Now Available for Public Comment: Notice of Proposed Rulemaking (NPRM) for FDAAA 801 and NIH Draft Reporting Policy for NIH-Funded Trials

Combination of gp96-Ig Vaccine, Theophylline and Oxygen for the Treatment of Patients With Advanced, Relapsed or Metastatic Non-Small Cell Lung Cancer

This study has been withdrawn prior to enrollment.
(Insufficient funding)
Sponsor:
Information provided by (Responsible Party):
Eckhard Podack, University of Miami
ClinicalTrials.gov Identifier:
NCT01799161
First received: February 22, 2013
Last updated: November 14, 2014
Last verified: November 2014
  Purpose

NSCLC tumors are appropriate targets for active immunotherapy, because they are non-immunogenic, which indicates that NSCLC does not stimulate a spontaneous immune response.

NSCLC tumor-secreted gp96-Ig is an ideal vaccine because it combines adjuvant activity with polyvalent peptide specificity. Tumor secreted gp96 activates dendritic cells (DC), natural killer cells (NK) and cytotoxic T lymphocytes (CTL). Tumor cells can be killed by NK-specific mechanisms, by promiscuous killing of CD8 CTL through NKG2D, and by MHC restricted CD8 CTL activity. The activation of DC and NK by tumor secreted gp96 may also counteract the generation of immuno-suppressive CD4 regulatory cells.

Suppression of adenosinergic pathways by oxygen and theophylline in combination with immunotherapy will improve tumor rejection.

Allogeneic, gp96-Ig secreting tumor cells used as vaccine are expected to generate NK and CTL with activity to the patient's autologous tumor.


Condition Intervention Phase
Non-Small Cell Lung Cancer
Non-small-cell Lung Carcinoma
Lung Cancer
NSCLC
Biological: gp96-Ig Vaccine
Drug: Theophylline
Other: Oxygen
Procedure: Immunologic Evaluation
Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase 1 Study of the Combination of gp96-Ig Cell Based Lung Cancer Vaccine With Suppression of Adenosinergic Pathways With Theophylline and Oxygen for the Treatment of Non-Small Cell Lung Cancer (NSCLC) Patients With Advanced (Stage IIIB), Relapsed or Metastatic (Stage IV) Disease Who Have Failed Palliative Therapy.

Resource links provided by NLM:


Further study details as provided by University of Miami:

Primary Outcome Measures:
  • Number of Adverse Events Experienced by Patients Receiving Study Treatment [ Time Frame: 36 months ] [ Designated as safety issue: Yes ]
    Evaluation of the safety of administering a heat shock protein gp96-Ig-secreting allogeneic tumor cell-vaccine (gp96-Ig vaccine) in combination with oxygen and theophylline in patients with advanced NSCLC.


Secondary Outcome Measures:
  • Immune response to vaccination [ Time Frame: 36 months ] [ Designated as safety issue: No ]
  • Clinical Response to gp96-Ig Vaccination [ Time Frame: 36 months ] [ Designated as safety issue: No ]
    Clinical Response to gp96-Ig Vaccination measured by CT scan and RECIST criteria v 1.1.

  • Recommended Dose-schedule Combination for further testing [ Time Frame: 36 Months ] [ Designated as safety issue: Yes ]
    The recommended Dose-schedule combination of gp96-Ig vaccine, Theophylline and Oxygen for NSCLC in further testing


Enrollment: 0
Study Start Date: December 2014
Estimated Primary Completion Date: April 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: DS-1
6 week course of gp96 Vaccine: >= 4 x 10^7 cells twice monthly on Day 1. Up to 3 courses, 9 vaccinations.
Biological: gp96-Ig Vaccine
Other Names:
  • gp96
  • AD100-A1-gp96Ig vaccine
  • Short gp96 Vaccine
  • gp96IG and HLA A1 Transfected NSCLC Cell Line
Drug: Theophylline
300 mg capsule daily of Theophylline during 1st course, then adjusted dose
Other Name: dimethylxanthine
Other: Oxygen
24-hr oxygen delivered via nasal cannula or oxygen mask during 1st course, then adjusted dose.
Other Name: O2
Procedure: Immunologic Evaluation
Frequency of IFN-y,CD8 cells in response to vaccine in available tumor samples Blood draw to assess immunological response [frequency of CD4+, FoxP3 (Treg), et al] in treated patients.
Other Names:
  • Peripheral Blood Sample
  • Tumor Sample
Active Comparator: DS-2
6 week course of gp96 Vaccine: >= 2 x 10^7 cells weekly on Day 1. Up to 3 courses, 18 vaccinations.
Biological: gp96-Ig Vaccine
Other Names:
  • gp96
  • AD100-A1-gp96Ig vaccine
  • Short gp96 Vaccine
  • gp96IG and HLA A1 Transfected NSCLC Cell Line
Drug: Theophylline
300 mg capsule daily of Theophylline during 1st course, then adjusted dose
Other Name: dimethylxanthine
Other: Oxygen
24-hr oxygen delivered via nasal cannula or oxygen mask during 1st course, then adjusted dose.
Other Name: O2
Procedure: Immunologic Evaluation
Frequency of IFN-y,CD8 cells in response to vaccine in available tumor samples Blood draw to assess immunological response [frequency of CD4+, FoxP3 (Treg), et al] in treated patients.
Other Names:
  • Peripheral Blood Sample
  • Tumor Sample
Active Comparator: DS-3
6 week course of gp96 Vaccine: >= 1 x 10^7 cells twice weekly on Days 1 and 4. Up to 3 courses, 36 vaccinations.
Biological: gp96-Ig Vaccine
Other Names:
  • gp96
  • AD100-A1-gp96Ig vaccine
  • Short gp96 Vaccine
  • gp96IG and HLA A1 Transfected NSCLC Cell Line
Drug: Theophylline
300 mg capsule daily of Theophylline during 1st course, then adjusted dose
Other Name: dimethylxanthine
Other: Oxygen
24-hr oxygen delivered via nasal cannula or oxygen mask during 1st course, then adjusted dose.
Other Name: O2
Procedure: Immunologic Evaluation
Frequency of IFN-y,CD8 cells in response to vaccine in available tumor samples Blood draw to assess immunological response [frequency of CD4+, FoxP3 (Treg), et al] in treated patients.
Other Names:
  • Peripheral Blood Sample
  • Tumor Sample

Detailed Description:

This is a proof of principle trial investigating a heat shock protein gp96 Ig-secreting, allogeneic tumor cell-vaccine (gp96-Ig vaccine) administered in combination with suppression of adenosinergic pathways by oxygen and Theophylline to patients with non-small cell lung cancer (NSCLC). Allogeneic, cultured lung adenocarcinoma cells transfected with HLA A1 and gp96-Ig will be irradiated and injected intradermally into patients suffering from advanced, relapsed, or metastatic NSCLC. HLA matching is not required. Safety and immunogenicity of the combined treatment will be studied in three patient cohorts that will receive twice monthly, weekly or twice weekly vaccination plus Theophylline and oxygen.

Immune response to vaccination of patients will be measured by determining adenocarcinoma-specific CD8 CTL precursor frequencies. ELI-spot assay for interferon-y (IFN-y) will be done to measure cytotoxic function of CD8 cells challenged in vitro with vaccine cells or autologous tumor cells. Multiparameter flow cytometry of CD8 and CD4 cells will be carried out to assess functional characteristics and to assess adenosine receptor levels and expression of hypoxia inducible factor-1alpha.

Patients will be randomized in equal allocation (1:1:1) to one of three dose-schedule (DS) cohorts defined by the frequency of vaccination. All patients will receive a total course dose of gp96 vaccine. A total of 36 patients, 12 per DS cohort, will be enrolled. We expect to accrue at a rate of two patients per month except at the onset of study when successive enrollment will be spaced to allow observation of first course toxicity in the first several patients. (See Section 3.3.4 for details.) Patients will be followed for a minimum of one year, thus study duration is expected to be three years.

  Eligibility

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

Inclusion Criteria:

  • Histologically confirmed NSCLC (squamous, adeno-, large cell anaplastic, bronchoalveolar, and non-small cell carcinoma NOS): stage IIIB with malignant pleural effusion, stage IV, or recurrent disease.
  • At least one site of measurable disease.
  • Brain metastasis if present and treated must be stable by CT scan or MRI for at least 4 weeks after treatment.
  • Patient must have received and failed at least one line of palliative therapy (chemotherapy or biological therapy)
  • Age >= 18 years.
  • ECOG performance status 0-2.
  • Life expectancy >= 3 months.
  • Laboratory parameters

    • Hemoglobin levels >= 10.0 (transfusions allowed if necessary).
    • ANC >= 1,500.
    • Platelets >= 100k.
    • Creatinine clearance >= 50 ml/min.
    • Total and direct bilirubin: < 3.0 x upper institution limit for normal.
    • Liver function tests: AST, ALT, and AlkP < 3.0 x upper institution limit for normal.
    • Signed informed consent.

Exclusion Criteria:

  • Active or symptomatic cardiac disease such as congestive heart failure, angina pectoris or recent myocardial infarction. Patients with history of these conditions who are stable taking cardiac medications will also be excluded.
  • Pregnant or lactating women (negative test for pregnancy is required of women of childbearing potential).
  • Known HIV infection.
  • Uncontrolled or untreated brain or spinal cord metastases.
  • Active infection.
  • Concomitant steroid or other immunosuppressive therapy.
  • Other active malignancies present within the past three years, except for basal and/or squamous cell carcinoma(s) or in situ cervical cancer.
  • Meningeal carcinomatosis.
  • Chemotherapy, radiation therapy, or other anti-tumor therapy during the last three weeks.
  • Immune deficiency syndromes, including the following: rheumatoid arthritis, systemic lupus erythematousus, Sjogren's disease, sarcoidosis, vasculitis, polymyositis, glomerulonephritis.
  • Compromised lung function:

    • FeV1 < 30% of the predicted value, or
    • DLCO < 30% of the predicted value, or
    • PCO2 > 45 mmHg.
  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: NCT01799161

Sponsors and Collaborators
Eckhard Podack
Investigators
Principal Investigator: Ikechukwu Akunyili, MD University of Miami
  More Information

No publications provided

Responsible Party: Eckhard Podack, Professor, University of Miami
ClinicalTrials.gov Identifier: NCT01799161     History of Changes
Other Study ID Numbers: 20110847
Study First Received: February 22, 2013
Last Updated: November 14, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by University of Miami:
NSCLC
Lung Cancer
gp96
gp96 Vaccine
AD100-gp96Ig-HLA A1

Additional relevant MeSH terms:
Carcinoma, Non-Small-Cell Lung
Lung Neoplasms
Bronchial Neoplasms
Carcinoma, Bronchogenic
Lung Diseases
Neoplasms
Neoplasms by Site
Respiratory Tract Diseases
Respiratory Tract Neoplasms
Thoracic Neoplasms
Theophylline
Anti-Asthmatic Agents
Autonomic Agents
Bronchodilator Agents
Cardiovascular Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Neurotransmitter Agents
Peripheral Nervous System Agents
Pharmacologic Actions
Phosphodiesterase Inhibitors
Physiological Effects of Drugs
Purinergic Agents
Purinergic Antagonists
Purinergic P1 Receptor Antagonists
Respiratory System Agents
Therapeutic Uses
Vasodilator Agents

ClinicalTrials.gov processed this record on November 25, 2014