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Natural Dendritic Cells for Immunotherapy of Chemo-naive Metastatic Castration-resistant Prostate Cancer Patients

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ClinicalTrials.gov Identifier: NCT02692976
Recruitment Status : Active, not recruiting
First Posted : February 26, 2016
Last Update Posted : December 12, 2018
Sponsor:
Information provided by (Responsible Party):
Radboud University

Brief Summary:

Prostate cancer is the only type of cancer in which conventional dendritic cells (DC) treatment has a beneficial effect on the overall survival. In this study investigators aim to show immunologic efficacy of tumor-peptide loaded natural DC in metastatic castration-resistant prostate cancer patients (mCRPC).

The immunomonitoring will include:

  1. functional response and tetramer analysis of delayed-type hypersensitivity infiltrating lymphocytes against tumor peptides and
  2. type I interferon (IFN) gene expression in peripheral blood mononuclear cells, and
  3. proliferative, effector cytokine- and humoral responses to keyhole limpet hemocyanin, a immunogenic protein providing T cell help.

The secondary objectives are the safety and feasibility of natural DC vaccinations, the influence on the quality of life during treatment with natural DC, and the clinical efficacy of treatment.


Condition or disease Intervention/treatment Phase
Prostatic Neoplasms Immunotherapy Dendritic Cells Vaccines Biological: mDC vaccination Biological: pDC vaccination Biological: mDC and pDC vaccination Phase 2

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 21 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Randomized Phase IIa Study: Natural Dendritic Cells for Immunotherapy of Chemo-naive Metastatic Castration-resistant Prostate Cancer Patients
Study Start Date : September 2015
Actual Primary Completion Date : September 2017
Estimated Study Completion Date : June 2019

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Prostate Cancer

Arm Intervention/treatment
Experimental: Myeloid dendritic cells (mDC) vaccinations
Patients will be vaccinated intranodally three times biweekly with mDC (5x 106 cells; n=7, arm A). DC will be loaded with major histocompatibility complex (MHC) class I binding peptides of tumor antigens and NY-ESO-1 and MUC1 PepTivator® which covers the complete antigen. DC will be stimulated with protamine/mRNA and loaded with keyhole limpet hemocyanin (KLH) as an immune control.
Biological: mDC vaccination
Intranodal mDC vaccination

Experimental: Plasmacytoid dendritic cells (pDC) vaccinations
Patients will be vaccinated intranodally three times biweekly with pDC (3x 106 cells; n=7, arm B). DC will be loaded with MHC class I binding peptides of tumor antigens and NY-ESO-1 and MUC1 PepTivator® which covers the complete antigen. DC will be stimulated with protamine/mRNA.
Biological: pDC vaccination
Intranodal pDC vaccination

Experimental: mDC and pDC vaccinations
Patients will be vaccinated intranodally three times biweekly with the combination of mDC and pDC (5x 106 mDC/ 3x 106 pDC; n=7, arm C). DC will be loaded with MHC class I binding peptides of tumor antigens and NY-ESO-1 and MUC1 PepTivator® which covers the complete antigen. DC will be stimulated with protamine/mRNA and loaded with KLH (mDC only) as an immune control.
Biological: mDC and pDC vaccination
Intranodal mDC/pDC vaccination




Primary Outcome Measures :
  1. The immunogenicity of tumor-peptide loaded natural blood dendritic cells (myeloid DC, plasmacytoid DC and the combination of mDC/pDC) in metastatic castration-resistant prostate cancer (mCRPC) patients [ Time Frame: 18 months ]
    a.functional response and tetramer analysis of delayed-type hypersensitivity infiltrating lymphocytes against tumor peptides.

  2. The immunogenicity of tumor-peptide loaded natural blood dendritic cells (myeloid DC, plasmacytoid DC and the combination of mDC/pDC) in metastatic castration-resistant prostate cancer (mCRPC) patients [ Time Frame: 18 months ]
    b.type I interferon (IFN) gene expression in peripheral blood mononuclear cells.

  3. The immunogenicity of tumor-peptide loaded natural blood dendritic cells (myeloid DC, plasmacytoid DC and the combination of mDC/pDC) in metastatic castration-resistant prostate cancer (mCRPC) patients [ Time Frame: 18 months ]
    c.proliferative, effector cytokine- and humoral responses to keyhole limpet hemocyanin, a immunogenic protein providing T cell help.


Secondary Outcome Measures :
  1. Treatment-related adverse events assessment by Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 [ Time Frame: 18 months ]

    Number of participants with treatment-related adverse events as assessed by CTCAE version 4.0 and establishing the feasibility of the st-udy protocol by looking at the enrollment duration. The CTCAE version 4.0 displays Grades 1 through 5 with unique clinical descriptions of severity for each adverse event (AE) based on this general guideline:

    Grade 1 Mild AE Grade 2 Moderate AE Grade 3 Severe AE Grade 4 Life-threatening or disabling AE Grade 5 Death related to AE


  2. Quality of life measurement by EORTC-QLQ-C30 [ Time Frame: 18 months ]
    Quality of life measured with EORTC-QLQ-C30 questionnaire. A higher functional scale score represents a higher level of functioning. A high score for Global Health Status represents a high HRQoL. A high symptom or single-item score represents a high symptomatology level. A clinically relevant difference was defined by a mean change of at least 10 points on a scale score

  3. Quality of life measurement by EORTC-QLQ-PR25 [ Time Frame: 18 months ]
    Quality of life measured with EORTC-QLQ-PR25 questionnaire. A higher score on functioning-related domains is indicative for better functioning, where a higher symptom-related domain score is indicative for more symptomatology. Sexual functioning questions required reversing of the response categories for 3 of 4 questions (question number 23-25). In line with the EORTC-QLQ-C30, a clinically relevant difference was defined by a mean change of at least 10 points on a scale scores.

  4. Quality of life measurement by BDI (PC) [ Time Frame: 18 months ]
    Quality of life measured with BDI (PC) questionnaire. The BDI-PC questionnaire is one of the rating scales for identifying a mood disorder in medical outpatients. BDI-PC is a seven item questionnaire with scores ranging from 0 to 21. Scores of 4 or higher are suggestive for a clinical relevant depression.

  5. Quality of life measurement by CIS20-R [ Time Frame: 18 months ]
    Quality of life measured with CIS20-R questionnaire. The CIS-20R is a self-report questionnaire assessing 20 items incarcerating four fatigue dimensions (subjective experience of fatigue (CIS1), reduction in concentration (CIS2), reduction in motivation (CIS3) and reduction in activity (CIS4)). Patients rated the extent to which each statement was true for the previous two weeks on a 7-category scale (ranging from score 1 'Yes, that is true' to 7 'No, that is not true'). A CIS1 score of 35 of higher indicates severe fatigue. A score between 27 and 35 represents an increased risk for fatigue.

  6. Prostate-specific antigen (PSA)-progression [ Time Frame: every 6 weeks, up to 24 months ]
    PSA progression will be defined according to the Prostate Cancer Clinical Trials Working Group 2 (PCWG2) criteria.

  7. Progression Free Survival (PFS) [ Time Frame: every 6 weeks, up to 24 months ]
    To evaluate PFS: serum PSA value will be determined every 6 weeks and a magnetic resonance imaging lymphangiography (MRL) will be performed every 3 months (combined with a 68Ga-PSMA-PET/CT scan at t=0 and t=3 months, and for long responders to therapy at t=12 months and t=24 months). PFS is defined as the time from randomization to the detection of progressive disease on MRL/68-Ga-PSMA-PET/CT scan or immune-related progressive disease, including new measurable lesions reported on successive MRLs. According to the PCWG2 criteria. In case of disease progression during vaccination the patient will be withdrawn from the study. In case of stable disease after three rounds of vaccinations follow-up with MRL will be performed until 24 months after study enrollment.

  8. Overall Survival (OS) [ Time Frame: 2 years ]
    OS will be determined at the end of study follow-up. The patient's general practitioner will be contacted for OS analysis.

  9. Time to opiate use [ Time Frame: every 3 months, up to 24 months ]
  10. Time to skeletal-related event (SRE) [ Time Frame: every 3 months, up to 24 months ]
    Defined by MRI

  11. World Health Organization (WHO) performance score decline [ Time Frame: every 6 weeks, up to 24 months ]
    Defined by 1 or more point decline in WHO/ECOG performance score

  12. Time to chemotherapy initiation after mDC/pDC vaccinations [ Time Frame: every 6 weeks, up to 24 months ]
  13. Radiologic profression-free survival [ Time Frame: MRI: every 3 months; 68-Ga-PSMA-PET/CT scan: t=0, 3, 12 en 24 months, up to 24 months. ]
    Determined on MRI scans/68-Ga-PSMA-PET/CT scan

  14. Feasibility of the natural DC vaccination trial [ Time Frame: 18 months ]
    Feasibility of participant recruitment and the collection of immunological and clinical data within the time frame of 18 months.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Men ≥ 18 years of age and older with confirmed (histologically or cytologically) adenocarcinoma of the prostate without neuroendocrine differentiation or small cell features
  • Human leukocyte antigen (HLA)-A2.1 positive
  • Asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC)
  • Metastatic castrate-resistant disease defined as one or more of the following criteria that occurred while the patient was on androgen deprivation therapy:

    • Prostate-specific antigen (PSA)-progression defined by Prostate Cancer Working Group 2 (PCWG2) criteria by a minimum of two rising PSA levels with an interval of ≥ 1 week between each determination
    • Progression of nodal metastases defined by Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1 criteria or progression on successive magnetic resonance imaging lymphangiographies (MRLs)
    • Bone disease progression defined by two or more new lesions on bone scan as described in PCWG2 criteria
  • Maintenance of castrate circumstances:

    • Ongoing primary androgen deprivation therapy (Gonadotropin-Releasing hormone agonist or antagonist) or bilateral orchiectomy
    • Serum testosterone level ≤ 1.73 nmol/L (50 ng/dL) at screening visit
  • 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 naive
  • Life expectancy ≥ 6 months
  • World Health Organization/Eastern Cooperative Oncology Group performance status 0-1 (Karnofsky index 100-70)
  • White blood cells >2.0x109/l, neutrophils >1.5x109/L, lymphocytes >0.8x109/L, platelets >100x109/L, hemoglobin >5,6 mmol/L (9.0 g/dL), serum creatinine <150 µmol/L, aspartate aminotransferase/alanine aminotransferase <3 x upper limit of normal (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 skeletal-related event (SRE)
  • Inhaled corticosteroids and topical creams for small body areas are permitted

Exclusion Criteria:

  • Hypercalcemia
  • History of any second malignancy in the previous five years, with the exception of adequately treated basal cell carcinoma
  • Known allergy to shell fish
  • Heart failure (New York Heart Association 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, ketoconazole or enzalutamide is permitted)
  • Treatment with flutamide, bicalutamide, or nilutamide within four weeks of study enrollment
  • Prior radiotherapy within four 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02692976


Locations
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Netherlands
Radboud University Nijmegen Medical Centre
Nijmegen, Gelderland, Netherlands, 6500 HB
Sponsors and Collaborators
Radboud University
Investigators
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Principal Investigator: Winald R Gerritsen, MD PhD Radboudumc, dep of Medical Oncology
Principal Investigator: Fred Witjes, MD PhD Radboudumc, dep of Urology
Study Director: Jolanda IM de Vries, PhD Radboudumc, dep of Tumor Immunology, laboratory study coordinator

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Responsible Party: Radboud University
ClinicalTrials.gov Identifier: NCT02692976     History of Changes
Other Study ID Numbers: EudraCT 2012-002531-29
First Posted: February 26, 2016    Key Record Dates
Last Update Posted: December 12, 2018
Last Verified: November 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Data will be shared after all clinical and immunological data collection and analysis in a scientific publication.
Keywords provided by Radboud University:
Castration-resistant prostate cancer
Dendritic Cells
Immunotherapy
Vaccines
Additional relevant MeSH terms:
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Prostatic Neoplasms
Genital Neoplasms, Male
Urogenital Neoplasms
Neoplasms by Site
Neoplasms
Genital Diseases, Male
Prostatic Diseases
Vaccines
Immunologic Factors
Physiological Effects of Drugs