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

Study Status: Active, not recruiting
Recruit Status: Active, not recruiting
Study Type: Interventional

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 Prosta

Brief Summary: 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.

Detailed Summary:

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
Sponsor: Sidney Kimmel Comprehensive Cancer Center

Current Primary Outcome:

• Intraprostatic CD8+ T cell infiltration [ Time Frame: 2 years ]
  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 ]
  To evaluate the safety and tolerability of ADT following vaccination with cyclophosphamide and GVAX 4 weeks prior to radical prostatectomy

Original Primary Outcome: Same as current

Current Secondary Outcome:

• Intraprostatic CD4+ T cell and Treg infiltration [ Time Frame: 2 years ]
  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 ]
  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 ]
  To quantify markers of apoptosis (activated caspase 3) and proliferation (Ki-67) in prostate tumor specimens
• Pathological complete responses [ Time Frame: 2 years ]
  To evaluate the proportion of pathological complete responses (pCR)
• Serum antibodies to prostate-associated antigens [ Time Frame: 2 years ]
  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 ]
  To determine the PSA response rate and time-to-PSA-recurrence after radical prostatectomy

Original Secondary Outcome: Same as current

Information By: Sidney Kimmel Comprehensive Cancer Center

Dates:
Date Received: September 14, 2012
Date Started: September 2012
Date Completion: April 2018
Last Updated: December 28, 2016
Last Verified: December 2016