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

Primary Purpose

Non-Small Cell Lung Cancer, Non-small-cell Lung Carcinoma, Lung Cancer

Status

Withdrawn

Phase

Phase 1

Locations

Study Type

Interventional

Intervention

gp96-Ig Vaccine

Theophylline

Oxygen

Immunologic Evaluation

About this trial

This is an interventional treatment trial for Non-Small Cell Lung Cancer focused on measuring NSCLC, Lung Cancer, gp96, gp96 Vaccine, AD100-gp96Ig-HLA A1

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Active Comparator

Arm Label

DS-1

DS-2

DS-3

Arm Description

6 week course of gp96 Vaccine: >= 4 x 10^7 cells twice monthly on Day 1. Up to 3 courses, 9 vaccinations.

6 week course of gp96 Vaccine: >= 2 x 10^7 cells weekly on Day 1. Up to 3 courses, 18 vaccinations.

6 week course of gp96 Vaccine: >= 1 x 10^7 cells twice weekly on Days 1 and 4. Up to 3 courses, 36 vaccinations.

Outcomes

Primary Outcome Measures

Number of Adverse Events Experienced by Patients Receiving Study Treatment

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

Clinical Response to gp96-Ig Vaccination

Clinical Response to gp96-Ig Vaccination measured by CT scan and RECIST criteria v 1.1.

Recommended Dose-schedule Combination for further testing

The recommended Dose-schedule combination of gp96-Ig vaccine, Theophylline and Oxygen for NSCLC in further testing

Full Information

NCT ID

NCT01799161

First Posted

February 22, 2013

Last Updated

November 14, 2014

Sponsor

Eckhard Podack

1. Study Identification

Unique Protocol Identification Number

NCT01799161

Brief Title

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

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.

Study Type

Interventional

2. Study Status

Record Verification Date

November 2014

Overall Recruitment Status

Withdrawn

Why Stopped

Insufficient funding

Study Start Date

December 2014 (undefined)

Primary Completion Date

April 2018 (Anticipated)

Study Completion Date

undefined (undefined)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor-Investigator

Name of the Sponsor

Eckhard Podack

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

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.

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Non-Small Cell Lung Cancer, Non-small-cell Lung Carcinoma, Lung Cancer, NSCLC

Keywords

NSCLC, Lung Cancer, gp96, gp96 Vaccine, AD100-gp96Ig-HLA A1

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

0 (Actual)

8. Arms, Groups, and Interventions

Arm Title

DS-1

Arm Type

Active Comparator

Arm Description

6 week course of gp96 Vaccine: >= 4 x 10^7 cells twice monthly on Day 1. Up to 3 courses, 9 vaccinations.

Arm Title

DS-2

Arm Type

Active Comparator

Arm Description

6 week course of gp96 Vaccine: >= 2 x 10^7 cells weekly on Day 1. Up to 3 courses, 18 vaccinations.

Arm Title

DS-3

Arm Type

Active Comparator

Arm Description

6 week course of gp96 Vaccine: >= 1 x 10^7 cells twice weekly on Days 1 and 4. Up to 3 courses, 36 vaccinations.

Intervention Type

Biological

Intervention Name(s)

gp96-Ig Vaccine

Other Intervention Name(s)

gp96, AD100-A1-gp96Ig vaccine, Short gp96 Vaccine, gp96IG and HLA A1 Transfected NSCLC Cell Line

Intervention Type

Drug

Intervention Name(s)

Theophylline

Other Intervention Name(s)

dimethylxanthine

Intervention Description

300 mg capsule daily of Theophylline during 1st course, then adjusted dose

Intervention Type

Other

Intervention Name(s)

Oxygen

Other Intervention Name(s)

Intervention Description

24-hr oxygen delivered via nasal cannula or oxygen mask during 1st course, then adjusted dose.

Intervention Type

Procedure

Intervention Name(s)

Immunologic Evaluation

Other Intervention Name(s)

Peripheral Blood Sample, Tumor Sample

Intervention Description

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.

Primary Outcome Measure Information:

Title

Number of Adverse Events Experienced by Patients Receiving Study Treatment

Description

Time Frame

36 months

Secondary Outcome Measure Information:

Title

Immune response to vaccination

Time Frame

36 months

Title

Clinical Response to gp96-Ig Vaccination

Description

Clinical Response to gp96-Ig Vaccination measured by CT scan and RECIST criteria v 1.1.

Time Frame

36 months

Title

Recommended Dose-schedule Combination for further testing

Description

The recommended Dose-schedule combination of gp96-Ig vaccine, Theophylline and Oxygen for NSCLC in further testing

Time Frame

36 Months

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility 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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Ikechukwu Akunyili, MD

Organizational Affiliation

University of Miami

Official's Role

Principal Investigator

12. IPD Sharing Statement

Learn more about this trial

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

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