Definitive Radiochemotherapy Plus/Minus Cetuximab in Unresectable Locally Advanced Esophageal Cancer

NCT ID: NCT01787006

Last Updated: 2020-03-10

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 74 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2011-09-30
• Study Completion Date: 2018-09-06

Brief Summary

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.

Detailed Description

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.

Conditions

Esophageal Cancer

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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-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.

Group Type: EXPERIMENTAL

Cetuximab

Intervention Type: DRUG

Initial doses 400mg/m2 (day 1), followed by weekly doses of 250mg/m2 for 14 weeks in total

Cisplatin, 5-FU

Intervention Type: 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

Intervention Type: 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.

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.

Group Type: ACTIVE_COMPARATOR

Cisplatin, 5-FU

Intervention Type: 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

Intervention Type: 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.

Interventions

Cetuximab

Initial doses 400mg/m2 (day 1), followed by weekly doses of 250mg/m2 for 14 weeks in total

Intervention Type: DRUG

Cisplatin, 5-FU

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

Intervention Type: DRUG

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.

Intervention Type: RADIATION

Other Intervention Names

Erbitux; CDDP, 5-fluorouracil; Irradiation

Eligibility Criteria

Inclusion Criteria

• Dated and signed written informed consent
• Male or female patients between 18 years and 75 years; patients > 75 years if their karnofsky performance status is ≥ 80.
• Histologically proven squamous cell carcinoma or adenocarcinoma of the esophagus which is not curatively resectable. Resectability has to be defined by a surgeon before radiochemotherapy. The tumor is considered unresectable due to T-stage, N-stage, performance status, nutritional status, co-morbidity (pulmonal function, other), tumor location upper third or other reasons
• Karnofsky Performance Status ≥ 70
• Women of child-bearing potential must have a negative pregnancy test
• Adequate cardial-, pulmonal- and ear function

Adequate bone marrow function:

• leukocytes ≥ 3.0 x 10^9/L
• neutrophiles ≥ 1.5 x 10^9/L
• thrombocytes ≥ 100 x 10^9/L
• hemoglobin ≥ 10.0 g/dl

Adequate liver function:

• bilirubin ≤ 2.0 mg/dl
• transaminases (serum glutamic pyruvic transaminase (SGPT), serum glutamic oxaloacetic transaminase (SGOT), gamma-GT) ≤ 3 x upper limit of normal (ULN)

Adequate kidney function:

• serum creatinine ≤ 1.5 mg/dl
• creatinine clearance ≥ 50 ml/min according to Cockcroft-Gault Formula
• no known allergies against chimeric antibodies
• effective contraception for male and female patients if there is a risk of conception

Exclusion Criteria

• distant metastasis
• previous treatment of esophageal cancer
• previous therapy with monoclonal antibodies and / or EGFR-targeted therapy
• previous second malignancies with exception of a history of a previous curatively treated basal cell carcinoma of the skin or pre-invasive cervix carcinoma
• serious concomitant disease or medical condition
• lung function: forced expiratory volume in one second (FEV1)) < 1.1
• clinically relevant coronary artery diseases or known myocardial infarction within the last 12 months or ventricular ejection fraction (LVEF) below normal
• every active dermatological condition > grade 1
• contraindications to receive cisplatin, 5-FU or cetuximab
• concurrent treatment with other experimental drugs or participation in another clinical trial within 30 days before study start
• patient pregnant or breast feeding
• known drug abuse, medication abuse, alcohol abuse
• social situations limiting the compliance with the study requirements

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University Hospital Schleswig-Holstein

OTHER

Sponsor Role: lead

Responsible Party

Prof. Dirk Rades, MD

Professor Dr. med.

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Dirk Rades, Prof. Dr.

Role: PRINCIPAL_INVESTIGATOR

Universität zu Lübeck, Klinik für Strahlentherapie

Locations

Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Klinik für Strahlentherapie

Lübeck, , Germany

Countries

Germany

References

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.

Reference Type: DERIVED

PMID: 32533228 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Document Type: Informed Consent Form

View Document

Other Identifiers

2010-023427-18

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

LEOPARD II

Identifier Type: -

Identifier Source: org_study_id