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

March 18, 2019 updated by: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

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

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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 (granulocytemacrophage-colony stimulating factor). The release of granulocytemacrophage-colony stimulating factor 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 granulocytemacrophage-colony stimulating factor-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 granulocytemacrophage-colony stimulating factor-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.

Study Type

Interventional

Enrollment (Actual)

29

Phase

  • Phase 2
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

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

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

19 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

Male

Description

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
  • Eastern Cooperative Oncology Group performance status 0-1, or Karnofsky score ≥ 70%

  • Adequate bone marrow, hepatic, and renal function:

    • White Blood Count > 3,000 cells/mm3
    • Absolute neutrophil count > 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
    • Alanine aminotransferase < 2 × upper limit of normal (ULN)
    • Aspartate aminotransferase < 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 Chronic obstructive pulmonary disease are permitted)
  • Use of experimental agents for prostate cancer within the past 3 months
  • Known allergy to cyclophosphamide or G-colony stimulating factor /granulocytemacrophage-colony stimulating factor
  • Known hypersensitivity to materials of bovine origin (e.g. fetal bovine serum), or other components of GVAX which include Dimethyl sulfoxide 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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Degarelix
Degarelix will be administered as three 80 mg subcutaneous injections, for a total dose of 240 mg at 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 prostate-specific antigen 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 Names:
  • Firmagon
Experimental: Cyclophosphamide, GVAX and Degarelix
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 will be administered as three 80 mg subcutaneous injections, for a total dose of 240 mg.
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 Names:
  • 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 granulocytemacrophage -colony stimulating factor -secreting allogeneic cell-based vaccine as immunotherapy for prostate cancer
Other Names:
  • granulocytemacrophage -colony stimulating factor -secreting cell-based (PC3/LNCaP)immunotherapy

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Intraprostatic CD8+ T Cell Infiltration
Time Frame: 2 years
CD8+ T cell infiltration (quantified as log[CD8 density]) into the prostate from harvested prostate glands in men with localized prostate cancer receiving neoadjuvant Androgen deprivation therapy alone (2 weeks prior to surgery), or cyclophosphamide and GVAX followed by Androgen deprivation therapy, (with cyclophosphamide/GVAX administered 4 weeks prior to prostatectomy, and Androgen deprivation therapy administered 2 weeks prior to prostatectomy).
2 years

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Intraprostatic CD4+ T Cell and Treg Infiltration
Time Frame: 2 years
Number of participants with CD4+ T cell and Treg infiltration into the prostate.
2 years
Quantification of Tissue Androgen Concentrations
Time Frame: 2 years
Tissue androgen concentrations (testosterone, dihydrotestosterone), and androgen receptor (AR) protein expression in prostate specimens
2 years
Quantification of Markers of Apoptosis
Time Frame: 2 years
Amount of apoptosis (activated caspase 3) and proliferation (Ki-67) in prostate tumor specimens
2 years
Pathological Complete Responses
Time Frame: 2 years
Number of participants with pathological complete response (pCR)
2 years
Serum Antibodies to Prostate-associated Antigens
Time Frame: 2 years
Number of participants with generation of novel antibodies to prostate-associated antigens in the serum of patients, after the initiation of protocol therapy
2 years
Prostate-specific Antigen Response Rate
Time Frame: 2 years
Number of participants with Prostate-specific antigen response
2 years
Percentage of Participants Without Prostate Specific Antigen Recurrence at 24 Months After Surgery
Time Frame: 2 years
Percentage of participants in each arm who were free of prostate specific antigen recurrence (i.e. prostate specific antigen remained undetectable after prostatectomy) at 24 months after undergoing surgery.
2 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Collaborators

BioSante Pharmaceuticals
David H. Koch Charitable Foundation

Investigators

  • Principal Investigator: Emmanual Antonarakis, M.D, Johns Hopkins University

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

January 18, 2013

Primary Completion (Actual)

August 1, 2017

Study Completion (Actual)

December 18, 2018

Study Registration Dates

First Submitted

September 14, 2012

First Submitted That Met QC Criteria

September 27, 2012

First Posted (Estimate)

October 1, 2012

Study Record Updates

Last Update Posted (Actual)

March 28, 2019

Last Update Submitted That Met QC Criteria

March 18, 2019

Last Verified

March 1, 2019

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • J1265
  • NA_00073453 (Other Identifier: JHMIRB)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on Prostate Cancer Adenocarcinoma in Situ

Clinical Trials on degarelix acetate

Search Similar Trials

Sponsors and Collaborators

Medical Conditions

Drug Interventions

CROs by country

CROs in Poland

Conditions

Rare Diseases

Drug Interventions

Dietary Supplements

Sponsor/Collaborators

Locations

3
Subscribe