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

NCT ID: NCT01696877

Last Updated: 2019-03-28

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 29 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-01-18
• Study Completion Date: 2018-12-18

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 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.

Conditions

Prostate Cancer Adenocarcinoma in Situ

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: ACTIVE_COMPARATOR

degarelix acetate

Intervention Type: DRUG

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.

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.

Group Type: EXPERIMENTAL

degarelix acetate

Intervention Type: DRUG

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.

Cyclophosphamide

Intervention Type: DRUG

Cyclophosphamide as a potent enhancer of immune responses to GVAX. cyclophosphamide is used as an immune suppressor in many autoimmune disorders.

GVAX

Intervention Type: DRUG

GVAX is granulocytemacrophage -colony stimulating factor -secreting allogeneic cell-based vaccine as immunotherapy for prostate cancer

Interventions

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.

Intervention Type: DRUG

Cyclophosphamide

Cyclophosphamide as a potent enhancer of immune responses to GVAX. cyclophosphamide is used as an immune suppressor in many autoimmune disorders.

Intervention Type: DRUG

GVAX

GVAX is granulocytemacrophage -colony stimulating factor -secreting allogeneic cell-based vaccine as immunotherapy for prostate cancer

Intervention Type: DRUG

Other Intervention Names

Firmagon; Cytoxan; Neosar; granulocytemacrophage -colony stimulating factor -secreting cell-based (PC3/LNCaP)immunotherapy

Eligibility 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
• 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

• Minimum Eligible Age: 21 Years
• Eligible Sex: MALE
• Accepts Healthy Volunteers: No

Sponsors

David H. Koch Charitable Foundation

UNKNOWN

Sponsor Role: collaborator

BioSante Pharmaceuticals

INDUSTRY

Sponsor Role: collaborator

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Emmanual Antonarakis, M.D

Role: PRINCIPAL_INVESTIGATOR

Johns Hopkins University

Locations

The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Baltimore, Maryland, United States

Countries

United States

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

NA_00073453

Identifier Type: OTHER

Identifier Source: secondary_id

J1265

Identifier Type: -

Identifier Source: org_study_id