A Neoadjuvant Study of Androgen Ablation Combined With Cyclophosphamide and GVAX Vaccine for Localized Prostate Cancer

This study is currently recruiting participants. (see Contacts and Locations)
Verified May 2014 by Sidney Kimmel Comprehensive Cancer Center
Sponsor:
Information provided by (Responsible Party):
Sidney Kimmel Comprehensive Cancer Center
ClinicalTrials.gov Identifier:
NCT01696877
First received: September 14, 2012
Last updated: May 6, 2014
Last verified: May 2014
  Purpose

This research is being done to see if an investigational prostate cancer vaccine, called GVAX, can safely be given together with a single intravenous injection of a drug called cyclophosphamide to men that will undergo surgery to remove their cancerous prostate glands who have also received standard hormonal therapy.


Condition Intervention Phase
Prostate Cancer Adenocarcinoma in Situ
Drug: degarelix acetate
Drug: Cyclophosphamide
Drug: GVAX
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:


Further study details as provided by Sidney Kimmel Comprehensive Cancer Center:

Primary Outcome Measures:
  • Intraprostatic CD8+ T cell infiltration [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
    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).

  • Number of participants with adverse events [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
    To evaluate the safety and tolerability of ADT following vaccination with cyclophosphamide and GVAX 4 weeks prior to radical prostatectomy


Secondary Outcome Measures:
  • Intraprostatic CD4+ T cell and Treg infiltration [ Time Frame: 2 years ] [ Designated as safety issue: No ]
    To quantify the extent of CD4+ T cell and Treg infiltration into the prostate, and to quantify the CD8+/Treg ratio as well as the CD4+/Treg ratio in prostate specimens

  • Quantification of tissue androgen concentrations [ Time Frame: 2 years ] [ Designated as safety issue: No ]
    To quantify tissue androgen concentrations (testosterone, dihydrotestosterone), and to quantify androgen receptor (AR) protein expression in prostate specimens

  • Quantification of markers of apoptosis [ Time Frame: 2 years ] [ Designated as safety issue: No ]
    To quantify markers of apoptosis (activated caspase 3) and proliferation (Ki-67) in prostate tumor specimens

  • Pathological complete responses [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
    To evaluate the proportion of pathological complete responses (pCR)

  • Serum antibodies to prostate-associated antigens [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
    To evaluate the generation of novel antibodies to prostate-associated antigens in the serum of patients, after the initiation of protocol therapy

  • PSA response rate and time-to-PSA-recurrence [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
    To determine the PSA response rate and time-to-PSA-recurrence after radical prostatectomy


Estimated Enrollment: 32
Study Start Date: September 2012
Estimated Study Completion Date: October 2015
Estimated Primary Completion Date: October 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Arm A
In Arm A, an identical dose of degarelix acetate will be administered 14 (±3) days prior to surgery. A telephone follow-up interview (or an in-person clinic visit) to evaluate for adverse events will occur 28 (±21) days after prostatectomy. Patients will then be followed by their urologists according to standard institutional practices, but will require PSA evaluations every 3 (±1) months during year 1 and every 6 (±2) months during years 2-3.
Drug: degarelix acetate
Degarelix Acetate is a gonadotropin-releasing hormone (GnRH) receptor antagonist. It works by decreasing the amount of testosterone in the body,which the tumor needs to grow.
Other Name: Firmagon
Experimental: Arm B
In Arm B, Cyclophosphamide will be given at a dose of 200 mg/m2 as a single intravenous infusion. 1 day later, prostate GVAX will be administered as five 0.8-mL intradermal injections of PC3 (2.5 × 108 cells) and five 0.5-mL intradermal injections of LNCaP (2.5 × 108 cells), for a total dose of 5 × 108 cells. On day 14, Degarelix acetate will be administered as three 80 mg subcutaneous injections, for a total dose of 240 mg. Prostate glands will be harvested 14 (±3) days later, at the time of radical prostatectomy, and prostate tissue will be examined for the primary endpoint.
Drug: degarelix acetate
Degarelix Acetate is a gonadotropin-releasing hormone (GnRH) receptor antagonist. It works by decreasing the amount of testosterone in the body,which the tumor needs to grow.
Other Name: Firmagon
Drug: Cyclophosphamide
Cyclophosphamide as a potent enhancer of immune responses to GVAX. cyclophosphamide is used as an immune suppressor in many autoimmune disorders.
Other Names:
  • Cytoxan
  • Neosar
Drug: GVAX
GVAX is GM-CSF-secreting allogeneic cell-based vaccine as immunotherapy for prostate cancer
Other Name: GM-CSF-secreting cell-based (PC3/LNCaP)immunotherapy

Detailed Description:

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 cancers.

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.

  Eligibility

Ages Eligible for Study:   21 Years and older
Genders Eligible for Study:   Male
Accepts Healthy Volunteers:   No
Criteria

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
  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: NCT01696877

Contacts
Contact: Robin T Gurganus, RN 410-614-6926 rgurganus@jhmi.edu
Contact: Avery S Spitz, RN 410-502-2043 aspitz2@jhmi.edu

Locations
United States, Maryland
The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Recruiting
Baltimore, Maryland, United States, 21231
Contact: Emmanuel Antonarakis, MD    443-287-0553    eantona1@jhmi.edu   
Contact: Charles Drake, MD, PHD    410-614-3616    drakech@jhmi.edu   
Principal Investigator: Emmanuel Antonarakis, MD         
Sponsors and Collaborators
Sidney Kimmel Comprehensive Cancer Center
Investigators
Principal Investigator: Emmanual Antonarakis, M.D Johns Hopkins University
  More Information

No publications provided

Responsible Party: Sidney Kimmel Comprehensive Cancer Center
ClinicalTrials.gov Identifier: NCT01696877     History of Changes
Other Study ID Numbers: J1265, NA_00073453
Study First Received: September 14, 2012
Last Updated: May 6, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Adenocarcinoma
Prostatic Neoplasms
Carcinoma in Situ
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Genital Neoplasms, Male
Urogenital Neoplasms
Neoplasms by Site
Genital Diseases, Male
Prostatic Diseases
Androgens
Cyclophosphamide
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Pharmacologic Actions
Immunosuppressive Agents
Immunologic Factors
Antirheumatic Agents
Therapeutic Uses
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists

ClinicalTrials.gov processed this record on July 28, 2014