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

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



Sponsors


Source

Sidney Kimmel Comprehensive Cancer Center

Oversight Info

Authority

United States: Food and Drug Administration

Has Dmc

Yes


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 (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.

Overall Status

Recruiting

Start Date

2012-09-01

Completion Date

2015-10-01

Primary Completion Date

2015-10-01

Phase

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

Primary Outcome

Measure

Time Frame

Safety Issue

Intraprostatic CD8+ T cell infiltration
2 years
Yes
Number of participants with adverse events
2 years
Yes

Secondary Outcome

Measure

Time Frame

Safety Issue

Intraprostatic CD4+ T cell and Treg infiltration
2 years
No
Quantification of tissue androgen concentrations
2 years
No
Quantification of markers of apoptosis
2 years
No
Pathological complete responses
2 years
Yes
Serum antibodies to prostate-associated antigens
2 years
Yes
PSA response rate and time-to-PSA-recurrence
2 years
Yes

Enrollment

32

Condition


Intervention

Intervention Type

Drug

Intervention Name


Description

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.

Arm Group Label

Arm A


Intervention Type

Drug

Intervention Name


Description

GVAX is GM-CSF-secreting allogeneic cell-based vaccine as immunotherapy for prostate cancer
Cyclophosphamide as a potent enhancer of immune responses to GVAX. cyclophosphamide is used as an immune suppressor in many autoimmune disorders.

Arm Group Label

Arm B



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

- 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

Gender

Male

Minimum Age

21 Years

Maximum Age

N/A

Healthy Volunteers

No


Overall Contact

Last Name

Robin T Gurganus, RN

Phone

410-614-6926

Email

rgurganus@jhmi.edu


Location

Facility

Status

Contact

Investigator

The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Baltimore Maryland 21231 United States
Recruiting
Last Name: Emmanuel Antonarakis, MD
Phone: 443-287-0553
Email: eantona1@jhmi.edu
Last Name: Emmanuel Antonarakis, MD
Role: Principal Investigator

Location Countries

Country

United States


Verification Date

2012-11-01

Lastchanged Date

2012-11-15

Firstreceived Date

2012-09-14

Responsible Party

Responsible Party Type

Sponsor


Is Fda Regulated

Yes

Has Expanded Access

No

Condition Browse


Secondary Id

NA_00073453

Number Of Arms

2

Intervention Browse

Mesh Term

Androgens

Cyclophosphamide



Is Section 801

Yes

Arm Group

Arm Group Label

Arm A

Arm Group Type

Active Comparator

Description

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.


Arm Group Label

Arm B

Arm Group Type

Experimental

Description

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.



Firstreceived Results Date

N/A

Overall Contact Backup

Last Name

Avery S Spitz, RN

Phone

410-502-2043

Email

aspitz2@jhmi.edu



Information obtained from ClinicalTrials.gov on January 22, 2013

Conditions

Conditions usually refer to a disease, disorder, syndrome, illness, or injury. In ClinicalTrials.gov, conditions include any health issue worth studying, such as lifespan, quality of life, health risks, etc.
Interventions

Interventions refer to the drug, vaccine, procedure, device, or other potential treatment being studied. Interventions can also include less intrusive possibilities such as surveys, education, and interviews.
Study Phase

Most clinical trials are designated as phase 1, 2, 3, or 4, based on the type of questions that study is seeking to answer:

In Phase 1 (Phase I) clinical trials, researchers test a new drug or treatment in a small group of people (20-80) for the first time to evaluate its safety, determine a safe dosage range, and identify side effects.

In Phase 2 (Phase II) clinical trials, the study drug or treatment is given to a larger group of people (100-300) to see if it is effective and to further evaluate its safety.

In Phase 3 (Phase III) clinical trials, the study drug or treatment is given to large groups of people (1,000-3,000) to confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow the drug or treatment to be used safely.

In Phase 4 (Phase IV) clinical trials, post marketing studies delineate additional information including the drug's risks, benefits, and optimal use.

These phases are defined by the Food and Drug Administration in the Code of Federal Regulations.



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