Preoperative TPF Chemotherapy in Molecularly Selected Locally Advanced Resectable Oral Cavity Squamous Cell Cancer

Preoperative TPF Chemotherapy in Molecularly Selected Locally Advanced Resectable Oral Cavity Squamous Cell Cancer

Phase II Study of Preoperative TPF Chemotherapy in Locally Advanced Resectable Oral Cavity Squamous Cell Cancer in Order to Improve the Rate of Pathological Complete Response

This is a phase II study of preoperative chemotherapy with docetaxel, cisplatin and 5-fluorouracil (TPF) in locally advanced resectable oral cavity squamous cell cancer. The aim is to improve the rate of pathological complete response to induction chemotherapy in a molecular enriched population, consisting of patients with tumour harbouring a functional p53 protein and/or showing low expression of beta-tubulin II.

Patients with stage T2 (> 3 cm) T3 N1-N3 and T4a any N primary OCSCC are considered for enrolment in this trial. Patients will be asked to sign the informed consent for being admitted to the clinical study and in order to analyze the tumour biopsy. If a functional p53 protein status and/or low expression of beta-tubulin II is identified, patient will be enrolled in therapeutic part of the study. In case of different molecular profile, patient will not be enrolled in the study. A radiological work up of disease is required before to start CT. A magnetic resonance imaging (MRI) with DWI, and if available, a dynamic contrast enhanced (DCE)-MRI will be performed before therapy. Each patient will receive induction CT, consisting of TPF (docetaxel 75 mg/sm and cisplatin 80 mg/sm day 1 and 5 fluorouracil 800 mg/sm each day in continuous infusion day 1-4, according to Paccagnella et al, ASCO 2008) for 3 cycles every 21 days, followed by surgery. Prophylactic antibiotic with ciprofloxacin 500 mg 2 times/day will be administered starting from day 5th to day 15th after each cycle; G-CSF is admitted as secondary prophylaxis in case of febrile neutropenia or neutropenia grade 4 at previous cycle. Patient will have clinical examination at baseline and before each CT cycle. Whenever a clinical suspicion of progressing disease will exist, a radiological restaging with MRI will be performed and in case of radiological progression according to RECIST 1.1 the patient will be submitted to surgical excision of the tumour. However, in any case the investigators may 14 judge that the disease is progressing and they consider that chemotherapy is no more indicated, the patient will be submitted to surgery even without a radiological confirmation of progression. In case of clinical SD or PR, a radiological restaging will be planned with MRI and DWI-MRI at least two weeks after the third cycle (a DWI- MRI and, if available a DCE-MRI, will be performed after 1st cycle in order to evaluate early response imaging). Surgery will be performed within one month after the last cycle of CT, if there are no clinical contraindications. After the surgical treatment, adjuvant treatment will be delivered according to recognized pathological risk factors (Bernier J, 2005). Patients will be followed up according to the Institutional follow-up policy.

Each patient will receive induction CT, consisting of TPF (docetaxel 75 mg/sm and cisplatin 80 mg/sm day 1 and 5 fluorouracil 800 mg/sm each day in continuous infusion day 1-4, according to Paccagnella et al, ASCO 2008) for 3 cycles every 21 days, followed by surgery.

For what concerns primary endpoint of pathologic complete remission achievement, the patients will be assessed at time of surgery, i.e., after about 9 weeks since chemotherapy start.

Evaluation in terms of the number of cycles administered, actual and total doses dministered, dose modifications, delays and omissions, as well as reasons for deviation from planned therapy and overall treatment duration will be described

Patients will be followed for what concerns PFS, defined as the time from the date of randomization up to the date of first progression, second primary malignancy or death from any cause, whichever comes first.

Inclusion Criteria: Signed informed consent Males and females age > 18 years Histologically proved primary oral cavity squamous cell cancer (tumour extending to oropharynx are accepted if oropharyngeal invasion is < 20% of the tumour size) Stage T2 (T2 stage is accepted if tumour size is 3 cm or larger).-T3, N1- N3 and T4a any N WHO performance status < 1 Availability of block of Formalin Fixed Paraffin Embedded (FFPE) biopsy of the tumour Radiological imaging of the tumour with MRI pre-therapy Effective contraception for both male and female subjects if risk of conception exists Exclusion Criteria: Prior antitumour therapy for head & neck cancer (chemotherapy or biological therapy and radiotherapy) Metastatic disease Medical condition that contraindicate administration of TPF scheme, in particular: clinically significant cardiac disease including unstable angina, acute myocardial infarction in the previous 2 years, congestive heart failure and arrhythmia requiring therapy chronic or current infectious disease that contraindicate administration of chemotherapy causing neutropenia; known HIV, Hepatitis B or C positivity uncontrolled renal, hepatic, neurological, cerebral, psychiatric, haematological, gastrointestinal, pulmonary, vascular or endocrine diseases that could interfere with antiblastic treatment Pre-existing peripheral neuropathy according to Common Toxicity Criteria (CTC) Adverse Event grade > 1 Pre-existing ototoxicity grade > 1 Previous diagnosis of other cancer in the last 3 years (in situ cervical cancer or completely excised basocellular/squamocellular skin cancer are always admitted ) Previous other cancer in oral cavity to less than 2 cm from existing primary Breast feeding women or women with a positive pregnancy test at Visit 0 or 1 Screening laboratory values: Neutrophils < 1.5 x 109/L Platelets < 100 x 109/L ALT or AST > 2.5 times upper limit of normal Calculated creatinine clearance < 60 mL/min Weight loss more than 20% in 3 months preceding the study Technical unresectability defined as: T4b staging or N ulcerating the skin or encasing internal carotid