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
Summary
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 survival1-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.
Eligibility
Minimum age: 18 Years.
Maximum age: N/A.
Gender(s): Both.
Criteria:
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
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