| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| metastatic or locally advanced colorectal cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
| Cancer of the bowel that is not completely removable by surgery or it has spread to elsewhere in the body |
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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 | 10052362 |
| E.1.2 | Term | Metastatic colorectal cancer |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 primary objectives are:
1) For patients with the same tumour type (characterised by the results of the molecular tests), do the proposed new agents significantly increase the length of time for a patient to die, or for their tumour to increase in size by at least 20% when compared to patients having a treatment break after their first-line chemotherapy, in the time period after standard first-line?
2) Do the patients who have a particular genetic mutation identified by the molecular tests respond better to a proposed new agent than the patients who do not have that particular mutation?
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| E.2.2 | Secondary objectives of the trial |
Secondary research questions are:
1) Do the patients taking the proposed new agents experience an unacceptably higher level of toxicity symptoms and side-effects compared to the patients in the no treatment comparison group?
2) Are there any differences in safety outcomes (eg. occurence of heart or kidney disease) between the patients taking the proposed new agents and those in the no treatment comparison group?
3) Does quality of life (measured by the EuroQol 5D questionnaire) differ between the patients taking the proposed new agents and those in the no treatment comparison group? This is currently only applicable to patients in FOCUS4-N. |
|
| 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 |
| Biopsy Sub-study: Fresh tumour biopsies before starting trial treatment and on progression will be requested from those patients with accessible tumour and who give consent to extra biopsies. Recent evidence has revealed how heterogeneous (variable) an individual's cancer is and that each cancer is unique to that individual. In addition, cancers can change as a result of exposure to therapy. This sub study will compare the molecular characteristics before starting trial treatment and on progression to those found in the original diagnostic biopsy. The aim is to identify more accurate biomarkers that predict response to one of the treatments. We also aim to discover the ways that resistance occurs to the treatments to see if we can identify better treatments in the future. |
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| E.3 | Principal inclusion criteria |
1.Male or female patients at least 18 years old at registration
2.FFPE tumour block taken prior to the commencement of standard first-line treatment and available for biomarker analysis
3.Histologically confirmed adenocarcinoma of the small bowel or colon or rectum
4.Inoperable metastatic or locoregional disease (synchronous or metachronous)
5.WHO performance status 0, 1 or 2 (see Appendix III)
6.Disease which could be RECIST reported v1.1 classification as unidimensionally measurable disease (see Appendix IV) from the CT scan taken following inclusion criteria 7.
7.Have had an electronically accessible CT scan performed. This scan should ideally be performed just before but no more than six weeks prior to commencement of standard first-line treatment. Unavoidable delays of a few days for scheduling reasons may be approvable, but sites must contact the MRC CTU prior to registering the patient. CT scans performed a few days after the start date of standard first-line treatment may also be approvable, but only due to uncontrollable circumstances and only after discussion with the MRC CTU team and prior to registering the patient.
8.Women of child bearing potential must be willing to use adequate contraceptive measures (see Appendix V for contraindications of oral contraceptives) from registration into FOCUS4 to 7 weeks after ending first-line treatment and during, and 6 weeks after any subsequent randomised treatment in one of the FOCUS4 comparisons, should not be breastfeeding and must have a negative pregnancy test at any point prior to registration. Women of non-child bearing potential should fulfil one of the following criteria at screening:
Post menopausal as defined by:
Aged ≥50 years and amenorrhoeic for at least 12 months following cessation of all exogenous hormonal treatments
Aged <50 years and amenorrhoeic for at least 12 months following cessation of all exogenous hormonal treatments and with luteinising hormone and follicular stimulating hormone levels in the post-menopausal range
Documentation of irreversible surgical sterilisation by hysterectomy, and/or bilateral oophorectomy and/or bilateral salpingectomy but excludes bilateral tubal ligation
9.Male patients with partners of child bearing potential should be willing to abstain or use barrier contraception (i.e., condoms) for the duration of standard first-line treatment following registration and for 3 months after stopping any treatment administered as part of FOCUS4 (standard first line treatment, or subsequent randomised treatment). Male patients wishing to father children whilst taking standard first-line treatment and 3 months after stopping standard first-line treatment should be counselled on freezing sperm samples before starting standard first-line treatment.
10.Consent for screening of an archival FFPE tumour block for biomarker analysis
11.Patients who have already commenced on standard first-line treatment must be registered for the trial during the first 12 weeks of first-line treatment (this allows approximately 6 weeks for return of their biomarker results prior to the end of first-line treatment)
12.Patients should have sufficient capacity for informed consent assessed at the treating physicians discretion
13.Patient has provided signed informed consent
For inclusion criteria for randomisation into FOCUS4-C, please refer to section 3.3.1 of the FOCUS4-C protocol v6.0 dated 17.09.2019.
For inclusion criteria for randomisation into FOCUS4-N, please refer to section 3.3.1 of the FOCUS4-N protocol v5.0 dated 11.09.2019. |
|
| E.4 | Principal exclusion criteria |
1.Any previous systemic palliative chemotherapy for established advanced or metastatic disease except single agent capecitabine as a radiosentiser in a setting with potential curative intent such as leading to possible resection.
2.Adjuvant chemotherapy given in the 6 months prior to commencing standard first-line treatment
3.Patients with brain metastases
4.Pregnant and lactating women
5.Patients with known HIV, hepatitis B or hepatitis C infection
For exclusion criteria for randomisation into FOCUS4-C, please refer to section 3.3.2 of the FOCUS4-C protocol v6.0 dated 17.09.2019.
For exclusion criteria for randomisation into FOCUS4-N, please refer to section 3.3.2 of the FOCUS4-N protocol v5.0 dated 11.09.2019. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
There are no primary outcome measures for the registration period as no interventions are being compared during this period.
The primary outcome measure for the subsequent FOCUS4 comparisons that commence at the end of the registration period will be Progression-Free Survival (PFS) defined as progression of disease according to RECIST v1.1 criteria or death from any cause. Analysis will be timed from randomisation with the baseline CT scan performed within 4 weeks prior to randomisation.
For trials that complete Stage III, at this point, a decision will be made on whether to revise power calculations to include Overall Survival (OS) as an additional primary outcome measure.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Each molecular cohort utilises the Multi-Arm, Multi-Stage (MAMS) design and incorporates pre-specified interim analyses. The nstage programme in STATA statistical software uses previous data on event rates for the primary outcome to anticipate when the interim analyses are likely to occur.
For FOCUS4-C (see specific trial protocol for details)
Stage I - 17 months
Stage II - 28 months
FOCUS4-N does not utilise a MAMS approach but interim analyses will still be performed with stopping rules based upon either harm or benefit in the capecitabine arm. An IDMC Charter will describe the decision-making processes including stopping rules and the timing of interim analyses. |
|
| E.5.2 | Secondary end point(s) |
| Secondary outcomes will include evaluation of disease control, safety and toxicity starting from time of randomisation. In some instances measurement of quality of life using the EuroQol 5D questionnaire may be used for trials that proceed beyond Stage II. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Analysis of the secondary endpoints is likely to coincide with the analyses for the primary outcomes but this will be at the discretion of the IDMC. |
|
| 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 | Yes |
| 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 | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| 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) | Yes |
| 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 | Yes |
| 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) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
|
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| 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 | 94 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| 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
|
The FOCUS4 Trial Programme will be considered closed 12 months after the last patient’, last visit
has been completed for the last comparison. Further long-term follow-up may be completed via
linkage with central NHS data registries for the patients who have consented for their data to be
used. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 8 |
| E.8.9.1 | In the Member State concerned months | 1 |
| E.8.9.1 | In the Member State concerned days | 31 |
| E.8.9.2 | In all countries concerned by the trial years | 8 |
| E.8.9.2 | In all countries concerned by the trial months | 1 |
| E.8.9.2 | In all countries concerned by the trial days | 31 |
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