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

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.

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 Performance status ≤2.

4. Measurable disease according to Response Evaluation Criteria in Solid Tumours
(RECIST) criteria version 1.1.

5. Previous definitive chemoradiotherapy 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)
≥1.5x10^9/l; white blood cell (WBC) count ≥3x10^9/l; platelets >100x10^9/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. Fertile men and women must agree to take adequate contraceptive precautions during,
and for at least six months after therapy.

9. Life expectancy of at least 3 months.

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. Known peripheral neuropathy ≥ grade 1 (absence of deep tendon reflexes as the sole
neurological abnormality does not render the patient ineligible).

15. Pre-existing hearing impairment.

16. Patients planning for a live vaccine.

17. Pregnant or lactating females.