Clinical and Biological Interest of Taxanes in Advanced Squamous Cell Anal Carcinoma

Study Overview
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Brief Summary
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Squamous cell carcinoma of the anal canal (SCCA) is a rare disease and mostly diagnosed at an early stage. After standard concurrent chemoradiation (CRT) with mitomycin (MMC) and 5-fluorouracil (5FU), the disease will recur in 20% of patients. After treatment failure (including salvage surgery), cisplatin-5FU combination is the standard option but complete response is a rare event and the prognosis remains poor with most patients' death occurring in the first 12 months. Decision making for physicians in this setting is only based on retrospective studies or small phase II clinical trials including less than 20 patients. Hence, no efficient standard of care is currently available for relapsing SCCA patients who are currently treated with a palliative intent. Between 2007 and 2013, 8 consecutive patients with advanced recurrent SCCA after CRT were treated with DCF regimen (docetaxel, cisplatin and 5-fluorouracil) in the Regional Cancer Institute of Franche Comté. After a median follow-up of 41 months, 4 patients (50%) achieved a complete response. Three patients underwent surgery of all involved metastatic sites. A pathological complete response was observed for all of them including in metastases occurring in irradiated fields, suggesting that taxane-based chemotherapy might be an effective strategy to circumvent resistance to radiotherapy (a preliminary cohort of 8 patients was published (Kim S et al Annals of oncology 2013). Furthermore, all complete responders were HPV 16, and high levels of specific T cell responses against Human Papillomavirus (HPV) HPV16-derived E6/E7 and telomerase were detected in 50% of complete responders suggesting the potential restoration of cancer immunosurveillance by this regimen. Then, the Epitopes-HPV02 multicenter phase II study will aim to confirm the new role of taxane-based chemotherapy in SCCA patients.

Detailed Description
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Epitopes-HPV02 study is a national multicenter open label phase II trial including 66 patients. Patients will receive 6 cycles of DCF regimen (docetaxel 75 mg/m2 day, CDDP 75 mg/m2 and 5FU at 750 mg/m2/day for 5 days) every 3 weeks or 8 cycles of modified-DCF regimen (docetaxel 40 mg/m2 day, CDDP 40 mg/m2 day and 5-FU at 1200 mg/m2/day for 2 days) every 2 weeks, according to their clinical status. CT scan will be planned at baseline, after 3 and after 6 cycles of DCF regimen (or after 4 and 8 cycles of modified-DCF regimen) and then every three months until disease progression or death. A Pet-scan will be performed before and after 6 cycles of DCF. Tumor assessment will be carried out according to RECIST V1.1 criteria. This study is carried out by the University Hospital of Besançon and were approved by the independent Est-II French Committee for Protection of Persons (CPP) and by the French Health Products Safety Agency (ANSM). This study will be conducted in 17 clinical centers in France.

Official Title
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Assessment of the Clinical Value of a Docetaxel, Cisplatin and 5-fluorouracil (DCF) Strategy Adapted to Patients for the Management of Metastatic or Locally Advanced Anal Resistant Radiochemotherapy Squamous Cell Anal Carcinoma.

Conditions
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Anal Canal Carcinoma

Intervention / Treatment
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* Drug: Docetaxel, Cisplatin and 5-Fluorouracil


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years Performance status ECOG-WHO ≤ 1 histologically proved and unresectable locally advanced or metastatic squamous cell anal carcinoma patient eligible to DCF regimen signed written informed consent Exclusion Criteria: known hypersensitivity or contraindication to any of the study drugs (docetaxel, cisplatin, 5-fluorouracil). previous chemotherapy for metastatic disease previous chemotherapy by paclitaxel, docetaxel or navelbine previous chemotherapy by cisplatin, except of concomitant radiotherapy SIDA clinically significant cardiac disease other malignancy within the last 3 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. simultaneous participation in another clinical study pregnancy, breast-feeding or absence of adequate contraception for fertile patients patient with any medical or psychiatric condition or disease which would make the patient inappropriate for entry into this study. patient under guardianship, curator or under the protection of justice.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: DCF regimen<br>docetaxel 75 mg/m2 day, Cisplatin75 mg/m2 and 5Fluorouracil at 750 mg/m2/day for 5 days | Drug: Docetaxel, Cisplatin and 5-Fluorouracil<br>* Patients will receive 6 cycles of DCF regimen (docetaxel 75 mg/m2 day, cisplatin 75 mg/m2 and 5 Fluorouracil at 750 mg/m2/day for 5 days) every 3 weeks or 8 cycles of modified-DCF regimen (docetaxel 40 mg/m2 day, cisplatin 40 mg/m2 day and 5-Fluorouracil at 1200 mg/m2/day for 2 days) every 2 weeks, according to their clinical status.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival rate | Progression-free survival observed = the number of patients alive without progression at 12 months. | 12 months after initiation of chemotherapy DCF. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival | time between the date of initiation of treatment and the date of death from any cause. | date of death from any cause (within 3 years after the initiation of the treatment) | 
| Progression free survival | time interval between the date of initiation of treatment and the date of first progression (local, remote [extent of the disease by RECIST v1.1] second cancer) or death from any cause. | date of first progression of the disease (within 3 years after the initiation of the treatment) | 
| response rate | response rate will be evaluated using Response Evaluation Criteria in Solid Tumor (RECIST) v1.1 by CT-scan | 4 weeks after the end of DCF regimen | 
| Tolerance of the DCF regimen ( Common Terminology Criteria for Adverse Events version 4.03) | description of toxicities and adverse events according to Common Terminology Criteria for Adverse Events version 4.03 | from the initiation of DCF regimen to 4 weeks after the end of DCF regimen | 
| quality of life related to health | EORTC-QLQ-C30 & time to QoL score deterioration | from the inclusion to patient death or for maximum 3 years after end of treatment | 
| HPV-specific T cell responses measured by ELISPOT assay before and after DCF treatment | HPV-specific T cell responses measured by ELISPOT assay | at baseline (inclusion) and 4 weeks after the end of DCF regimen | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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gastrointestinal oncology, immunology, taxane