Neoplasms

All Conditions

Respiratory Tract (Lung and Bronchial) Diseases

Carcinoma

Carcinoma, Non-Small-Cell Lung

Lung Neoplasms

Carcinoma, Bronchogenic

Bronchial Neoplasms

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

Antineoplastic Agents

All Drugs and Chemicals

Paclitaxel

Albumin-Bound Paclitaxel

Carboplatin

AEG35156 will be given as a 2-hour intravenous infusion once weekly with a 2-hour loading dose given daily in the 2 days immediately prior to Day 1 (on Days -2 and -1) only in Cycle 1.

AEG35156

Robert M Jotte, MD

Jacques Jolivet, MD, FACP

This is an open-label multicenter, phase 1-2 study. Following determination of the recommended AEG35156 dose in combination with carboplatin and paclitaxel in the initial Phase 1 part of this study, additional patients will be enrolled in the Phase 2 part of the study to assess the activity of the combination in advanced non small cell lung cancer.

Apoptotic induction in cancer cells is a sought after therapeutic goal. Most successful anticancer agents activate apoptosis pathways in the cancers they treat. Apoptotic pathways in cells appear to converge on a single family of enzymes, the caspases, which are proteases that dismantle the cell in an orderly, non-inflammatory fashion, resulting in cell death. The X-linked Inhibitor of Apoptosis (XIAP) is the only known cellular inhibitor of caspases, its over expression thereby blocking the principal means of apoptosis. A wide range of evidence indicates that cellular overexpression of members of the IAP family is a fundamental means by which many cancer cells evade death, even in the presence of strong extrinsic (death receptor-mediated) and intrinsic (mitochondria-mediated) apoptotic cues. The inhibition of cellular XIAP activity, specifically in cancer cells under stress and primed for apoptosis by chemotherapeutic agents, is viewed as a powerful means of tipping the balance towards cell death. In particular, XIAP down regulation has been shown to enhance taxane cytotoxicity preclinically. AEG35156 is a second generation antisense which targets XIAP mRNA to lower XIAP levels and the apoptotic threshold of cancer cells, enhancing their sensitivity to intrinsic death and chemotherapy. AEG35156 may thus enhance the anticancer activity of carboplatin and paclitaxel in patients with advanced non small cell lung cancer

A Phase 1-2 XIAP Antisense AEG35156 With Carboplatin and Paclitaxel in Patients With Advanced Non-Small Cell Lung Cancer

A Phase 1-2, Multicenter, Open-Label Study of the X-Linked Inhibitor of Apoptosis (XIAP) Antisense AEG35156 Given in Combination With Carboplatin and Paclitaxel in Patients With Advanced Non-Small Cell Lung Cancer

Aegera Therapeutics

Jacques Jolivet, MD, Senior VP Clinical

Symptoms and General Pathology

Nervous System Diseases

Neoplasm Metastasis

Brain Neoplasms

Neoplastic Processes

Central Nervous System Neoplasms

Nervous System Neoplasms

Brain Diseases

Central Nervous System Diseases

Patients will receive cabozantinib at 60 mg orally once daily and continue on treatment until disease progression, death or unacceptable adverse events.

Treatment cycles are 4 weeks in duration

cabozantinib

Liza Villaruz, MD

This is an open-label phase II clinical trial designed to allow a preliminary assessment of the efficacy and safety of cabozantinib in unselected Non-Small Cell Lung Cancer (NSCLC) patients with metastases to the brain and in the subset of patients with c-MET amplified Non-Small Cell Lung Cancer with metastases to the brain. Previously treated patients with non-squamous NSCLC who have had brain metastases at any point in their treatment history are eligible for enrollment on this clinical trial. Patients with clinically asymptomatic untreated brain metastases will be allowed on trial at the discretion of the treating investigator. Patients who have undergone treatment for their brain metastases with Whole-Brain Radiation Therapy (WBRT), stereotactic radiosurgery (SRS) or surgery must be clinically stable and recovered from all procedures at the time of study enrollment.

This is a Phase 2, single-arm, open-label study of cabozantinib in subjects with molecularly unselected Non-Small Cell Lung Cancer (NSCLC) with metastases to the brain and in patients with c-MET amplified Non-Small Cell Lung Cancer (NSCLC) with metastases to the brain.

Patients will receive cabozantinib at 60 mg orally once daily and continue on treatment until disease progression, death or unacceptable adverse events. Treatment cycles are 4 weeks in duration.

The primary endpoint is Overall Response Rate (ORR) in both the unselected NSCLC population and the molecularly selected patients on the basis of c-MET amplification.

Trial of Cabozantinib (XL184) in Non-Small Cell Lung Cancer With Brain Metastases

A Single-Arm Phase II Clinical Trial of Cabozantinib (XL184) in Patients With Previously Treated Non-Small Cell Lung Cancer (NSCLC) With Brain Metastases With and Without C Met Amplification

The proportion of response-evaluable patients who achieve Complete Response (CR) or Partial Response (PR) as best response by RECIST v1.1 criteria. Per RECIST v1.1, Complete Response (CR) is defined as disappearance of all target lesions; disappearance of all non-target lesions and normalization of tumor marker level. Partial Response (PR) is defined as at least a 30% decrease in the sum of the LD of target lesions, taking as reference the baseline sum LD.

Proportion of response-evaluable patients that experienced Complete Response (CR) + Partial Response (PR) + Stable Disease (SD) as best response (RECIST v1.1 criteria) per the total study population criteria. Per RECIST v1.1, Complete Response (CR) is defined as disappearance of all target lesions; disappearance of all non-target lesions and normalization of tumor marker level. Partial Response (PR) is defined as at least a 30% decrease in the sum of the LD of target lesions, taking as reference the baseline sum LD. Stable Disease (SD) is defined as, neither sufficient shrinkage (compared to baseline) to qualify for partial or complete response (CR or PR) nor sufficient increase (taking as reference the smallest sum of diameters at baseline or while on study, whichever is smallest) to qualify for progressive disease (PD).

Progression-free survival is the time measured from the initial date of treatment to the date of documented progression, or the date of death (in the absence of progression), whichever occurs first, with progression defined by RECIST v 1.1. Progressive disease (PD) is defined as at least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions; appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions.

The length of time from the start of treatment that patients remain alive, until death from any cause.

Time from initiation of study treatment to disease progression per RECIST v1.1, excluding death from causes unrelated to the disease. As defined by RECIST v 1.1. Progressive disease (PD) is defined as at least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions; appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions.

Worst Grade of Adverse Events Reported as assessed by the investigator. Severity/grade defined by the Cancer Therapy Evaluation Program (CTEP) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.

Subjects monitored continuously for Adverse Events (AE's) throughout the study and for 30 days after the last dose of study treatment.

Exelixis

Assistant Professor of Medicine

Serious Adverse Events are defined as grade 3 and higher toxicity events, per CTCAE v4.0

Cabozantinib - 60 mg orally, once daily (4 weeks treatment cycles)

Treatment until disease progression, death or unacceptable adverse events.

Cabozantinib (XL184)

Age, Continuous

Sex: Female, Male

Race (NIH/OMB)

c-Met, also called tyrosine-protein kinase Met or hepatocyte growth factor receptor (HGFR), is a protein that in humans is encoded by the MET gene. Over-expression of c-Met protein has been associated with poor prognosis in some solid tumors.

c-MET amplification

Histology

Stage 0. Cancer in situ; the cancer is only located in the place of origin.

Stage I. Small tumor with no deep growth into surrounding tissues; no spread to the lymph nodes or other body parts.

Stage II and Stage III. Larger cancers or tumors that have grown more deeply into surrounding tissue and may have spread to lymph nodes (only).

Stage IV. Cancer has spread to other body organs (metastasis).

Stage of Disease

Barbara Stadterman, MPH MCCR

Patients evaluable for response: Received at least one dose of study drug, and, underwent at least one radiologic scan follow-up.

Overall Response

As no patients who received at least one dose of study drug and underwent at least one follow-up radiologic scan were able to be evaluated later than 15 weeks, this endpoint cannot be assessed.

Disease Control Rate (DCR)

Only one patient was assessed as having disease progression.

Progression-free Survival (PFS)

All patients

c-MET positive patients (only)

"All patients" includes all 5 of the patients for whom survival data were available, regardless of c-MET status. "c-MET positive patients" (only) does not include patients for who c-MET status was not positive.

Overall Survival (OS)

Only one participant experienced disease progression.

Time to Progression (TTP)

Grade 1

Grade 2

Grade 3

Grade 4

Grade 5

Patients that received at least one dose of study drug.

Worst Grade of Adverse Events Reported

Worst Grade of AE at Least Possibly Related to Treatment Reported

Worst Grade of AE at Least Probably Related to Treatment Reported

Worst Grade of AE Definitely Related to Treatment Reported:

Overall Study

Pemetrexed

Aerosolized BIO-11006 (125mg BID) plus standard of care (Pemetrexed plus Carboplatin) is administered for three months.

Pemetrexed (500 mg/meter square) and Carboplatin (AUC6, Calvert's Formula) is administered every three weeks for three months.

BIO-11006 is administered 125mg BID plus standard of care.

BIO-11006 plus standard of care

Pemetrexed (500 mg/meter square) and Carboplatin (AUC6, Calvert's formula) are administered every three weeks for three months.

Standard of Care

Devesh Verma, PhD

This Phase 2 is a randomized study in advanced Non-Small Cell lung cancer patients to evaluate safety and efficacy of aerosolized BIO-11006 in conjunction with chemotherapy.

This randomized, open label, multicenter Phase 2 study is to evaluate safety and efficacy of BIO-11006 in Stage IIIB Non Small Cell Lung cancer (NSCLC) patients who are not candidates for curative surgery, radiation, or immunotherapy and who are also receiving Pemetrexed and Carboplatin as standard of care (SOC). This study will be conducted at ten clinical centers in India under an IND from US-FDA and an IND from Indian FDA.

This is a parallel 2- Arm study in which a total of 60 patients will be randomized. One Arm of 30 subjects will receive aerosolized 125mg BIO-11006 BID using Pari eFlow nebulizer in conjunction with SOC chemotherapy (Pemetrexed plus Carboplatin). A second Arm of 30 subjects will receive only SOC chemotherapy (Pemetrexed plus Carboplatin). The treatment period will be three months and nine months survival follow up period (every three months).

Primary efficacy endpoint will be Progression-free survival (PFS) in patients who receive BIO-11006 plus SOC compared to those who receive SOC alone. The secondary efficacy endpoints will include: a. Response rate at three months (4 cycles) per RECIST V1.1; (b) overall survival; and (c) patient body weight maintenance.

Patients will be randomized in 1:1 ratio to either BIO-11006 plus Standard of Care (intervention) or Standard of Care (Pemetrexed plus Carboplatin) (intervention).

A Study of BIO-11006 in the Treatment of Advanced Non-Small Cell Lung Cancer

A Randomized Study of the Safety and Efficacy of BIO-11006 in Treatment of Advanced Non-Small Cell Lung Cancer in Patients Who Are Not Candidates for Curative Surgery and/or Radiation and Who Are Receiving Pemetrexed and Carboplatin

Survival period of patients in both arms of the study is measured in absence of tumor progression.

Patient's body weight in kilograms measured at three month and at 12 month to assess possible disease related cachexia.

Treatment-emergent adverse events including headache, bronchitis, dyspnea, cough, pyrexia, chest discomfort and liver function will be evaluated.

BioMarck Pharmaceuticals, Ltd.

Micronutrients

Vitamins

Vaccines

Vitamin A

Retinol palmitate

Retinol

vaccine composed of lethally irradiated semi-allogeneic human fibroblasts transfected with genomic tumor DNA from the patient's own tumor

Each vaccine consists of 1 x 10e7 DNA-transfected irradiated fibroblasts. A total of 4 weekly immunizations will be delivered to each patient. Each vaccine will be administered i.d. using a 1 mL syringe and a 25 gauge needle.

Subjects will have immunizations administered at 4 different sites for each vaccination as follows:

Site #1: Right arm Site #2: Left arm Site #3: Right thigh Site #4: Left thigh Approximately equal numbers of transfected fibroblasts will be administered at each site.

semi-allogeneic human fibroblasts (MRC-5) transfected with DNA

Mark A Socinski, MD

The study of the vaccine will proceed in two stages after the method of Simon (102). In the first stage, 15 patients will be accrued and treated. If two or fewer objective immunologic responses occur, the study will be terminated. If 3 or more responses are observed, the study will proceed to the second stage, accruing an additional 22 patients. If the second stage is complete and a total of 9 or more immunologic responses are observed among the 37 patients treated, the treatment response rate for the vaccine will be considered high enough to warrant further study. Conversely, if the evaluation of the vaccine concludes at the first stage, or if 8 or fewer total immunologic responses occur after completing the second stage, the vaccine will not be considered for further study.

This is an uncontrolled, non-randomized trial to evaluate safety, immunogenicity and feasibility of a new vaccine, consisting of semi-allogeneic fibroblasts transfected with autologous tumor-derived DNA. Briefly, the plan is to use a two-stage trial design and to initially enroll 15 patients with non small cell lung cancer (NSCLC) over a period of 2 years. The patients will undergo surgery and a portion of the primary tumor specimen not necessary for the pathologic diagnosis will be obtained to serve as a source of tumor DNA. Each DNA-based vaccine will contain 1 x 10e7 DNA-transfected human allogeneic fibroblasts. The vaccine will be lethally irradiated before it is used for immunization. It will be administered intradermally in the Outpatient Clinic. Patients delayed-type hypersensitivity (DTH) responses will be tested but will not be an eligibility criterion. Immunologic response to the vaccine will be evaluated. If there is no evidence of toxicity, and \>3 of the 15 initial patients show immunologic response, the second stage of the study will be opened for accrual of 22 patients. All patients will be monitored by IFN-g secretion in ELISPOT assays prior to and after vaccination for the frequency of T-cells responsive to autologous tumor (if available) and/or to the vaccine. The patients will also be evaluated before and after vaccination for the capability of their T cells to respond to activating signals delivered via the T cell receptor (TcR).

Immunization of Patients With Non Small Cell Lung Cancer (NSCLC)

Active Immunization of Patients With Non Small Cell Lung Cancer (NSCLC) Using Fibroblasts Transfected With DNA From Autologous Tumor (Phase IB Study)

Immune Cell Therapy Inc.

Theresa Whiteside, PhD

Professor of Pathology,Director of the UPCI IMCPL Facility

Patients with NSCLC undergoing non-contrast CT scan of the chest will have a second, high resolution, non-contrast CT scan of the chest performed on the same day.

Patients with NSCLC undergoing non-contrast CT scan of the chest will have a second, high resolution, non-contrast CT scan of the chest performed on the same day. The scans will be performed on the same CT scanner, generally within 30 minutes. Unidimensional, bi-dimensional, and volume measurements for the primary NSCLC lesion will be determined on both scans and the values compared. After completing the second scan, the patient will have completed participation in the protocol.

CT Scan

Mark Kris, MD

The purpose of this study is to compare the results of two CT scans of the chest performed within minutes of each other. We will compare several different measurements of lung cancer tumors. This study will help show whether we can get accurate results when we compare measurements on different CT scans. This information is important for patients with cancer, who often have more than one CT scan during their treatment.

Standard criteria for tumor response assessment have used uni-dimensional or bi-dimensional measurements as a surrogate for volume determination. Modern CT scan techniques, in combination with algorithms developed at MSKCC, allow the calculation of tumor volume. This protocol is designed to evaluate the reproducibility of the calculated volume of pulmonary masses on separate CT scans obtained on the same day in patients with non-small cell lung cancer (NSCLC). Patients with NSCLC undergoing non-contrast CT scan of the chest will have a second, non-contrast CT scan of the chest performed. Uni-dimensional, bi-dimensional, and volume measurements for the primary NSCLC lesion will be determined on both scans and the values compared.

Assess the Variability of Uni-Dimensional, Bi-Dimensional, and Volumetric CT Scan Measurement of Non-Small Cell Lung Cancer Tumors

A Prospective Trial to Assess the Variability of Uni-Dimensional, Bi-Dimensional, and Volumetric CT Scan Measurement of Non-Small Cell Lung Cancer Tumors

Memorial Sloan Kettering Cancer Center

Adenocarcinoma

Neoplastic Cells, Circulating

Mitogens

Blood samples every 3 months till disease progression or intolerable due to side effect.

Chao-Chi Ho

Correlation of epithelial growth factor receptor mutation in blood of lung cancer patient and clinical outcome.

EGFR tyrosine kinase mutation is frequently seen in our NSCLC, especially adenocarcinoma.1 The epidermal growth factor receptor (EGFR) of receptor tyrosine kinases (TKs) regulate many developmental, metabolic and physiological processes. In tumor cells, the TK activity of EGFR may be dysregulated by several mechanisms, including EGFR gene mutation, increased gene copy number and EGFR protein overexpression.1 Improper activation of EGFR TK results in increased malignant cell survival, proliferation, invasion and metastasis. EGFR overexpression is observed in tumors from more than 60% of patients with metastatic non-small-cell lung cancer (NSCLC) and is correlated with poor prognosis.2 Treatment with the reversible EGFR TK inhibitors (TKIs), gefitinib and erlotinib, results in dramatic antitumor activity in a subset of patients with NSCLC. Sequencing of the EGFR gene revealed that a majority of tumors responding to EGFR TKIs harbored mutations in the TK domain of EGFR. For patients whose tumors exhibit EGFR mutations, the response rate to gefitinib and erlotinib is approximately 75%, suggesting that these mutations, at least in part, drive malignant transformation.

However, the disease-free time to progression was still less than 1 year in most study.3-5 More than half of patients acquired resistant by new EGFR T790M resistance mutation. A second biopsy at the time of progression is becoming an issue. However, Only around 30% of NSCLC patients can receive gene testing to predict target therapy response because of the risk and difficulty in obtaining adequate tissues from the primary lung tumors by biopsy. Serial monitoring the emergence of resistant mutations is almost not possible. Recently, circulating free DNAs (cfDNAs) become a promising topic in cancer research. cfDNA can be used as a liquid biopsy, allowing repeated blood samples to be taken and changes in mutation status to be tracked throughout a cancer treatment, paving the way for a potential use in following up of treatment response, gauging prognosis, or monitoring of recurrence.6 It has been known for over a hundred years that disseminated tumor cells can be found in the circulation of patients with metastatic cancer and it has been hypothesized that these circulating tumor cells (CTCs) may represent cancer stem cells or a high metastatic potential cellular population.7 The major challenge since as few as one CTC may be found in the background of 105-106 peripheral blood mononuclear cells.8 CTCs are an attractive alternative to tumor tissue for biomarker analysis including EGFR mutation. CTCs can be obtained from a routine blood draw with minimal risk and inconvenience to the patient compared to a fresh biopsy. Another appealing facet of CTCs as a surrogate diagnostic tissue is the idea that CTCs could also constitute a "liquid biopsy" like cfDNA and provide real-time information about the patient's current disease state.9,10 Analysis of biomarker status in CTCs collected prior to treatment could potentially be used to select an appropriate targeted therapy, while repeated longitudinal sampling during treatment could be used to detect appearance of resistance markers and potentially enable switching to a more appropriate therapy.

A side-by-side comparison of EGFR mutation analysis in DNA extracted from circulating tumour cells (CTCs) versus cfDNA from plasma suggested that mutational analysis of CTCs captured on the CellSearch platform was low by comparison with the frequency of EGFR mutations identified in plasma.11 However, this limitation might be related to the CellSearch platform used,11 because other CTC platforms (eg, CTC biochip) have greater sensitivity and specificity for EGFR mutational analyses.12 New technologies, such as next generation sequencing and digital PCR (Figure 1), which can permit more precise quantification of cfDNA and also the CTCs, offer opportunities to design more appropriate treatments. Longitudinal analyses of EGFR and other mutations in cfDNA and CTCs might well prove to be an ideal non-invasive technique to be included in the oncologist's repertoire at the time of assigning or monitoring treatment in patients with NSCLC.

In this study, the investigators will collect blood from NSCLC patients who harbor EGFR mutation in biopsy specimens. Buffy coat and serum/plasma will be separated and DNA will be extracted. The investigators will check the EGFR mutation by next generation sequencing or digital PCR. Blood from volunteers without lung cancer patient will be also collected as standard. Serial follow-up the change of EGFR mutation every month in cancer patient will be correlated with clinical course. The Investigators hope the detection of EGFR mutation and serial change in the patient blood could offer as a marker for early diagnosis and early relapse.

Correlation Between EGFR Mutation Using cfDNAs and Circulating Tumor Cells in Patients With NSCLC

Correlation Between Epithelial Growth Factor Receptor(EGFR) Mutation Using cfDNA and CTCs in Patients With Non-Small Cell Lung Cancer

National Taiwan University Hospital

Cisplatin

Ipilimumab

Tubulin Modulators

Antimitotic Agents

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

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

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

Neoadjuvant (Pre-Surgery) Cycle 1: Paclitaxel 175 mg/m2 IV over 3 hours , followed by Cisplatin 75 mg/m2 IV over 60 minutes or carboplatin AUC 6 IV over 30-60 minutes on day 1(Every 21 days x 1 cycle)

Cycles 2 and 3: Ipilimumab 10 mg/kg IV over 90 minutes, Paclitaxel 175 mg/m2 IV over 3 hours , followed by Cisplatin 75 mg/m2 IV over 60 minutes or carboplatin AUC 6 IV over 30-60 minutes on day 1(Every 21 days x 2 cycles)

Paclitaxel, Cisplatin, Carboplatin

Neal Ready, MD

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.

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.

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

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 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.

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)

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.

Number of patients experiencing a metastasis between baseline and cycle 3

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)

Duke University

Neoadjuvant: Cycles 2 and 3: Ipilimumab 10 mg/kg IV over 90 minutes Adjuvant: 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: Neoadjuvant: 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

Paclitaxel, Cisplatin, Carboplatin: Neoadjuvant (Pre-Surgery) Cycle 1: Paclitaxel 175 mg/m2 IV over 3 hours , followed by Cisplatin 75 mg/m2 IV over 60 minutes or carboplatin AUC 6 IV over 30-60 minutes on day 1(Every 21 days x 1 cycle)

Cycles 2 and 3: Ipilimumab 10 mg/kg IV over 90 minutes, Paclitaxel 175 mg/m2 IV over 3 hours , followed by Cisplatin

Ethnicity (NIH/OMB)

Intent to treat. Note that the 16.7% of patients that had detectable T-cell responses also had responses at baseline

Percentage of Subjects With Detectable Circulating T Cells After Treatment

Patients receiving 3 cycles

Patients undergoing surgical exploration

Patients undergoing lobectomy

Patients experiencing a DLT

Feasibility and Tolerability of Neoadjuvant Chemotherapy Plus Ipilimumab and Surgery

Patients were no longer followed for recurrence following surgery, so this outcome was not captured

Median Disease-Free Survival

Number of Subjects Experiencing a Metastasis by Site of Metastasis

Note: pathological response was not captured for study participants. Therefore, the RECIST responses for patients at neoadjuvant month 3 are reported.

Patterns of Pathologic Response and Response Evaluation Criteria in Solid Tumor (RECIST) Response

Neoadjuvant: Cycles 2 and 3: Ipilimumab 10 mg/kg IV over 90 minutes Adjuvant: 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: Neoadjuvant: 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

Paclitaxel, Cisplatin, Carboplatin: Neoadjuvant (Pre-Surgery) Cycle 1: Paclitaxel 175 mg/m2 IV over 3 hours , followed by Cisplatin 75 mg/m2 IV over 60 minutes or carboplatin Area Under Curve (AUC) 6 IV over 30-60 minutes on day 1(Every 21 days x 1 cycle)

Cycles 2 and 3: Ipilimumab 10 mg/kg IV over 90 minutes, Paclitaxel 175 mg/m2 IV over 3 hours , followed by Cisplatin

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
A Phase 1-2 XIAP Antisense AEG35156 With Carboplatin and Paclitaxel in Patients With Advanced Non-Small Cell Lung Cancer	NCT00558922	Carcinoma, Non-...	AEG35156	18 Years -	Aegera Therapeutics
A Phase 1-2 XIAP Antisense AEG35156 With Carboplatin and Paclitaxel in Patients With Advanced Non-Small Cell Lung Cancer	NCT00558922	Carcinoma, Non-...	AEG35156	18 Years -	Aegera Therapeutics
Trial of Cabozantinib (XL184) in Non-Small Cell Lung Cancer With Brain Metastases	NCT02132598	Non Small Cell ... Metastases to t...	cabozantinib	18 Years -	University of Pittsburgh
A Phase 1-2 XIAP Antisense AEG35156 With Carboplatin and Paclitaxel in Patients With Advanced Non-Small Cell Lung Cancer	NCT00558922	Carcinoma, Non-...	AEG35156	18 Years -	Aegera Therapeutics
A Study of BIO-11006 in the Treatment of Advanced Non-Small Cell Lung Cancer	NCT03472053	Non Small Cell ...	BIO-11006 plus ... Standard of Car...	18 Years - 70 Years	BioMarck Pharmaceuticals, Ltd.
Immunization of Patients With Non Small Cell Lung Cancer (NSCLC)	NCT00793208	Non Small Cell ...	semi-allogeneic...	18 Years -	University of Pittsburgh
Assess the Variability of Uni-Dimensional, Bi-Dimensional, and Volumetric CT Scan Measurement of Non-Small Cell Lung Cancer Tumors	NCT00579852	Lung Cancer Non Small Cell	CT Scan	18 Years -	Memorial Sloan Kettering Cancer Center
Correlation Between EGFR Mutation Using cfDNAs and Circulating Tumor Cells in Patients With NSCLC	NCT02422628	Lung Cancer		20 Years - 85 Years	National Taiwan University Hospital
Trial of Cabozantinib (XL184) in Non-Small Cell Lung Cancer With Brain Metastases	NCT02132598	Non Small Cell ... Metastases to t...	cabozantinib	18 Years -	University of Pittsburgh
Evaluation of Circulating T Cells and Tumor Infiltrating Lymphocytes (TILs) During / After Pre-Surgery Chemotherapy in Non-Small Cell Lung Cancer (NSCLC)	NCT01820754	Non Small Cell ...	Ipilimumab Paclitaxel, Cis...	18 Years -	Duke University
Study of IDE397 in Participants With Solid Tumors Harboring MTAP Deletion	NCT04794699	Solid Tumor	IDE397 Docetaxel Paclitaxel Sacituzumab gov...	18 Years -	IDEAYA Biosciences
Lymphocyte Depletion and Change in Lymphocyte Functionality	NCT04273893	Lymphocyte Depl...	SBRT with addit... SBRT with stand... Blood Draws	18 Years -	University of Virginia

Spots Global Cancer Trial Database for non small cell