Hormone Therapy With or Without Definitive Radiotherapy in Metastatic Prostate Cancer

October 10, 2018 updated by: Ana Frobe, University Hospital "Sestre Milosrdnice"

PART I

Hormone therapy with or without definitive radiotherapy in metastatic prostate cancer

The goal of this clinical study PART I is to determine impact of radiotherapy treatment in combination with standard androgen deprivation therapy comparing with androgen deprivation therapy alone at controlling metastatic prostate cancer. The primary objective: to determine disease progression free survival in man with metastatic (M1) prostate cancer (PC) undergoing androgen deprivation therapy with or without definitive radiotherapy of the primary tumor.The secondary objective: to determine disease progression (local, bone marrow, visceral) in men with metastatic prostate cancer (M1PC) undergoing systemic therapy with/without definitive radiotherapy of the primary tumor, to determine expression in number of genes analysed 8: 2 housekeeping genes; integrin subunits αv, β3, β5, α4β1 ; 3 EMT markers N-cadherin, E-cadherin, vimentin before radiotherapy, after radiotherapy and at the time of the disease progression , to determine plasma serotonin (5HT, 5 hydroxytryptamine). Subgroup analysis in locally advanced prostate cancer (serves as a control group for integrins analysis): to determine expression in number of genes analysed 8: 2 housekeeping genes; integrin subunits αv, β3, β5, α4β1 ; 3 epithelial-mesenchymal transition (EMT) markers N-cadherin, E-cadherin, vimentin before radiotherapy, after radiotherapy and at the time of the disease progression.

PART II

Identification of genetic determinants of disease progression and castrate resistance in metastatic prostate cancer.

The goal of this clinical study PART II is to assess feasibility of genomic testing in the multidisciplinary clinical management of metastatic prostate cancer, to gain insight in specific genomic signature(s) of progressive metastatic prostate cancer in the natural course of disease spanning from primary tumor to metastases, to test if 'treatment selection' and/or 'treatment adaptation' as means of evolutionary pressures represent the mechanistic models of castrate resistance and ultimate treatment failure following course of androgen deprivation therapy (ADT).

Study Overview

Status

Unknown

Conditions

Intervention / Treatment

Detailed Description

PART I

Standard therapy for men presenting with metastatic prostate cancer is initiation of androgen suppression, whereas radiotherapy or surgery are currently used only in palliative efforts to relieve symptoms of bleeding, pain, or obstruction. The integration of radiation to the prostate has not been prospectively explored in the metastatic setting.

Although there is no study evidence on the effect of local therapy on outcomes in metastatic prostate cancer, there are hypotheses-generating data that support this concept as an appropriate question to be answered in the context of a randomized trial. Prospective data show improved outcomes for men with locally advanced prostate cancer undergoing multimodality therapy with androgen-deprivation therapy (ADT) or radiation therapy (RT) compared to systemic monotherapy alone . Continuing on the spectrum of the disease, recent data presented at the 2014 European Society for Medical Oncology Annual Meeting showed improved failure-free survival in men with clinically positive lymph nodes receiving combination ADT and RT versus ADT alone.

Several population-based studies have shown improved overall survival in men with metastatic disease undergoing combination local and systemic therapy versus standard-of-care systemic therapy alone .

Previous studies showed that initial event at a metastatic site is not the arrival of tumor cells but rather the clustering of bone marrow-derived cells . This cells make the local microenvironment of the secondary organ more receptive to tumor cell colonization and are stimulated by endocrine factors released by the primary tumor . According to this, local treatment of the primary tumor could postpone the formation and the growth of distant metastases; metastatic prostate cancer may represent a heterogeneous population and the impact of local treatment on disease progression on survival might be influenced by primary tumor characteristics.

Many studies support the importance of integrins in prostate cancer development and progression by promoting proliferation, invasion and metastasis. Targeting specific integrins and their matrix interaction may provide a way to prevent metastatic bone prostate cancer.

Serotonin or 5-hydroxytryptamine (5-HT) is a well-known neurotransmitter that mediates a wide variety of physiological effects. An increase in the number of 5-HT-releasing neuroendocrine (NE) cells has been correlated with prostate tumor progression. However, it is particularly unclear whether released 5-HT or the release of 5-HT has a role in tumor cell growth .

Serotonin is a well-known mitogen which mediates a wide variety of physiological effects via multiple receptors, of which receptor subtype 1 (5-HTR1) has been identified in prostate cancer (PC) cell lines. Recently, 5-HT has been found to show growth-promoting activity and to be functionally related to oncogenes .

Previous studies showed that 5-HT stimulated the proliferation of prostate cancer cells mediated by 5-HT receptors 5-HTR1A and R1B and the secretion system of prostate NE cells is capable of 5-HT synthesis and metabolism plays a significant role in prostate tumor generation and progression. These findings are crucial for the development of potential drugs to slow prostate tumor progression.

PART II

Genomic alternations leading to development of metastasis, treatment resistance and ultimate disease progression include multistep mutational events on androgen signalling axis, in tumor suppressor genes and oncogenes and finally DNA repair defects which are currently being intensively studied using large multinational collaborative efforts (Robinson Cell 2015, PCF Stand up to Cancer West Coast Dream Team). Despite this growing body of data on biology behind the different phenotypes of metastatic prostate cancer seen in clinic, little is known on how discovery of specific gene/pathway involved in multi-step process of disease progression impact clinical decisions, especially in limited resource setting. Furthermore, there is a knowledge gap addressing the impact of ADT, which is mainstay of the treatment of metastatic prostate cancer, on mutational landscape in the context of hormone sensitive disease. For programs starting to embrace personalised treatment paradigm it is essential to gain insight how to integrate genomic data in the clinic and even more, to test whether genomic testing in the course of disease of patient with metastatic prostate cancer is feasible.

Primary goal of this PART II study is to assess feasibility of genomic testing in the pilot group of five patients with prostate cancer who develop metastases from the large pool of patients with prostate cancer followed prospectively in our multidisciplinary clinic. Secondary goal is to determine level of genomic instability and principal mutational events in the metastases as opposed to the primary tumor, with addition of differentiating genomic outlook of metastases before and after emergence of castrate resistant disease.

(i) Aims 1, 2, 3: To assess feasibility of genomic testing in the critical steps in management of the patient with metastatic prostate cancer and to characterise genomic signature of progressive metastatic prostate cancer

In prospectively followed cohort of participants with prostate cancer, participants who develop metastatic disease will be identified, and approached for genomic testing before initiation of ADT. The investigators plan to characterize the genomics of metastatic prostate cancer using whole exome sequencing for single nucleotide variations (SNVs), gene rearrangements (GRs) and copy number variants/alternations (CNVs). Eligible participants are those who develop measurable and biopsiable metastatic disease (i.e. lymph nodes or bone lesion) that is detected using classical radiological staging methods (bone scan, computerized tomography) regardless of underwent primary treatment method (radical prostatectomy or radiotherapy). DNA will be extracted from archived tissue (formalin-fixed paraffin embedded - FFPE) for all biological specimens - either in dominant lesion in radical prostatectomy or diagnostic prostate biopsy and metastasis, using approved protocol for nucleic acid extraction. Availability of radical prostatectomy specimen and largest metastasis would allow for significant amounts of tissue for initial whole exome sequencing (WES) of the primary tumor and metastasis (200x deep sequencing relative to 30x normal blood DNA sequencing). The plan is to obtain tissue from the same metastasis after onset of castrate resistance (if clinically available) as well. Bioinformatics analyses will be performed to obtain panel of genomic changes encompassing whole disease spectrum. The investigators will then compare all these clonal signals to determine if these metastatic clones were present in primary tumor at the time of the initial diagnosis, prior to any treatment and if treatment-resistant clones were present early, before initiation of therapy for metastatic disease. This will test the concept of treatment (ADT)-induced selection versus adaptation during a course of ADT and develop novel signatures of SNV, CNV and GRs within two levels of metastases that have not yet been clearly defined.

(ii) Aim 4, 5: Comparative analysis between DNA profile of primary tumor and metastases, so this project might augment knowledge on site-specific signature(s) predictive for this outcome in highly heterogeneous population of prostate cancer patients.

Translational relevance

The results generated from the proposed work might be relevant in the push towards personalised therapies in prostate cancer patient's management. Currently, there is no personalized approach in this area as all patients are being treated in the same manner regardless of underlying biology of the disease. In the case example of metastatic prostate cancer where ADT is primary treatment modality, there is a potential for clinical utility of genomic signature that predicts failure to hormonal therapy and gives insight of driving mutations of disease progression, from primary tumor to metastases. Finally, relevant data will be gathered on feasibility of genomic testing in the multimodal management of patients with metastatic prostate cancer for the first time in Croatia. There is also a point of assessing utility of obtained genetic information for presumable use of targeted therapies and making treatment decisions in the real-world clinical setting in transitional eastern European country with emerging pharmaceutical market.

Study Type

Interventional

Enrollment (Anticipated)

60

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

  • Name: Ana Fröbe, MD, PhD
  • Phone Number: 468 +38513787111
  • Email: afrobe@irb.hr

Study Locations

  • Croatia
      • Zagreb, Croatia, 10000
        • Recruiting
        • Ana Frobe
        • Contact:
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 80 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

Male

Description

Inclusion Criteria:

  1. Male patients with newly diagnosed metastatic prostate cancer
  2. Androgen dependent disease measured by declining PSA
  3. ECOG PS 0 or 1
  4. Life-expectancy based on comorbid conditions >2 years
  5. Ability to understand and willingness to sign informed consent
  6. Must be candidate for radiation therapy

Exclusion Criteria:

  1. Poor performance status, history of connective tissue disorder
  2. Psychiatric or medical conditions which would not allow the patient to undergo the proposed treatment safely
  3. Known brain metastasis

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: pelvic radiotherapy
long-term hormonal therapy (LHRH agonist and/or antiandrogens) plus radiotherapy to the pelvis and prostate
Radiation: Radiotherapy to the pelvis
Radiotherapy to the pelvis and prostate
Drug: Hormonal therapy (LHRH agonist and/or antiandrogens)
life-long hormonal therapy (LHRH agonist and/or antiandrogens)
Other Names:
  • medical castration and/or antiandrogens
Active Comparator: No pelvic radiotherapy
long-term hormonal therapy ( LHRH agonist and/or antiandrogens) alone
Drug: Hormonal therapy (LHRH agonist and/or antiandrogens)
life-long hormonal therapy (LHRH agonist and/or antiandrogens)
Other Names:
  • medical castration and/or antiandrogens

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Disease progression-free survival
Time Frame: 4 years
Time to prostate specific antigen (PSA) progression
4 years

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Prostate, bone marrow and viscera progression-free survival
Time Frame: 4 years
Number of participants with radiographic disease progression in prostate, bone and visceral organs
4 years
Expression of integrins
Time Frame: 4 years
Number of participants with expression of analysed genes : 2 housekeeping genes; integrin subunits αv, β3, β5, α4β1 ; 3 EMT markers N-cadherin, E-cadherin, vimentin before radiotherapy, after radiotherapy and at the time of the disease progression
4 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University Hospital "Sestre Milosrdnice"

Investigators

  • Principal Investigator: Ana Fröbe, MD, PhD, UHC Sestre Milosrdnice, Department of Oncology and Nuclear Medicine, Vinogradska 29, 10 000 Zagreb, Croatia

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

September 1, 2018

Primary Completion (Anticipated)

December 1, 2020

Study Completion (Anticipated)

December 1, 2020

Study Registration Dates

First Submitted

September 13, 2016

First Submitted That Met QC Criteria

September 21, 2016

First Posted (Estimate)

September 26, 2016

Study Record Updates

Last Update Posted (Actual)

October 11, 2018

Last Update Submitted That Met QC Criteria

October 10, 2018

Last Verified

October 1, 2018

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • UHSestre

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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