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A Neoadjuvant Immunologic Study of Androgen Deprivation Therapy Combined With a GM-CSF-secreting Allogeneic Prostate Cancer Vaccine and Low-dose Cyclophosphamide in Men With High-risk Localized Prostate Cancer Undergoing Radical Prostatectomy

Phase 1/Phase 2
21 Years
Open (Enrolling)
Prostate Cancer Adenocarcinoma in Situ

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Trial Information

A Neoadjuvant Immunologic Study of Androgen Deprivation Therapy Combined With a GM-CSF-secreting Allogeneic Prostate Cancer Vaccine and Low-dose Cyclophosphamide in Men With High-risk Localized Prostate Cancer Undergoing Radical Prostatectomy

Cancer immunotherapy refers broadly to approaches which attempt to treat cancer by
activating immune responses directed against malignant tissue. Prostate GVAX is an
allogeneic cell-based prostate cancer vaccine composed of two irradiated cell lines (PC3 and
LNCaP) that have been genetically modified to secrete granulocyte-macrophage
colony-stimulating factor (GM-CSF). The release of GM-CSF by these modified tumor cells
serves to recruit dendritic cells which then present tumor antigens to T-cells, thus
initiating antitumor immune responses.

However, abundant preclinical data show that, when used alone, cell-based immunotherapy is
unable to break specific T-cell tolerance in tumor-bearing hosts. Studies in an
autochthonous prostate cancer mouse model have shown that giving low-dose cyclophosphamide
prior to a cell-based GM-CSF-secreting vaccine abrogates immune tolerance through
augmentation of CD8+ T cell infiltration in the prostate, transient depletion of regulatory
T cells (Tregs), and increased expression of dendritic cell maturation markers. Enhancement
of antitumor immunity has also been observed in other preclinical models where
cyclophosphamide was given in sequence with GM-CSF-secreting immunotherapy for the treatment
of breast and pancreatic cancers. These preclinical data are supported by early-phase
clinical trials combining GVAX with low-dose cyclophosphamide in pancreatic and breast

Furthermore, emerging evidence suggests that androgen deprivation therapy (ADT) itself has
profound effects on the host immune system, resulting in thymic regeneration and enhancement
of antitumor immunity. In addition, preclinical and clinical studies demonstrate that ADT
augments prostate cancer-specific immune responses induced by immunotherapy, suggesting that
ADT may act synergistically with immunotherapy. Based on data from mouse models as well as
human clinical trials, it has been suggested that prostate cancer immunotherapy may be most
effective when administered in the setting of an androgen-suppressed environment.

Building on these findings, investigators have designed a study to assess the use of ADT
given alone or administered following immunization with low-dose cyclophosphamide and
prostate GVAX, in patients undergoing radical prostatectomy. Investigators aim (1) to
determine whether ADT is immunogenic in men with localized prostate cancer by evaluating
T-cell infiltration in harvested prostate glands; (2) to determine whether administering ADT
after low-dose cyclophosphamide and prostate GVAX augments immune infiltration into the
prostate gland; and (3) to investigate whether this combinatorial immuno-hormonal approach
is safe and feasible. Investigators hypothesize that the combination of ADT and
cyclophosphamide/GVAX will produce significantly greater antitumor immune responses than
would ADT used alone.

Inclusion Criteria:

- Histologically confirmed adenocarcinoma of the prostate (clinical stage T1c-T3b, N0,
M0) without involvement of lymph nodes, bone, or visceral organs

- Initial prostate biopsy is available for central pathologic review, and is confirmed
to show at least 2 positive cores and a maximum Gleason sum of ≥ 7

- Radical prostatectomy has been scheduled at Johns Hopkins Hospital

- Age ≥ 21 years

- ECOG performance status 0-1, or Karnofsky score ≥ 70%

- Adequate bone marrow, hepatic, and renal function:

- WBC > 3,000 cells/mm3

- ANC > 1,500 cells/mm3

- Hemoglobin > 9.0 g/dL

- Platelet count > 100,000 cells/mm3

- Serum creatinine < 2.0 mg/dL

- Serum bilirubin < 2 mg/dL

- ALT < 2 × upper limit of normal (ULN)

- AST < 2 × ULN

- Alkaline phosphatase < 2 × ULN

- Willingness to provide written informed consent and HIPAA authorization for the
release of personal health information, and the ability to comply with the study
requirements (note: HIPAA authorization will be included in the informed consent)

- Willingness to use barrier contraception from the time of cyclophosphamide and/or
GVAX administration until the time of prostatectomy.

Exclusion Criteria:

- Presence of known lymph node involvement or distant metastases

- Other histologic types of prostate cancers such as ductal, sarcomatous, lymphoma,
small cell, and neuroendocrine tumors

- Prior radiation therapy, hormonal therapy, biologic therapy, or chemotherapy for
prostate cancer

- Prior immunotherapy/vaccine therapy for prostate cancer

- Previous or concurrent use of cyclophosphamide

- Concomitant treatment with other hormonal therapy or 5a-reductase inhibitors

- Current use of systemic corticosteroids or use of corticosteroids within 4 weeks of
enrollment (inhaled corticosteroids for asthma or COPD are permitted)

- Use of experimental agents for prostate cancer within the past 3 months

- Known allergy to cyclophosphamide or G-CSF/GM-CSF

- Known hypersensitivity to materials of bovine origin (e.g. fetal bovine serum), or
other components of GVAX which include DMSO and hydroxyethyl starch as well as small
amounts of porcine trypsin and DNase

- History or presence of autoimmune disease requiring systemic immunosuppression
(including but not limited to: inflammatory bowel disease, systemic lupus
erythematosus, vasculitis, rheumatoid arthritis, scleroderma, multiple sclerosis,
hemolytic anemia, Sjögren syndrome, and sarcoidosis)

- Other concurrent malignancies, with the exception of non-melanoma skin cancers and
superficial bladder cancer

- Uncontrolled major active infectious, cardiovascular, pulmonary, hematologic, or
psychiatric illnesses that would make the patient a poor study candidate

- Known prior or current history of HIV and/or hepatitis B/C

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Safety Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Intraprostatic CD8+ T cell infiltration

Outcome Description:

To quantify the extent of CD8+ T cell infiltration into the prostate from harvested prostate glands in men with localized prostate cancer receiving neoadjuvant ADT alone (2 weeks prior to surgery), or cyclophosphamide and GVAX followed by ADT, (with CY/GVAX administered 4 weeks prior to prostatectomy, and ADT administered 2 weeks prior to prostatectomy).

Outcome Time Frame:

2 years

Safety Issue:


Principal Investigator

Emmanual Antonarakis, M.D

Investigator Role:

Principal Investigator

Investigator Affiliation:

Johns Hopkins University


United States: Food and Drug Administration

Study ID:




Start Date:

September 2012

Completion Date:

October 2015

Related Keywords:

  • Prostate Cancer Adenocarcinoma in Situ
  • Adenocarcinoma
  • Adenocarcinoma, Mucinous
  • Prostatic Neoplasms
  • Carcinoma in Situ



The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Baltimore, Maryland  21231