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Autologous Tumor Cell Vaccs and ISCOMATRIX(TM) Adjuvant With Metronomic Oral Cyclophosphamide and Celecoxib in Pts Undergoing Resection of Sarcomas, Melanomas, Germ Cell Tumors, or Epithelial Malignancies Metastatic to Lungs, Pleura or Mediastinum


Phase 1
18 Years
N/A
Open (Enrolling)
Both
Sarcoma, Melanoma, Epithelial Malignancies, Pleural Malignancy

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Trial Information

Autologous Tumor Cell Vaccs and ISCOMATRIX(TM) Adjuvant With Metronomic Oral Cyclophosphamide and Celecoxib in Pts Undergoing Resection of Sarcomas, Melanomas, Germ Cell Tumors, or Epithelial Malignancies Metastatic to Lungs, Pleura or Mediastinum


Background:

Cancer-testis (CT) antigens (CTAs) have emerged as attractive targets for cancer
immunotherapy. Whereas cancers of various histologies exhibit CTA expression, primary or
vaccine-induced immune responses to these antigens appear uncommon in patients with these
malignancies, possibly due to low-level, heterogeneous antigen expression, and inadequate
vaccination strategies. Because numerous CT antigens can be induced in tumor cells by DNA
demethylating agents and HDAC inhibitors, it is conceivable that vaccination of cancer
patients with autologous tumor cells exposed to chromatin remodeling agents will enhance
anti-tumor immunity in these individuals. In order to examine this issue, patients
undergoing complete resection of sarcomas, melanomas, germ cell tumors and epithelial
malignancies metastatic to the lungs, pleura or mediastinum will be vaccinated with
autologous tumor cells exposed ex-vivo to decitabine and radiation following completion of
appropriate combined modality therapy. Vaccines will be administered in conjunction with
ISCOMATRIX(Trademark) adjuvant as well as 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 delayed type hypersensitivity to autologous epigenetically modified tumor
cells will be assessed before and after vaccination.

Primary Objective:

-To assess the safety of an epigenetically modified autologous tumor cell vaccine
administered with ISCOMATRIX(Trademark) adjuvant in combination with metronomic oral
cyclophosphamide and celecoxib in patients undergoing thoracic metastasectomy.

Secondary Objectives:

- To ascertain if autologous epigenetically modified tumor cell vaccines induce immunity
to CTAs in patients following thoracic metastasectomy

- To compare CT-X gene expression profiles in established autologous parental tumor cells
relative to epigenetically modified cell lines

- To examine if oral metronomic cyclophosphamide and celecoxib therapy diminishes the
number and percentage of T regulatory cells in patients with resected thoracic
metastases who are at risk of recurrence

Eligibility:

- Patients with histologically or cytologically proven sarcoma, melanoma, or epithelial
malignancies metastatic to lungs, pleura or mediastinum who can be rendered no evidence
of disease (NED) by metastasectomy.

- Patients must be 18 years or older with an ECOG performance status of 0 - 2, without
evidence of unstable or decompensated myocardial disease. Patients must have adequate
pulmonary reserve evidenced by FEV1 and DLCO equal to or greater than 30% predicted;
pCO2 less than 50 mm Hg and pO2 greater than 60 mm Hg on room air ABG; and be on no
immunosuppressive medications except inhaled corticosteroids at the time vaccination
commences.

- Patients must have a platelet count greater than 100,000, an ANC equal to or greater
than 1500 without transfusion or cytokine support, a normal PT, and adequate hepatic
function as evidenced by a total bilirubin of < 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) at the time vaccination commences.

Design:

- Patients will undergo thoracic metastasectomy using standard of practice guidelines.

- Portions of the resected tumors will be transferred to the Thoracic Oncology
Laboratory. Cells will be processed to establish a cancer cell line.

- Following recovery from surgery and appropriate adjuvant chemotherapy and/or radiation,
patients will be vaccinated with epigenetically-modified autologous tumor cells
periodically over 6 months in conjunction with metronomic oral cyclophosphamide and
celecoxib.

- Systemic toxicities and delayed type hypersensitivity responses to autologous tumor
cells and serologic responses to a variety of CT antigens will be assessed before and
after vaccination.

- Patients will be followed with routine staging scans until disease recurrence.

- As the exact set of comparisons and analyses to be performed will be determined
following completion of the trial, and will be based on limited numbers of patients,
the analyses will be considered exploratory and hypothesis generating rather than
definitive.

- Approximately 80 patients will be accrued to this trial in order to obtain up to 20
evaluable patients.

Inclusion Criteria


- INCLUSION CRITERIA:

1. Patients with sarcomas, melanomas, germ cell tumors, or epithelial malignancies
metastatic to the lungs, mediastinum, or pleura who can be rendered no evidence
of active disease (NED) following standard surgical therapy. Note: (Bullet)
Patients with active disease outside the thorax may be eligible for the study
once the extrathoracic disease is definitively treated by local modalities such
as radiation, surgery, or radiofrequency ablation.

2. Patients must have received or refused first line standard systemic therapy for
their metastases.

3. Patients with no more than 3 intracranial metastases, which have been
definitively treated by surgery or radiation therapy may be eligible for study
provided there is no evidence of active disease for at least 2 months.

4. Patients must have an ECOG performance status of 0 - 2.

5. Patients must be 18 years of age or older due to the unknown effects of
immunologic responses to germ cell-restricted gene products during childhood and
adolescent development.

6. Seronegative for HIV antibody. Note: The experimental treatment being evaluated
in this protocol depends on an intact immune system. Patients who are HIV
seropositive can have decreased immune competence and thus may be less
responsive to the experimental treatment.

7. 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.

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

9. Patients must be willing to sign an informed consent and undergo resection of
their malignancies at the NCI, to ensure vaccine development.

INCLUSION CRITERIA FOR TREATMENT PHASE OF PROTOCOL (Standard Consent):

1. Patients must have signed the Screening Consent.

2. Patients who were initially rendered NED by surgical resection must remain NED at the
time of treatment.

3. Patients with no more than 3 intracranial metastases, which have been definitively
treated by surgery or radiation therapy may be eligible for the study, provided there
is no evidence of active disease for at least 2 months and no requirement for
anticonvulsant therapy or steroids following treatment.

4. Patients must have an ECOG performance status of 0 - 2.

5. 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 creatin ine less than or equal to 1.6 mg/ml or the creatinine clearance must be
greater than 70 ml/min/1.73m2.

6. Seronegative for HIV antibody. Note: The experimental treatment being evaluated in
this protocol depends on an intact immune system.

Patients who are HIV seropositive can have decreased immune competence and thus may
be less responsive to the experimental treatment.

7. 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.

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

9. Patients must be willing to sign the standard informed consent.

EXCLUSION CRITERIA

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

2. Patients with life expectancy less than 12 months will be excluded.

3. Patients receiving warfarin anticoagulation, who cannot be transferred to other
agents such as enoxaparin or dabigatran, and for whom anticoagulants cannot be held
for up to 24 hours will be excluded.

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

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

6. Patients with any of the following pulmonary function abnormalities will be excluded:
FEV, < 30% predicted; DLCO < 30% predicted (post-bronchodilator); pO2 < 60% or
pCO2 >= 50 on room air arterial blood gas.

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.

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

Type of Study:

Interventional

Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

To assess the safety of an epigenetically modified autologous tumor cell vaccine administered with ISCOMATRIX(Trademark) adjuvant in combination with metronomic oral cyclophosphamide and celecoxib in patients undergoing thoracic metastasectomy.

Outcome Time Frame:

5 years

Safety Issue:

Yes

Principal Investigator

David S Schrump, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Cancer Institute (NCI)

Authority:

United States: Federal Government

Study ID:

110148

NCT ID:

NCT01341496

Start Date:

April 2011

Completion Date:

January 2018

Related Keywords:

  • Sarcoma
  • Melanoma
  • Epithelial Malignancies
  • Pleural Malignancy
  • Metastatic Cancer
  • Cancer Vaccine
  • Immunotherapy
  • Chest Metastases
  • Sarcoma
  • Melanoma
  • Neoplasms
  • Melanoma
  • Sarcoma

Name

Location

National Institutes of Health Clinical Center, 9000 Rockville PikeBethesda, Maryland  20892