Phase 1 Trial of Ipilimumab and GVAX in Patients With Metastatic Castration-resistant Prostate Cancer

Prostate Cancer Clinical Trial

Official title:

A Phase 1 Dose Escalation Trial of Ipilimumab in Combination With CG1940 and CG8711 in Patients With Metastatic Hormone-Refractory Prostate Cancer

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01510288
• Other study ID #: G-0016
• Status: Terminated
• Phase: Phase 1
• First received: January 4, 2012
• Last updated: January 10, 2012
• Start date: November 2004
• Est. completion date: November 2011

Study information

• Verified date: January 2012
• Source: VU University Medical Center
• Contact: n/a
• Is FDA regulated: No
• Health authority: Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)
• Study type: Interventional

Clinical Trial Summary

Ipilimumab, an antibody that blocks cytotoxic T-lymphocyte antigen 4, and GVAX have demonstrated anti-tumor activity in prostate cancer. Pre-clinical studies with this combination have demonstrated potent synergy. The purpose of this study is to investigate, using a phase-I 3+3 dose escalation design followed by an expansion cohort, the safety and efficacy of combined treatment with GVAX and ipilimumab in castration-resistant metastatic prostate cancer (CRPC) patients.

Description:

A promising immunotherapeutic approach in prostate cancer is whole-cell vaccination. Irradiated allogeneic tumor cells expressing GM-CSF generate a long-lasting and specific anti-tumor immunity in preclinical models. Results from several phase I and II trials showed Prostate GVAX (GVAX) to be well tolerated and suggested improved survival. Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) is a crucial immune checkpoint molecule that down-regulates T-cell activation and proliferation. Ipilimumab, a fully human monoclonal antibody (IgG1) that blocks CTLA-4, promotes antitumor immunity, and has been demonstrated in two phase III trials to improve overall survival in metastatic melanoma patients. Pre-clinical studies of the anti-CTLA-4 antibody in combination with GM-CSF secreting tumor cell vaccines demonstrated a potent synergy. In this phase I study the investigators examine in CRPC patients whether ipilimumab can be safely combined with GVAX. In addition, the investigators will treat an additional 16 patients at a dose level of 3•0 mg/kg to determine the safety profile and antitumor effects of GVAX and ipilimumab in patients with CRPC.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 28
• Est. completion date: November 2011
• Est. primary completion date: December 2007
• Accepts healthy volunteers: No
• Gender: Male
• Age group: 18 Years to 80 Years

Eligibility

Inclusion Criteria:

• Males age 18-80 years

• Histologic diagnosis of adenocarcinoma of the prostate

• Metastatic prostate cancer deemed to be unresponsive or refractory to hormone therapy

• Detectable metastases by bone scan, CT scan or MRI

• Two consecutive rising PSA values obtained at least two weeks apart and both obtained at least 4-6 weeks after discontinuation of hormone therapy. Second PSA value must be > 5.0 ng/mL. LHRH agonist should not be discontinued.

• Testosterone < 50 ng/dL. Must have had orchiectomy or is currently receiving an LHRH agonist.

• WBC > 3.0 x 109/L, ANC > 1.5 x 109/L, hemoglobin > 6.2 mmol/L, and platelets > 100 x 109/L

• Serum creatinine < 177 umol/L Bilirubin < 1.5 times the upper limit of normal AST < 3 times the upper limit of normal

• ECOG performance status 0-2

• Life expectancy of at least 6 months

• If sexually active, willing to use barrier contraception during the treatment phase of the protocol

• The ability to understand and willingness to sign a written informed consent

Exclusion Criteria:

• Transitional cell, small cell, neuroendocrine, or squamous cell prostate cancer

• Bone pain severe enough to require routine narcotic analgesia use

• Clinical evidence of brain metastases or history of brain metastases

• Seropositive for HIV, Hepatitis B antigen positive and/or Hepatitis C viremic

• Prior chemotherapy or immunotherapy for prostate cancer

• Radiation therapy within 4 weeks of the first treatment

• Surgery within 4 weeks of the first treatment. Must have recovered from all side effects.

• Flutamide within 4 weeks of the first treatment Megesterol acetate (Megace), finasteride (Proscar), bicalutamide (Casodex),nilutamide, aminoglutethimide, ketoconazole or diethylstilbestrol within 6 weeks of the first treatment.

• Systemic corticosteroid use within 4 weeks of the first treatment

• History of autoimmune disease

• History of another malignancy, except for the following: adequately treated basal cell or squamous cell skin cancer, superficial bladder cancer, adequately treated Stage I or II cancer currently in complete remission or any other cancer that has been in complete remission for at least 5 years

Study Design

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Prostate Cancer
• Prostatic Neoplasms

Intervention

Drug:
• GVAX and ipilimumab
All patients receive a 500 million cell priming dose of granulocyte-macrophage colony-stimulating factor-transduced allogeneic prostate cancer cells (GVAX) intradermally on day 1 followed by bi-weekly intradermal injections of 300 million cells for a 24 week period. The vaccinations are combined with monthly intravenous administrations of ipilimumab. The dose-escalation part of this study will be performed using the standard 3+3 phase-I trial design. Patients will be enrolled in cohorts of three; each cohort will receive an escalating dose of ipilimumab at 0•3, 1•0, 3•0 or 5•0 mg/kg. Sixteen patients will be treated in an expansion cohort with GVAX and 3•0 mg/kg ipilimumab.

Locations

Country	Name	City	State
Netherlands	VU university medical center	Amsterdam

Sponsors (3)

Lead Sponsor	Collaborator
VU University Medical Center	Cell Genesys, Medarex

Country where clinical trial is conducted

Netherlands, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of patients with adverse events		7 months	Yes
Secondary	number of patients that have a tumor/PSA response		7 months	No
Secondary	number of patients that will develop a tumor-specific (e.g. PSMA, NY-ESO) antibody response as measured by ELISA		7 months	No
Secondary	the number of patients that have activated T cells and dendritic cells as measured by FACS		7 months	No