| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Inoperable, locally recurrent or metastatic squamous cell carcinoma of the anus |
|
| E.1.1.1 | Medical condition in easily understood language |
| Inoperable or metastatic tumour of the anus |
|
| 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 | 16.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10041815 |
| E.1.2 | Term | Sq cell Ca anus |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The primary objective of the study is to compare the activity, in terms of overall response rate, of two combination chemotherapy regimens (cisplatin plus 5-fluorouracil vs. carboplatin plus weekly paclitaxel) for the first line treatment of patients with inoperable relapsed or metastatic squamous cell carcinoma of the anus. The results of the study will be used to inform the design of future phase III trials testing the addition of a targeted agent to the preferred chemotherapy regimen. |
|
| E.2.2 | Secondary objectives of the trial |
| The secondary objectives of the study are to provide estimates of differences in survival, toxicity and quality-of-life (QoL) endpoints between the two study arms. Exploratory biomarker research will also be undertaken in order to further investigate the role of the epidermal growth factor receptor (EGFR) pathway and other molecular pathways in predicting response or resistance to systemic chemotherapy. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Histologically or cytologically verified, uni-dimensionally measurable, inoperable, locally recurrent or metastatic squamous cell carcinoma of the anus.
2. Age ≥18 years.
3. ECOG PS ≤2.
4. Measurable disease according to Response Evaluation Criteria in Solid Tumours (RECIST) criteria version 1.1.
5. Previous definitive chemo-radiation is permitted for early stage squamous cell carcinoma of the anus.
6. HIV+ patients will be considered eligible with a CD4 count of ≥200.
7. Adequate cardiac and respiratory function; absolute neutrophil count (ANC) ≥1.5x109/l; white blood cell (WBC) count ≥3x109/l; platelets ≥100x109/l; haemoglobin (Hb) ≥9g/dl; creatinine clearance ≥50ml/minute; serum bilirubin ≤1.5x upper limit of normal (ULN); alanine transaminase (ALT)/aspartate transaminase (AST) ≤2.5x ULN; alkaline phosphatase (ALP) ≤3x ULN.
8. Life expectancy of at least 3 months.
|
|
| E.4 | Principal exclusion criteria |
1. Tumours of adenocarcinoma, melanoma, small cell and basal cell histology are
excluded.
2. Previous chemotherapy, radiotherapy or other investigational drug for surgically unresectable locally recurrent or advanced squamous cell carcinoma of the anus.
3. Current or recent (within 30 days of first study dosing) treatment with another investigational drug or participation in another investigational study.
4. Documented or symptomatic brain metastases and/or central nervous system metastases or leptomeningeal disease.
5. Surgery or palliative radiotherapy within 28 days of randomisation.
6. Clinically significant (i.e. active) cardiac disease (e.g. symptomatic coronary artery disease, uncontrolled cardiac arrhythmia, or myocardial infarction within the last 6 months). Any history of clinically significant cardiac failure.
7. History of interstitial lung disease (e.g. pneumonitis or pulmonary fibrosis) or evidence of interstitial lung disease on baseline chest CT scan.
8. Lack of physical integrity of the gastro-intestinal tract, malabsorption syndrome (naso-gastric or jejunostomy feeding tube is permitted).
9. Acute hepatitis C and/or chronic active hepatitis B infection.
10. Serious active infection requiring i.v. antibiotics at enrolment.
11. Other malignancy within the last 5 years, except for adequately treated carcinoma in situ of the cervix or squamous carcinoma of the skin, or adequately controlled limited basal cell skin cancer.
12. Other clinically significant disease or co-morbidity that may adversely affect the safe delivery of treatment within this trial.
13. Known hypersensitivity to any of the study drugs or excipients.
14. Pregnant or lactating females.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint of thes study is best overall response rate. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Best overall response rate is defined as the percentage of patients achieving confirmed partial(PR) or complete responses (CR) as per RECIST v1.1 by 24 weeks post treatment start in the intention to treat population.
The ORR will be summarised as the percentage (including 95% confidence intervals) of responders and will be compared between groups using Mantel-Haenszel chi-squared test stratifying by country. |
|
| E.5.2 | Secondary end point(s) |
- To assess the feasibility of conducting this study globally in 50 international centres and recruiting within a reasonable time frame. This will be measured by (i) the proportion of centres that successfully engage in the study, non-engagement being measured by the proportion of centres leaving the study or recruiting very few patients (<2) with reasons related to rarity of the disease/ toxicity of regimens/ any other logistical issues and (ii) overall recruitment rate. We anticipate and would be able to confirm feasibility if 80% of the centres fully engaged with the study. The aim would be to recruit 80 patients in 36 months (10 by month 6, 20 by month 12, 50 by month 24 and 80 by month 36) These centres would open at an average rate of 2/month for six months, starting with UK centres expected to recruit approximately 10 patients per year and then the international centres expected to recruit approximately 10 patients per year. After 36 months we expect to have recruited 80 patients.
- PFS. This is calculated from the date of randomisation to the date of confirmed clinical/radiological progression or death from any cause. Patients who are lost to follow-up, withdraw from follow-up or alive and progression free will be censored at the date of last follow-up.
- OS. This is calculated from the date of randomisation to the date of death from any cause. Patients, in whom no death is recorded, will be censored at the date they were last seen alive.
- DCR at 12 and 24 weeks post treatment start. This is defined as CR, PR or SD, and will be assessed in accordance with the RECIST criteria v1.1.
- Best ORR of non-irradiated lesions. This is defined as the percentage of patients achieving confirmed PR or CR as per RECIST v1.1 of non-irradiated sites of disease by 24 weeks post treatment start in the ITT population.
- Anti-tumour activity and magnitude of response as captured by waterfall plot analyses.
- Toxicity. Toxicity will be graded according to the NCI CTCAE version 4.0.
- QoL. QoL will be evaluated using the EORTC QLQ C30 and EQ-5D-5L questionnaires. The functional and symptomatic scales and global health status from the QLQ C30 and EQ-5D-5L questionnaire will be calculated as per EORTC and EuroQol guidelines, respectively.
Exploratory analysis:
- Biomarkers: Archived tumour tissue (if available) and blood sample will be taken at baseline with a repeat blood sample taken upon progression. Patient can enrol in an optional biomarker study where a fresh biopsy would be requested when they progress. The aim of this exploratory analysis is to evaluate the expression of tumour biomarkers in the study population and investigate the association of these with treatment outcome.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
PFS will be measured from date of randomisation to date of disease progression, relapse or death from any cause.
OS will be calculated from date of randomisation to date of death from any cause. Patients without an event were censored at last follow-up.
PFS and OS will be analysed once all patients have been followed up for at least 12 months post treatment.
Toxicity will be analysed once all patients have been followed for at leat 30 days post treatment.
QoL will be analysed duering treatment and every 3 months after the completion of study treatment. |
|
| 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 | No |
| 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) | No |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| 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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| 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 | 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 |
| Australia |
| Brazil |
| European Union |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| 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 recruitment is anticipated to be completed within 3 years. The end of trial for the purposes of the European Clinical Trials Directive will be defined as the end of the period of serious adverse event (SAE) notification, that is 30 days after the last patient has had their last active study treatment. Patient follow-up will continue until death to evaluate the secondary end points of the trial. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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