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A Randomized Phase II Study of Induction Chemotherapy Followed by Concurrent Chemoradiation Therapy According to EGFR Mutation Status in Patients With Unresectable Stage III NSCLC

Phase 2
18 Years
Open (Enrolling)
Lung Cancer, NSCLC

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Trial Information

A Randomized Phase II Study of Induction Chemotherapy Followed by Concurrent Chemoradiation Therapy According to EGFR Mutation Status in Patients With Unresectable Stage III NSCLC

Concurrent Chemoradiation therapy is widely accepted as a standard treatment of locally
advanced unresectable stage III NSCLC. When compared with the result of radiation therapy
alone of CALGB 8433 trial (i.e., 9.7 months), the median survival times have almost doubled
over the last 2 decades, but rarely exceeded 18 months after chemoradiation therapy in most
randomized trials. On the other hand, a significant portion of patients had to endure the
side effects of grade 3/4 esophagitis and also pneumonitis, which resulted in
treatment-related deaths in some cases. There is a great need to develop more effective but
less toxic treatment strategies. Recently, molecular-targeted therapy using EGFR-TKIs
brought new enthusiasm to the NSCLC therapy. The investigators observed a median survival
time of 20.1 months in chemo-naïve never-smoker Korean patients with adenocarcinoma of the
lung. The benefit of EGFR-TKI was also demonstrated in never-smokers who participated in the
phase III trial of carboplatin/paclitaxel with or without Erlotinib (TRIBUTE). Despite a
lack of benefit in the overall patient population, Erlotinib conferred a survival benefit to
those who had never smoked cigarettes, In this analysis, 105 patients who were identified as
never smokers had a median survival of 10 months, similar to the entire study population,
when treated with carboplatin/paclitaxel plus placebo. However, for the patients in this
subpopulation who were treated with Erlotinib and the same chemotherapy regimen, the median
survival increased to 22.5 months (P = 0.01). Furthermore, EGFR mutation was associated with
significantly higher response rate and longer survival as compared with those without EGFR
mutation. More importantly, the median survival time of those patients with EGFR
mutation-positive tumors exceeded 20 months in the majority of the studies. These results
are very provocative given the fact that only the patients with stage IIIb not amenable to
chemoradiation therapy and stage IV NSCLC patients were included in the study and in many
studies, the majority of the patients were heavily pre-treated with multiple chemotherapy
regimens. The investigators postulate that if the case were properly selected, EGFR-TKI
would significantly improve the overall survival of the patients with locally advanced
unresectable stage III NSCLC. The investigators therefore propose a randomized phase II
trial to evaluate the efficacy and toxicity of EGFR-TKI Erlotinib in selected group of NSCLC
patients with EGFR mutation-positive stage III tumors. The use of induction chemotherapy is
feasible and effective. It is also logistically beneficial for decreasing micrometastases
and radiation-related toxicity by decreasing tumor burden before definite locoregional
concurrent therapy. Previously the investigators conducted several phase II study of IP
chemotherapy in advanced NSCLC and demonstrated that IP chemotherapy has a promising
activity and readily manageable toxicity profile. Given the encouraging activity of IP
chemotherapy in the advanced stage setting, the investigators postulated that their further
investigation in the stage III setting might lead to further prolongation of survival times.
In addition to cisplatin, Irinotecan has been demonstrated to act as radiation sensitizers
in preclinical and clinical setting. Therefore, their use with concurrent radiotherapy might
lead to radiation sensitization and improved locoregional control.

Inclusion Criteria:

1. Histologically or cytologically confirmed NSCLC: it is recommended to obtain adequate
tissue samples for EGFR mutation analysis.

2. Unresectable stage IIIA (N2) or stage IIIB NSCLC defined as:unresectability confirmed
by Surgeon /Stage IIIa T1-3 N2/Stage IIIb T1-4 N3/Stage IIIb T4 N2

3. Age 18 years over.

4. ECOG performance status of 0 or 1.

5. Tumor work-up: within 4 weeks prior 1st day of treatment: chest X-ray; CT of chest,
liver, and adrenal glands; bone scan; brain MRI

6. Measurable or un-measurable disease (according to RECIST criteria), documented by CT,
MRI, X-ray, or physical exam, as appropriate.

7. Hematology (within 1 week before 1st day of treatment)Absolute Neutrophil Count ³2.0
x 109/L; Platelet ³100 x 109/L; Hemoglobin ³10 g/dl

8. Liver function test (within 1 week before 1st day of treatment)Serum bilirubin £1 x
UNL; AST & ALT £2.5 x UNL

9. Renal function (within 1 week before 1st day of treatment)Serum creatinine £1 x UNL.
In case of borderline value, 24h creatinine clearance should be > 60 mL/min.

10. Pulmonary function (within 4 weeks before 1st day of treatment)FEV1 ³ 1 Liter

11. ECG without significant abnormalities within 4 weeks before 1st day of treatment.

12. Written informed consent.

Exclusion Criteria:

1. T4 with malignant pleural effusion.

2. Any prior therapy (chemotherapy, immunotherapy, biologic therapy such as
EGFR-targeted therapy, radiotherapy) for lung cancer.

3. History of prior malignancies, except for cured non-melanoma skin cancer, curatively
treated in-situ carcinoma of the cervix or other cancer curatively treated and with
no evidence of disease for at least 5 years.

4. Unintended weight loss > 10% within the last 3 months.

5. Other serious concomitant illness or medical conditions:

6. Congestive heart failure or angina pectoris except if it is medically controlled.
Previous history of myocardial infarction within 1 year from study entry,
uncontrolled hypertension or arrhythmia.

7. History of significant neurological or psychiatric disorders including dementia or

8. Active infection requiring IV antibiotics.

9. Active ulcer, unstable diabetes mellitus or other contra-indication of corticosteroid

10. Significant gastrointestinal abnormalities, including requirement for intravenous
nutrition, active peptic ulcer disease, prior surgical procedures affecting

11. Pregnant or lactating women-Patients (male or female) with reproductive potential not
implementing adequate contraceptive measures.

12. Concurrent treatment with any other experimental anti-cancer drugs.

13. Concurrent use of phenytoin, carbamazepin, barbiturates, or rifampin.

14. Mental condition rendering the patient unable to understand the nature, scope, and
possible consequence of the study.

15. Patient unlikely to comply with protocol, i.e., uncooperative attitude, inability to
return for follow-up visits, and not likely to complete the study.

Type of Study:


Study Design:

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

Outcome Measure:

Response rate

Outcome Time Frame:

every 8 weeks

Safety Issue:


Principal Investigator

Jin Soo Lee, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Cancer Center, Korea


South Korea: Korea Food and Drug Administration (KFDA)

Study ID:




Start Date:

February 2008

Completion Date:

March 2015

Related Keywords:

  • Lung Cancer
  • EGFR mutation
  • Erlotinib
  • IP chemotherapy
  • CCRT
  • Carcinoma, Non-Small-Cell Lung
  • Lung Neoplasms