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BARCODE 2: Targeting cancer care with the use of genetic profiling

The BARCODE 2 trial is a single arm, single site phase II study with the aim to investigate how having genetic changes in deoxyribonucleic acid (DNA) repair genes can affect response to treatment. This study will utilise knowledge of the germline status of DNA repair genes to alter the treatment pathway for metastatic castration resistant prostate cancer patients.

It is formed of two parts that aim to determine the response rate to two cycles of platinum chemotherapy in patients with metastatic castration resistant prostate cancer (mCRPC) and a germline mutation in a DNA repair gene.

In part 1 of the study, the investigators will invite men with mCRPC who have not had genetic testing before to join the study by initially undergoing genetic screening within the study. The DNA repair gene mutation carrier status of enrolled patients will be assessed using a gene panel. 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 with carboplatin chemotherapy. 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.

Initially, participants will be offered two courses of Carboplatin (AUC6) followed by assessment of response based on prostate specific antigen (PSA) levels and radiological assessment. Participants who show a response to treatment or stable disease will continue with four more courses of Carboplatin.

A further confirmatory scan follows after the third cycle. Men who show disease progression after two cycles will end the study and proceed with standard off-study care. This is a hypothesis generating study, to test 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.

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, where possible. Patients who have not previously undergone a prostate (or metastatic) biopsy but are confirmed to have a raised PSA (>80ng/ml at any time), metastatic disease on imaging and have undergone treatment for mCRPC are eligible.

3.     Castration-resistant disease defined as biochemical or radiological progression on/after treatment with orchidectomy or Luteinizing hormone-releasing hormone (LHRH) analogues as per the Prostate Cancer Working Group 3 (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 at least one of the following:

a) Docetaxel (either in hormone sensitive or resistant setting; Patients who have completed treatment with or are currently undergoing Cabazitaxel chemotherapy are also eligible).

b) Androgen receptor-directed therapy (e.g., Enzalutamide or Abiraterone).

6.     Adequate renal function measured by calculated glomerular filtration rate (GFR) (Cockcroft-Gault) >30ml/min. 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 to allow study entry in line with local hospital practice or at the investigator’s discretion.

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 androgen receptor-directed therapy (e.g., abiraterone or enzalutamide) with documented disease progression prior to entry to part 2 (rising PSA and/or radiographic progression). Patients previously treated with cabazitaxel and who have documented disease progression are also eligible.

3.     Adequate haematological function: Haemoglobin (Hb) ≥8.0g/dL, neutrophil count ≥1.5x109/L and platelets ≥100x109/L.

4.     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.

5.     Adequate renal function: creatinine clearance >30ml/min measured by glomerular filtration rate (GFR) clearance test. If measure GFR test is not available, the calculated GFR is acceptable (measured GFR must be carried out by cycle 2 of carboplatin).

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 investigator’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.