Download Management of patients with locally advanced non

SAKK 16/08
Preoperative chemotherapy and radiotherapy concomitant to
Cetuximab in non-small cell lung cancer (NSCLC) patients with IIIB
disease. A multicenter phase II trial.
Protocol synopsis
Management of patients with locally advanced non-small cell lung cancer (NSCLC) remains
a challenge. Both local relapses and distant metastases are frequent and lead to a poor
prognosis with a 5-year overall survival estimated between 3% and 7% for inoperable
disease.
Staging has historically subdivided stage III disease into stage IIIA, considered potentially
amenable to surgery and stage IIIB, treated by definitive radiotherapy (RT) or chemo-RT.
Progress in anesthesia coupled with improved surgical techniques and surgical specialization
allowed in recent years to redefine the surgical limits. Among the patients with locally
advanced stage IIIB NSCLC, there is a group that is technically operable. Patients with N3 or
T4 disease with involvement of the carina, the pulmonary artery, vertebral bodies or the vena
cava may be technically resectable.
Reports on carefully selected patients with stage IIIB disease have shown a similar survival
to patients with stage IIIA disease, when treated with induction therapy followed by resection
with 5-year survival rates up to 20-30%.
The Swiss Group of Clinical Cancer Research (SAKK) has focused since several years on
the improvement of the treatment of advanced non-small cell lung cancer. The present study
should allow defining the best induction therapy for patients having an operable stage IIIB.
Indeed, the combination of cisplatine and docetaxel used as an induction therapy in previous
SAKK trials has shown its effectiveness. Within stages IIIB, the SAKK already demonstrated
in the literature that this combined chemotherapy followed by radiotherapy as a preoperative
phase gives promising results. In the present trial, cetuximab will be added at this
preoperative scheme, in order to improve further this induction treatment. Cetuximab is a
primary antibody already known to be effective in the treatment of several solid tumors and
especially in the treatment of advanced non-small cell lung cancer. Moreover, its use in
combination either chemotherapy or radiotherapy, seems to not induce further secondary
effects.
The translational part of this trial will explore some candidate molecular markers which could
contribute to recognition of the patients who would benefit most from the addition of
cetuximab to the induction treatment of chemo-RT. Markers helping to predict more generally
a benefit from this trimodality approach will also be analyzed.
OBJECTIVES
The main objective of this trial is to evaluate efficacy and safety of sequential neoadjuvant
chemo-radiotherapy with concomitant targeted therapy of cetuximab in patient with operable
stage IIIB NSCLC.
ENDPOINTS
Primary endpoint:
Progression free survival (PFS) at 1 year
Secondary endpoints:
 Treatment-related death during chemo-immunotherapy, radio-immunotherapy and perioperatively
 Metabolic response evaluated by PET
 Response status after chemo-immunotherapy and after radio-immunotherapy
 Complete pathological response
 Overall survival
 PFS
 Adverse events
 Operability
 Resection
 Failure pattern
Endpoints for additional research questions:
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FcR polymorphism
Tumor immunohistochemical EGFR expression
Tumor EGFR gene amplification (FISH)
KRAS mutations
Immunohistochemical ERCC1 expression
Immunohistochemical GSTPI expression
TRIAL DESIGN
Prospective multicenter, phase II trial
12 weeks
Cisplatin 50 mg/m2 on day 1 and 2 of 21 day cycles
Docetaxel 85 mg/m2 day 1 of 21 day cycles
3 cycles
Radiotherapy
44 Gy
(PTV 1 = 30 Gy, PTV 2 = 14 Gy)
3 weeks
Follow up
400 mg/m2 initial dose on day 1
250 mg/m2 weekly starting on day 8
Surgery
Registration
Cetuximab
SELECTION OF PATIENTS
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Histologically proven NSCLC stage IIIB: T4N0-3M0 or T1-4N3M0 (according to Error!
Reference source not found.). Excluded are IIIB stages with malignant pleural or
pericardial effusion; invasion of the aorta, esophagus, myocardium and
supraclavicular/scalene nodes N3; or stages IIIB defined only by satellite lesions in the
same lobe.
Performance status 0-1
Patient medically fit for all protocol therapy, including operability
Age 18-75
Written informed consent
No previous chemo- or radiotherapy
TRIAL DURATION
The inclusion of patients is planned to start in Q3 2009 and will stop after the inclusion of 69
patients, which is expected in Q3 2012. End of trial treatment (last patient, last treatment
visit) is expected for Q1 2013.
STATISTICAL CONSIDERATIONS
The sample size is calculated for PFS at 1 year. The PFS rate of ≤ 50% is considered
uninteresting and ≥ 65% promising. Fleming- A’Hern single-stage phase II procedure with a
power of 80%, a significance level of 5% and a sample size of 69 evaluable patients is
chosen.