Trial organization
NEAR has been designed by the Trial Center of the Department of Radiation Oncology, University of Heidelberg in cooperation with the Thoraxklinik in Heidelberg. The trial is carried out by the Department of Radiation Oncology together with the German Cancer Research Center (DKFZ) and Department of Medical Oncology of the Thoraxklinik Heidelberg. The trial is an investigator initiated trial. Trial medication (cetuximab) is supplied by Merck KGaA, Darmstadt, Germany.
Coordination
The trial is co-ordinated by the Department of Radiation Oncology of the University of Heidelberg in cooperation with the DKFZ and the Department of Medical Oncology at the Thoraxklinik Heidelberg. The Dept. of Radiation Oncology is responsible for overall trial management, trial registration (ClinicalTrials.gov Identifier: NCT00115518), database management, quality assurance including monitoring, reporting and for the scientific program of all trial related meetings.
Investigators
Patients will be recruited by the Department of Radiation Oncology at the University of Heidelberg and by the Department of Medical Oncology of the Thoraxklinik Heidelberg. Due to the multi-modal nature of the trial, all investigators are experienced oncologists from the fields of radiation oncology and medical oncology.
Adverse events committee
This committee consists of 2 physicians (medical oncologist, radiation oncologist) and decides on the final diagnostic classification of critical clinical events. For all serious adverse events the documentation and relevant patient data are verified by the co-ordinating personnel before submitting the data to the Adverse Events Committee for diagnostic classification.
Analysis of safety related data is performed with respect to frequency of:
• Serious Adverse Events and Adverse Events stratified by organ-system
• Adverse Events stratified by severity
• Adverse Events stratified by causality.
Patient toxicities will be assessed using the NCI Common Toxicity Criteria (CTC). Toxicity will be evaluated prior to treatment, weekly prior to each course of infusional Cetuximab and at follow-up. Unacceptable toxicity is defined as unpredictable, or irreversible Grade 4 toxicity. Decisions regarding cetuximab dose-adjustment will be made using the guidelines below and based on haematological parameters (ANC and platelets) monitored weekly during radiation before each dose of cetuximab.
On-site monitoring
During recruitment of patients monitoring on site is performed according to good clinical practice (GCP) guidelines. The data management will be performed by the Trial Centre of the Department of Radiation Oncology, University of Heidelberg.
Ethics, informed consent and safety
The final protocol was approved by the ethics committee of the University of Heidelberg, Medical School (L-284/2004) and the Paul-Ehrlich-Institute ((PEI-registration number 1209/01). This study complies with the Helsinki Declaration in its recent German version, the Medical Association's professional code of conduct, the principles of Good Clinical Practice (GCP) guidelines and the Federal Data Protection Act. The trial will also be carried out in keeping with local legal and regulatory requirements. The medical secrecy and the Federal Data Protection Act will be followed.
Written informed consent is obtained from each patient in oral and written form before inclusion in the trial and the nature, scope, and possible consequences of the trial have been explained by a physician. The investigator will not undertake any measures specifically required only for the clinical trial until valid consent has been obtained.
Study design
The NEAR-study is a prospective phase II feasibility study combining a monoclonal EGF-receptor antibody with loco-regional irradiation in patients with stage III NSCLC. This trial aims at testing the combination's safety and efficacy and rate of development of distant metastases with an accrual of 30 patients. These are treated by the Dept. of Radiation Oncology and Radiation Therapy, University of Heidelberg, in co-operation with the German Cancer Research Centre (DKFZ), Heidelberg, the Dept. of Medical Oncology, Thoraxklinik, Heidelberg, and the Dept. of Nuclear Medicine, University of Heidelberg.
Primary endpoints are toxicities and feasibility of the combined treatment.
Secondary endpoints are remission rates, 3-year-survival and local/systemic progression-free survival.
Patient selection
In order to be included in the NEAR trial, patients were required to have histologically confirmed NSCLC and documented inoperable NSCLC stage III disease, where combined chemo-radiotherapy is either deemed medically contra-indicated or refused by the patient. Each patient is discussed by a commitee consisting of a thoracic surgeon, a medical oncologist, a pulmonologist, a radiologist and a radiation oncologist. Evaluation of EGFR status is recommended but not compulsory. Patients also need to have sufficient remaining lung function (FeV1 ≥ 1.5 l/s or at least 50% of the respective individual norm value) as well as a Karnofsky Performance score of 70 % or higher.
Patients should be ≥ 18 years and individual life expectancy be estimated to ≥ 6 months. Accrued patients will be expected to demonstrate sufficient compliance, they should also live in relative proximity of the centre of care to ensure adequate follow-up after treatment. In addition, adequate haematological, hepatic, and renal function is essential for inclusion in the trial (wbc ≥ 3000 × 103 /ml, thc ≥ 100 × 106 /ml, hb ≥ 10 g/dl).
Female patients are required to use adequate contraception during and at least up to 3 months after treatment. Naturally, written informed consent is obtained prior to commencement of treatment in this trial.
Patients are not eligible with active infections, inadequate liver function (bilirubin ≥ 2 × above normal, GOT/GPT > 5 × above normal) or haemodynamically relevant haemoptyses (hb-drop of 1 g/dl within 24 h), superior vena cava syndrome, or malignant pleural effusions. Patients with severe concurrent systemic disease or other malignant disease (apart from cervical carcinoma in-situ, basal cell carcinoma, or unless previously treated and in remission for ≥ 5 years without further treatment) can also not be included in this trial. Furthermore, hypersensitivity to foreign proteins or x-ray contrast medium, or use of other test substances within one month prior to commencement of the NEAR trial and previous chemotherapy will prohibit inclusion as will pregnancy or breast feeding.
Work-up
Patients with pathologically or cytologically documented NSCLC stage III receive a complete work-up including thoracic and cerebral CT scans, abdominal ultrasound, bone scan (plus x-ray exams of suspect areas where applicable). Patients with positive mediastinal lymph nodes, (either pathologically documented or found suspect in the CT-scan due to diameter >1.5 cm) will be sent for surgical consultation and evaluation of operability. Should operation be found impossible, in,-and exclusion criteria are examined. In the event of patients meeting the required inclusion criteria, information about participation in the study with possible risks and benefits is given to the patients and written informed consent is obtained. Patients can then be included in the study, documentation is provided by the study centre (Studienzentrale Klinische Radiologie, Abt. Strahlentherapie und Radioonkolgie, INF 400, 69120 Heidelberg).
After inclusion, patients are referred to FDG-PET scanning in order to optimise target volume definition. Each patient receives a radiation therapy planning CT-scan in individually-adjusted precision immobilisation devices.
In the event of patients declining treatment within the NEAR trial, irradiation alone is offered.
Safety and discontinuation of treatment
Toxicities are classified by grade, type, duration, onset, and relationship to study treatment.
Treatment of cetuximab-induced adverse reactions is carried according to recommendations by the provider.
For grade 1 or 2 allergic reactions, a decrease of infusion rate for current and subsequent infusions is suggested. For ≥°3, persistent °1 or °2 allergic reactions despite reduction of infusion rate, it is recommended to discontinue treatment with cetuximab. Skin reactions in terms of acne-like rash after cetuximab are common. In patients with °3 acne-like rash cetuximab should be delayed for up to two subsequent infusions. Treatment also includes concomitant topical and/or oral antibiotics where necessary. Therapy can be resumed on resolution of the rash to <°2. Cetuximab needs to be delayed on a 2nd or 3rd occurrence of a °3 skin reaction for up to two consecutive cycles with dose reduction to 200 mg/m2 or 150 mg/m2 respectively. Any further occurrence of grade °3 acne-like rash will lead to discontinuation of cetuximab treatment.
Drug supply
The monoclonal antibody cetuximab (Erbitux®) is provided by Merck KGaA, Darmstadt, Germany, and stored by the University Hospital Pharmacy, Heidelberg.
The respective cetuximab dose applied in this setting corresponds to the recommended and approved dosage tested in combination with irinotecan in metastatic colo-rectal carcinoma [19]. Cetuximab is given with a loading dose of 400 mg/m2 as an intravenous infusion on day 1. Subsequently, the regular weekly dose during radiotherapy is 250 mg/m2 on days 8, 15, 22, 29, 36, 43, and 50. After completion of irradiation, patients continue to receive 250 mg/m2 weekly for another 13 weeks. Administration of cetuximab is discontinued if patients show local or systemic progression.
Radiation therapy
Irradiation is applied as intensity-modulated radiation therapy (IMRT). The primary tumour and mediastinal lymph nodes receive a dose of 50 Gy in daily fractions of 2 Gy (Monday to Friday).
Primary tumour and involved lymph nodes are subsequently boosted to a total dose of 66 Gy in daily fractions of 2 Gy. Tolerances of thoracic organs at risk should not be exceeded.
The schedule of the treatment is shown in Figure 1:
Supportive therapy
Whenever necessary, metoclopramide or 5-HT3-antagonists are used for antiemesis.
Antihistamines such as clemastine or dimetinden and steroids are administered prior to cetuximab-application. Skin reactions, especially acne-like rashes can be treated by topic or systemic antibiotics (i.e. tetracyclines or metronidazole) if necessary. Radiation induced skin reactions are treated according to in-house protocols with mild moisturizing lotion (i.e. Bepanthen®-lotio) or local application of steroids.
Trial duration
Individual participation is completed either three years after enrolment or death of the patient.
Individual exclusion criteria are serious adverse reactions or the patient's voluntary withdrawal from the trial.
Assessment of therapeutic efficacy
Methods/Investigations
• Chest x-ray on completion of irradiation to exclude disease progression under current treatment
• CT-thorax q3 months until completion of study
• Abdominal ultrasound q6 months until completion of study
• Bone scan q12 months until completion of study
• FDG-PET scan prior and after completion of the treatment (last cetuximab infusion)
Evaluation
Local response is evaluated in accordance with the RECIST Criteria (Response Evaluation Criteria in Solid Tumours) [21].
1. complete remission (CR): is defined as complete regression of the treated tumour mass (confirmation after at least 4 weeks of treatment or later)
2. partial remission (PR) is defined as reduction of sum of largest tumour diameters by at least 30% (confirmation after at least 4 weeks of treatment or later)
3. stable disease (NC := no change): neither PR nor PD
4. progressive disease (PD): increase of sum of largest tumour diameters by 20%