International Multicentre Study in Advanced Anal Cancer Comparing Cisplatin Plus 5 FU vs Carboplatin Plus Weekly Paclitaxel (InterAACT)

• Best overall response rate by 24 weeks post treatment [ Time Frame: 24 weeks ]
  Best overall response rate is defined as the percentage of patients achieving confirmed partial or complete responses as per RECIST v1.1 by 24 weeks post treatment start in the intention to treat population. Sensitivity analyse will also be performed.
  
  

• Feasibility of conducting a multicentre, international study on squamous cell carcinoma of the anus and recruiting within a reasonable time frame. [ Time Frame: 3 years ]
  The study will be conducted in approximately 50 international centres. This secondary endpoint will be measured by (i) the proportion of centres that successfully recruit at least one patient 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).
  
  
• Toxicity [ Time Frame: Toxicity will be analysed once all patients have been followed up for at least 4 weeks post treatment. ]
  Toxicity will be graded according to the NCI CTCAE Version 4.0
  
  
• Progression-free survival [ Time Frame: PFS will be analysed once all patients have been followed up for at least 12 months post treatment. ]
  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.
  
  
• Overall survival [ Time Frame: Overall survival will be analysed once all patients have been followed up for at least 12 months post treatment. ]
  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.
  
  
• Disease control rate [ Time Frame: 12 and 24 weeks post treatment start ]
  Disease control rate is defined as complete response, partial response or stable disease, and will be assessed in accordance with the RECIST criteria v1.1.
  
  
• Best overall response rate of non-irradiated lesions [ Time Frame: 24 weeks post treatment start ]
  Best overall response of non-irradiated lesions is defined as the percentage of patients achieving confirmed partial response or complete response as per RECIST v1.1 of non-irradiated sites of disease.
  
  
• Anti-tumour activity and magnitude of tumour response [ Time Frame: 24 weeks ]
  Anti-tumour activity and magnitude of response will be captured by waterfall plot analyses and indicate the percentage change in tumour size from baseline to the time of best response.
  
  
• Quality of Life [ Time Frame: 3 years ]
  Quality of Life 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.
  
  
• Identification of potential tumour biomarker [ Time Frame: 3 years ]
  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 an additional tumour 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.
  
  

Study design: This is an international, multicentre, open label, randomised phase II trial. Patients will be randomised to receive either cisplatin plus 5-FU or carboplatin plus weekly paclitaxel. Region (Europe, North America, South America & Australia), (Eastern Cooperative Oncology Group- ECOG) ECOG performance status (PS) (0-1 vs. 2), HIV status (positive vs. negative) and extent of disease (locally recurrent vs. metastatic) will be used as stratification factors. Overall response rate is the primary endpoint.

Indication: First line treatment of patients with inoperable locally recurrent or metastatic squamous cell carcinoma of the anus.

Length of study: Recruitment should be completed within 3 years. The estimated recruitment rate is between 4-6 patients per month once it is established at multiple centres.

Primary Objective: To evaluate best overall response rate by 24 weeks post treatment in the cisplatin plus 5-fluorouracil arm versus the carboplatin plus weekly paclitaxel arm

Secondary Objectives: To evaluate: - Progression-free survival - Overall survival - Disease control rate (stable disease or better) at 12 and 24 weeks - Best overall response of metastatic lesions - Toxicity (graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE Version 4) - Quality of Life (using EORTC QLQ-C30 version 3 and EQ-5D-5L questionnaires).

To assess: The feasibility of conducting a multicentre international study on squamous cell carcinoma of the anus and recruit within a reasonable time frame.

Exploratory Objective: Explorative biomarker analysis including the collection of archived tumour tissue and blood sample at baseline and upon progression.