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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


Phase 1
18 Years
N/A
Open (Enrolling)
Both
Non Small Cell Lung Cancer

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Trial Information

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
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 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
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.


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 IB (≥4cm per CT), Stage IIA/IIB, or Stage III (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 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

Type of Study:

Interventional

Study Design:

Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Percentage of subjects with detectable circulating T cells after treatment

Outcome Description:

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.

Outcome Time Frame:

2 years

Safety Issue:

No

Principal Investigator

Frank R Dunphy, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Duke University Medical Center / Thoracic Oncology Program

Authority:

United States: Food and Drug Administration

Study ID:

Pro00038093

NCT ID:

NCT01820754

Start Date:

March 2013

Completion Date:

May 2018

Related Keywords:

  • Non Small Cell Lung Cancer
  • Non Small Cell Lung Cancer
  • Lung Cancer
  • Non Small Cell
  • Carcinoma, Non-Small-Cell Lung
  • Lung Neoplasms

Name

Location

Duke University Medical CenterDurham, North Carolina  27710