To show immunologic efficacy of tumor-peptide loaded natural DC in mCRPC patients. Further we will demonstrate that natural DC vaccinations are safe, feasible and clinically effective. Also the therapy effect on quality of life will be studied.
Source
Brief title
Condition
- Renal and urinary tract neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary objective of this Radboudumc initiated study is to evaluate the
immunogenicity of tumor-peptide loaded natural DC in mCRPC patients.
Immunogenicity is defined as the antitumor immune response induced in prostate
cancer patients.
Therefore, immunomonitoring will be performed that includes:
a) Functional response and tetramer analysis of DTH-infiltrating T cells
against tumor peptides. The occurrence and magnitude of the response will be
compared.
b) Type I IFN gene expression in PBMC shortly after vaccination. The occurrence
and magnitude of the type I IFN response in patients will be compared.
c) Proliferative, effector cytokine- and humoral responses to keyhole limpet
hemocyanin (KLH), a immunogenic protein providing T cell help.
Secondary outcome
The secondary objectives are the safety and feasibility of vaccinations, the
quality of life and the clinical efficacy of mDC and pDC vaccinations. Clinical
efficacy is defined as the proportion of subjects who remain 6 months free of:
radiological progression, PSA progression, progression free survival, opiate
use for cancer-related pain, a skeletal-related event (SRE), decline in
WHO/ECOG performance score by * 1 point and initiation of cytotoxic
chemotherapy. Overall survival will be verified by gathering the date of death
using the electronic hospital records or the electronic records of the general
practitioner. Safety will be evaluated by adverse events, WHO performance
status, physical examinations and laboratory tests until 6 weeks following the
last study treatment. Toxicity will be assessed according to the Common
Terminology Criteria for Adverse Events version 4.03. To assess the quality of
life four validated questionnaires will be collected every 6 weeks. The
EORTC-QLQ-C30103-105 questionnaire, the EORTC-QLQ-PR25106-110 questionnaire,
the CIS20-R questionnaire111-114 and the BDI-(PC)119,120 will be used. These
screening tools are validated and available in the Dutch language.
Background summary
Dendritic cell vaccination
Prevention of infectious diseases through immunization is one of the greatest
achievements of modern medicine. Nonetheless, considerable challenges remain
for improving the efficacy of existing vaccines for therapeutic immunizations
for diseases such as cancer. We were amongst the first groups worldwide that
introduced tumor antigen-loaded dendritic cell (DC)-based vaccines in the
clinic. Effective immune responses and favorable clinical outcomes have indeed
been observed. Thus far, mainly conventional in vitro generated
monocyte-derived DCs (moDC) have been used in clinical trials worldwide. In the
past 14 years we have treated more than 375 patients and proven that DC therapy
is feasible and non-toxic. We observed that long lasting tumor specific T
cell-mediated immunological responses are clearly linked to increased
progression free survival as well as overall survival.
However, moDC may not be the optimal source of DCs for DC vaccination studies,
due to extensive culture periods and compounds required to obtain mature moDC.
Peripheral blood-derived DC (plasmacytoid dendritic cells (pDC) and myeloid
dendritic cells (mDC)) are possibly a better alternative since they do not
require extensive culture periods. We recently completed a clinical trial in
stage IV melanoma patients using plasmacytoid pDC. The results on both
immunological outcome as well as clinical outcome are promising. These freshly
isolated natural pDC prolonged median overall survival to 22 months in
comparison to 7.6 months in matched historical melanoma patients who had
received standard chemotherapy. In terms of immunological outcome transcription
of both interferon-alpha (IFN-*) and interferon-beta (IFN-*) genes was clearly
induced 4 hours after vaccination and decreased 20 hours later. An IFN gene
signature is known to be highly important for eradication of viruses. This
signature is indicative for a temporal systemic induction of type I IFNs. Type
I IFN might also stimulate mDC and enhance their ability to cross-prime CD8+ T
cells, thereby inducing more efficient anti-tumor T cell responses when
compared with in vitro generated DC. This is supported by studies in mice: type
I IFN were critical for the induction of anti-tumor immune responses. In the 14
stage IV melanoma patients included in our mDC trial we observed already in 3
patients tumour-specific T-cells in DTH sites coinciding with tumour
regression. For comparison: in our trials with monocyte-derived DC, less
bonafide T cell responses were seen after DC vaccination.
In conclusion, based on all these observations we are convinced that pDC and
mDC employ different, and probably more optimal mechanisms to combat cancer.
Immunotherapy in prostate cancer
Prostate cancer is the most common noncutaneous cancer in men. In recent years
novel therapies have been studied extensively. Prostate cancer is usually
diagnosed in men above 65 years of age. Depending on the severity of the
disease, current treatment options for prostate cancer consist of active
surveillance, prostatectomy, radiation therapy, hormonal therapy, or
chemotherapy. Up to one-third of patients with a localized tumor eventually
fails on local therapy and progress to advanced-stage or metastatic disease
within 10 years. For advanced prostate cancer, androgen deprivation therapy is
the standard of care. Although the majority of patients initially respond, most
tumors become resistant to primary hormonal therapy within 14 to 30 months. For
men with metastatic castration-resistant prostate cancer (mCRPC), the median
survival in phase III studies range from 15 to 19 months. The chemotherapeutic
drug docetaxel was for several years the only treatment option for mCRPC,
resulting in a median overall survival benefit of two to three months compared
to the previous treatment regimes mitoxantrone and prednisone. Recently,
sequential androgen deprivation therapy (abiraterone acetate and enzalutamide),
sipuleucel-T (Provenge®), radium-223 treatment, and the new chemotherapeutic
taxane cabazitaxel have expanded the treatment repertoire for mCRPC. Further,
there are several therapies studied in ongoing phase III trials, such as
PROSTVAC-VF (NCT01145508 and NCT01322490), an viral vector based prostate
cancer vaccine strategy, and the immune checkpoint inhibitor ipilimumab
(NCT01057810), an anti-cytotoxic T-lymphocyte antigen 4 monoclonal antibody.
Sipuleucel-T, a DC-based vaccine for patients suffering from prostate cancer
has shown to be clinically effective and is approved by the FDA for mCRPC
patients. The European Commission granted marketing authorization in September
2013. A major advantage of cellular immunotherapy when compared to radio- and
chemotherapy is its low toxicity. Currently, there is no consensus among
prostate cancer experts worldwide on the first choice of treatment in mCRPC
patients. Hence, there is an urgent need for more potent treatment modalities
in metastasized prostate cancer. The promising immunological and clinical
outcome with natural DC in metastatic melanoma warrants further testing of
these DC in prostate cancer.
Study objective
To show immunologic efficacy of tumor-peptide loaded natural DC in mCRPC
patients. Further we will demonstrate that natural DC vaccinations are safe,
feasible and clinically effective. Also the therapy effect on quality of life
will be studied.
Study design
This study is a randomized, phase IIa, single-centre study.
Intervention
Leukapheresis
Venapunction
Intranodal administration of the natural DC
Delayed-type hypertensitivity test and biopsies of the challanged skin
Study burden and risks
Based on the experience with pDC and mDC inoculations in melanoma patients, we
expect that both DC types will be well tolerated by mCRPC patients. Common and
expected side effects of natural DC vaccination are usually mild and include
flu-like symptoms and local reaction at injection site, both not greater than
Common Terminology Criteria for Adverse Events (CTCAE) grade 1. Patient
material that will be requested during the current study is summarized in the
table
Table: study related events
Day Event Patient material
-21 to -28 Inclusion 30 ml blood
-1/-2 Apheresis Mononuclear cells, 80 ml heparin blood , 5 ml serum
0 Vaccination I PAXgene tube (four hours after vaccination)
1 Blood draw* PAXgene tube (24 hours after vaccination)*
14 Vaccination II 80 ml heparin blood, 5 ml serum, PAXgene tube (four hours
after vaccination)
15 Blood draw* PAXgene tube (24 hours after vaccination)*
28 Vaccination III 80 ml heparin blood, 5 ml serum, PAXgene tube (four hours
after vaccination)
29 Blood draw* PAXgene tube (24 hours after vaccination)*
35 DTH 80 ml heparin blood, 5 ml serum
37 Biopsies of DTH lesions 4 skin biopsies + 1 control skin biopsy
*Optional blood draw
Geert Grooteplein zuid 26
Nijmegen 6525GA
NL
Geert Grooteplein zuid 26
Nijmegen 6525GA
NL
Listed location countries
Age
Inclusion criteria
All patients:
* Men * 18 years of age and older with confirmed (histologically or cytologically) adenocarcinoma of the prostate without neuroendocrine differentiation or small cell features
* HLA-A2.1 positive
* Asymptomatic or minimally symptomatic mCRPC
* Metastatic castrate-resistant disease defined as one or more of the following criteria that occurred while the patient was on androgen deprivation therapy:
o PSA progression defined by PCWG2 criteria by a minimum of two rising PSA levels with an interval of 1 week between each determination
o Progression of nodal metastases defined by RECIST version 1.1 criteria or progression on successive MRLs
o Bone disease progression defined by two or more new lesions on bone scan as described in PCWG2 criteria
* Maintenance of castrate circumstances:
o Ongoing primary androgen deprivation therapy (GnRH agonist or antagonist)
o Serum testosterone level < 1.73 nmol/L (50 ng/dL)
* PSA value > 2 ng/ml
* Absence of visceral metastases, malignant ascites or pleural effusion
* Clinical absence of brain metastases
* Inclusion within three months after the moment of manifestation of progressive disease as defined above
* Chemotherapy naïve
* Life expectancy * 3 months
* WHO/ECOG performance status 0-1 (Karnofsky index 100-70)
* WBC >2.0*109/l, neutrophils >1.5*109/L lymphocytes >0.8*109/L, platelets >100*109/L, hemoglobin >5,6 mmol/L (9.0 g/dL), serum creatinine <150 µmol/L, AST/ALT <3 x ULN, serum bilirubin <1.5 x ULN (exception: Gilbert*s syndrome is permitted)
* Expected adequacy of follow-up
* Written informed consent;Acceptable concomitant therapy
* The use of oral or intravenous bisphosphonates
* Radiotherapy for pain relief in patients with bone metastases may be used as a treatment modality, but the need for a radiotherapeutic intervention during the study will be documented as an SRE
* Inhaled corticosteroids and topical creams for small body areas are permitted
Exclusion criteria
Exclusion criteria:
* Hypercalcemia
* History of any second malignancy in the previous 5 years, with the exception of adequately treated basal cell carcinoma
* Known allergy to shell fish
* Heart failure (NYHA class III/IV)
* Serious active infections
* Active hepatitis B, C or HIV infection
* Active syphilis infection
* Autoimmune diseases (exception: vitiligo is permitted)
* Organ allografts
* An uncontrolled co-morbidity, e.g. psychiatric or social conditions interfering which participation
* Previous treatment with sipuleucel-T,PROSTVAC, GVAX, chemotherapy, ipilimumab or denosumab (previous treatment with abiraterone acetate or enzalutamide is permitted)
* Prior radiotherapy within 4 weeks prior to planned vaccination or presence of treatment-related toxicity
* Continued use of non-steroidal anti-inflammatory drugs
* Concurrent use of systemic corticosteroids > 10 mg daily prednisone equivalent
* Requirement of opiate use for cancer-related pain (at screening)
* Any serious clinical condition that may interfere with the safe administration of DC vaccinations
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
Register | ID |
---|---|
EudraCT | EUCTR2012-002531-29-NL |
CCMO | NL49143.000.14 |