Not provided
| ID | Type | Description | Link |
|---|---|---|---|
| 2010-023427-18 | EudraCT Number |
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Esophageal cancer is a highly aggressive tumor. Treatment options are various and range from chemotherapy to radiotherapy and several surgical techniques. Nevertheless, the overall survival rates for this disease remain poor.
During the last years the combination of cetuximab with standard chemotherapy or radiotherapy has mainly be investigated in clinical trials focusing on colorectal and/or head and neck cancer.
The results obtained from theses studies were very encouraging and led to the initiation of active clinical research in esophageal cancer patients with antibody inhibition of the epidermal growth factor receptor (EGFR).
The first data in this indication are encouraging showing that cetuximab can safely be added to chemoradiation for esophageal cancer patients with first hints of efficacy.
Based on the experiences with cetuximab in colorectal cancer and in combination with radiotherapy in head and neck cancer, the aim of the present study is to evaluate the feasibility of a combined treatment of cetuximab with continuous infusional 5-FU, cisplatin and radiotherapy in patients with esophageal cancer and to assess if the overall survival rates can be increased by addition of an EGFR-targeted therapy.
Esophageal cancer is a highly aggressive neoplasm which is fatal in the great majority of patients. On a global basis, cancer of the esophagus is the sixth leading cause of cancer death worldwide. In fact, gastric and esophageal cancers together accounted for nearly 1.3 million new cases and 980,000 deaths worldwide in 2000 - more than lung, breast, or colorectal cancer. With advances in surgical techniques and treatment, the prognosis of esophageal cancer has slowly improved over the past decades. However, with a 5-year overall survival rate of approximately 14%, at the time of development of the LEOPARD-II protocol, survival was poor, even in comparison with the dismal survival rates (4%) from the 1970s. Underlying reasons for this disappointingly low survival rate are above all the difficulties in cancer detection at an advanced stage, with over 50% of patients with unresectable disease or distant metastasis at presentation and the limited survival achieved with palliative chemotherapy alone for patients with metastatic or unresectable disease.
Clearly, additional strategies are needed to improve the systemic treatment options for esophageal cancer.
The optimal treatment of locally advanced esophageal cancer, a potentially curable disease, is controversial. Through several non-randomized cooperative group trials, concurrent cisplatin-based chemoradiation or surgery alone represent acceptable standards of care for patients with resectable tumors.
Metastatic or unresectable esophageal cancer is found at presentation in more than 50% of patients and is considered incurable. At the time of protocol development, chemotherapy was palliative, improving quality of life and dysphagia in 60%-80% of patients. Typical clinical and radiographic responses lasted for fewer than 4 months, with a median overall survival time of 8-10 months.
Combination chemotherapies have been demonstrated to be superior to best supportive care and chemotherapy given as a single agent, with occasional patients achieving complete responses (0%-11%). However, even with the combination regimens, the median survival time remained less than 10 months.
An improved understanding of the molecular pathogenesis of cancer has facilitated the development of novel agents designed to target critical pathways involved in cancer development and progression. Epidermal growth factor receptor (EGFR) plays a crucial role in tumour growth. EGFR-dependent signaling is involved in cell proliferation, apoptosis, angiogenesis, and metastatic spread.
The overexpression of EGFR has repeatedly been shown to predict poor prognosis in both esophageal squamous cell carcinoma and gastro esophageal junction adenocarcinoma. EGFR blockade through monoclonal antibodies (Cetuximab, Matuzumab and Panitumumab) and tyrosine kinase inhibitors (gefitinib, erlotinib) has translated into promising evidence of clinical benefit in clinical trials.
Cetuximab is a targeted therapeutic agent, a chimeric monoclonal antibody that specifically binds to the EGFR with high affinity, internalising the receptor and preventing ligands from interacting with the receptors and thus effectively blocking ligand-induced EGFR phosphorylation. In addition, cetuximab had been found to potentiate the effects of chemotherapy and radiotherapy in experimental systems. The dose of cetuximab (initial dose 400 mg/m2 and subsequent weekly doses of 250 mg/m2) has been found to be generally safe and effective in several studies in major tumor types expressing the EGFR. These included colorectal cancer and squamous cell carcinoma of the head and neck, with cetuximab given either in combination studies with chemotherapy and radiotherapy or as monotherapy.
In two phase I studies prior to LEOPARD-II, EGFR-directed antibodies had shown activity in patients with esophageal cancer. In the phase I study of the humanized EGFR monoclonal antibody (mAb) EMD72000, one patient with metastatic, pretreated squamous cell carcinoma had had a durable, 6-month partial response.
In addition, a phase I trial with a fully human EGFR mAb, had reported stable disease for 7 months in one esophageal cancer patient. Preclinical and these early clinical studies suggested potential activity and minimal toxicities with EGFR antibodies for esophageal cancer.
Furthermore, a randomised phase II compared cisplatin + 5-FU (CF) to cisplatin + 5-FU + cetuximab (CET-CF) (n=62). Cetuximab did not increase grade 3/4 toxicity, except for rash (6% versus 0%) and diarrhea (16% versus 0%). The overall response rates were 19% and 13% for the CET-CF and CF arms respectively, and the disease control rates were 75% and 57%, respectively. The median progression free survival was 5.9 and 3.6 months and median overall survival 9.5 and 5.5 months for CET-CF and CF, respectively.
With respect to the combination of Cetuximab with radiotherapy, preclinical studies have shown, that Cetuximab enhanced the radiosensitivity of EGFR expressing tumour cells in vitro and in tumour xenografts and the repopulation of epithelial tumour cells after exposure to radiation was related to the activation and expression of EGFR. Cetuximab also enhanced the efficacy of docetaxel chemoradiotherapy in human adenocarcinoma xenografts.
Rationale for the LEOPARD-II study Esophageal cancer is a highly aggressive tumor and one of the most frequent malignant diseases worldwide.
Treatment options are various and range from chemotherapy to radiotherapy and several surgical techniques. Nevertheless, the overall survival rates for this disease remain poor. During the last years before protocol development the combination of cetuximab with standard chemotherapy or radiotherapy had mainly been investigated in clinical trials focusing on colorectal and/or head and neck cancer. The results obtained from these studies had been very encouraging and led to the initiation of active clinical research in esophageal cancer patients with antibody inhibition of the EGFR. The first data in this indication were encouraging showing that cetuximab could safely be added to chemoradiation for esophageal cancer patients with first hints of efficacy. Based on the experiences with cetuximab in colorectal cancer and in combination with radiotherapy in head and neck cancer, the aim of the LEOPARD-II study was to evaluate the feasibility of a combined treatment of cetuximab with continuous infusional 5-FU, cisplatin and radiotherapy in patients with esophageal cancer and to assess if the overall survival rates could be increased by addition of an EGFR-targeted therapy.
Not provided
Not provided
Not provided
Not provided
| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Cetuximab, Cisplatin, 5-FU, Radiotherapy | Experimental | Cetuximab: Initial doses 400mg/m2 (day 1), followed by weekly doses of 250mg/m2 for 14 weeks in total, IV 5-fluorouracil (5-FU): 1000mg/m2 per day as continuous infusion on day 8-11 and 36-39, 750mg/m2/day as continuous infusion on day 71-74 and 99-102 Cisplatin 20mg/m2/day as intravenous bolus over 60 min on day 1-4 of every cycle (day 8-11, 36-39, 71-74 and 99-102) radiotherapy: 59.4 Gy (33 fractions of 1.8 Gy) over 6.5-7 weeks (5 x 1.8 Gy per week)on primary tumor. 50.4 Gy on locoregional lymphnodes. If resectability is reached after 4-4.5 weeks (36-41.4 Gy) the radiotherapy stops after 45 Gy and the patient undergoes surgery. |
|
| Cisplatin, 5-FU, Radiotherapy | Active Comparator | 5-FU: 1000mg/m2 per day as continuous infusion on day 1-4 and 29-32, 750mg/m2/day as continuous infusion on day 64-67 and 92-95 Cisplatin 20mg/m2/day as intravenous bolus over 60 min on day 1-4 of every cycle (day 1-4, 29-32, 64-67 and 92-95) radiotherapy: 59.4 Gy (33 fractions of 1.8 Gy) over 6.5-7 weeks (5 x 1.8 Gy per week)on primary tumor. 50.4 Gy on locoregional lymphnodes. If resectability is reached after 4-4.5 weeks (36-41.4 Gy) the radiotherapy stops after 45 Gy and the patient undergoes surgery. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Cetuximab | Drug | Initial doses 400mg/m2 (day 1), followed by weekly doses of 250mg/m2 for 14 weeks in total |
|
| Measure | Description | Time Frame |
|---|---|---|
| Rate of Participants Who Were Alive at 2 Years | Overall Survival (OS) was defined as freedom from death of any cause. Time to death was calculated from the day of randomization, and the patients were followed for a maximum of 24 months (2 years). | 2 years |
| Measure | Description | Time Frame |
|---|---|---|
| Rate of Participants Who Were Alive at 1 Year | Overall Survival (OS) was defined as freedom from death of any cause. Time to death was calculated from the day of randomization. | 1 year |
| Rate of Participants Who Were Alive Without Progression of Disease at 1 Year |
Not provided
Inclusion Criteria:
Adequate bone marrow function:
Adequate liver function:
Adequate kidney function:
Exclusion Criteria:
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
| Name | Affiliation | Role |
|---|---|---|
| Dirk Rades, Prof. Dr. | Universität zu Lübeck, Klinik für Strahlentherapie | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Klinik für Strahlentherapie | Lübeck | 23538 | Germany |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 32533228 | Derived | Rades D, Bartscht T, Hunold P, Schmidberger H, Konig L, Debus J, Belka C, Homann N, Spillner P, Petersen C, Kuhnt T, Fietkau R, Ridwelski K, Karcher-Kilian K, Kranich A, Mannikko S, Schild SE, Maderer A, Moehler M. Radiochemotherapy with or without cetuximab for unresectable esophageal cancer: final results of a randomized phase 2 trial (LEOPARD-2). Strahlenther Onkol. 2020 Sep;196(9):795-804. doi: 10.1007/s00066-020-01646-4. Epub 2020 Jun 12. |
Not provided
Not provided
Not provided
Not provided
Not provided
| ID | Title | Description |
|---|---|---|
| FG000 | Cetuximab, Cisplatin, 5-FU, Radiotherapy | Cetuximab: Initial doses 400mg/m2 (day 1), followed by weekly doses of 250mg/m2 for 14 weeks in total, IV 5-FU: 1000mg/m2 per day as continuous infusion on day 8-11 and 36-39, 750mg/m2/day as continuous infusion on day 71-74 and 99-102 Cisplatin 20mg/m2/day as intravenous bolus over 60 min on day 1-4 of every cycle (day 8-11, 36-39, 71-74 and 99-102) radiotherapy: 59.4 Gy (33 fractions of 1.8 Gy) over 6.5-7 weeks (5 x 1.8 Gy per week)on primary tumor. 50.4 Gy on locoregional lymphnodes. If resectability is reached after 4-4.5 weeks (36-41.4 Gy) the radiotherapy stops after 45 Gy and the patient undergoes surgery. |
| FG001 | Cisplatin, 5-FU, Radiotherapy | 5-FU: 1000mg/m2 per day as continuous infusion on day 1-4 and 29-32, 750mg/m2/day as continuous infusion on day 64-67 and 92-95 Cisplatin 20mg/m2/day as intravenous bolus over 60 min on day 1-4 of every cycle (day 1-4, 29-32, 64-67 and 92-95) radiotherapy: 59.4 Gy (33 fractions of 1.8 Gy) over 6.5-7 weeks (5 x 1.8 Gy per week)on primary tumor. 50.4 Gy on locoregional lymphnodes. If resectability is reached after 4-4.5 weeks (36-41.4 Gy) the radiotherapy stops after 45 Gy and the patient undergoes surgery. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
Not provided
Not provided
| ID | Title | Description |
|---|---|---|
| BG000 | Cetuximab, Cisplatin, 5-FU, Radiotherapy | Cetuximab: Initial doses 400mg/m2 (day 1), followed by weekly doses of 250mg/m2 for 14 weeks in total, IV 5-FU: 1000mg/m2 per day as continuous infusion on day 8-11 and 36-39, 750mg/m2/day as continuous infusion on day 71-74 and 99-102 Cisplatin 20mg/m2/day as intravenous bolus over 60 min on day 1-4 of every cycle (day 8-11, 36-39, 71-74 and 99-102) radiotherapy: 59.4 Gy (33 fractions of 1.8 Gy) over 6.5-7 weeks (5 x 1.8 Gy per week)on primary tumor. 50.4 Gy on locoregional lymphnodes. If resectability is reached after 4-4.5 weeks (36-41.4 Gy) the radiotherapy stops after 45 Gy and the patient undergoes surgery. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Median |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Rate of Participants Who Were Alive at 2 Years | Overall Survival (OS) was defined as freedom from death of any cause. Time to death was calculated from the day of randomization, and the patients were followed for a maximum of 24 months (2 years). | Posted | Number | 95% Confidence Interval | percentage of participants | 2 years |
|
2 years
Common Terminology Criteria for Adverse Events (CTCAE), version 4.03
Not provided
| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Cetuximab, Cisplatin, 5-FU, Radiotherapy | Cetuximab: Initial doses 400mg/m2 (day 1), followed by weekly doses of 250mg/m2 for 14 weeks in total, IV 5-FU: 1000mg/m2 per day as continuous infusion on day 8-11 and 36-39, 750mg/m2/day as continuous infusion on day 71-74 and 99-102 Cisplatin 20mg/m2/day as intravenous bolus over 60 min on day 1-4 of every cycle (day 8-11, 36-39, 71-74 and 99-102) radiotherapy: 59.4 Gy (33 fractions of 1.8 Gy) over 6.5-7 weeks (5 x 1.8 Gy per week)on primary tumor. 50.4 Gy on locoregional lymphnodes. If resectability is reached after 4-4.5 weeks (36-41.4 Gy) the radiotherapy stops after 45 Gy and the patient undergoes surgery. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Lung infection | Respiratory, thoracic and mediastinal disorders | CTCAE 4.03 (MedDRA) | Non-systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Nausea | Gastrointestinal disorders | CTCAE 4.03 (MedDRA) | Non-systematic Assessment |
Not provided
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Prof. Dr. med. Dirk Rades | Department of Radiation Oncology, University of Lübeck, Germany | 0049 451 500 | 45401 | dirk.rades@uksh.de |
Not provided
| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Oct 6, 2016 | Feb 24, 2020 | Prot_SAP_000.pdf |
| ICF | No | No | Yes | Informed Consent Form | Aug 6, 2012 | Mar 9, 2020 | ICF_001.pdf |
Not provided
| ID | Term |
|---|---|
| D004938 | Esophageal Neoplasms |
| ID | Term |
|---|---|
| D005770 | Gastrointestinal Neoplasms |
| D004067 | Digestive System Neoplasms |
| D009371 | Neoplasms by Site |
| D009369 | Neoplasms |
Not provided
Not provided
| ID | Term |
|---|---|
| D000068818 | Cetuximab |
| D002945 | Cisplatin |
| D005472 | Fluorouracil |
| D011878 | Radiotherapy |
| D011827 | Radiation |
| ID | Term |
|---|---|
| D061067 | Antibodies, Monoclonal, Humanized |
| D000911 | Antibodies, Monoclonal |
| D000906 | Antibodies |
| D007136 | Immunoglobulins |
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
| Cisplatin, 5-FU | Drug | 5-FU: 1000mg/m2 per day as continuous infusion on day 1-4 of cycle 1 and 2, 750mg/m2/day as continuous infusion on day 1-4 of cycle 3 and 4 Cisplatin 20mg/m2/day as intravenous bolus over 60 min on day 1-4 of every cycle |
|
|
| Radiotherapy | Radiation | 59.4 Gy (33 fractions of 1.8 Gy) over 6.5-7 weeks (5 x 1.8 Gy per week)on primary tumor. 50.4 Gy on locoregional lymphnodes. If resectability is reached after 4-4.5 weeks (36-41.4 Gy) the radiotherapy stops after 45 Gy and the patient undergoes surgery. |
|
|
For progression-free survival (PFS), the event was defined as first occurrence of radiologically proven progression or clinical progression or death due to progressive disease. Time to event was referenced from the day of randomization. |
| 1 year |
| Rate of Participants Who Were Alive Without Progression of Disease at 2 Years | For progression-free survival (PFS), the event was defined as first occurrence of radiologically proven progression or clinical progression or death due to progressive disease. Time to event was referenced from the day of randomization. | 2 years |
| Number of Participants Experiencing at Least One Grade >=3 Toxicity | Toxicity was assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) (version 4.03). | up to 2 years |
| Rate of Participants Who Were Alive Without Distant Metastases at 1 Year | For metastases-free survival (MFS), the event was defined as first occurrence of distant metastasis. Time to event was referenced from the day of randomization. | 1 year |
| Rate of Participants Who Were Alive Without Distant Metastases at 2 Years | For metastases-free survival (MFS), the event was defined as first occurrence of distant metastasis. Time to event was referenced from the day of randomization. | 2 years |
| Number of Participants Who Achieved at Least Partial Response (Responders) | Response was defined according to the RECIST criteria (Version 1.1) based on the assessments (computed tomography, magnetic resonance imaging or other) for target lesions, non-target lesions as well as considering the occurrence of new lesions. The best overall response (RECIST) was chosen for each patient out of all valid tumour assessments before start of next-line therapy (complete response=CR being the best and progressive disease=PD the worst). Frequencies with percentages were to be given for each category (CR, partial response (PR), stable disease (SD), PD) by treatment group. The data were to be presented as the dichotomous endpoint of objective response, for which patients with best overall response of CR or PR were considered as responders, and those with best overall response of SD or PD as non-responders. The difference between objective response rates in the two treatment arms was to be compared with a Chi-square test. | up to 2 years |
| Rate of Participants Who Were Alive Without Loco-regional Failure at 1 Year | Loco-regional failure was defined as progressive primary tumor and/or regional lymph nodes on endoscopy, endoscopic ultrasound or computed tomography.Time to event was referenced from the day of randomization. | 1 year |
| Rate of Participants Who Were Alive Without Loco-regional Failure at 2 Years | Loco-regional failure was defined as progressive primary tumor and/or regional lymph nodes on endoscopy, endoscopic ultrasound or computed tomography. Time to event was referenced from the day of randomization. | 2 years |
| Change in Quality of Life Between Baseline and End of Treatment (After 5 to 13 Weeks) | Quality of Life was assessed with EORTC QLQ-C30 and QLQ-OES18 questionnaires. For QLQ-C30, global health status, functional scales (physical, role, emotional, cognitive and social functioning) and symptom scales (fatigue, nausea/vomiting, pain, dyspnea, loss of appetite, constipation, diarrhea, financial difficulties) were calculated. Scores ranged from 0 to 100; higher scores represented higher levels of quality of life, functioning, or symptoms/problems. Score were calculated using mean values. For QLQ-OES18, symptom scales (problems with eating, reflux, pain, problems swallowing saliva, dry mouth, taste disorders, problems while coughing or speaking) and functional scale (dysphagia) were assessed the same way. A change between two time points, i.e. baseline (prior to treatment) and end of treatment (after 5 to 13 weeks, depending on treatment arm (6.5 weeks without and 13 weeks with cetuximab) and achievement of resectability (end of treatment after 5 weeks), is reported. | end of treatment (after 5 to 13 weeks) |
| BG001 | Cisplatin, 5-FU, Radiotherapy | 5-FU: 1000mg/m2 per day as continuous infusion on day 1-4 and 29-32, 750mg/m2/day as continuous infusion on day 64-67 and 92-95 Cisplatin 20mg/m2/day as intravenous bolus over 60 min on day 1-4 of every cycle (day 1-4, 29-32, 64-67 and 92-95) radiotherapy: 59.4 Gy (33 fractions of 1.8 Gy) over 6.5-7 weeks (5 x 1.8 Gy per week)on primary tumor. 50.4 Gy on locoregional lymphnodes. If resectability is reached after 4-4.5 weeks (36-41.4 Gy) the radiotherapy stops after 45 Gy and the patient undergoes surgery. |
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race/Ethnicity, Customized | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| Histology | Count of Participants | Participants |
|
| Histologic grading | The histological grading was performed using the following scale: GX Grade cannot be assessed G1 Well differentiated (Low grade) G2 Moderately differentiated (Intermediate grade) G3 Poorly differentiated (High grade) | Count of Participants | Participants |
|
| clinical T-category | T describes the size depth of local invasion by the primary tumor. A higher T-category represents a more advanced primary tumor, generally associated with a worse prognosis. Patients were staged for T-category using computed tomography and endoscopic ultrasound. | Count of Participants | Participants |
|
| clinical N-category | N describes the extent of the involvement of regional lymph nodes. A higher N-category represents a higher number of refional lymph nodes, generally associated with a worse prognosis. Patients were staged for N-category using computed tomography and endoscopic ultrasound. | Count of Participants | Participants |
|
| clinical M-category | M describes thew presence or absence of distant metastasis. In the 6th edition of the TNM-classification, M1a indicated metastases to the cervical or celiac axis lymph nodes, and M1b metastases to distant sites. The TNM-classification from 2009 (7th edition) used only M0 (absence) and M1 (presence) for distant metastasis. M1 is generally associated with a worse prognosis. Patients were staged for M-category using computed tomography (thorax and abdomen). | Count of Participants | Participants |
|
| Tumor site | Count of Participants | Participants |
|
| Karnofsky Performance Score (KPS) | 100 - Normal; no evidence of disease. 90 - Normal activity; minor signs/symptoms. 80 - Normal activity with effort; some signs/symptoms. 70 - Cares for self; unable for normal activity or active work. 60 - Requires occasional assistance, cares for most personal needs. 50 - Requires considerable assistance + frequent medical care. 40 - Disabled; requires special care and assistance. 30 - Severely disabled; hospital admission indicated. 20 - Very sick; hospital admission + supportive treatment necessary. 10 - Moribund; fatal processes progressing rapidly. 0 - Dead | Count of Participants | Participants |
|
| OG001 | Cisplatin, 5-FU, Radiotherapy | 5-FU: 1000mg/m2 per day as continuous infusion on day 1-4 and 29-32, 750mg/m2/day as continuous infusion on day 64-67 and 92-95 Cisplatin 20mg/m2/day as intravenous bolus over 60 min on day 1-4 of every cycle (day 1-4, 29-32, 64-67 and 92-95) radiotherapy: 59.4 Gy (33 fractions of 1.8 Gy) over 6.5-7 weeks (5 x 1.8 Gy per week)on primary tumor. 50.4 Gy on locoregional lymphnodes. If resectability is reached after 4-4.5 weeks (36-41.4 Gy) the radiotherapy stops after 45 Gy and the patient undergoes surgery. |
|
|
| Secondary | Rate of Participants Who Were Alive at 1 Year | Overall Survival (OS) was defined as freedom from death of any cause. Time to death was calculated from the day of randomization. | Posted | Number | 95% Confidence Interval | percentage of participants | 1 year |
|
|
|
| Secondary | Rate of Participants Who Were Alive Without Progression of Disease at 1 Year | For progression-free survival (PFS), the event was defined as first occurrence of radiologically proven progression or clinical progression or death due to progressive disease. Time to event was referenced from the day of randomization. | Posted | Number | 95% Confidence Interval | percentage of participants | 1 year |
|
|
|
| Secondary | Rate of Participants Who Were Alive Without Progression of Disease at 2 Years | For progression-free survival (PFS), the event was defined as first occurrence of radiologically proven progression or clinical progression or death due to progressive disease. Time to event was referenced from the day of randomization. | Posted | Number | 95% Confidence Interval | percentage of participants | 2 years |
|
|
|
| Secondary | Number of Participants Experiencing at Least One Grade >=3 Toxicity | Toxicity was assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) (version 4.03). | Posted | Count of Participants | Participants | up to 2 years |
|
|
|
| Secondary | Rate of Participants Who Were Alive Without Distant Metastases at 1 Year | For metastases-free survival (MFS), the event was defined as first occurrence of distant metastasis. Time to event was referenced from the day of randomization. | Posted | Number | 95% Confidence Interval | percentage of participants | 1 year |
|
|
|
| Secondary | Rate of Participants Who Were Alive Without Distant Metastases at 2 Years | For metastases-free survival (MFS), the event was defined as first occurrence of distant metastasis. Time to event was referenced from the day of randomization. | Posted | Number | 95% Confidence Interval | percentage of participants | 2 years |
|
|
|
| Secondary | Number of Participants Who Achieved at Least Partial Response (Responders) | Response was defined according to the RECIST criteria (Version 1.1) based on the assessments (computed tomography, magnetic resonance imaging or other) for target lesions, non-target lesions as well as considering the occurrence of new lesions. The best overall response (RECIST) was chosen for each patient out of all valid tumour assessments before start of next-line therapy (complete response=CR being the best and progressive disease=PD the worst). Frequencies with percentages were to be given for each category (CR, partial response (PR), stable disease (SD), PD) by treatment group. The data were to be presented as the dichotomous endpoint of objective response, for which patients with best overall response of CR or PR were considered as responders, and those with best overall response of SD or PD as non-responders. The difference between objective response rates in the two treatment arms was to be compared with a Chi-square test. | Posted | Count of Participants | Participants | up to 2 years |
|
|
|
| Secondary | Rate of Participants Who Were Alive Without Loco-regional Failure at 1 Year | Loco-regional failure was defined as progressive primary tumor and/or regional lymph nodes on endoscopy, endoscopic ultrasound or computed tomography.Time to event was referenced from the day of randomization. | Posted | Number | 95% Confidence Interval | percentage of participants | 1 year |
|
|
|
| Secondary | Rate of Participants Who Were Alive Without Loco-regional Failure at 2 Years | Loco-regional failure was defined as progressive primary tumor and/or regional lymph nodes on endoscopy, endoscopic ultrasound or computed tomography. Time to event was referenced from the day of randomization. | Posted | Number | 95% Confidence Interval | percentage of participants | 2 years |
|
|
|
| Secondary | Change in Quality of Life Between Baseline and End of Treatment (After 5 to 13 Weeks) | Quality of Life was assessed with EORTC QLQ-C30 and QLQ-OES18 questionnaires. For QLQ-C30, global health status, functional scales (physical, role, emotional, cognitive and social functioning) and symptom scales (fatigue, nausea/vomiting, pain, dyspnea, loss of appetite, constipation, diarrhea, financial difficulties) were calculated. Scores ranged from 0 to 100; higher scores represented higher levels of quality of life, functioning, or symptoms/problems. Score were calculated using mean values. For QLQ-OES18, symptom scales (problems with eating, reflux, pain, problems swallowing saliva, dry mouth, taste disorders, problems while coughing or speaking) and functional scale (dysphagia) were assessed the same way. A change between two time points, i.e. baseline (prior to treatment) and end of treatment (after 5 to 13 weeks, depending on treatment arm (6.5 weeks without and 13 weeks with cetuximab) and achievement of resectability (end of treatment after 5 weeks), is reported. | All scales used for the rows below in the outcome measure data table ranged between 0 and 100. For scales indicated [H], a higher score represents a better situation (quality of life, functioning). For scales indicated [L], a lower value represents a better outcome (symptoms/problems). | Posted | Mean | Standard Deviation | score on a scale | end of treatment (after 5 to 13 weeks) |
|
|
|
| 13 |
| 32 |
| 21 |
| 32 |
| 32 |
| 32 |
| EG001 | Cisplatin, 5-FU, Radiotherapy | 5-FU: 1000mg/m2 per day as continuous infusion on day 1-4 and 29-32, 750mg/m2/day as continuous infusion on day 64-67 and 92-95 Cisplatin 20mg/m2/day as intravenous bolus over 60 min on day 1-4 of every cycle (day 1-4, 29-32, 64-67 and 92-95) radiotherapy: 59.4 Gy (33 fractions of 1.8 Gy) over 6.5-7 weeks (5 x 1.8 Gy per week)on primary tumor. 50.4 Gy on locoregional lymphnodes. If resectability is reached after 4-4.5 weeks (36-41.4 Gy) the radiotherapy stops after 45 Gy and the patient undergoes surgery. | 20 | 36 | 24 | 36 | 36 | 36 |
| Esophagitis | Gastrointestinal disorders | CTCAE 4.03 (MedDRA) | Non-systematic Assessment |
|
| White blood cell decreased | Investigations | CTCAE 4.03 (MedDRA) | Non-systematic Assessment |
|
| Thromboembolic event | Vascular disorders | CTCAE 4.03 (MedDRA) | Non-systematic Assessment |
|
| Diarrhea | Gastrointestinal disorders | CTCAE 4.03 (MedDRA) | Non-systematic Assessment |
|
| Nausea | Gastrointestinal disorders | CTCAE 4.03 (MedDRA) | Non-systematic Assessment |
|
| Vomiting | Gastrointestinal disorders | CTCAE 4.03 (MedDRA) | Non-systematic Assessment |
|
| Hypokalemia (low potassium) | Metabolism and nutrition disorders | CTCAE 4.03 (MedDRA) | Non-systematic Assessment |
|
| Sepsis | Infections and infestations | CTCAE 4.03 (MedDRA) | Non-systematic Assessment |
|
| Stoma site infection | Infections and infestations | CTCAE 4.03 (MedDRA) | Non-systematic Assessment |
|
| Dysphagia | Gastrointestinal disorders | CTCAE 4.03 (MedDRA) | Non-systematic Assessment |
|
| Dyspnoea | Respiratory, thoracic and mediastinal disorders | CTCAE 4.03 (MedDRA) | Non-systematic Assessment |
|
| Neutrophil count decreased | Investigations | CTCAE 4.03 (MedDRA) | Non-systematic Assessment |
|
| Anemia | Blood and lymphatic system disorders | CTCAE 4.03 (MedDRA) | Non-systematic Assessment |
|
| Liver enzymes increased/elevated | Investigations | CTCAE 4.03 (MedDRA) | Non-systematic Assessment |
|
| Allergic reaction | Immune system disorders | CTCAE 4.03 (MedDRA) | Non-systematic Assessment |
|
| Infection (not specified) | Infections and infestations | CTCAE 4.03 (MedDRA) | Non-systematic Assessment |
|
| Pancytopenia | Investigations | CTCAE 4.03 (MedDRA) | Non-systematic Assessment |
|
| Febrile neutropenia | Blood and lymphatic system disorders | CTCAE 4.03 (MedDRA) | Non-systematic Assessment |
|
| Atrial fibrillation | Cardiac disorders | CTCAE 4.03 (MedDRA) | Non-systematic Assessment |
|
| Myocardial infarction | Cardiac disorders | CTCAE 4.03 (MedDRA) | Non-systematic Assessment |
|
| Ventricular tachycardia | Cardiac disorders | CTCAE 4.03 (MedDRA) | Non-systematic Assessment |
|
| Abdominal pain | Gastrointestinal disorders | CTCAE 4.03 (MedDRA) | Non-systematic Assessment |
|
| Esophageal hemorrhage | Gastrointestinal disorders | CTCAE 4.03 (MedDRA) | Non-systematic Assessment |
|
| Gastric hemorrhage | Gastrointestinal disorders | CTCAE 4.03 (MedDRA) | Non-systematic Assessment |
|
| Gastric ulcer | Gastrointestinal disorders | CTCAE 4.03 (MedDRA) | Non-systematic Assessment |
|
| Gastrointestinal fistula | Gastrointestinal disorders | CTCAE 4.03 (MedDRA) | Non-systematic Assessment |
|
| Gastrointestinal bleeding | Gastrointestinal disorders | CTCAE 4.03 (MedDRA) | Non-systematic Assessment |
|
| Peritonitis | Gastrointestinal disorders | CTCAE 4.03 (MedDRA) | Non-systematic Assessment |
|
| Hematemesis | Gastrointestinal disorders | CTCAE 4.03 (MedDRA) | Non-systematic Assessment |
|
| Death (not specified) | General disorders | CTCAE 4.03 (MedDRA) | Non-systematic Assessment |
|
| Fatigue | General disorders | CTCAE 4.03 (MedDRA) | Non-systematic Assessment |
|
| Fever | General disorders | CTCAE 4.03 (MedDRA) | Non-systematic Assessment |
|
| Immune system disorder (not specified) | Immune system disorders | CTCAE 4.03 (MedDRA) | Non-systematic Assessment |
|
| Appendicitis | Infections and infestations | CTCAE 4.03 (MedDRA) | Non-systematic Assessment |
|
| Device related infection | Infections and infestations | CTCAE 4.03 (MedDRA) | Non-systematic Assessment |
|
| Abdominal infection | Gastrointestinal disorders | CTCAE 4.03 (MedDRA) | Non-systematic Assessment |
|
| Enterocilitis | Infections and infestations | CTCAE 4.03 (MedDRA) | Non-systematic Assessment |
|
| Nail infection | Infections and infestations | CTCAE 4.03 (MedDRA) | Non-systematic Assessment |
|
| Skin infection | Infections and infestations | CTCAE 4.03 (MedDRA) | Non-systematic Assessment |
|
| Upper respiratory infection | Respiratory, thoracic and mediastinal disorders | CTCAE 4.03 (MedDRA) | Non-systematic Assessment |
|
| Wound infection | Infections and infestations | CTCAE 4.03 (MedDRA) | Non-systematic Assessment |
|
| Radiation dermatitis | Injury, poisoning and procedural complications | CTCAE 4.03 (MedDRA) | Non-systematic Assessment |
|
| Anastomotic leak | Injury, poisoning and procedural complications | CTCAE 4.03 (MedDRA) | Non-systematic Assessment |
|
| Fistula | Gastrointestinal disorders | CTCAE 4.03 (MedDRA) | Non-systematic Assessment |
|
| Morphine overdose | Injury, poisoning and procedural complications | CTCAE 4.03 (MedDRA) | Non-systematic Assessment |
|
| Tumor bleeding | Injury, poisoning and procedural complications | CTCAE 4.03 (MedDRA) | Non-systematic Assessment |
|
| Doslocation of feeding tube (PEG) | Injury, poisoning and procedural complications | CTCAE 4.03 (MedDRA) | Non-systematic Assessment |
|
| Platelet count decreased | Blood and lymphatic system disorders | CTCAE 4.03 (MedDRA) | Non-systematic Assessment |
|
| Acidosis | Metabolism and nutrition disorders | CTCAE 4.03 (MedDRA) | Non-systematic Assessment |
|
| Alcalosis | Metabolism and nutrition disorders | CTCAE 4.03 (MedDRA) | Non-systematic Assessment |
|
| Dehydration/Exsiccosis | Metabolism and nutrition disorders | CTCAE 4.03 (MedDRA) | Non-systematic Assessment |
|
| Hypoalbuminemia | Metabolism and nutrition disorders | CTCAE 4.03 (MedDRA) | Non-systematic Assessment |
|
| Hypocalcemia | Metabolism and nutrition disorders | CTCAE 4.03 (MedDRA) | Non-systematic Assessment |
|
| Hypomagnesemia | Metabolism and nutrition disorders | CTCAE 4.03 (MedDRA) | Non-systematic Assessment |
|
| Cognitive disturbance | Nervous system disorders | CTCAE 4.03 (MedDRA) | Non-systematic Assessment |
|
| Seizure | Nervous system disorders | CTCAE 4.03 (MedDRA) | Non-systematic Assessment |
|
| Stroke | Nervous system disorders | CTCAE 4.03 (MedDRA) | Non-systematic Assessment |
|
| Vertigo | Ear and labyrinth disorders | CTCAE 4.03 (MedDRA) | Non-systematic Assessment |
|
| renal failure | Renal and urinary disorders | CTCAE 4.03 (MedDRA) | Non-systematic Assessment |
|
| Nephrotoxicity, tubular function impaired | Renal and urinary disorders | CTCAE 4.03 (MedDRA) | Non-systematic Assessment |
|
| Pulmonary fistula | Respiratory, thoracic and mediastinal disorders | CTCAE 4.03 (MedDRA) | Non-systematic Assessment |
|
| Pneumonitis | Respiratory, thoracic and mediastinal disorders | CTCAE 4.03 (MedDRA) | Non-systematic Assessment |
|
| Pleural effusion | Respiratory, thoracic and mediastinal disorders | CTCAE 4.03 (MedDRA) | Non-systematic Assessment |
|
| Pneumothorax | Respiratory, thoracic and mediastinal disorders | CTCAE 4.03 (MedDRA) | Non-systematic Assessment |
|
| Palma-plantar erythrodysesthesia syndrome | Skin and subcutaneous tissue disorders | CTCAE 4.03 (MedDRA) | Non-systematic Assessment |
|
| Acneiforme rash | Skin and subcutaneous tissue disorders | CTCAE 4.03 (MedDRA) | Non-systematic Assessment |
|
| Reduced overall health condition | General disorders | CTCAE 4.03 (MedDRA) | Non-systematic Assessment |
|
| Hypokalemia (low potassium) | Metabolism and nutrition disorders | CTCAE 4.03 (MedDRA) | Non-systematic Assessment |
|
| Anemia | Blood and lymphatic system disorders | CTCAE 4.03 (MedDRA) | Non-systematic Assessment |
|
| Fatigue | General disorders | CTCAE 4.03 (MedDRA) | Non-systematic Assessment |
|
| Esophagitis | Gastrointestinal disorders | CTCAE 4.03 (MedDRA) | Non-systematic Assessment |
|
| White blood cell decreased | Investigations | CTCAE 4.03 (MedDRA) | Non-systematic Assessment |
|
| Dysphagia | Gastrointestinal disorders | CTCAE 4.03 (MedDRA) | Non-systematic Assessment |
|
| Platelet count decreased | Investigations | CTCAE 4.03 (MedDRA) | Non-systematic Assessment |
|
| Constipation | Gastrointestinal disorders | CTCAE 4.03 (MedDRA) | Non-systematic Assessment |
|
| Hypomagnesemia | Metabolism and nutrition disorders | CTCAE 4.03 (MedDRA) | Non-systematic Assessment |
|
| Vomiting | Gastrointestinal disorders | CTCAE 4.03 (MedDRA) | Non-systematic Assessment |
|
| Lung infection | Respiratory, thoracic and mediastinal disorders | CTCAE 4.03 (MedDRA) | Non-systematic Assessment |
|
| Diarrhea | Gastrointestinal disorders | CTCAE 4.03 (MedDRA) | Non-systematic Assessment |
|
| Oral mucositis | Gastrointestinal disorders | CTCAE 4.03 (MedDRA) | Non-systematic Assessment |
|
| Weight loss | General disorders | CTCAE 4.03 (MedDRA) | Non-systematic Assessment |
|
| Cough | Respiratory, thoracic and mediastinal disorders | CTCAE 4.03 (MedDRA) | Non-systematic Assessment |
|
| Hypocalcemia | Metabolism and nutrition disorders | CTCAE 4.03 (MedDRA) | Non-systematic Assessment |
|
| Acneiforme rash | Skin and subcutaneous tissue disorders | CTCAE 4.03 (MedDRA) | Non-systematic Assessment |
|
| Radiation dermatitis | Injury, poisoning and procedural complications | CTCAE 4.03 (MedDRA) | Non-systematic Assessment |
|
| Edema | General disorders | CTCAE 4.03 (MedDRA) | Non-systematic Assessment |
|
| Neutrophil count decreased | Investigations | CTCAE 4.03 (MedDRA) | Non-systematic Assessment |
|
| Dizziness | Nervous system disorders | CTCAE 4.03 (MedDRA) | Non-systematic Assessment |
|
| Dyspnoea | Respiratory, thoracic and mediastinal disorders | CTCAE 4.03 (MedDRA) | Non-systematic Assessment |
|
| Maculopapular rash | Skin and subcutaneous tissue disorders | CTCAE 4.03 (MedDRA) | Non-systematic Assessment |
|
| Pain | General disorders | CTCAE 4.03 (MedDRA) | Non-systematic Assessment |
|
| Insomnia | Nervous system disorders | CTCAE 4.03 (MedDRA) | Non-systematic Assessment |
|
| Alopecia | Skin and subcutaneous tissue disorders | CTCAE 4.03 (MedDRA) | Non-systematic Assessment |
|
| Pleural effusion | Respiratory, thoracic and mediastinal disorders | CTCAE 4.03 (MedDRA) | Non-systematic Assessment |
|
| GGT increased | Investigations | CTCAE 4.03 (MedDRA) | Non-systematic Assessment |
|
| Infection (not specified) | Infections and infestations | CTCAE 4.03 (MedDRA) | Non-systematic Assessment |
|
| Paresthesia | Nervous system disorders | CTCAE 4.03 (MedDRA) | Non-systematic Assessment |
|
| Thrombembolic event | Vascular disorders | CTCAE 4.03 (MedDRA) | Non-systematic Assessment |
|
| Allergic reaction | Immune system disorders | CTCAE 4.03 (MedDRA) | Non-systematic Assessment |
|
| Dehydration | Metabolism and nutrition disorders | CTCAE 4.03 (MedDRA) | Non-systematic Assessment |
|
| Stoma site infection | Infections and infestations | CTCAE 4.03 (MedDRA) | Non-systematic Assessment |
|
| Hyponatremia (low sodium) | Metabolism and nutrition disorders | CTCAE 4.03 (MedDRA) | Non-systematic Assessment |
|
| Weight gain | General disorders | CTCAE 4.03 (MedDRA) | Non-systematic Assessment |
|
| Syncope | Nervous system disorders | CTCAE 4.03 (MedDRA) | Non-systematic Assessment |
|
| Urinary retention | Renal and urinary disorders | CTCAE 4.03 (MedDRA) | Non-systematic Assessment |
|
| Esophageal pain | Gastrointestinal disorders | CTCAE 4.03 (MedDRA) | Non-systematic Assessment |
|
The only disclosure restriction on the PI is that the sponsor can review results communications (presentation of results obtained at a participating center at scientific meetings or publication of these results) prior to public release and can embargo communications regarding trial results prior to submission of the results of the entire study for publication.
| D006258 |
| Head and Neck Neoplasms |
| D004066 | Digestive System Diseases |
| D004935 | Esophageal Diseases |
| D005767 | Gastrointestinal Diseases |
| D007162 |
| Immunoproteins |
| D001798 | Blood Proteins |
| D011506 | Proteins |
| D000602 | Amino Acids, Peptides, and Proteins |
| D012712 | Serum Globulins |
| D005916 | Globulins |
| D017606 | Chlorine Compounds |
| D007287 | Inorganic Chemicals |
| D017672 | Nitrogen Compounds |
| D017671 | Platinum Compounds |
| D014498 | Uracil |
| D011744 | Pyrimidinones |
| D011743 | Pyrimidines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D013812 | Therapeutics |
| D055585 | Physical Phenomena |
| Change in role functioning [H] |
|
| Change in emotional functioning [H] |
|
| Change in cognitive functioning [H] |
|
| Change in social functioning [H] |
|
| Change regarding fatigue [L] |
|
| Change regarding nausea/vomiting [L] |
|
| Change regarding pain [L] |
|
| Change regarding dyspnoea [L] |
|
| Change regarding insomnia [L] |
|
| Change regarding loss of appetite [L] |
|
| Change regarding constipation [L] |
|
| Change regarding diarrhea [L] |
|
| Change regarding financial difficulties [L] |
|
| Change regarding problems with eating [L] |
|
| Change regarding reflux [L] |
|
| Change regarding pain while eating [L] |
|
| Change regarding problems swallowing saliva [L] |
|
| Change regarding dry mouth [L] |
|
| Change regarding taste disorders [L] |
|
| Change regarding problems while coughing [L] |
|
| Dysphagia [H] |
|