InductionChemo-Radio-Antibody-Treatment

Study Overview
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Brief Summary
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This is an open-label, randomized, Phase II-study to evaluate the efficacy of a standard-TPF induction chemotherapy (IC) and an alternative TPF induction chemotherapy followed by radio-antibody-therapy, in patients with unresectable LA-SCC of the HN region (oro-hypopharynx carcinoma, cancer of the oral cavity). The primary objective of the study is to assess the feasibility of an experimental 'fractionated' TPF regimen compared to a current standard TPF regimen. Composite endpoint of compliance and feasibility in terms of response (RECIST1.1) and hematological acute toxicity (CTCAE v.4.02) on time application of RAT following an experimental or standard TPF IC. Secondary endpoints are Treatment intensity achieved Toxicity (according to CTCAE v.4.02) Response rates after completion of induction chemotherapy and after completion of entire protocol treatment (RECIST1.1) Survival (progression-free, metastasis-free, recurrence-free, overall) 1 year after randomisation Quality of life according to EORTC QoL C30 & HN35 The study will be conducted at 5-6 investigational sites in Germany recruiting 90 patients in total. Eligible patients will have a diagnosis of histologically confirmed SSC of the HN. Patients will receive one of 2 different regimens of TPF IC followed by cetuximab together with radiotherapy (RAT) or a standard radiochemotherapy(RCT) regimen.

Official Title
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Randomized Phase II Study of Two Different Regimens of TPF Induction Chemotherapy Regimen Followed by Radiation Therapy Plus Cetuximab (TPF-CET-HART) vs. HART and Cis-platinum, 5-FU (PF-HART) in Patients With Locally Advanced Unresectable Squamous Cell Carcinomas of the Head and Neck

Conditions
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Squamous Cell Carcinoma of the Head, Squamous Cell Carcinoma of the Neck

Intervention / Treatment
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* Drug: TPF induction chemotherapy
* Drug: TPF experimental
* Radiation: Standard Radiochemotherapy (HART)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically proven unresectable SCC of the oral cavity, oropharynx and hypopharynx (stage IVA & IVB) Written and signed informed consent Karnofsky PS > 70 % Age ≥ 18 years Curative treatment intent Adequate bone marrow, hepatic and renal functions as evidenced by the following: Hematology (Bone marrow): Neutrophils > 2.0 109/L Platelets > 100 x 109/L Hemoglobin > 10 g/dL Hepatic function: Total serum bilirubin < 1 time the UNL of the participating center ASAT (SGOT) and ALAT (SGPT) < 2.5 x UNL Alkaline phosphatase < 5 x UNL Renal function : serum creatinine (SC) < 120 µmol/L (1.4 mg/dl); if values are > 120 µmol/L, the creatinine clearance should be > 60 ml/min (actual or calculated by the Cockcroft-Gault method as follows : weight (kg) x (140 - age) --------------------------------- K x serum creatinine serum creatinine in mg/dL: K = 72 in man K = 85 in woman serum creatinine in µmol/L: K = 0.814 in man K = 0.96 in woman • If of childbearing potential, willingness to use effective contraceptive method for the study duration and 2 months post-dosing. All patients require: dental examination and appropriate dental preservation if needed 1 week prior to the beginning of radiotherapy, gastric feeding tube and Portal-catheter. Exclusion Criteria: Other neoplasia within the past 5 years with the exception of a controlled skin cancer or in situ cervix cancer Unknown primary (CUP), nasopharynx, laryngeal or salivary gland cancer Distant metastatic disease (M1) Serious co-morbidity, e.g. arteriosclerosis with apoplexy, recent myocardial infarction, high-grade carotid stenoses, unstable cardiac disease despite treatment, congestive heart failure NYHA grade 3 and 4, insulin-dependent diabetes mellitus, uncontrolled hypertension, liver cirrhosis (Quick < 75%, total protein <3.0 g/dl, bilirubin >2mg/ml) or kidney insufficiency (creatinine >1.4 mg/ml, the creatinine clearance should be > 60 ml/min) patients with ASAT or ALAT > 2.5 UNL associated with alkaline phosphatase > 5 UNL are not eligible for the study Known HIV-infection Pregnancy or lactation Women of child-bearing potential with unclear contraception Previous treatment of the disease with chemotherapy, radiotherapy, EGFR-targeting agents or surgery exceeding biopsy in head and neck Concurrent treatment with other experimental drugs or participation in another clinical trial with any investigational drug within 30 days prior to study screening Social situations that limit compliance with study requirements Deficient dental preservation status or not accomplished wound healing Legal incapacity Prior accommodation in an institution under officially or judicially orders (§ 40 1 p. 3 No. 4 AMG) Symptomatic peripheral neuropathy National Cancer Institute-Common Toxicity Criteria (NCI-CTC) grade 2 and/or ototoxicity grade 2, except if due to trauma or mechanical impairment due to tumor mass Known allergic/hypersensitivity reaction to any of the components of the treatment

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: TPF standard<br>TPF version 1 (standard) Induction chemotherapy: Docetaxel 75 mg/m2 d 1 Cis-platinum 75 mg/m2 d 1 5-FU 750 mg/m2/d c.i. d 1-4 every 21 days for 3 cycles Antibody therapy with: cetuximab loading dose of 400 mg/m2 1 week prior to RTX, and 250 mg/m2 weekly x 6 concurrent to RTX RTX: HART (72 Gy), IMRT or 3D-conformal techniques | Drug: TPF induction chemotherapy<br>* Docetaxel 75 mg/m2 d 1 Cis-platinum 75 mg/m2 d 1 5-FU 750 mg/m2/d c.i. d 1-4 Cetuximab loading dose of 400 mg/m2 1 week prior to RTX, and 250 mg/m2 weekly x 6 concurrent to RTX<br>* Other names: Cetuximab (Erbitux);|
| Experimental: TPF experimental<br>TPF version 2 (experimental) Induction chemotherapy: Docetaxel 40 mg/m2 d 1+8 Cis-platinum 40 mg/m2 d 1+8 5-FU 1500 mg/m2/24h c.i. d 1+8 every 21 day for 3 cycles Antibody therapy with: cetuximab loading dose of 400 mg/m2 1 week prior to RTX, and 250 mg/m2 weekly x 6 concurrent to RTX RTX: HART (72 Gy), IMRT or 3D-conformal techniques | Drug: TPF experimental<br>* Docetaxel 40 mg/m2 d 1+8 Cis-platinum 40 mg/m2 d 1+8 5-FU 1500 mg/m2/24h c.i. d 1+8 every 21 day for 3 cycles 2. Antibody therapy with: cetuximab loading dose of 400 mg/m2 1 week prior to RTX, and 250 mg/m2 weekly x 6 concurrent to RTX<br>* Other names: Certuximab;|
| Active Comparator: Standard RCT<br>Standard RCT: HART (72 Gy), IMRT or 3D-conformal techniques with concurrent chemotherapy: Cis-platinum 30 mg/m2 once weekly d 1, 8, 15, 22, 29, 36 5-FU 600mg/m² /24h c.i. d 1-5 | Radiation: Standard Radiochemotherapy (HART)<br>* Hyperfractionated accelerated radiotherapy with concurrent Cisplatin and 5-Fluorouracil chemotherapy<br>* Other names: 5-FU;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Feasibility of an experimental 'fractionated' TPF regimen compared to a current standard TPF regimen. | acute hematological toxicity | August 2010- December 2012 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Survival and late morbidity | All adequate items illustrating acute toxicity and late morbidity, in particular by hematological measures until one year after treatment (according to NCI-CTCAE v.4.02) Survival (progression-free, metastases-free, recurrence-free, Overall survival) after 1 year Response rates after TPF IC (RECIST1.1) Response rates after completion of multimodal treatment (see follow-up for scheduling RECIST1.1) Efficacy in relation to HPV status (p16 IHC) Quality of life according to EORTC QLC-30 & HN35 | 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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induction chemotherapy, radiotherapy, locally advanced head neck tumor, toxicity, LA SCCHN, Unresectable squamous cell cancer of the head and neck,, Stage IV (UICC)