Prostate Cancer
Conditions
Brief summary
The purpose of this study is to assess the safety and activity of a type of vaccine as immune therapy for prostate cancer. This vaccine will be made for each participant's own immune cells (called dendritic cells) obtained by blood donation. Dendritic cells are immune cells, whose role is to identify foreign antigens (bacteria, viruses, or tumor cells, for example) in the body and to activate other cells of the immune system to mount an attack on that foreign antigen. Each participant will be randomized into either Arm 1 (experimental treatment only) or Arm 2 (placebo first, then the experimental treatment). Participants will be given the vaccine and three boosters as an injection. After the placebo phase, each participant in Arm 2 will crossover to the treatment phase so that all participants will eventually receive the experimental treatment.
Detailed description
This is a Phase I/II dendritic cell vaccine study for patients with prostate cancer. Our laboratory has demonstrated that effective tumor immunity in humans is associated with, and likely mediated at least in part by tumor antigen-specific killer T cells (Albert et al., 1998a; Darnell, 1999; Darnell and Posner, 2003). Moreover, we have demonstrated that apoptotic material derived from dying tumor cells are a potent means of delivering antigen to DCs and subsequently triggering tumor antigen-specific T cell responses ex vivo (Albert et al., 1998a; Albert et al., 1998c). In this study, patients with 3 consecutive rises in PSA measured at least 2 week apart, after definite local therapy (prostatectomy or radiation) will be recruited. Peripheral blood monocytes will be collected by leukapheresis and dendritic cells will be generated in the Cleanroom in the Laboratory of Molecular Neuro-Oncology. These dendritic cells will be pulsed with apoptotic prostate cancer cells from a cell line (LNCaP), harvested, tested for certain release criteria, and then injected as vaccine. When patients are found to be eligible for the study, they will be randomized into either the experimental group or the placebo group for the purposes of comparing adverse events between groups only. Vaccine plus 3 boosters (or placebo) will be given, each two weeks apart. After the third booster, patients will be unblinded. Those receiving the vaccine will when enter the follow up phase which includes a post treatment leukapheresis. Those in the placebo group will cross over and receive the vaccine and boosters. The primary outcomes to be evaluated are toxicity and activity. Patients will be evaluated for both local and systemic toxicity. For activity, we measure both immunological and clinical responses to the vaccine, comparing measures taken before and after vaccination, combining patients in both arms.
Interventions
BIOLOGICALvaccine vehicle only
Subcutaneous injection of vaccine vehicle only (5% DMSO in normal saline), followed by cross-over to Arm 1 design.
BIOLOGICALDC/LNCaP
Subcutaneous injection of DC/LNCaP, DC/LNCaP-M1, DC/KLH
Sponsors
Rockefeller University
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Disease Characteristics * Histologically confirmed prostate carcinoma * Progressive, disease required, i.e.: elevated PSA documented to be rising on 3 occasions, either despite castrate testosterone levels (below 50 ng/dl), or after definitive local therapy (prostatectomy or radiation). Prior/Concurrent Therapy -Biologic therapy: * Recovered from toxicity of any prior therapy -Chemotherapy: * At least 4 weeks since chemotherapy -Endocrine evaluation/therapy * 3 rising PSA values at least 2 weeks apart * At least 2 weeks since concurrent corticosteroids (other than for replacement therapy for adrenal insufficiency) * Medical hormonal therapy to maintain castrate testosterone levels permitted -Radiotherapy: * At least 4 weeks since radiotherapy -Surgery: * Prior surgery allowed Patient Characteristics * Age: 18 and over, able to give written informed consent. Individuals unable to provide informed consent must have consent provided by the legal guardian, or person designated by the subject to give consent on his behalf. * Performance status: Karnofsky 70-100% * Life expectancy: At least 1 year * Hematopoietic: obtained twice, once within 45 days prior to study entry, and again within 72 hours of study entry. * WBC greater than 3,800 * Absolute neutrophils greater than 1,500 * Absolute lymphocytes greater than 500 * Platelets greater than 120,000 * Hb at least 10 g/dl * Hepatic: --Bilirubin less than 2.0 mg/dl OR --SGOT less than 2 x ULN * Renal: * Creatinine no greater than 2.0 mg/dl OR * Creatinine clearance at least 40 ml/min * Rheumatologic: --ANA no greater than upper limit of normal, or ANA abnormal in absence of clinical signs of autoimmunity. * Rheumatoid factor (RF) no greater than upper limit of normal, or RF abnormal in absence of clinical signs of autoimmunity. * Anti-ds DNA no greater than upper limit of normal, or anti ds DNA abnormal in absence of clinical signs of autoimmunity. * Immunologic: * Influenza serology (assessment made at time of screening). * Assessment of DTH response to a standard anergy panel (to include candida, trichophyton and tetanus) or to a Multitest CMI (a disposable kit for DTH testing with standardized preloaded antigens). * Endocrine: --TSH, T3, and T4 no greater than upper limit of normal * Radiographic: * Baseline bone scan * Baseline CT or MRI of abdomen and pelvis
Exclusion criteria
Disease Characteristics -No active CNS metastases Prior/Concurrent Therapy * Biologic therapy: * No prior autologous or allogeneic tumor vaccines * No concurrent other immunotherapy * Chemotherapy --Not previously treated with more than 2 chemotherapy regimens * No concurrent chemotherapy * Radiotherapy --No concurrent radiotherapy Patient Characteristics -Cardiovascular: No NYHA class III/IV status No active angina, clinically significant cardiac arrythmia, recent (6 months) myocardial infarction * Pulmonary: --No severe debilitating pulmonary disease * Other: * No active infection requiring antibiotics * No active pain requiring chronic opioid analgesics. * Not HIV, hepatitis B or hepatitis C virus positive; anti-HIV, HbsAg and Hep C antibody negative * No history of hypersensitivity to vaccine components * No serious uncontrolled medical illness * No currently active second malignancy other than non-melanoma skin cancer (note: a patient is NOT considered to have currently active malignancy if they have completed therapy and are now considered by their physician to be at less than 30% risk for relapse) * No history of total lymph node irradiation * No history of vasculitis, including but not limited to systemic necrotizing vasculitides (polyarteritis nodosa group), hypersensitivity vasculitis, Wegener's granulomatosis. * No history of autoimmune disease. * No use of hydroxyurea within 45 days of study entry * No receipt of immune modulators or suppressors within 30 days prior to study entry, including but not limited to interferons and thalidomide. No active requirement for corticosteroids; prior use is acceptable. * No psychiatric illness or social condition that, in the opinion of the investigator, would interfere with adherence to study requirements. * No alcohol or drug use or dependence that, in the opinion of the investigator, would interfere with adherence to study requirements.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Adverse Event | End of blinded phase (wk 9) | Occurrence of adverse events (AE) was compared between the placebo and vaccine groups during the blinded phase (the 1st 9 weeks). At the end of this phase, all were unblinded, and those who received placebo crossed over to now receive vaccine. All serious AEs and any other AEs that occurred 5 times or more are reported. The exact binomial test was used to compare the occurrence of each AE between groups. |
| Immunogenicity of the DC/LNCaP Vaccine. Pre- vs Post-vaccination Bulk T Cell Proliferation (3H Thymidine Incorporation) by Type of Antigen. The Number Indicated is the Median Difference of Post-Pre, of Each Antigen Group. | pre- vs post-vaccination. Pre-vaccination T cells were collected at Wk 0 and post-vaccination T cells were collected at Wk 13 | The difference between post minus pre-vaccination bulk T cell proliferation was calculated for each antigen. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in PSA Slope, Pre- vs Post-vaccination. | pre- vs post- vaccination PSA slopes. | To model the evolution of PSA (in log-scale) during the three study phases (pre-vaccine, vaccine, and post-vaccine phases), a mixed linear spline model was used. Two knots (one at the start of the vaccine phase and the other at the start of the post-vaccine phase) were used to directly quantify the differences in slopes between each phase. To account for the heterogeneous treatment effect and the repeated measures structure, random effects are incorporated into the model. For the general model, random effects for the intercept, slope and the first knot were considered. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Dendritic Cells Pulsed With LNCaP (DC/LNCaP) 12 patients, receiving DC/LNCaP vaccine and the DC/LNCaP-M1 and DC/KLH immunizations over 8 weeks. THE PURPOSE OF THESE 2 ARMS IS TO COMPARE ADVERSE EVENTS (AEs) DURING THE 1ST 8 WKS ONLY. | 12 |
| Placebo | 12 |
| Total | 24 |
Baseline characteristics
| Characteristic | Placebo | Dendritic Cells Pulsed With LNCaP (DC/LNCaP) | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 6 Participants | 5 Participants | 11 Participants |
| Age, Categorical Between 18 and 65 years | 6 Participants | 7 Participants | 13 Participants |
| Age Continuous | 65.7 years STANDARD_DEVIATION 9.2 | 62.5 years STANDARD_DEVIATION 6.7 | 64.0 years STANDARD_DEVIATION 7.9 |
| Region of Enrollment United States | 12 participants | 12 participants | 24 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 12 Participants | 12 Participants | 24 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 12 / 12 | 12 / 12 | 12 / 12 | 22 / 24 |
| serious Total, serious adverse events | 0 / 12 | 1 / 12 | 0 / 12 | 1 / 24 |
Outcome results
Primary
Adverse Event
Occurrence of adverse events (AE) was compared between the placebo and vaccine groups during the blinded phase (the 1st 9 weeks). At the end of this phase, all were unblinded, and those who received placebo crossed over to now receive vaccine. All serious AEs and any other AEs that occurred 5 times or more are reported. The exact binomial test was used to compare the occurrence of each AE between groups.
Time frame: End of blinded phase (wk 9)
Population: All AEs occurring 5 or more times during the study were analyzed. All AEs reported are grade 1 except as noted.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Dendritic Cells Pulsed With LNCaP (DC/LNCaP) | Adverse Event | albumin, serum, low | 0 Adverse Events |
| Dendritic Cells Pulsed With LNCaP (DC/LNCaP) | Adverse Event | albumin, urine, high | 2 Adverse Events |
| Dendritic Cells Pulsed With LNCaP (DC/LNCaP) | Adverse Event | BUN, serum, high | 4 Adverse Events |
| Dendritic Cells Pulsed With LNCaP (DC/LNCaP) | Adverse Event | chloride, serum, high | 1 Adverse Events |
| Dendritic Cells Pulsed With LNCaP (DC/LNCaP) | Adverse Event | potassium, serum, high | 0 Adverse Events |
| Dendritic Cells Pulsed With LNCaP (DC/LNCaP) | Adverse Event | potassium, serum, high (grade 2) | 0 Adverse Events |
| Dendritic Cells Pulsed With LNCaP (DC/LNCaP) | Adverse Event | rash | 2 Adverse Events |
| Dendritic Cells Pulsed With LNCaP (DC/LNCaP) | Adverse Event | URI | 3 Adverse Events |
| Dendritic Cells Pulsed With LNCaP (DC/LNCaP) | Adverse Event | glucose, serum, high, non-fasting | 6 Adverse Events |
| Dendritic Cells Pulsed With LNCaP (DC/LNCaP) | Adverse Event | ketones, urine, high | 1 Adverse Events |
| Dendritic Cells Pulsed With LNCaP (DC/LNCaP) | Adverse Event | injection site reaction | 22 Adverse Events |
| Dendritic Cells Pulsed With LNCaP (DC/LNCaP) | Adverse Event | injection site reaction (grade 2) | 4 Adverse Events |
| Dendritic Cells Pulsed With LNCaP (DC/LNCaP) | Adverse Event | ALT, serum, high | 3 Adverse Events |
| Dendritic Cells Pulsed With LNCaP (DC/LNCaP) | Adverse Event | ANA, high | 1 Adverse Events |
| Dendritic Cells Pulsed With LNCaP (DC/LNCaP) | Adverse Event | CO2 serum, low | 3 Adverse Events |
| Dendritic Cells Pulsed With LNCaP (DC/LNCaP) | Adverse Event | creatinine, serum, high | 3 Adverse Events |
| Dendritic Cells Pulsed With LNCaP (DC/LNCaP) | Adverse Event | diarrhea/loose stools | 5 Adverse Events |
| Dendritic Cells Pulsed With LNCaP (DC/LNCaP) | Adverse Event | edema, lower extremities | 0 Adverse Events |
| Dendritic Cells Pulsed With LNCaP (DC/LNCaP) | Adverse Event | eosinophils, high | 1 Adverse Events |
| Dendritic Cells Pulsed With LNCaP (DC/LNCaP) | Adverse Event | fatigue | 6 Adverse Events |
| Dendritic Cells Pulsed With LNCaP (DC/LNCaP) | Adverse Event | Hospitalization: cardioversion/atrial fibrillation | 1 Adverse Events |
| Placebo | Adverse Event | creatinine, serum, high | 1 Adverse Events |
| Placebo | Adverse Event | injection site reaction (grade 2) | 0 Adverse Events |
| Placebo | Adverse Event | albumin, urine, high | 3 Adverse Events |
| Placebo | Adverse Event | albumin, serum, low | 1 Adverse Events |
| Placebo | Adverse Event | BUN, serum, high | 1 Adverse Events |
| Placebo | Adverse Event | Hospitalization: cardioversion/atrial fibrillation | 0 Adverse Events |
| Placebo | Adverse Event | ketones, urine, high | 2 Adverse Events |
| Placebo | Adverse Event | ALT, serum, high | 4 Adverse Events |
| Placebo | Adverse Event | potassium, serum, high | 3 Adverse Events |
| Placebo | Adverse Event | diarrhea/loose stools | 1 Adverse Events |
| Placebo | Adverse Event | potassium, serum, high (grade 2) | 1 Adverse Events |
| Placebo | Adverse Event | ANA, high | 1 Adverse Events |
| Placebo | Adverse Event | rash | 2 Adverse Events |
| Placebo | Adverse Event | chloride, serum, high | 4 Adverse Events |
| Placebo | Adverse Event | URI | 3 Adverse Events |
| Placebo | Adverse Event | fatigue | 5 Adverse Events |
| Placebo | Adverse Event | eosinophils, high | 3 Adverse Events |
| Placebo | Adverse Event | glucose, serum, high, non-fasting | 5 Adverse Events |
| Placebo | Adverse Event | CO2 serum, low | 4 Adverse Events |
| Placebo | Adverse Event | edema, lower extremities | 2 Adverse Events |
| Placebo | Adverse Event | injection site reaction | 2 Adverse Events |
Comparison: for injection site reaction onlyp-value: 0.001Fisher Exact
Comparison: for all other adverse eventsp-value: >0.2Fisher Exact
Primary
Immunogenicity of the DC/LNCaP Vaccine. Pre- vs Post-vaccination Bulk T Cell Proliferation (3H Thymidine Incorporation) by Type of Antigen. The Number Indicated is the Median Difference of Post-Pre, of Each Antigen Group.
The difference between post minus pre-vaccination bulk T cell proliferation was calculated for each antigen.
Time frame: pre- vs post-vaccination. Pre-vaccination T cells were collected at Wk 0 and post-vaccination T cells were collected at Wk 13
Population: The Arm/Group Title is different for this outcome. In the 1st outcome analysis, AEs were being compared between placebo and tx groups. After the blinded phase, placebo pts crossover and we compare pre-vs post vaccination T cell proliferation in all pts. 22 of 24 pts'assays were analyzed. Two were excluded as they failed internal controls.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Dendritic Cells Pulsed With LNCaP (DC/LNCaP) | Immunogenicity of the DC/LNCaP Vaccine. Pre- vs Post-vaccination Bulk T Cell Proliferation (3H Thymidine Incorporation) by Type of Antigen. The Number Indicated is the Median Difference of Post-Pre, of Each Antigen Group. | Control Antigen (3T3) | 10299.3967 cells *10^3 per minute |
| Dendritic Cells Pulsed With LNCaP (DC/LNCaP) | Immunogenicity of the DC/LNCaP Vaccine. Pre- vs Post-vaccination Bulk T Cell Proliferation (3H Thymidine Incorporation) by Type of Antigen. The Number Indicated is the Median Difference of Post-Pre, of Each Antigen Group. | No Antigen | 4375.64 cells *10^3 per minute |
| Dendritic Cells Pulsed With LNCaP (DC/LNCaP) | Immunogenicity of the DC/LNCaP Vaccine. Pre- vs Post-vaccination Bulk T Cell Proliferation (3H Thymidine Incorporation) by Type of Antigen. The Number Indicated is the Median Difference of Post-Pre, of Each Antigen Group. | KLH | 16873.92 cells *10^3 per minute |
| Dendritic Cells Pulsed With LNCaP (DC/LNCaP) | Immunogenicity of the DC/LNCaP Vaccine. Pre- vs Post-vaccination Bulk T Cell Proliferation (3H Thymidine Incorporation) by Type of Antigen. The Number Indicated is the Median Difference of Post-Pre, of Each Antigen Group. | LNCaP | 20334.1581 cells *10^3 per minute |
| Dendritic Cells Pulsed With LNCaP (DC/LNCaP) | Immunogenicity of the DC/LNCaP Vaccine. Pre- vs Post-vaccination Bulk T Cell Proliferation (3H Thymidine Incorporation) by Type of Antigen. The Number Indicated is the Median Difference of Post-Pre, of Each Antigen Group. | PC3 | 23950.125 cells *10^3 per minute |
Secondary
Change in PSA Slope, Pre- vs Post-vaccination.
To model the evolution of PSA (in log-scale) during the three study phases (pre-vaccine, vaccine, and post-vaccine phases), a mixed linear spline model was used. Two knots (one at the start of the vaccine phase and the other at the start of the post-vaccine phase) were used to directly quantify the differences in slopes between each phase. To account for the heterogeneous treatment effect and the repeated measures structure, random effects are incorporated into the model. For the general model, random effects for the intercept, slope and the first knot were considered.
Time frame: pre- vs post- vaccination PSA slopes.
Population: 23 of 24 patients were analyzed. 1 patient was not evaluable.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dendritic Cells Pulsed With LNCaP (DC/LNCaP) | Change in PSA Slope, Pre- vs Post-vaccination. | -0.093 log₂(ng/ml)/month |
p-value: 0.016Linear Spline model