Safety and Effectiveness of a Vaccine for Prostate Cancer That Uses Each Patients' Own Immune Cells.

• Sponsor: Rockefeller University (Other)
• Overall Status: Completed
• CT.gov ID: NCT00289341
• Collaborator: (none)
• Enrollment: 24
• Location: 1
• Arms: 2
• Duration (Months): 80.1
• Patients Per Site Per Month: 0.3

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Prostate Cancer	Biological: vaccine vehicle only; Biological: DC/LNCaP	Phase 1/Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 24 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Single (Participant)
• Primary Purpose: Treatment
• Official Title: A Phase I/II Study of Autologous Dendritic Cells Pulsed With Apoptotic Tumor Cells (DC/LNCaP) Administered Subcutaneously to Prostate Cancer Patients.
• Study Start Date: Mar 1, 2002
• Actual Primary Completion Date: Nov 1, 2008
• Actual Study Completion Date: Nov 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo 12 patients in the placebo Arm for 8 weeks followed by DC/LNCAP, DC/LNCaP-M1 and DC/KLH immunizations over 8 weeks.	Biological: vaccine vehicle only; Subcutaneous injection of vaccine vehicle only (5% DMSO in normal saline), followed by cross-over to Arm 1 design.
Experimental: DC/LNCaP 12 patients, receiving DC/LNCaP, DC/LNCaP-M1 and DC/KLH immunizations over 8 weeks	Biological: DC/LNCaP; Subcutaneous injection of DC/LNCaP, DC/LNCaP-M1, DC/KLH

Outcome Measures

Primary Outcome Measures

1. 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.

2. 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 Outcome Measures

1. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: Male
• Accepts 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Rockefeller University Hospital	New York	New York	United States	10021

Sponsors and Collaborators

• Rockefeller University

Investigators

• Principal Investigator: Robert B. Darnell, MD, PHD, Rockefeller University

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Robert Darnell, Principal Investigator, Rockefeller University
• ClinicalTrials.gov Identifier: NCT00289341
• Other Study ID Numbers: RDA 0466
• First Posted: Feb 9, 2006
• Last Update Posted: Jan 18, 2013
• Last Verified: Jan 1, 2013

• Additional relevant MeSH terms: Prostatic Neoplasms

Study Results

Participant Flow

Arm/Group Title	Dendritic Cells Pulsed With LNCaP (DC/LNCaP)	Placebo
Arm/Group Description	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.
Period Title: Overall Study
STARTED	12	12
COMPLETED	12	12
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Dendritic Cells Pulsed With LNCaP (DC/LNCaP)	Placebo	Total
Arm/Group Description	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.	Total of all reporting groups
Overall Participants	12	12	24
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	7 58.3%	6 50%	13 54.2%
>=65 years	5 41.7%	6 50%	11 45.8%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	62.5 (6.7)	65.7 (9.2)	64.0 (7.9)
Sex: Female, Male (Count of Participants)
Female	0 0%	0 0%	0 0%
Male	12 100%	12 100%	24 100%
Region of Enrollment (participants) [Number]
United States	12 100%	12 100%	24 100%

Outcome Measures

1. Primary Outcome

Title	Adverse Event
Description	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)

Outcome Measure Data

Analysis Population Description

All AEs occurring 5 or more times during the study were analyzed. All AEs reported are grade 1 except as noted.

Arm/Group Title	Dendritic Cells Pulsed With LNCaP (DC/LNCaP)	Placebo
Arm/Group Description	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 patients receiving vehicle only
Measure Participants	12	12
injection site reaction	22	2
injection site reaction (grade 2)	4	0
albumin, serum, low	0	1
albumin, urine, high	2	3
ALT, serum, high	3	4
ANA, high	1	1
BUN, serum, high	4	1
chloride, serum, high	1	4
CO2 serum, low	3	4
creatinine, serum, high	3	1
diarrhea/loose stools	5	1
edema, lower extremities	0	2
eosinophils, high	1	3
fatigue	6	5
glucose, serum, high, non-fasting	6	5
ketones, urine, high	1	2
potassium, serum, high	0	3
potassium, serum, high (grade 2)	0	1
rash	2	2
URI	3	3
Hospitalization: cardioversion/atrial fibrillation	1	0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Dendritic Cells Pulsed With LNCaP (DC/LNCaP), Placebo
	Comments	for injection site reaction only
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.001
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Dendritic Cells Pulsed With LNCaP (DC/LNCaP), Placebo
	Comments	for all other adverse events
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	>0.2
	Comments
	Method	Fisher Exact
	Comments

2. Primary Outcome

Title	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.
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Median Difference, Post-Pre Vaccination
Arm/Group Description	For each antigen group, the difference between the post and pre-vaccination T cell proliferation response was calculated.
Measure Participants	22
No Antigen	4375.64
KLH	16873.92
LNCaP	20334.1581
PC3	23950.125
Control Antigen (3T3)	10299.3967

3. Secondary Outcome

Title	Change in PSA Slope, Pre- vs Post-vaccination.
Description	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.

Outcome Measure Data

Analysis Population Description

23 of 24 patients were analyzed. 1 patient was not evaluable.

Arm/Group Title	Pre-vs Post-vaccination PSA Slope
Arm/Group Description
Measure Participants	23
Number (95% Confidence Interval) [log₂(ng/ml)/month]	-0.093

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Dendritic Cells Pulsed With LNCaP (DC/LNCaP)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.016
	Comments
	Method	Linear Spline model
	Comments

Adverse Events

Time Frame	AEs were collected for 29 weeks.
Adverse Event Reporting Description	All AEs other than SAEs are Grade 1 (NCI, CTCAE). As this reporting table does not allow having 2 arms initially then 1, all AEs are entered as 1 arm. Specifics for each arm separately is reported in Outcome 1.
Arm/Group Title	Arm 2 Placebo Phase		Arm 1 Vaccine Phase		Arm 2 Vaccine Phase		Arm 1 and 2 Post-Vaccination Phase
Arm/Group Description	Single-blind		Single blind		Unblinded		unblinded
All Cause Mortality
	Arm 2 Placebo Phase		Arm 1 Vaccine Phase		Arm 2 Vaccine Phase		Arm 1 and 2 Post-Vaccination Phase
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Arm 2 Placebo Phase		Arm 1 Vaccine Phase		Arm 2 Vaccine Phase		Arm 1 and 2 Post-Vaccination Phase
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/12 (0%)		1/12 (8.3%)		0/12 (0%)		1/24 (4.2%)
Cardiac disorders
Hospitalization: cardioversion for atrial fibrillation	0/0 (NaN)	0	1/12 (8.3%)	1	0/12 (0%)	0	0/24 (0%)	0
Gastrointestinal disorders
Elective Hosptalization: cholecystectomy	0/12 (0%)	0	0/12 (0%)	0	0/12 (0%)	0	1/24 (4.2%)	1
Renal and urinary disorders
Hospitalization: urinary retention	0/0 (NaN)	0	0/12 (0%)	0	0/12 (0%)	0	1/24 (4.2%)	1
Surgical and medical procedures
Elective Hospitalization: inguinal hernia repair	0/0 (NaN)	0	0/12 (0%)	0	0/12 (0%)	0	1/24 (4.2%)	1
Other (Not Including Serious) Adverse Events
	Arm 2 Placebo Phase		Arm 1 Vaccine Phase		Arm 2 Vaccine Phase		Arm 1 and 2 Post-Vaccination Phase
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	12/12 (100%)		12/12 (100%)		12/12 (100%)		22/24 (91.7%)
Blood and lymphatic system disorders
eosinophils, high	3/12 (25%)		1/12 (8.3%)		1/12 (8.3%)		1/24 (4.2%)
Gastrointestinal disorders
diarrhea/loose stools	1/12 (8.3%)		3/12 (25%)		0/12 (0%)		0/24 (0%)
General disorders
ALT, serum, high	3/12 (25%)		2/12 (16.7%)		1/12 (8.3%)		2/24 (8.3%)	2
ANA	1/12 (8.3%)		1/12 (8.3%)		3/12 (25%)		4/24 (16.7%)
BUN, serum, high	1/12 (8.3%)		3/12 (25%)		2/12 (16.7%)		1/24 (4.2%)
CO2, serum, low	4/12 (33.3%)		2/12 (16.7%)		2/12 (16.7%)		1/24 (4.2%)
albumin, serum, low	0/12 (0%)		1/12 (8.3%)		3/12 (25%)		0/24 (0%)
albumin, urine, high	1/12 (8.3%)		3/12 (25%)		0/12 (0%)		3/24 (12.5%)
chloride, serum, high	4/12 (33.3%)		1/12 (8.3%)		0/12 (0%)		2/24 (8.3%)
creatinine, serum, high	1/12 (8.3%)		2/12 (16.7%)		2/12 (16.7%)		2/24 (8.3%)
edema, lower extremities	2/12 (16.7%)		0/12 (0%)		1/12 (8.3%)		1/24 (4.2%)
fatigue	5/12 (41.7%)		5/12 (41.7%)		4/12 (33.3%)		0/24 (0%)
glucose, serum, high, non-fasting	5/12 (41.7%)		6/12 (50%)		1/12 (8.3%)		6/24 (25%)
potassium, serum, high	4/12 (33.3%)		0/12 (0%)		5/12 (41.7%)		1/24 (4.2%)
Renal and urinary disorders
ketones, urine, high	2/12 (16.7%)		1/12 (8.3%)		1/12 (8.3%)		3/24 (12.5%)
Respiratory, thoracic and mediastinal disorders
URI	3/12 (25%)		3/12 (25%)		1/12 (8.3%)		0/24 (0%)
Skin and subcutaneous tissue disorders
rash	2/12 (16.7%)		1/12 (8.3%)		0/12 (0%)		2/24 (8.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.