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

This study is currently recruiting participants. (see Contacts and Locations)
Verified January 2014 by National Institutes of Health Clinical Center (CC)
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
ClinicalTrials.gov Identifier:
NCT02054104
First received: February 1, 2014
Last updated: September 6, 2014
Last verified: January 2014
  Purpose

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 PO BID x 7d 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 EBVtransformed 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:

  1. 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.
  2. 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 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 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.

Condition Intervention Phase
Lung Cancer
Esophageal Cancer
Malignant Pleural Mesothelioma
Sarcoma
Thymic Carcinoma
Biological: H1299 Lysate Vaccine
Drug: Cyclophosphamide
Drug: Celecoxib
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Adjuvant Tumor Lysate Vaccine and Iscomatrix With or Without Metronomic Oral Cyclophosphamide and Celecoxib in Patients With Malignancies Involving Lungs, Esophagus, Pleura, or Mediastinum

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:
  • Comparison of immune response rates in patients taking vaccine alone versus those taking vaccine plus metronomic chemotherapy. [ Time Frame: 6-12 months ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Immune response rate in patients taking vaccine alone [ Time Frame: 6-12 months ] [ Designated as safety issue: No ]
  • Immune response rate in pateitns taking vaccine plus metronomic chemotherapy. [ Time Frame: 6-12 months ] [ Designated as safety issue: No ]

Estimated Enrollment: 60
Study Start Date: January 2014
Estimated Study Completion Date: November 2017
Estimated Primary Completion Date: November 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Vaccine with metronomic chemotherapy Biological: H1299 Lysate Vaccine
1x10^8 H1299 cells administered in 2 IM injections q cycle. (1 cycle = 28 days) for 6 cycles if no toxicity and then up to an additional 6 cycles if immune response is evident after the first 6 cycles.
Drug: Cyclophosphamide
50 mg PO 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 for 6 cycles if no toxicity and then up to an additional 6 cycles if immune response is evident after the first 6 cycles.
Drug: Celecoxib
400 mg PO BID for 7 days prior to the first dose of vaccine and then on days 1 through 28 of each vaccine cycle for 6 cycles if no toxicity and then up to an additional 6 cycles if immune response is evident after the first 6 cycles.
Active Comparator: Vaccine alone Biological: H1299 Lysate Vaccine
1x10^8 H1299 cells administered in 2 IM injections q cycle. (1 cycle = 28 days) for 6 cycles if no toxicity and then up to an additional 6 cycles if immune response is evident after the first 6 cycles.

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria
  • INCLUSION CRITERIA

2.1.1.1 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.

2.1.1.2 Diagnosis must be confirmed by the NCI Laboratory of Pathology.

2.1.1.3 Patients must be enrolled within 52 weeks following completion of therapy.

2.1.1.4 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.

2.1.1.5 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.

2.1.1.6 Patients must have an ECOG performance status of 0 2

2.1.1.7 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.

2.1.1.8 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/mm3
  • Platelet count greater than 100,000/mm3
  • Hemoglobin greater than 8g/dl (patients may receive transfusions to meet this parameter)
  • PT within 2 seconds of the 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/1.73m2.

2.1.1.9 Seronegative for 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.

2.1.1.10 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 RT-PCR and be HCV RNA negative.

2.1.1.11 Patients must be aware of the neoplastic nature of their illnesses, the experimental nature of the therapy, alternative treatments, potential benefits, and risks.

2.1.1.12 Patients must be willing to practice birth control during and for four months following treatment.

2.1.1.13 Patients must be willing to sign an informed consent.

EXCLUSION CRITERIA

2.1.2.1 Patients who are initially rendered NED or have MRD following standard therapy but exhibit disease progression prior to initiation of vaccination will be excluded from the study.

2.1.2.2 Patients requiring corticosteroids (other than inhaled) will be excluded.

2.1.2.3 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.

2.1.2.4 Patients with uncontrolled hypertension (> 160/95), unstable coronary disease evidenced by uncontrolled arrhythmias, unstable angina, decompensated CHF (> NYHA Class II), or myocardial infarction within 6 months of study will be excluded.

2.1.2.5 Patients with other cardiac diseases may be excluded at the discretion of the PI following consultation with Cardiology consultants.

2.1.2.6 Patients with any of the following pulmonary function abnormalities will be excluded: FEV, < 30% predicted; DLCO < 30% predicted (post-bronchodilator); oxygen saturation less than 92% on room air.

2.1.2.7 Pregnant and/or lactating women will be excluded due to the unknown, potentially harmful effects of immune response to CT-X antigens and stem cell proteins that may be expressed in placenta, fetus, and neonates.

2.1.2.8 Patients with active infections, including HIV, will be excluded, due to unknown effects of the vaccine on lymphoid precursors.

2.1.2.9 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.

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02054104

Contacts
Contact: Tricia Kunst, R.N. (301) 451-1233 kunstt@mail.nih.gov
Contact: David S Schrump, M.D. (301) 496-2128 david_schrump@nih.gov

Locations
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact NCI/Surgery Branch Recruitment Center    866-820-4505    ncisbirc@mail.nih.gov   
Sponsors and Collaborators
Investigators
Principal Investigator: David S Schrump, M.D. National Cancer Institute (NCI)
  More Information

Additional Information:
Publications:
Responsible Party: National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
ClinicalTrials.gov Identifier: NCT02054104     History of Changes
Other Study ID Numbers: 140053, 14-C-0053
Study First Received: February 1, 2014
Last Updated: September 6, 2014
Health Authority: United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):
Lung Cancer
Cancer Vaccine
Immunotherapy
Adjuvant Therapy
Surgical Intervention

Additional relevant MeSH terms:
Lung Neoplasms
Esophageal Neoplasms
Mesothelioma
Neoplasms, Mesothelial
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
Gastrointestinal Neoplasms
Digestive System Neoplasms
Head and Neck Neoplasms
Digestive System Diseases
Esophageal Diseases
Gastrointestinal Diseases
Adenoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Cyclophosphamide
Celecoxib
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Antirheumatic Agents
Therapeutic Uses
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on September 18, 2014