Dendritic Cell (DC)-Based Vaccines Loaded With Allogeneic Prostate Cell Lines in Combination With Androgen Ablation in Patients With Prostate Cancer

Feasibility, Safety and Efficacy Evaluation of Alpha-Type 1 Dendritic Cell(DC)-Based Vaccines Loaded With Allogeneic Prostate Cell Lines in Combination With Androgen Ablation in Patients With PSA Progression After Local Therapy for Prostate Cancer

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT00970203

Enrollment

Registered

2009-09-02

Start date

2009-09-30

Completion date

2019-10-05

Last updated

2020-11-03

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Cancer of Prostate, Cancer of the Prostate, Neoplasms, Prostate, Neoplasms, Prostatic, Prostate Cancer, Prostate Neoplasms, Prostatic Cancer

Keywords

Vaccine, Androgen Ablation, PSA Progression

Brief summary

This study will evaluate the feasibility, safety, and efficacy of intradermal vaccination of prostate cancer patients with alpha-type-1-polarized dendritic cells (DC1) loaded with apoptotic allogeneic tumor (LNCap). The study will target men with recurrent prostate cancer, who failed local therapy, have no measurable metastasis, but have a rising PSA with a doubling time of less than 10 months. The selection of this study group enables us to evaluate time to PSA progression, a highly relevant, clinical primary endpoint of efficacy in this two arm study. In order to facilitate infiltration of vaccination-induced T cells into tumor site(s) and to reduce tumor-specific tolerance, subjects will receive the vaccine in combination with limited androgen ablation (AA) with a LHRH analogue for 3 months. Subjects will be randomly assigned to one of two cohorts. In cohort A subjects will be first treated with limited AA alone for 3 months, and at the time of PSA relapse (PSA ≥ 1 ng/dL) will receive the DC vaccine in conjunction with AA. In cohort B, the sequence of treatment will be reversed. Efficacy will be estimated as the within-subject difference in time to PSA relapse following the combination treatment as compared to the AA alone, thus, each subject will serve as his own control. All subjects will commence the DC1-based vaccination 2 weeks prior to treatment with the LHRH analogue. Each subject will receive 1 intradermal (i.d.) dose of the vaccine at weeks 1, 5, 9, and 13 for a total of 4 doses. Additional courses of vaccination may be administered to subjects without evidence of disease progression every 3 months (±1 month) for up to 12 months depending on the number of doses originally produced and available after the 4 intended protocol doses. All doses of the vaccine will be administered intradermally (i.d.).

Detailed description

Dendritic cells or DCs are special white blood cells that stimulate the immune system. This study is being done to test the feasibility, safety and efficacy of a specific type of dendritic cell when injected under the skin of patients with prostate cancer. The researchers conducting this study will evaluate the time to prostate specific antigen (PSA) progression and will also be performing tests to see how the immune system is responding to the injections. This is a 2 group crossover trial in which patients are randomly assigned to one of two treatment arms: A. 3 months of androgen ablation (AA) to be followed at PSA progression by 3 months of the combination of AA and alpha-type 1 dendritic cell vaccine (DC1); B. 3 months of the combination of AA and alpha-type 1 dendritic cell vaccine followed at PSA progression by 3 months of AA. Primary Objectives * Feasibility objective: the ability to successfully generate and administer the alpha-DC1 vaccine. * Safety objective: assess the tolerability and toxicity of the alpha-DC1 vaccine. * Efficacy objective: evaluate the effect of the alpha-DC1 vaccine on time to PSA progression compared to AA alone. PSA progression is defined as a rise in the PSA value to e 1.0 ng/mL. Secondary Objectives * To determine the change in PSA velocity prior to and following the proposed treatment. * To evaluate (in all subjects) the vaccination-induced DTH responses to LNCap, the cell line vaccine, and to compare this with vaccination-induced responses to tumor-untreated antigen (KLH). * To evaluate the vaccination-induced changes of Th1/Th2 profiles of the responses to PAP and PSMA. * To evaluate the CTL responses in blood to the whole LNCap cells (in all subjects) and (in all subjects who are HLA-A2 positive) the CTL responses to HLA-A2.1 restricted peptides derived from PAP and PSMA. * To comprehensively evaluate the CD4+ and CD8+ T cell responses (fine specificity and Th1/Th2/Treg cytokine profile) to the previously-identified and novel immunogenic epitopes of PAP and PSMA, using the EPIMAX system. This is a 2 group crossover trial in which patients are randomly assigned to one of two treatment arms: A. 3 months of androgen ablation (AA) to be followed at PSA progression by 3 months of the combination of AA and alpha-type 1 dendritic cell vaccine (DC1); B. 3 months of the combination of AA and alpha-type 1 dendritic cell vaccine followed at PSA progression by 3 months of AA. In this crossover trial each patient will serve as their own control. Following either therapy the time to PSA progression, defined as the time between treatment and the first instance of PSA increase to 1ng/ml. The endpoint is the difference between time to PSA progression for the combination of AA + DC1 compared to AA alone. A total of 12 evaluable patients (6 patients/arm) will be enrolled on the trial. Patients who do not complete both courses (AA and AA+DCV) will be replaced. This schema will also help us better estimate the time to PSA recovery following 3 months of limited androgen ablation in our cohort of patients. All patients in Cohort B, will commence DC1-based vaccination 2 weeks prior to treatment with the LHRH analogue. Each patient will receive four i.d. doses of the vaccine at weeks 1, 4, 8, and 12. The LHRH analogue (Lupron 22.5 mg or Zoladex 10.8 mg), will be administered 2 weeks after the 1st dose of the DC vaccine. Additional courses of vaccination can be administered to any patients without evidence of disease progression, every 3 months for up to 12 months. Patients will undergo a thorough pre-study evaluation, and then undergo leukapheresis to generate the DC-based vaccine. Each patient will receive 4 doses of intradermal (i.d.) DC1-based vaccine at weeks 1, 4, 8, and 12.

Interventions

BIOLOGICALandrogen ablation (AA)

Lupron 22.5 mg or Zoladex 10.8 mg

BIOLOGICALDC1 vaccine

3-5 x 10e6 cells total

Study design

Allocation

RANDOMIZED

Intervention model

CROSSOVER

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

MALE

Age

18 Years to No maximum

Healthy volunteers

Inclusion criteria

Eligibility Criteria * Patients with histologically proven prostate cancer and tumors limited to the prostate (including seminal vesicle involvement, provided all visible disease was surgically removed) who have completed local therapy and have an elevated PSA after surgery or rising PSA after radiation therapy, as defined below. * Age 18 years or older * Histologically confirmed diagnosis of prostate cancer. * Previous treatment with definitive surgery or radiation therapy or both. * No evidence of metastatic disease on physical exam, CT/MRI/CXR (see Section 7.1 for radiologic imaging), and bone scan within 4 weeks prior to randomization. * Prior neoadjuvant/adjuvant hormonal, androgen deprivation therapy, or chemotherapy is allowed if it was last used \> 12 months prior to first vaccination. * No therapy modulating testosterone levels (such as leuteinizing-hormone releasing-hormone agonists/antagonists and antiandrogens) is permitted within 12 months prior to first vaccination. Agents such as 5α-reductase inhibitors, ketoconazole, megestrol acetate, systemic steroids (replacement doses of steroids are allowed), PC-SPES, and Saw Palmetto are not permitted at any time during the period that the PSA values are being collected. * Hormone-sensitive prostate cancer as evident by a serum total testosterone level \> 150 ng/dL or \> 6 nmol/L at the time of enrollment within 4 weeks prior to randomization. * All patients must have evidence of biochemical progression as determined by a reference PSA value followed by 1 confirmatory rising PSA value, higher than the previous value, obtained at least 2 weeks apart. All of these PSA values must be obtained at the same reference lab, and all must be done within 6 months prior to enrollment. * The most recent of the PSA values must be ≥ 2.0 ng/mL. This measurement must be obtained within 1 month prior to enrollment. * The PSA doubling time (PSA-DT) must be less than 12 months. * ECOG performance status 0 or 1. * Patients must have normal organ and marrow function as defined below: * Absolute neutrophil count \> 1,500/µL * Platelets \> 100,000/µL * Total bilirubin 1.5 x upper limit of normal (ULN) * SGOT (AST) and SGPT (ALT) \< 2.5 x institutional ULN * Creatinine 1.5 x ULN * The effects of dendritic cell vaccines on the developing human fetus are unknown. For this reason men must agree to use adequate contraception (hormonal or barrier method of birth control) prior to study entry and for the duration of study participation.

Exclusion criteria

* Patients must not be receiving other investigational agents or concurrent anticancer therapy. * No uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. * Patients must not have active eczema, atopic dermatitis, or other exfoliative skin conditions (e.g., burns, impetigo, varicella zoster, severe acne, contact dermatitis, psoriasis, herpes or other open rashes or wounds). * Presence of an active acute or chronic infection, including urinary tract infection, HIV or viral hepatitis. HIV patients are excluded based on immunosuppression which may render them unable to respond to the vaccine; patients with chronic hepatitis are excluded because of concern that hepatitis could be exacerbated by the injections. If clinically indicate, HIV/viral hepatitis testing will be performed to confirm status. * Patients with a history of auto-immune disease such as, but not restricted to, inflammatory bowel disease, systemic lupus erythematosus, ankylosing spondylitis, scleroderma, or multiple sclerosis. Patients receiving replacement thyroid hormone would be eligible. * No concurrent use of systemic steroids, except for local (topical, nasal, or inhaled) steroid use. Adrenal replacement doses of corticosteroids are allowed. * Subjects with concurrent additional malignancy (with exception of non-melanoma skin cancers and superficial bladder cancer or malignancy within last 3 years).

Design outcomes

Primary

Measure	Time frame	Description
Percentage of Patients to Successfully Generate and Administer the Alpha-DC1 Vaccine	16 weeks	The percentage of patients for which the alpha-DC1 vaccine was generated and for which 4 vaccine injections were administered (1 injection every 4 weeks).
Tolerability and Toxicity of the Alpha-DC1 Vaccine	16 weeks	The percentage of patients who experienced vaccine related toxicity.
The Effect of the DC1 Vaccine on Time to PSA Progression Compared to AA Alone	Approximately 18 months	The mean difference between time to relapse on androgen ablation plus alpha DC-1 vaccine vs androgen ablation

Secondary

Measure	Time frame
Evaluate the CTL Responses in Blood to the Whole LNCap Cells (in All Subjects) and (in All Subjects Who Are HLA-A2 Positive) the CTL Responses to HLA-A2.1 Restricted Peptides Derived From PAP and PSMA	Approximately 18 to 24 months
Change in PSA Velocity Prior to and Following the Proposed Treatment.	Approximately 18 months
Comprehensively Evaluate the CD4+ and CD8+ T Cell Responses (Fine Specificity and Th1/Th2/Treg Cytokine Profile) to the Previously-identified and Novel Immunogenic Epitopes of PAP and PSMA, Using the EPIMAX System	Approximately 18 to 24 months
Evaluate (in All Subjects) the Vaccination-induced DTH Responses to LNCap, the Cell Line Vaccine, and to Compare This With Vaccination-induced Responses to Tumor-untreated Antigen (KLH)	Approximately 17 weeks
Evaluate the Vaccination-induced Changes of Th1/Th2 Profiles of the Responses to PAP and PSMA	Approximately 18 to 24 months

Countries

United States

Participant flow

Participants by arm

Arm	Count
Cohort A 3 months of androgen ablation followed at PSA progression by 3 months of the combination of androgen ablation + DC1 vaccine AA: Lupron 22.5 mg or Zoladex 10.8 mg DC vaccine: intradermal (id) vaccine of 3-5 x 10e6 cells androgen ablation (AA): Lupron 22.5 mg or Zoladex 10.8 mg DC1 vaccine: 3-5 x 10e6 cells total	7
Cohort B 3 months of the combination of androgen ablation + DC1 vaccine followed at PSA progression by 3 months of androgen ablation AA: Lupron 22.5 mg or Zoladex 10.8 mg DC vaccine: intradermal (id) vaccine of 3-5 x 10e6 cells androgen ablation (AA): Lupron 22.5 mg or Zoladex 10.8 mg DC1 vaccine: 3-5 x 10e6 cells total	6
Total	13

Baseline characteristics

Characteristic	Cohort B	Total	Cohort A
Age, Continuous	64 years STANDARD_DEVIATION 6.4	64 years STANDARD_DEVIATION 6.4	64 years STANDARD_DEVIATION 6.9
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Black or African American	0 Participants	1 Participants	1 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) White	6 Participants	12 Participants	6 Participants
Sex: Female, Male Female	0 Participants	0 Participants	0 Participants
Sex: Female, Male Male	6 Participants	13 Participants	7 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	0 / 7	0 / 6
other Total, other adverse events	7 / 7	6 / 6
serious Total, serious adverse events	0 / 7	0 / 6

Outcome results

Primary

Percentage of Patients to Successfully Generate and Administer the Alpha-DC1 Vaccine

The percentage of patients for which the alpha-DC1 vaccine was generated and for which 4 vaccine injections were administered (1 injection every 4 weeks).

Time frame: 16 weeks

Population: All treated and eligible patients

Arm	Measure	Value (NUMBER)
Cohort A	Percentage of Patients to Successfully Generate and Administer the Alpha-DC1 Vaccine	100 percentage of participants
Cohort B	Percentage of Patients to Successfully Generate and Administer the Alpha-DC1 Vaccine	100 percentage of participants

Primary

The Effect of the DC1 Vaccine on Time to PSA Progression Compared to AA Alone

The mean difference between time to relapse on androgen ablation plus alpha DC-1 vaccine vs androgen ablation

Time frame: Approximately 18 months

Population: Despite numerous attempts to obtain required data from the previous IND holder where the data is housed, including attempts to contact study PI and team, no responses were obtained and no data are available for this Outcome Measure.

Primary

Tolerability and Toxicity of the Alpha-DC1 Vaccine

The percentage of patients who experienced vaccine related toxicity.

Time frame: 16 weeks

Population: All treated and eligible patients

Arm	Measure	Value (NUMBER)
Cohort A	Tolerability and Toxicity of the Alpha-DC1 Vaccine	0 percentage of participants
Cohort B	Tolerability and Toxicity of the Alpha-DC1 Vaccine	0 percentage of participants

Secondary