncology Program
United States: Food and Drug Administration
|Duke University Medical Center||Durham, North Carolina 27710|