Adjuvant Tumor Lysate Vaccine and Iscomatrix With or Without Metronomic Oral Cyclophosphamide and Celecoxib in Patients With Malignancies Involving Lungs, Esophagus, Pleura, or Mediastinum

Study Overview
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Brief Summary
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Background: During recent years, cancer-testis (CT) antigens (CTA), particularly those encoded by genes on the X chromosome (CT-X genes), have emerged as attractive targets for cancer immunotherapy. Whereas malignancies of diverse histologies express a variety of CTAs, immune responses to these proteins appear uncommon in cancer patients, possibly due to low-level, heterogeneous antigen expression, as well as immunosuppressive regulatory T cells present within tumor sites and systemic circulation of these individuals. Conceivably, vaccination of cancer patients with tumor cells expressing high levels of CTAs in combination with regimens that deplete or inhibit T regulatory cells will induce broad immunity to these antigens. In order to examine this issue, patients with primary lung and esophageal cancers, pleural mesotheliomas, thoracic sarcomas, thymic neoplasms and mediastinal germ cell tumors, as well as sarcomas, melanomas, germ cell tumors, or epithelial malignancies metastatic to lungs, pleura or mediastinum with no evidence of disease (NED) or minimal residual disease (MRD) following standard multidisciplinary therapy will be vaccinated with H1299 tumor cell lysates with Iscomatrix adjuvant. Vaccines will be administered with or without metronomic oral cyclophosphamide (50 mg by mouth (PO) twice a day (BID) x 7day (d) every (q) 14d), and celecoxib (400 mg PO BID). Serologic responses to a variety of recombinant CTAs as well as immunologic responses to autologous tumor or epigenetically modified autologous Epstein-Barr virus (EBV) transformed lymphocytes will be assessed before and after a six month vaccination period. Primary Objectives: 1. To assess the frequency of immunologic responses to CTAs in patients with thoracic malignancies following vaccinations with H1299 cell lysate/Iscomatrix(TM) vaccines alone in comparison to patients with thoracic malignancies following vaccinations with H1299 cell lysate/Iscomatrix vaccines in combination with metronomic cyclophosphamide and celecoxib. Secondary Objectives: To examine if oral metronomic cyclophosphamide and celecoxib therapy diminishes the number and percentage of T regulatory cells and diminishes activity of these cells in patients with thoracic malignancies are at risk of recurrence. To examine if H1299 cell lysate/Iscomatrix(TM) vaccination enhances immunologic response to autologous tumor or epigenetically modified autologous EBV-transformed lymphocytes (B cells). Eligibility: Patients with histologically or cytologically proven small cell or non-small cell lung cancer (SCLC;NSCLC), esophageal cancer (EsC), malignant pleural mesothelioma (MPM), thymic or mediastinal germ cell tumors, thoracic sarcomas, or melanomas, sarcomas, or epithelial malignancies metastatic to lungs, pleura or mediastinum who have no clinical evidence of active disease (NED), or minimal residual disease (MRD) not readily accessible by non-invasive biopsy or resection/radiation following standard therapy completed within the past 26 weeks. Patients must be 18 years or older with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 - 2. Patients must have adequate bone marrow, kidney, liver, lung and cardiac function. Patients may not be on systemic immunosuppressive medications at time vaccinations commence. Design: Following recovery from surgery, chemotherapy, or chemo/radiotherapy (XRT), patients with NED or MRD will be vaccinated via IM injection with H1299 cell lysates and Iscomatrix(TM) adjuvant monthly for 6 months. Vaccines will be administered with or without with metronomic oral cyclophosphamide and celecoxib. Systemic toxicities and immunologic response to therapy will be recorded. Pre and post vaccination serologic and cell mediated responses to a standard panel of CT antigens as well as autologous tumor cells (if available) and EBV-transformed lymphocytes will be assessed before and after vaccination. Numbers/percentages and function of T regulatory cells in peripheral blood will be assessed before, during, and after vaccinations. Patients will be followed in the clinic with routine staging scans until disease recurrence. The trial will randomize 28 evaluable patients per arm to either receive vaccine alone or vaccine plus chemotherapy in order to have 80% power to determine if the frequency of immune responses on the combination arm exceeds that of the vaccine alone arm, if the expected frequencies of immune responses on the two arms were 20% and 50%, using a one-sided 0.10 alpha level Fisher's exact test. Approximately 60 patients will be accrued to this trial.

Detailed Description
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Background: During recent years, cancer-testis (CT) antigens (CTA), particularly those encoded by genes on the X chromosome (CT-X genes), have emerged as attractive targets for cancer immunotherapy. Whereas malignancies of diverse histologies express a variety of CTAs, immune responses to these proteins appear uncommon in cancer patients, possibly due to low-level, heterogeneous antigen expression, as well as immunosuppressive regulatory T cells present within tumor sites and systemic circulation of these individuals. Conceivably, vaccination of cancer patients with tumor cells expressing high levels of CTAs in combination with regimens that deplete or inhibit T regulatory cells will induce broad immunity to these antigens. In order to examine this issue, patients with primary lung and esophageal cancers, pleural mesotheliomas, thoracic sarcomas, thymic neoplasms and mediastinal germ cell tumors, as well as sarcomas, melanomas, germ cell tumors, or epithelial malignancies metastatic to lungs, pleura or mediastinum with no evidence of disease (NED) or minimal residual disease (MRD) following standard multidisciplinary therapy will be vaccinated with H1299 tumor cell lysates with Iscomatrix (Trademark) adjuvant. Vaccines will be administered with or without metronomic oral cyclophosphamide (50 mg by mouth (PO) twice a day (BID) x 7day (d) every (q) 14d), and celecoxib (400 mg PO BID). Serologic responses to a variety of recombinant CTAs as well as immunologic responses to autologous tumor or epigenetically modified autologous Epstein-Barr Virus (EBV) transformed lymphocytes will be assessed before and after receiving 6 vaccines. Primary Objectives: -To assess the frequency of immunologic responses to CTAs in patients with thoracic malignancies following vaccinations with H1299 cell lysate/Iscomatrix (Trademark) vaccines alone in comparison to patients with thoracic malignancies following vaccinations with H1299 cell lysate/Iscomatrix (Trademark) vaccines in combination with metronomic cyclophosphamide and celecoxib. Eligibility: -Patients with histologically or cytologically proven small cell or non-small cell lung cancer (SCLC;NSCLC), esophageal cancer (EsC), malignant pleural mesothelioma (MPM), thymic or mediastinal germ cell tumors, thoracic sarcomas, or melanomas, sarcomas, or epithelial malignancies metastatic to lungs, pleura or mediastinum who have no clinical evidence of active disease (NED), or minimal residual disease (MRD) not readily accessible by non-invasive biopsy or resection/radiation following standard therapy completed within the past 56 weeks. Patients must be 18 years or older with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 - 2. Patients must have adequate bone marrow, kidney, liver, lung and cardiac function. Patients may not be on systemic immunosuppressive medications at time vaccinations commence. Design: Following recovery from surgery, chemotherapy, or chemo/XRT, patients with NED or MRD will be vaccinated via deep subcutaneous (SQ) injection with H1299 cell lysates and Iscomatrix (Trademark) adjuvant monthly until 6 vaccinations have been given. Vaccines will be administered with or without with metronomic oral cyclophosphamide and celecoxib. Systemic toxicities and immunologic response to therapy will be recorded. Pre and post vaccination serologic and cell mediated responses to a standard panel of CT antigens as well as autologous tumor cells (if available) and EBV-transformed lymphocytes will be assessed before and after vaccination. Numbers/percentages and function of T regulatory cells in peripheral blood will be assessed before, during, and after vaccinations. Patients will be followed in the clinic with routine staging scans until disease recurrence. The trial will randomize 28 evaluable patients per arm to either receive vaccine alone or vaccine plus chemotherapy in order to have 80% power to determine if the frequency of immune responses on the combination arm exceeds that of the vaccine alone arm, if the expected frequencies of immune responses on the two arms were 20% and 50%, using a one-sided 0.10 alpha level Fisher's exact test. Approximately 60 patients will be accrued to this trial.

Official Title
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Adjuvant Tumor Lysate Vaccine and Iscomatrix With or Without Metronomic Oral Cyclophosphamide and Celecoxib in Patients With Malignancies Involving Lungs, Esophagus, Pleura, or Mediastinum

Conditions
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Thoracic Sarcomas, Thorasic Cancers, Cancers of Non-thoracic Origin With Metastases to the Lungs or Pleura, Sarcoma, Melanoma

Intervention / Treatment
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* Biological: H1299 cell lysates
* Drug: Cyclophosphamide
* Drug: Celecoxib
* Biological: Iscomatrix adjuvant


Participation Criteria
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Eligibility Criteria
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-INCLUSION CRITERIA: Patients with histologically or cytologically proven lung or esophageal cancers, thymic or mediastinal germ cell tumors, malignant pleural mesotheliomas, or primary thoracic sarcomas, as well as patients with sarcomas, melanomas, germ cell tumors, or epithelial malignancies metastatic to the lungs, mediastinum, or pleura that have no clinical evidence of active disease (NED) or minimal residual disease (MRD) not readily accessible by non-invasive biopsy or resection/radiation following standard therapy. Diagnosis must be confirmed by the National Cancer Institute (NCI) Laboratory of Pathology. Patients must be enrolled within 56 weeks following completion of therapy. Patients must have completed standard therapy for their malignancy and recovered from all toxicities to less than or equal to Grade 2 within 3 weeks prior to enrollment. Patients with intracranial metastases, which have been treated by surgery or radiation therapy, may be eligible for study provided there is no evidence of active disease and no requirement for anticonvulsant therapy or steroids following treatment. Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 - 2 Patients must be 18 years of age or older due to the unknown effects of immunologic responses to this vaccine during childhood and adolescent development. Patients must have evidence of adequate bone marrow reserve, hepatic and renal function as evidenced by the following laboratory parameters: Absolute neutrophil count greater than 1500/mm^3 Platelet count greater than 100,000/mm^3 Hemoglobin greater than 8g/dl (patients may receive transfusions to meet this parameter) Prothrombin (PT) within 2 seconds of the upper limit of normal (ULN) Total bilirubin <1.5 x upper limits of normal Serum creatinine less than or equal to 1.6 mg/ml or the creatinine clearance must be greater than 70 ml/min/1.73m^2. Seronegative for human immunodeficiency virus (HIV) antibody. Note: The experimental treatment being evaluated in this protocol depends on an intact immune system. Patients who are HIV seropositive may have decreased immune competence and thus may be less responsive to the experimental treatment. Seronegative for active hepatitis B, and seronegative for hepatitis C antibody. If hepatitis C antibody test is positive, then patient must be tested for the presence of antigen by reverse transcription polymerase chain reaction (RT-PCR) and be hepatitis C virus (HCV) ribonucleic acid (RNA) negative. The effects of the study treatment on the developing human fetus are unknown; thus, women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) within 28 days prior to study entry, for the duration of study participation and up to 120 days after the last dose of the drug. 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. Patients must be willing to sign an informed consent. Ability and willingness to co-enroll on the screening and tissue collection protocol 06C0014, 'Prospective Evaluation of Genetic and Epigenetic Alterations in Patients with Thoracic Malignancies'. EXCLUSION CRITERIA: Patients who are initially rendered no clinical evidence of active disease (NED) or have minimal residual disease (MRD) following standard therapy but exhibit disease progression prior to initiation of vaccination will be excluded from the study. Patients requiring chronic systemic treatment with steroids will be excluded. Patients receiving warfarin anticoagulation, who cannot be transitioned to other agents such as enoxaparin or dabigatran, and for whom anticoagulants cannot be held for up to 24 hours will be excluded. Patients with uncontrolled hypertension (>160/95), unstable coronary disease evidenced by uncontrolled arrhythmias, unstable angina, decompensated congested heart failure (CHF) (>New York Heart Association (NYHA) Class II), or myocardial infarction within 6 months of study will be excluded. Patients with other cardiac diseases may be excluded at the discretion of the PI following consultation with Cardiology consultants. Patients with any of the following pulmonary function abnormalities will be excluded: forced expiratory volume (FEV), < 30% predicted; carbon monoxide (DLCO) < 30% predicted (post-bronchodilator); oxygen saturation less than 92% on room air. Female patients who are pregnant or breastfeeding. Because there is unknown, potentially harmful effects of immune response to CT-X antigens and stem cell proteins that may be expressed in placenta, fetus, and neonates. 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 3 months prior to enrollment that would limit compliance with study requirements.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1/Vaccine Plus Chemotherapy<br>H1299 cell lysates with iscomatrix vaccine with metronomic chemotherapy | Biological: H1299 cell lysates<br>* H1299 cell lysate with iscomatrix adjuvant vaccine via subcutaneous injections once every cycle (cycle=28 days) for 6 cycles total. Additional 2 injections for patients with immunologic response and no clinical evidence of active disease (NED).<br>Drug: Cyclophosphamide<br>* 50 mg by mouth (PO) twice a day (BID) for 7 days prior to the first dose of vaccine and then on days 8 through 14, and 22 through 28 of each treatment cycle.<br>* Other names: Cytoxan;Drug: Celecoxib<br>* 400 mg by mouth (PO) twice a day (BID) for 7 days prior to the first dose of vaccine and then on days 1 through 28 of each treatment cycle.<br>* Other names: Celebrex;Biological: Iscomatrix adjuvant<br>* H1299 cell lysate with iscomatrix adjuvant vaccine via subcutaneous injections once every cycle (cycle=28 days) for 6 cycles total. Additional 2 injections for patients with immunologic response and no clinical evidence of active disease (NED).<br>|
| Experimental: 2/Vaccine Alone<br>H1299 cell lysates with iscomatrix adjuvant vaccine | Biological: H1299 cell lysates<br>* H1299 cell lysate with iscomatrix adjuvant vaccine via subcutaneous injections once every cycle (cycle=28 days) for 6 cycles total. Additional 2 injections for patients with immunologic response and no clinical evidence of active disease (NED).<br>Biological: Iscomatrix adjuvant<br>* H1299 cell lysate with iscomatrix adjuvant vaccine via subcutaneous injections once every cycle (cycle=28 days) for 6 cycles total. Additional 2 injections for patients with immunologic response and no clinical evidence of active disease (NED).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With an Immunologic Responses | Immunologic responses are defined as an appearance of new serologic reactivity, or increase in existing antibody response to cancer-testis on the X chromosome (CT-X) antigen. Antigens such as New York esophageal squamous cell carcinoma-1 (NY-ESO1) and melanoma antigen gene (MAGE) family members assessed by enzyme-linked immunosorbent assay (ELISA) one month after the 6th vaccine. | one month after the 6th vaccine | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Fold Change From Baseline of Intensity of Programmed Cell Death Protein 1(PD-1) Expression on Tregs | The Mann=Whitney U test was used to compare the fold change of intensity of PD-1 expression on Tregs between the two groups. A decrease in the fold change is consistent with a better outcome. The difference, or the relative difference, in the values at the two time points were obtained and tested to determine if the difference is equal to zero. If a paired t-test is able to be used, with at least 20 evaluable participants, there is 81% power to detect a change equal to ¾ of a standard deviation of the change at the two-sided 0.025 significance level. This was done in order to allow for a conservative adjustment due to determining the significance of the change in the percent of Tregs on two arms. | one month after first 6 vaccinations | 
| Fold Change From Baseline of Percent Tregs | The Mann-Whitney U test was used to compare the fold change of percent Tregs between the two groups. A decrease in the fold change is consistent with a better outcome. The difference, or the relative difference, in the values at the two time points were obtained and tested to determine if the difference is equal to zero. If a paired t-test is able to be used, with at least 20 evaluable participants, there is 81% power to detect a change equal to ¾ of a standard deviation of the change at the two-sided 0.025 significance level. This was done in order to allow for a conservative adjustment due to determining the significance of the change in the percent of Tregs on two arms. | one month after first 6 vaccinations | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Minimal Residual Disease, Cancer Vaccine, Immunotherapy, No Clinical Evidence of Active Disease