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.

Study Overview

• Status: Completed
• Conditions: Locally Advanced Resectable Oral Cavity Squamous Cell Cancer
• Intervention / Treatment: Drug: docetaxel, cisplatin, 5 fluorouracil

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 14
• Phase: Phase 2

Contacts and Locations

Study Locations

• Italy
  • Milano, Italy, 20133
    • Istituto Nazionale Tumori

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 99 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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:

  1. clinically significant cardiac disease including unstable angina, acute myocardial infarction in the previous 2 years, congestive heart failure and arrhythmia requiring therapy
  2. chronic or current infectious disease that contraindicate administration of chemotherapy causing neutropenia; known HIV, Hepatitis B or C positivity
  3. 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: induction TPF chemotherapy; 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.	Drug: docetaxel, cisplatin, 5 fluorouracil; Other Names: taxotere, cisplatin, tolerak

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
pathologic complete remission	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.	After 9 weeks since chemotherapy start

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression free survival	Patients will be followed up to 5 years for what concerns PFS	5 years
Overall Survival	Patients will be followed up to 5 years for what concerns OS	5 years
Early functional response evaluation by DWI and DCE MRI	radiological evaluation after 1 cycle of induction chemotherapy	3 weeks
Comparison between (DWI - DCE) MRI response and pathological response	comparison between radiological assessment of response and pathological one	9 weeks
Compliance to induction chemotherapy	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	9 weeks
Percentage of patient receiving postoperative radiotherapy and chemotherapy	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.	6 months

Collaborators and Investigators

• Sponsor: Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
• Investigators: Principal Investigator: Lisa Licitra, MD, Fondazione IRCCS Istituto Nazionale dei tumori - Milan

Study record dates

Study Major Dates

• Study Start: June 1, 2012
• Primary Completion (Actual): January 1, 2015
• Study Completion (Actual): March 1, 2015

Study Registration Dates

• First Submitted: July 29, 2013
• First Submitted That Met QC Criteria: July 31, 2013
• First Posted (Estimated): August 2, 2013

Study Record Updates

• Last Update Posted (Actual): October 19, 2023
• Last Update Submitted That Met QC Criteria: October 18, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: TP53; induction chemotherapy; oral cavity cancer; beta tubulin II
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Carcinoma; Neoplasms, Glandular and Epithelial; Carcinoma, Squamous Cell; Neoplasms, Squamous Cell; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Docetaxel; Cisplatin; Fluorouracil
• Other Study ID Numbers: INT40/10