Biomarker-driven Intermittent Docetaxel Versus Standard-of-care (SOC) Docetaxel in Metastatic Castration-resistant Prostate Cancer

Study Overview
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Brief Summary
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The purpose of this study is to see if a prostate cancer marker in the blood (mGSTP1) can be used to guide chemotherapy treatment. Based on the level of this blood marker, some men may be able to have breaks in treatment rather than having chemotherapy continuously which is the current standard of care. This study will tell us if having these treatment breaks guided by mGSTP1 can improve how men feel during treatment while still treating the prostate cancer effectively. Docetaxel is a chemotherapy drug that is approved to treat prostate cancer and has been used for many years to treat prostate cancer like yours. Your doctor has already discussed this with you and you have both agreed that docetaxel is the best treatment for you to have at this time. You will have already started this chemotherapeutic treatment with docetaxel.

Official Title
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A Randomised Non-comparative Phase II Trial of Biomarker-driven Intermittent Docetaxel Versus Standard-of-care (SOC) Docetaxel in Metastatic Castration-resistant Prostate Cancer (mCRPC)

Conditions
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Castration Resistant Prostatic Cancer

Intervention / Treatment
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* Drug: Docetaxel intermittent
* Drug: Docetaxel standard of care


Participation Criteria
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Eligibility Criteria
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PRESCREENING INCLUSION CRITERIA Patient has provided written informed consent using the GUIDE pre-screening PICF Age ≥ 18 years at the time of pre-screening consent Males with metastatic castration-resistant prostate cancer (as per PCWG3) AND are planned to commence docetaxel chemotherapy WHO Eastern Cooperative Oncology Group (ECOG) performance status 0-2 (Appendix 1) Histological confirmation of prostate cancer Patients must have adequate bone marrow and hepatic function within 14 days prior Cycle 1 day 1: Haemoglobin ≥ 90 g/L independent of transfusions (no red blood cell transfusion in last 4 weeks) Platelets ≥ 100 x 109/L Absolute neutrophil count (ANC) ≥ 1.5 x 109/L Serum total bilirubin ≤ 1.5 x upper limit of normal (ULN) Alanine aminotransferase (ALT)/Aspartate aminotransferase (AST) ≤ 2.5 x ULN Willing and able to comply with all pre-screening study requirements, including blood tests for mGSTP1 analysis before and during docetaxel treatment PRESCREENING EXCLUSION CRITERIA Prior docetaxel or cabazitaxel chemotherapy for castration-resistant prostate cancer Prior docetaxel in the castration sensitive prostate cancer setting within the previous 2 years Known hypersensitivity to docetaxel or its excipients Concurrent illness, including severe infection that may jeopardise the ability of the patient to undergo the procedures outlined in this protocol with reasonable safety Serious medical or psychiatric conditions that might limit the ability of the patient to comply with the protocol MAIN SCREENING INCLUSION CRITERIA Patient has provided written informed consent for the main GUIDE study PICF Patient has a detectable plasma mGSTP1 deoxyribonucleic acid (DNA) as measured by central laboratory at prescreening prior to commencing first cycle of docetaxel chemotherapy Patient has commenced 3 cycles of docetaxel Patient has undetectable plasma mGSTP1 DNA as measured by central laboratory from blood taken prior to the third cycle of docetaxel Patient is willing and able to comply with all study requirements, including treatment, timing and/or nature of required assessments. MAIN SCREENING EXCCLUSION CRITERIA Known hypersensitivity to docetaxel or its excipients Concurrent illness, including severe infection that may jeopardise the ability of the patient to undergo the procedures outlined in this protocol with reasonable safety Serious medical or psychiatric conditions that might limit the ability of the patient to comply with the protocol Progressive disease by RECIST 1.1 within the first 3 cycles of docetaxel

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Parallel Assignment randomised non-comparative
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1: Intermittent docetaxel treatment<br>suspend docetaxel prior to cycle 4, recommencement based on mGSTP1 monitoring | Drug: Docetaxel intermittent<br>* After 3 cycles of docetaxel chemotherapy (75mg/m^2 every 21) in combination with an undetectable mGSTP1 level, patients randomised to this arm will stop docetaxel treatment. Plasma mGSTP1 is measured every 21 days and docetaxel treatment will be recommenced if it mGSTP1 becomes detectable again.<br>|
| Active Comparator: Arm 2: Standard of Care docetaxel treatment<br>Docetaxel administered as per Standard of Care: as per clinician recommendation | Drug: Docetaxel standard of care<br>* After 3 cycles of docetaxel chemotherapy (75mg/m^2 every 21) in combination with an undetectable mGSTP1 level, patients randomised to this arm will continue with standard Docetaxel treatment (75mg/m^2 every 21)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Radiographic progression free survival (rPFS) | Radiographic progression free survival (rPFS) is defined as the time from randomisation (i.e. prior to cycle 4), the date of first documented progression on imaging by site investigator (PCWG3 criteria for bone lesions and RECIST 1.1 for soft tissue lesions) or death due to any cause. | From randomisation until last patient has completed 2 years in follow up, on average 3.5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time on treatment holidays | Time on treatment holidays is defined as the total length of time patients on the intermittent docetaxel arm spend off docetaxel within the treatment period i.e. prior to permanent treatment discontinuation | From randomisation until last patient has completed 2 years in follow up, on average 3.5 years | 
| Overall treatment safety | Incidence and severity of adverse events (AEs) using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5. | From the date of signing consent on the Main study until 90 days after the last day of protocol treatment, on average 3.5 years | 
| Overall survival | Overall survival is defined as the time from randomisation to the date of death due to any cause | From randomisation until last patient has completed 2 years in follow up, on average 3.5 years | 
| Overall quality of life | Quality of Life using the EORTC QLQ-C30 (European Organisation for Research on Treatment of Cancer - Quality of Life Questionnaire for cancer patients) instrument. The instrument uses 28 questions about overall quality of life with each question answerable using a scale from 1 (not at all) to 4 (very much). Overall scores can be from a minimum of 28 indicating a better quality of life and higher scores with a maximum of 112 indicating lower overall quality of life. The questionnaire also has two summary questions which asks participants to rank 1) overall health and 2) overall quality of life on scale of from 1, very poor, to 7, excellent. | From randomisation until last patient has completed 2 years in follow up, on average 3.5 years | 
| Fatigue | Fatigue, using the EORTC FA-12 (European Organisation for Research on Treatment of Cancer - Fatigue) instrument. This instrument uses 12 questions for participants about fatigue with each question answerable on a scale of 1 (not at all) to 4 (Very Much) to a maximum score of 48 indicating worse overall self-rated fatigue. | From randomisation until last patient has completed 2 years in follow up, on average 3.5 years | 
| Fear of progression | Fear of progression using the short FOP12 (Fear of Progression) instrument. This instrument uses 12 questions about participant's own Fear of Progression with each question answerable using a scale from Never to very often with lower scores indicating a better outcome. | From randomisation until last patient has completed 2 years in follow up, on average 3.5 years | 
| Patient reported adverse events | Patient reported adverse events using the patient reported modified PRO-CTCAE instrument | From randomisation until last patient has completed 2 years in follow up, on average 3.5 years | 
| Frequency of health resource utilisation | To compare resource use associated with mGSTP1 directed therapy per treatment group. Will be measured from trial based eCRFs and will include frequency of mGSTP1 testing, use of docetaxel and corticosteroids, pathology tests and imaging. Men participating in the GUIDE study will be consented for access to their Medicare claims data providing information on outpatient use of PBS listed therapies (such as those for metastatic bone disease) and Medicare services (such as outpatient clinician services) | From time of consent until End of Study, on average 3.5 years | 
| Overall cost associated with treatment | To compare costs associated with treatment per treatment group. Will be reported by type of health care used and the total cost of health care used over the period of the trial and follow-up. Market prices will be applied to items of resource use to estimate costs. | From time of consent until End of Study, on average 3.5 years |