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Cisplatin and 5-FU +/- Panitumumab for Patients With Nonresectable,Advanced or Metastatic Esophageal Squamous Cell Cancer

Information source: AIO-Studien-gGmbH
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Esophageal Squamous Cell Cancer

Intervention: Cisplatin, 5-FU (Drug); Panitumumab (Drug)

Phase: Phase 3

Status: Recruiting

Sponsored by: AIO-Studien-gGmbH

Official(s) and/or principal investigator(s):
Markus Möhler, PD Dr., Principal Investigator, Affiliation: I. Medizinische KLinik und Poliklinik, Johannes-Gutenberg-Universität Mainz

Overall contact:
Ralph Keller, Phone: 0049 30 814534434, Email: mailto:ralph.keller@aio-studien-ggmbh.de


More than 50% of patients with esophageal cancer have locally advanced or metastatic disease at presentation. The use of chemotherapy for this patient group is increasing with the intention of local and distant tumor control, improving quality of life and prolongation of survival. Previous data suggested not only that EGFR antibody targeted therapy may be safely combined with cisplatin and 5-FU but also may increase the efficacy of standard cisplatin / 5-FU regime. In the present study, patients with nonresectable, advanced or metastatic esophageal squamous cell cancer (ESCC) will receive chemotherapy or chemotherapy plus panitumumab every 3 weeks until disease progression occurs. The primary objective is to demonstrate superiority of 5-FU, Cisplatin and Panitumumab over 5-FU and Cisplatin alone in terms of overall survival in esophageal cancer.

Clinical Details

Official title: An Open-label, Randomized Phase III Trial of Cisplatin and 5-fluorouracil With or Without Panitumumab for Patients With Nonresectable, Advanced or Metastatic Esophageal Squamous Cell Cancer

Study design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome: Overall Survival

Secondary outcome:

Progression-free survival

1-year survival

Response rate

Overall incidence of patients with adverse events

Quality of life

Detailed description: More than 50% of patients with esophageal cancer have locally advanced or metastatic disease at presentation. The use of chemotherapy for this patient group is increasing with the intention of local and distant tumor control, improving quality of life and prolongation of survival. The most frequently used agents are 5-fluorouracil, cisplatin, with or without various anthracyclines. Cisplatin plus continuous 5-fluorouracil are the standard of care regimens. Taxanes and anthracyclins are eligible agents for possible future studies, however with higher incidences of toxicities and life threatening complications. Response rates for single agents range from 15%-30%. Combination regimens usually tend to produce higher response rates and occasionally patients achieve complete responses (0%-11%). However, with the combination regimens, the median survival time remains clearly less than 10 months, mostly between 4-8 months [Homs MY et al]. In comparison of different chemotherapy protocols, there was no consistent benefit of any specific chemotherapy regimen. So far, cisplatin combined with 5-fluorouracil is one of the approved standard regimens in esophageal cancer world wide[Medical Research Council Oesophageal Cancer Group]. This so called three-weekly MRC regimen has a better toxicity profile than the four weekly CF regimen given in Central Europe with the higher Cisplatin dose[Lorenzen S et al], but less overall chemotherapy given per 4 months. Advances in molecular biology and new molecular technologies can possibly contribute to improvement of response to neoadjuvant or palliative therapy in ESCC patients as well. EGFR1 blockade with platinum-based chemotherapy already significantly improved response rates as well as the progression-free and overall survival compared to chemotherapy alone in patients with head and neck tumors, which are also squamous cancers[Vermorken JB et al]. Even more, the Arbeitsgemeinschaft Internistische Onkologie (AIO) has performed a randomized phase II study of the EGFR antibody cetuximab plus cisplatin/5-fluorouracil versus cisplatin/5-fluorouracil alone in first-line metastatic ESCC[Lorenzen S et al]. For a maximum of six 28-day cycles, patients received cisplatin 100 mg/m(2), day 1, plus 5-FU 1000 mg/m(2) days 1-5 (CF), either alone or in combination with cetuximab (CET-CF). The primary endpoint was tumor response. From 62 eligible patients included, 32 receiving CET-CF and 30 CF. Cetuximab weekly did not exacerbate grade 3/4 toxicity, except for rash (6% vs 0%) and diarrhea (16% vs 0%). The overall response rate according to RECIST criteria were 19% and 13% and the disease control rates, were 75% and 57% for the CET-CF and CF arms, respectively. With a median follow-up of 21. 5 months, 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. No KRAS codon 12/13 tumor mutations were identified in the 37 evaluated samples. Thus, with respect to the AIO data and in concordance with the head and neck data by Vermorken, EGFR antibody targeted therapy may not only be safely combined with CF, but may also very likely increase the efficacy of standard CF, particularly with regard to a chosen primary endpoint of overall survival. Therefore, the aim of this study is to investigate if the overall survival of patients with squamous cell carcinoma of the esophagus can be prolonged if panitumumab is added to the standard CF chemotherapy.


Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.


Inclusion Criteria: 1. Signed written informed consent 2. Male or female ≥18 years of age 3. Histologically proven squamous cell carcinoma of the esophagus, which is not curatively resectable* or locally recurrent disease and both not eligible** for definitive radiochemotherapy, or clearly metastatic disease (Tx, Nx, M1, locally unresectable T4, Nx, M0 or TX, N3, M0)* or residual (post-resection) disease not eligible** for definitive radiochemotherapy

- resectability has to be defined prior to randomization according to local

standards: The tumor is considered unresectable due to: T-stage, N-stage, performance status/nutritional status, co-morbidity (pulmonary function, other), tumor location upper third of the esophagus, relation to other organs/structures), patient refusal, other reasons.

- eligibility to definitive radiochemotherapy will be determined according to

local standards based on the extent of disease, performance status/nutritional status, co-morbidity (pulmonary function, other), volume of neighboring organs within the radiation field, patient refusal, other reasons. 4. Measurable or non-measurable disease according to RECIST 1. 1 5. ECOG 0-1 6. Women of child-bearing potential must have a negative pregnancy test 7. Laboratory requirements

- Hematology:

- Absolute neutrophil count ≥1. 5x10^9/L

- Platelet count ≥100x10^9/L

- Leukocyte count ≥ 3. 0x10^9/L

- Hemoglobin ≥ 9 g/dL or 5. 59 mmol/l

- Hepatic Function:

- Total bilirubin ≤ 1. 5 time the upper normal limit (UNL)

- AST ≤ 2. 5xUNL in absence of liver metastases, or ≤5xUNL in presence of

liver metastases

- ALT ≤ 2. 5xUNL in absence of liver metastases, or ≤5xUNL in presence of

liver metastases

- Renal Function:

- Creatinine clearance ≥ 50 mL/min according to Cockroft-Gault formula

- Metabolic Function

- Magnesium ≥ 0. 5 mmol/L or 1. 2 mg/dL

- Calcium ≥ 2 mmol/L or 8. 0 mg/dL

Exclusion Criteria: 1. Previous chemotherapy of esophageal cancer in the metastatic setting. Previous neoadjuvant chemotherapy or definitive radiochemotherapy with a maximum cumulative dose of 120 mg cisplatin and without recurrence of disease within 4 months after the end of treatment is allowed. 2. Concurrent radiotherapy involving target lesions used for this study. Concurrent palliative radiation for non-target lesions is allowed if other lesions are available outside the involved field. Previous pre- operative or post-operative radiotherapy is allowed. 3. Previous exposure to EGFR-targeted therapy 4. Other previous malignancy with exception of a history of a previous curatively treated basal cell carcinoma of the skin or pre-invasive carcinoma of the cervix or other curatively treated malignant disease without recurrence after at least 5 years of follow-up 5. Known brain metastases unless adequately treated (surgery or radiotherapy) with no evidence of progression and neurologically stable off anticonvulsants and steroids 6. Serious concomitant disease or medical condition that in the judgment of the investigator renders the subject at high risk of treatment complication or reduces the probability of assessing clinical effect. 7. Clinically significant cardiovascular disease (including myocardial infarction, unstable angina, symptomatic congestive heart failure, serious uncontrolled cardiac arrhythmia) ≤ 1 year before enrollment 8. Inadequate pulmonary function according to the investigator's judgment, history of interstitial lung disease e. g. pneumonitis or pulmonary fibrosis or evidence of interstitial lung disease on baseline chest CT scan. 9. Hearing loss ≥ NCI-CTC V. 4.03 Grade 3 10. Subject pregnant or breast feeding, or planning to become pregnant within 6 months after the end of treatment. 11. Subject (male or female) is not willing to use highly effective methods of contraception (per institutional standard) during treatment and for 6 months (male or female) after the end of treatment. 12. Contraindications to receive any platin, 5-FU or panitumumab 13. Concurrent treatment with other experimental drugs or participation in another clinical trial with any investigational drug within 30 days prior to treatment start 14. Known drug abuse/alcohol abuse 15. Peripheral polyneuropathy ≥ NCI-CTC V 4. 03 Grade 2 16. Chronic inflammatory bowels diseases 17. Social situations limiting the compliance with the study requirements. 18. History of HIV infection or chonic hepatitis B or C 19. Concurrent treatment with brivudin or sorivudin or its chemically related analogues. There must be at least a 4-week wash-out period between end of treatment with brivudin, sorivudin or its chemically related analogues and start of therapy with 5-FU.

Locations and Contacts

Ralph Keller, Phone: 0049 30 814534434, Email: mailto:ralph.keller@aio-studien-ggmbh.de

Johannes-Gutenberg-Universität Mainz, I. Medizinische Klinik und Poliklinik, Mainz, Rheinland-Pfalz 55101, Germany; Recruiting
Markus Möhler, PD Dr., Phone: 0049 6131 17 5712, Email: moehler@mail.uni-mainz.de
Markus Möhler, Prof. Dr. med., Principal Investigator
Additional Information

Related publications:

Vermorken JB, Mesia R, Rivera F, Remenar E, Kawecki A, Rottey S, Erfan J, Zabolotnyy D, Kienzer HR, Cupissol D, Peyrade F, Benasso M, Vynnychenko I, De Raucourt D, Bokemeyer C, Schueler A, Amellal N, Hitt R. Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med. 2008 Sep 11;359(11):1116-27. doi: 10.1056/NEJMoa0802656.

Lorenzen S, Schuster T, Porschen R, Al-Batran SE, Hofheinz R, Thuss-Patience P, Moehler M, Grabowski P, Arnold D, Greten T, Müller L, Röthling N, Peschel C, Langer R, Lordick F. Cetuximab plus cisplatin-5-fluorouracil versus cisplatin-5-fluorouracil alone in first-line metastatic squamous cell carcinoma of the esophagus: a randomized phase II study of the Arbeitsgemeinschaft Internistische Onkologie. Ann Oncol. 2009 Oct;20(10):1667-73. doi: 10.1093/annonc/mdp069. Epub 2009 Jun 23.

Homs MY, v d Gaast A, Siersema PD, Steyerberg EW, Kuipers EJ. Chemotherapy for metastatic carcinoma of the esophagus and gastro-esophageal junction. Cochrane Database Syst Rev. 2006 Oct 18;(4):CD004063. Review. Update in: Cochrane Database Syst Rev. 2010;(5):CD004063.

Medical Research Council Oesophageal Cancer Working Group. Surgical resection with or without preoperative chemotherapy in oesophageal cancer: a randomised controlled trial. Lancet. 2002 May 18;359(9319):1727-33.

Starting date: May 2012
Last updated: January 13, 2015

Page last updated: August 23, 2015

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