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Adjuvant Allogeneic Tumor Cell Vaccine With Metronomic Oral Cyclophosphamide and Celecoxib in Patients 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 Malignancies

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Trial Information

Adjuvant Allogeneic Tumor Cell Vaccine With Metronomic Oral Cyclophosphamide and Celecoxib in Patients Undergoing Resection of Sarcomas, Melanomas, Germ Cell Tumors, or Epithelial Malignancies Metastatic to Lungs, Pleura, or Mediastinum


Background:

During recent years, the cancer-testis (CT) antigens (CTA) have emerged as attractive
targets for cancer immunotherapy. Whereas malignancies of diverse histologies express a
variety of CTAs, immune responses to these antigens appear uncommon in cancer patients,
possibly due to low-level, heterogeneous antigen expression, as well as immunosuppressive
regulatory T cells. Conceivably, vaccination of cancer patients with allogeneic tumor cells
expressing high levels of multiple CTAs in combination with depletion of T regulatory cells
will induce broad immunity to these antigens. In order to examine this issue, patients with
sarcomas, melanomas, germ cell tumors, or epithelial malignancies metastatic to lungs,
pleura or mediastinum will be vaccinated with irradiated K562 erythroleukemia cells
expressing GM-CSF (K562-GM) following thoracic metastasectomy. Vaccines will be administered
in conjunction with 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 will be
assessed before and after vaccination.

Primary Objectives:

-To assess the safety of K562-GM allogeneic tumor cell vaccines in combination with oral
metronomic cyclophosphamide and celecoxib in patients undergoing thoracic metastasectomy.

Secondary Objectives:

- To ascertain if K562-GM cell vaccines induce immunity to CTAs in patients following
thoracic metastasectomy

- 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 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 clinical
evidence of active disease (NED).

- 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 times 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:

- Following recovery from thoracic metastasectomy, patients with NED or MRD will be
vaccinated via deep subcutaneous injection with 1x10(8) irradiated K562 GM-tumor cells
periodically over 6 months.

- Vaccines will be administered in conjunction with metronomic oral cyclophosphamide and
celecoxib.

- Systemic toxicities, and immunologic response to therapy will be recorded. Pre and post
vaccination serologic responses to a standard panel of CT antigens as well as cell
mediated responses to epigenetically-modified autologous EBV-transformed B and
autologous tumor cells (if available) 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.

- 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 25 patients will be accrued to this trial.

Inclusion Criteria


- INCLUSION CRITERIA:

1. 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).

2. Patients with active disease outside the thorax may be eligible for study once
the extrathoracic disease is definitively treated by local modalities such as
radiation, surgery, or radiofrequency ablation.

3. Patients must have received or refused first line standard systemic therapy for
their metastases (if applicable).

4. Patients must be enrolled within 52 weeks following completion of metastasectomy
and have shown no evidence of disease during that time.

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.

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

7. 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.

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/mm(3)

- Platelet count greater than 100,000/mm(3)

- Hemoglobin greater than 8g/dl (patients may receive transfusions to meet
this parameter)

- PT within 2 seconds of the ULN

- Total bilirubin < 1.5 times 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).

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 can have decreased immune competence and thus may be less
responsive to the experimental treatment.

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.

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

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

13. Patients must be willing to sign an informed consent.

EXCLUSION CRITERIA:

1. Patients who are initially rendered NED by surgical therapy but exhibit disease
progression prior to initiation of vaccination will be excluded from the study.

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

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

4. 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.

5. 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.

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

7. Patients with any of the following pulmonary function abnormalities will be excluded:
FEV, < 30% predicted; DLCO < 30% predicted (postbronchodilator); Oxygen Saturation
less than 90% on room air.

8. 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.

9. 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 K562-GM allogeneic tumor cell vaccines in combination with oral metronomic cyclophosphamide and celecoxib in patients undergoing thoracic metastasectomy.

Outcome Time Frame:

14 months

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:

110111

NCT ID:

NCT01313429

Start Date:

February 2011

Completion Date:

February 2018

Related Keywords:

  • Sarcoma
  • Melanoma
  • Epithelial Malignancies
  • Pleural Malignancies
  • Metastatic Cancer
  • Cancer Vaccine
  • Immunotherapy
  • Adjuvant Therapy
  • Chest Metastases
  • Cancer
  • Melanoma
  • Lung Cancer
  • Sarcoma
  • Neoplasms
  • Melanoma
  • Neoplasms, Germ Cell and Embryonal
  • Sarcoma

Name

Location

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