| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced Castration Resistant Prostate Cancer |
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| E.1.1.1 | Medical condition in easily understood language |
| Prostate cancer that has spread to other areas in the body and that is resistant to hormonal treatment. |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10001198 |
| E.1.2 | Term | Adenocarcinoma of the prostate metastatic |
| E.1.2 | System Organ Class | 100000004864 |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
The principal research question is: Can CTCs be used for early identification of patients that are not receiving benefit from docetaxel chemotherapy?
The primary research objective is to determine if the use of serial CTC counts can direct early discontinuation of docetaxel chemotherapy and switch to cabazitaxel in patients with metastatic castration resistant prostate cancer (mCRPC) without adversely impacting overall survival, when compared with standard approaches to guide treatment switch decisions.
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| E.2.2 | Secondary objectives of the trial |
The secondary research objectives are:
• To determine clinician and patient acceptance and the feasibility of using CTC counts to guide patient treatment
• To determine if the use of serial CTC counts will decrease the administration of cytotoxic chemotherapy in this patient population.
• To determine if using serial CTC counts result in decreased toxicity burden of systemic therapy.
• To compare the quality of life assessment in patients whose chemotherapy treatment is switched with or without guidance from CTC monitoring
• To correlate progression free survival (PFS), radiographic progression free survival (rPFS) and time to symptomatic skeletal related events (SSRE) with CTC progression.
• To correlate treatment related changes in Prostate-Specific Antigen (PSA) and CTC.
• To establish the rate of response to docetaxel and cabazitaxel in CRPC patients who have received docetaxel in the hormone sensitive setting.
• To use CTC counts to develop a model to predict outcomes based on est |
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
TRANSLATIONAL SUB-STUDY:
The translational sub-study will include patients who have consented to the use of archival tissue, additional fresh tumour sample biopsies and/or blood collected for translational studies.
The main objective of the sub-study is to better understand; why people develop prostate cancer, the types of prostate cancer seen in patients and why some patients react to treatments differently.
QUALITY OF LIFE (QOL) SUB-STUDY:
The QOL sub-study is optional and will include only those patients who have confirmed their consent to participate. QOL will be assessed using validated questionnaires [Functional Assessment of Cancer Therapy-Prostate (FACT-P) and the European Quality of Life 5 Dimensions (EQ-5D)].
We anticipate that the switch from docetaxel to cabazitaxel treatment will be earlier in the Intervention Group, and that these patients will therefore be exposed to fewer cycles of ineffective docetaxel chemotherapy treatment and associated risk of toxicity.
The main objective of the QOL sub-study is therefore to assess if there is a difference in the number of side effects reported across the two treatment groups.
HEALTH ECONOMIC EVALUATION:
We anticipate that the switch from docetaxel to cabazitaxel treatment will be earlier in Intervention Group, minimizing exposure to potentially toxic and costly chemotherapy agents. The aim of the Health Economic Evaluation is therefore to assess any resource and cost savings resulting from this earlier evaluation of treatment response and switch to 2nd line chemotherapy treatment.
The health economic evaluation will be carried out in accordance with current NHS guidelines and with reference to the Consolidated Health Economic Evaluation Reporting Standards (CHEERS).
WHOLE BODY MAGNETIC RESONANCE IMAGING SUB-STUDY
Patients who consent to CTC-STOP may also be asked to consent to participate in an imaging sub-study. The imaging sub-studies will be undertaken at participating centres that have the necessary resources to comply with the sub-study requirements. All patients who consent to participate in the imaging sub-study will undergo WB-MRI using a standardised imaging protocol before and at 9 +/- 1 weeks after initiating chemotherapy (docetaxel). These MRI scans will be performed in addition to standard imaging tests (CT and BS) typically performed within the NHS at 3 to 6 months after starting therapy. The clinical team/ oncologists will be blinded to all MRI results so that these will not influence the trial management decision-making.
The WB-MRI images of participating patients in this sub-study will be evaluated centrally at the RMH/ICR using developmental software by an expert imaging team. The results derived from the first 48 patients will be used to establish the diagnostic criteria of WB-MRI for assessing treatment response in patients with prostate bone disease. |
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| E.3 | Principal inclusion criteria |
1. Written informed consent.
2. Age ≥18 years
3. Histologically confirmed diagnosis of adenocarcinoma of the prostate with availability of archival tumour tissue for molecular analyses (small cell prostate cancer is an exclusion); if no histological diagnosis has ever been acquired a fresh bone marrow trephine tumour biopsy confirming the presence of CRPC must be pursued.
o Tumour tissue blocks will be requested for processing. Sections will be cut with the blocks then returned to the referring hospital. If the block is not available, at least ten tumour tissue sections (formalin-fixed paraffin-embedded) at 5 microns each will be requested.
4. Metastatic castration-resistant disease with only bone metastases, confirmed by bone scan (within 4 weeks) or CT/whole body MRI (within 6 weeks), of starting this trial (Cycle 1 Day 1). Patients with local recurrence, and bone metastases with an associated soft tissue component, will be allowed into the trial. Pelvic lymphadenopathy <1.5cm in short axis is not an exclusion.
5. Systemic chemotherapy indicated for disease progression, defined as:
o Bone Scan Progression: Two or more new documented bone lesions over previous 6 months.
AND/OR
o Increasing serum PSA level: Two consecutive increases in PSA levels documented over a previous reference value obtained at least one week apart are required. If the third PSA value is less than the second, an additional fourth test to confirm the rising PSA is required.
6. Baseline laboratory values as stated below:
o Creatinine ≤1.5 x upper limit of normal (ULN)
o Bilirubin ≤1.0 x ULN
o SGOT (AST) and SGPT (ALT) ≤2.5x ULN
o Castrate serum testosterone level (<50 ng/dL-or-<1.7 nmol/L)
o ANC ≥1.5 x 109cells/L
o Platelet count ≥100 x 109/L
o PSA ≥ 5ng/mL
7. CTC levels ≥ 5 cells / 7.5 mL
8. Prior treatment with abiraterone and/or enzalutamide, discontinued due to disease progression.
9. Patient willing to continue primary androgen suppression with gonadotropin-releasing hormone (GnRH) analogues (either agonists or antagonists) throughout the study, unless treated with bilateral orchiectomy.
10. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1 (see Appendix A2).
11. At least 3 weeks should have elapsed since stopping any investigational agent at the time of randomisation. More than 4 weeks since completion of radiotherapy, other than when a single palliative fraction is administered when only a two week interval is required before trial treatment commencement.
12. Patient recovered from any therapy-related toxicity to ≤ grade 2, (except alopecia, anaemia and any signs or symptoms of androgen deprivation therapy).
13. Patient willing to comply with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial
14. Participants must be surgically sterile or must agree to use effective contraception during the period of the therapy and for 12 months after the last dose of study treatment. Effective contraception is defined as double barrier contraception (e.g. condom plus spermicide in combination with a female condom, diaphragm, cervical cap or intrauterine device).
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| E.4 | Principal exclusion criteria |
1. Received any prior cytotoxic chemotherapy as treatment for castration-resistant prostate cancer. Patients that have received chemotherapy for hormone-sensitive metastatic prostate cancer will be allowed onto the trial, if the patient merits retreatment with docetaxel and at least 12 months has elapsed since the patient has completed that previous docetaxel therapy.
2. Measurable soft tissue or lymph node metastases or any metastatic disease outside the bone that is RECIST measurable will be an exclusion (unless it is pelvic nodal disease <1.5cm in short axis). Bone metastases with associated soft tissue components will also not be an exclusion.
3. Received any cycling, intermittent or continuous hormonal treatment 28 days prior to randomisation with the exception of the continuous LHRH analogues.
4. History of or current documented brain metastasis or carcinomatous meningitis, treated or untreated. Brain imaging for asymptomatic patients is not required.
5. Current symptomatic cord compression requiring surgery or radiation therapy. (Once the patient is successfully treated the patient will be considered eligible for the study).
6. Active second malignancy (except non-melanoma skin or superficial bladder cancer) defined as requiring anticancer therapy or within the previous two years.
7. Serious medical conditions such as heart failure, myocardial infarction, pulmonary thromboembolism within 12 months; stroke or treatment of a major active infection within 3 months of randomisation, as well as any significant medical illness that in the opinion of the Investigator would preclude protocol therapy.
8. Planned concomitant participation in another clinical trial of an experimental agent, vaccine, or device. Concomitant participation in observational studies is acceptable.
9. Hypersensitivity to the active substance, to any of its excipients (including polysorbate 80) or to other taxanes.
10. Concomitant vaccination with yellow fever vaccine
11. Concomitant use of medicinal products that are strong CYP3A inducers |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Overall survival - defined as the time from the date of randomisation to the date of death (due to any cause). Patients alive at end of follow-up will be censored at the last documented date of follow-up.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The principal primary outcome analysis will be evaluated after all patients have been followed up for overall survival for a minimum of 24 months. No formal interim analysis to stop early for futility or efficacy are planned. The IDMC will monitor an excess of mortality rate in the intervention group. |
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| E.5.2 | Secondary end point(s) |
The secondary endpoints of CTC-STOP are:
1. Proportion of patients in the intervention group that undergo a chemotherapy switch from docetaxel to cabazitaxel guided by CTC results that fulfil the pre-specified criteria for progression.
2. Number of cycles of chemotherapy administered in each of the docetaxel groups.
3. Rate of adverse events and toxicity with first and second line chemotherapy.
4. Quality of life analysis by evaluation of outcome measures in the Functional Assessment of Cancer Therapy-Prostate (FACT-P) and EuroQoL 5D (EQ-5D) questionnaires.
5. Progression Free Survival (PFS)
6. Radiographic Progression Free Survival (rPFS)
7. Time to First Symptomatic Skeletal Related Event (SSRE)
8. Time to CTC progression
9. % Change from baseline values of CTC, PSA and pain (assessed by the Brief Pain Inventory (BPI)) during first and second line therapy.
10. Rate of pain response, PSA declines and CTC response to first and second-line chemotherapy.
11. Proportion of patients with a stable CTC count by 12-weeks (or earlier if 1st line treatment discontinued).
12. Health economic assessments
Translational sub-study: Will include only patients who have consented to the use of archival tissue, additional fresh tumour sample biopsies (bone trephine biopsy of the posterior iliac crest) and/or blood collected for translational studies. The translational objectives are:
1. To conduct tumour molecular analysis for predictive biomarkers of primary and acquired resistance to treatment, analysing tumour tissue, CTC, MDSCs, exosomes and plasma, evaluating the impact of these genomic aberrations on disease outcome.
2. To correlate treatment related changes in plasma cfDNA and CTC.
3. To analyse EpCam-negative CTC and CTC fragments in CELLSEARCH System instrument waste.
4. To evaluate pre-treatment whole blood expression analyses in treated patients, and the association of whole blood expression profiles with disease outcome.
5. To identify circulating biomarkers of primary and acquired resistance to taxane chemotherapy.
6. To evaluate the impact of the association of treatment and outcome with the neutrophil-lymphocyte ratio.
7. To associate white blood cell subpopulations at baseline, and changes following treatment, with disease outcome.
8. To associate MDSCs and NLR at baseline and their changes following treatment.
9. To analyse the feasibility of circulating tumour cell culture in a subset of patients.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
The feasibility of the intervention will be assessed after 200 patients have been randomised (>=100 patients in the intervention group) and have been followed for at least 24 weeks or until docetaxel discontinuation, whatever occurs first.
Other secondary endpoints will usually not be analysed in advance of the primary endpoint, and any change of timing of analyses of the secondary endpoints will need approval from the IDMC so as not to compromise the results of the primary endpoint.
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
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| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Information not present in EudraCT |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Standard of Care vs CTC count guided |
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| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 57 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.5.1 | Number of sites anticipated in the EEA | 3 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| End of trial is defined as date of last data capture. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | 12 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 12 |
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