InductionChemo-Radio-Antibody-Treatment (ICRAT)

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

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.

Study Overview

• Status: Completed
• Conditions: Squamous Cell Carcinoma of the Neck; Squamous Cell Carcinoma of the Head
• Intervention / Treatment: Drug: TPF induction chemotherapy; Drug: TPF experimental; Radiation: Standard Radiochemotherapy (HART)

• Study Type: Interventional
• Enrollment (Actual): 94
• Phase: Phase 2

Contacts and Locations

Study Locations

• Germany
  • Berlin, Germany, 13353
    • Charité Universitaetsmedizin Berlin, CVK, CBF
  • Hamburg, Germany, 20246
    • University Medical Center Hamburg - Eppendorf
  • Hannover, Germany, 30625
    • Medizinische Hochschule Hannover
  • Marburg, Germany, 35043
    • Universitätsklinikum Gießen und Marburg
  • Regensburg, Germany, 93053
    • Universitätsklinikum Regensburg

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: TPF standard; 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; 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; Other Names: Cisplatin; Cetuximab (Erbitux); Docetaxel (Taxotere); 5-Flurouracil
EXPERIMENTAL: TPF experimental; 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; 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; Other Names: Cisplatin; Docetaxel (Taxotere); 5-Flurouracil; Certuximab
ACTIVE_COMPARATOR: Standard RCT; 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); Hyperfractionated accelerated radiotherapy with concurrent Cisplatin and 5-Fluorouracil chemotherapy; Other Names: 5-FU; Cis-platinum

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Charite University, Berlin, Germany
• Investigators: Principal Investigator: Volker Budach, MD, PhD, Charite Universitaetsmedizin Berlin

Publications and helpful links

General Publications

• Vermorken JB, Remenar E, van Herpen C, Gorlia T, Mesia R, Degardin M, Stewart JS, Jelic S, Betka J, Preiss JH, van den Weyngaert D, Awada A, Cupissol D, Kienzer HR, Rey A, Desaunois I, Bernier J, Lefebvre JL; EORTC 24971/TAX 323 Study Group. Cisplatin, fluorouracil, and docetaxel in unresectable head and neck cancer. N Engl J Med. 2007 Oct 25;357(17):1695-704. doi: 10.1056/NEJMoa071028.
• Posner MR, Hershock DM, Blajman CR, Mickiewicz E, Winquist E, Gorbounova V, Tjulandin S, Shin DM, Cullen K, Ervin TJ, Murphy BA, Raez LE, Cohen RB, Spaulding M, Tishler RB, Roth B, Viroglio Rdel C, Venkatesan V, Romanov I, Agarwala S, Harter KW, Dugan M, Cmelak A, Markoe AM, Read PW, Steinbrenner L, Colevas AD, Norris CM Jr, Haddad RI; TAX 324 Study Group. Cisplatin and fluorouracil alone or with docetaxel in head and neck cancer. N Engl J Med. 2007 Oct 25;357(17):1705-15. doi: 10.1056/NEJMoa070956.
• Haddad R, Colevas AD, Tishler R, Busse P, Goguen L, Sullivan C, Norris CM, Lake-Willcutt B, Case MA, Costello R, Posner M. Docetaxel, cisplatin, and 5-fluorouracil-based induction chemotherapy in patients with locally advanced squamous cell carcinoma of the head and neck: the Dana Farber Cancer Institute experience. Cancer. 2003 Jan 15;97(2):412-8. doi: 10.1002/cncr.11063.
• Bonner JA, Harari PM, Giralt J, Cohen RB, Jones CU, Sur RK, Raben D, Baselga J, Spencer SA, Zhu J, Youssoufian H, Rowinsky EK, Ang KK. Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival. Lancet Oncol. 2010 Jan;11(1):21-8. doi: 10.1016/S1470-2045(09)70311-0. Epub 2009 Nov 10. Erratum In: Lancet Oncol. 2010 Jan;11(1):14.

Study record dates

Study Major Dates

• Study Start: August 1, 2010
• Primary Completion (ACTUAL): April 1, 2015
• Study Completion (ACTUAL): August 1, 2015

Study Registration Dates

• First Submitted: August 12, 2010
• First Submitted That Met QC Criteria: August 12, 2010
• First Posted (ESTIMATE): August 13, 2010

Study Record Updates

• Last Update Posted (ACTUAL): January 31, 2019
• Last Update Submitted That Met QC Criteria: January 29, 2019
• Last Verified: January 1, 2019

More Information

Terms related to this study

• Keywords: radiotherapy; toxicity; induction chemotherapy; locally advanced head neck tumor; LA SCCHN; Unresectable squamous cell cancer of the head and neck,; Stage IV (UICC)
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Squamous Cell; Carcinoma; Carcinoma, Squamous Cell; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Immunological; Docetaxel; Cisplatin; Cetuximab
• Other Study ID Numbers: EudraCT No. 2010-019347-18