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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

Phase 3
18 Years
Open (Enrolling)
Esophageal Squamous Cell Cancer

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Trial Information

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

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

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.

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

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 ≥ lower limit of normal

- Calcium ≥ lower limit of normal.

Exclusion Criteria:

1. Previous chemotherapy of esophageal cancer except for neoadjuvant treatment without
recurrence within 6 months after the end of treatment.

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 enrolment

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.

Type of Study:


Study Design:

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

Outcome Measure:

Overall Survival

Outcome Description:

Kaplan-Meier estimate of the median time between date of randomization and the date of death from any cause or the date of last follow-up in case of no documentation of death. Comparison of Overall survival of treatment arms "Panitumumab + Chemotherapy" and "Chemotherapy only" in patients with nonresectable, advanced or metastatic ESCC.

Outcome Time Frame:

3 years

Safety Issue:


Principal Investigator

Markus Möhler, PD Dr.

Investigator Role:

Principal Investigator

Investigator Affiliation:

I. Medizinische KLinik und Poliklinik, Johannes-Gutenberg-Universität Mainz


Germany: Paul-Ehrlich-Institut

Study ID:




Start Date:

May 2012

Completion Date:

Related Keywords:

  • Esophageal Squamous Cell Cancer
  • nonresectable
  • advanced
  • metastatic esophageal squamous cell cancer
  • Panitumumab
  • Carcinoma, Squamous Cell
  • Neoplasms, Squamous Cell
  • Esophageal Diseases