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

Sponsor

Amsterdam UMC, location VUmc (Other)

Overall Status

Terminated

CT.gov ID

NCT01510288

Collaborator

Cell Genesys (Industry), Medarex (Industry)

Enrollment

Location

Arm

Duration (Months)

0.3

Patients Per Site Per Month

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
Prostate Cancer	Drug: GVAX and ipilimumab	Phase 1

Detailed 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.

Study Design

Study Type:

Interventional

Actual Enrollment :

28 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Study Start Date :

Nov 1, 2004

Actual Primary Completion Date :

Dec 1, 2007

Actual Study Completion Date :

Nov 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Ipilimumab and GVAX	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.

Arm

Intervention/Treatment

Experimental: Ipilimumab and GVAX

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.

Outcome Measures

Primary Outcome Measures

Number of patients with adverse events [7 months]

Secondary Outcome Measures

number of patients that have a tumor/PSA response [7 months]
number of patients that will develop a tumor-specific (e.g. PSMA, NY-ESO) antibody response as measured by ELISA [7 months]
the number of patients that have activated T cells and dendritic cells as measured by FACS [7 months]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 80 Years

Sexes Eligible for Study:

Male

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	VU university medical center	Amsterdam		Netherlands	1081 HV

Sponsors and Collaborators

Amsterdam UMC, location VUmc
Cell Genesys
Medarex

Investigators

Principal Investigator: Winald Gerritsen, Prof. MD PhD, Amsterdam UMC, location VUmc
Principal Investigator: Fons van den Eertwegh, MD PhD, Amsterdam UMC, location VUmc