The BARCODE 2 Study - The Use of Genetic Profiling to Guide Prostate Cancer Treatment (BARCODE2)

• ClinicalTrials.gov Identifier: NCT02955082
• Recruitment Status: Recruiting
• First Posted: November 4, 2016
• Last Update Posted: February 17, 2020
• Sponsor: Institute of Cancer Research, United Kingdom
• Collaborators: Royal Marsden NHS Foundation Trust; European Research Council; Colchester Hospital University NHS Foundation Trust; Imperial College Healthcare NHS Trust; Dartford and Gravesham NHS Foundation Trust; Medway NHS Foundation Trust; Southend University Hospital Foundation NHS Trust; Great Ormond Street Hospital for Children NHS Foundation Trust; Maidstone & Tunbridge Wells NHS Trust; East and North Hertfordshire NHS Trust; Royal Free Hampstead NHS Trust; The Whittington Hospital NHS Trust; Luton and Dunstable Hospital NHS Foundation Trust; Buckinghamshire Healthcare NHS Trust; Chelsea and Westminster NHS Foundation Trust; Frimley Park Hospital NHS Trust; North Middlesex University Hospital NHS Trust; Whipps Cross University NHS Trust; Barts & The London NHS Trust; Heatherwood and Wexham Park Hospitals NHS Foundation Trust
• Information provided by (Responsible Party): Institute of Cancer Research, United Kingdom

Study Description

Brief Summary:

Prostate cancer (PrCa) is one of the commonest cancer in men in the Western world, with over 40,000 new cases diagnosed each year in the United Kingdom (UK). Research studies have identified several genetic changes that are thought to increase the risk of developing prostate cancer. Some of these genetic changes occur in deoxyribonucleic acid (DNA) repair genes. The BARCODE 2 study is formed of two parts that aim to investigate how having genetic changes in DNA repair genes can affect response to treatment. In part 1 of the study, the investigators will invite men with metastatic castration resistant prostate cancer (mCRPC) who have not had genetic testing before to join the study by initially undergoing genetic screening within the study. If a pathogenic mutation is confirmed in one of these genes, patients will be given the option to proceed to part 2 of the study. In part 2 of the study, men with mCRPC who are known to be carriers of a mutation in DNA repair gene(s) will be assessed for eligibility for treatment on the study. The aim of the study will be to determine how patients with mCRPC and a germline mutation in a DNA repair gene(s) respond to platinum chemotherapy. This study will help researchers to investigate the platinum sensitivity of prostate tumours that have developed due to a germline mutation in a DNA repair gene. This study will provide data to use in a larger clinical trial of platinum chemotherapy based on patients' germline genetic signature and/or tumour genetic profile.

Condition or disease	Intervention/treatment	Phase
Hormone Refractory Prostate Cancer	Drug: Carboplatin	Phase 2

Detailed Description:

Purpose and Design

BARCODE 2 is a single arm, single site phase II study with the aim to determine the response rate to two cycles of platinum chemotherapy in patients with mCRPC and a germline mutation in a DNA repair gene. Response will be measured with prostate specific antigen (PSA) levels and radiological assessment. The study will be divided into two parts. In part 1 of the study, enrolled patients' DNA repair gene mutation carrier status will be assessed using a gene panel. Men who are found to carry a pathogenic mutation or are already known to carry a germline mutation can enrol in part 2 of the study and be offered treatment with carboplatin.

Eligibility and Recruitment

Patients with mCRPC which has progressed after docetaxel and abiraterone or enzalutamide may be assessed for eligibility for study entry.

Inclusion Criteria

All study participants will be assessed according to the part 1 and/ or part 2 inclusion criteria depending on which part of the study they enter initially.

Informed Consent

Participants will be given the current ethically approved BARCODE 2 patient information sheet for their consideration. Patients will only be asked to consent to the study after they have had sufficient time to consider the trial, and the opportunity to ask any further questions. Patients who have not had previous genetic testing will sign the part 1 consent form to undergo genetic profiling for a germline mutation in a DNA repair gene. Patients who are found to have a pathogenic mutation in part 1 or who are already known to carry a germline mutation must sign the part 2 consent form prior to undergoing part 2 study related procedures.

Patient Confidentiality

Patients will be asked to consent to their full name being collected at trial entry in addition to their date of birth, hospital number, postcode and National Health Service (NHS) number or equivalent to allow linkage with routinely collected NHS data and ensure accuracy in handling biological samples.

Investigators will ensure that all participants' personal identifier information is kept on a separate log.

Investigators will retain trial documents in strict confidence. Investigators will maintain the confidentiality of participants at all times and will not reproduce or disclose any information to third parties by which participants could be identified (without consent).

Data Protection

The study will comply with all applicable data protection laws.

Subject Withdrawal

Participants may discontinue from trial at any time at their own request, or they may be discontinued from trial treatment at the discretion of the Principal Investigator (PI). Reasons for discontinuation will include:

• Clinical or radiological disease progression.
• Unacceptable toxicity (e.g. unresolving grade ≥2 neuropathy or neutropenia)
• Any other reason deemed appropriate by investigator. Increases in PSA will not be a criterion for treatment discontinuation in the absence of clinical or radiological progression. Participants who discontinue treatment should continue to be followed up until death.

Post-treatment Follow-up

Follow up data will be collected on all patients entering part 2 of the study until death, including cause of death. Participants who discontinue treatment should continue to be followed up until death.

Discontinuation from Follow-up

If a patient withdraws from further follow-up a trial deviation form should be submitted to Oncogenetics Team stating whether the patient has withdrawn consent for information to be sent to the Oncogenetics Team or whether they simply no longer wish to attend trial follow up visits. In the very rare event that a patient requests that their data is removed from the study entirely, the implications of this should be discussed with the patient first to ensure that this is their intent and, if confirmed, the Oncogenetics Team should be notified in writing. If this request is received after results have been published the course of action will be agreed between the Sponsor and Independent Data Monitoring and Steering Committee.

Trial Management

A Trial Management Group (TMG) will be set up and will include the Chief Investigator, the Trial Statistician and Trial Manager. Key study personnel will be invited to join the TMG as appropriate to ensure representation from a range of professional groups, including a PI from a Participant Identification Centre (PIC). The TMG will meet at regular intervals, and at least annually.

Independent Data Monitoring and Steering Committee (IDMSC)

A joint Independent Data Monitoring and Steering Committee (IDMSC) will be set up to oversee the safety of the trial participants, monitor the data produced by the trial, put these data into overall context and supervise the progress of the trial towards its interim and overall objectives.

Publication and Data Sharing Policy

The main trial results will be published in a peer-reviewed journal, on behalf of all collaborators. Anonymised data can be applied for via the Data Access Committee.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 450 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: The BARCODE 2 Study - The Use of Genetic Profiling to Guide Prostate Cancer Treatment
• Actual Study Start Date: May 25, 2017
• Estimated Primary Completion Date: September 30, 2020
• Estimated Study Completion Date: April 25, 2022

Arms and Interventions

Arm	Intervention/treatment
Experimental: Carboplatin; Patients with a germline DNA repair gene mutation identified in part 1 of the study, or who are already known to have a germline mutation will undergo assessment for inclusion in part 2 of the study to receive Carboplatin treatment.	Drug: Carboplatin; Intravenous carboplatin infusion every 3 weeks.; Other Name: Paraplatin

Outcome Measures

Primary Outcome Measures :

1. Radiographic Treatment Response [ Time Frame: 6 weeks ]
   Response rate to two cycles of platinum chemotherapy in patients with mCRPC and germline DNA repair gene mutations using the modified response evaluation criteria in solid tumours (RECIST) 1.1 criteria
2. Biochemical Treatment Response [ Time Frame: 6 weeks ]
   Reduction of more than 50% in PSA levels in response to two cycles of platinum chemotherapy in patients with mCRPC and germline DNA repair gene mutations.

Secondary Outcome Measures :

1. Overall survival of men with mCRPC and germline DNA repair gene mutations [ Time Frame: This will be evaluated 3 months after end of study treatment ]
   Overall survival of patients with mCRPC and a DNA repair gene mutation treated with carboplatin.
2. Progression-free survival of men with mCRPC and germline DNA repair gene mutations [ Time Frame: This will be evaluated 3 months after end of study treatment ]
   Progression free survival of patients with mCRPC and a DNA repair gene mutation treated with carboplatin.
3. Incidence of germline DNA repair gene mutations in a population of mCRPC cases [ Time Frame: Through study completion, up to 3 years ]
   Incidence of germline DNA repair gene mutations will be calculated from the rate of pathogenic mutations observed in the group of men who undergo genetic profiling within part 1 of the study.
4. Cause specific survival [ Time Frame: This will be evaluated 3 months after end of study treatment ]
   Cause specific survival from date of first diagnosis of prostate cancer in patients with DNA repair gene mutations.
5. Radiographic progression free survival [ Time Frame: This will be evaluated 3 months after end of study treatment ]
   Radiographic Progression free survival will be measured from the date of trial entry to the first occurrence of radiographic progression or death.
6. Time to radiographic progression [ Time Frame: This will be evaluated 3 months after end of study treatment ]
   Time to radiographic progression will be measured from the date of trial entry to the first occurrence of radiographic progression.
7. PSA objective responses [ Time Frame: This will be evaluated 3 months after end of study treatment ]
   PSA response and PSA progression are defined according to the consensus guidelines of the Prostate Cancer Working Group 3 (PCWG3).

Eligibility Criteria

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

Criteria

Inclusion Criteria:

All study participants will be assessed according to the part 1 and/ or part 2 inclusion criteria depending on which part of the study they enter initially.

For Part 1 (genetic screening) of the study:

1. Age ≥ 18 years.
2. Histologically confirmed prostate adenocarcinoma. A copy of the original histology report from biopsy or surgery must be obtained.
3. Castration-resistant disease defined as biochemical or radiological progression on/after treatment with orchidectomy or Luteinizing hormone-releasing hormone (LHRH) analogues as per PCWG3 criteria.
4. Confirmed metastatic disease on conventional imaging methods such as computed tomography (CT), bone scan or positron emission tomography (PET) imaging.
5. Current or previous treatment including docetaxel and/or enzalutamide/ abiraterone
6. Adequate renal function measured by calculated glomerular filtration rate (GFR) (Cockcroft-Gault) >30ml/min. This must be documented within 7 days of registration. If a patient had renal dysfunction that is expected to improve, they may be considered for part 1 of the study
7. Adequate haematological function (haemoglobin ≥10g/dl, neutrophil count >1.5x109/L and platelets >100x109/L). This must be documented within 7 days of registration.
8. World Health Organisation (WHO) performance status 0-2 as assessed and documented by study doctor.
9. Life expectancy >12 weeks
10. Patients with stable, treated brain metastases will be eligible providing informed consent can be given and that other sites of measurable disease are present
11. The subject is capable of understanding and complying with the protocol requirements and has signed the BARCODE 2 informed consent form.

In addition to the above, for Part 2 of the study:

1. Confirmed pathogenic germline mutation in a DNA repair gene. (Patients with a known germline mutation will need to provide a report from the external laboratory where genetic testing was carried out)
2. Previous treatment with docetaxel and abiraterone or enzalutamide with documented disease progression prior to entry to part 2 (rising PSA and/or radiographic progression)
3. Adequate liver function: Total bilirubin ≤1.5 x upper limit of normal (ULN) except for patients with known Gilbert's syndrome; aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5x ULN in the presence of liver metastases.
4. Adequate renal function: creatinine clearance >40ml/min measured by ethylenediaminetetraacetic acid (EDTA) clearance.

Exclusion Criteria (for part 1 and 2):

1. Critical organ metastases (e.g. spinal metastases with risk of cord compression) as documented on most recent imaging report.
2. Patients with bleeding tumours.
3. Previous treatment with a platinum chemotherapy drug for prostate cancer.
4. Previous treatment with a poly adenosine diphosphate (ADP) ribose polymerase (PARP) inhibitor
5. Patients with a history of severe allergic reaction to carboplatin or other platinum-containing compounds
6. Exposure to yellow fever vaccine in the previous 6 months.
7. Patients unfit for chemotherapy or those with ongoing neuropathy >grade 1 (sensory or motor) according to the National Cancer Institute (NCI) common terminology criteria for adverse events (CTCAE) V4.02.
8. Known and documented hearing impairment
9. Other active malignancies or previous malignancies likely, in the PI's opinion, to impact on management of mCRPC.
10. Significant documented cardiovascular disease: severe/unstable angina, myocardial infarction less than 6 months prior to trial entry, arterial thrombotic events less than 6 months prior to trial entry, clinically significant cardiac failure requiring treatment (New York Heart Association (NYHA) classes II-IV).
11. Cerebrovascular disease (cerebrovascular accident (CVA) or transient ischaemic attach (TIA)) in the preceding 2 years to entry to Part 2 of study.
12. Presence of symptomatic brain metastases.

Contacts and Locations

Contacts

Contact: Elizabeth K Bancroft, PhD; +44 207 808 2136; elizabeth.bancroft@icr.ac.uk

Contact: Eva McGrowder, PhD; +44 20 8722 4483; eva.mcgrowder@icr.ac.uk

Locations

United Kingdom

Institute of Cancer Research and Royal Marsden Hospital; Recruiting

Sutton, Surrey, United Kingdom, SM2 5PT

Contact: Rosalind A Eeles, FRCP FRFR 02086613642 rosalind.eeles@icr.ac.uk

Principal Investigator: Rosalind A Eeles, FRCP FRCR

Sponsors and Collaborators

Institute of Cancer Research, United Kingdom

Royal Marsden NHS Foundation Trust

European Research Council

Colchester Hospital University NHS Foundation Trust

Imperial College Healthcare NHS Trust

Dartford and Gravesham NHS Foundation Trust

Medway NHS Foundation Trust

Southend University Hospital Foundation NHS Trust

Great Ormond Street Hospital for Children NHS Foundation Trust

Maidstone & Tunbridge Wells NHS Trust

East and North Hertfordshire NHS Trust

Royal Free Hampstead NHS Trust

The Whittington Hospital NHS Trust

Luton and Dunstable Hospital NHS Foundation Trust

Buckinghamshire Healthcare NHS Trust

Chelsea and Westminster NHS Foundation Trust

Frimley Park Hospital NHS Trust

North Middlesex University Hospital NHS Trust

Whipps Cross University NHS Trust

Barts & The London NHS Trust

Heatherwood and Wexham Park Hospitals NHS Foundation Trust

Investigators

• Principal Investigator: Rosalind A Eeles, FRCP, FRFR; Institute of Cancer Research and Royal Marsden Hospital

More Information

Publications:

Scher HI, Morris MJ, Stadler WM, Higano C, Basch E, Fizazi K, Antonarakis ES, Beer TM, Carducci MA, Chi KN, Corn PG, de Bono JS, Dreicer R, George DJ, Heath EI, Hussain M, Kelly WK, Liu G, Logothetis C, Nanus D, Stein MN, Rathkopf DE, Slovin SF, Ryan CJ, Sartor O, Small EJ, Smith MR, Sternberg CN, Taplin ME, Wilding G, Nelson PS, Schwartz LH, Halabi S, Kantoff PW, Armstrong AJ; Prostate Cancer Clinical Trials Working Group 3. Trial Design and Objectives for Castration-Resistant Prostate Cancer: Updated Recommendations From the Prostate Cancer Clinical Trials Working Group 3. J Clin Oncol. 2016 Apr 20;34(12):1402-18. doi: 10.1200/JCO.2015.64.2702. Epub 2016 Feb 22.

• Responsible Party: Institute of Cancer Research, United Kingdom
• ClinicalTrials.gov Identifier: NCT02955082
• Other Study ID Numbers: CCR4520
• First Posted: November 4, 2016
• Last Update Posted: February 17, 2020
• Last Verified: February 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: Anonymised data can be applied for via the Data Access Committee.

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Prostatic Neoplasms; Genital Neoplasms, Male; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Prostatic Diseases; Carboplatin; Antineoplastic Agents