Erlotinib Versus Gemcitabine/Carboplatin in Chemo-naive Stage IIIB/IV Non-Small Cell Lung Cancer Patients With Epidermal Growth Factor Receptor (EGFR) Exon 19 or 21 Mutation (ML20981)

• ClinicalTrials.gov Identifier: NCT00874419
• Recruitment Status: Completed
• First Posted: April 2, 2009
• Last Update Posted: September 25, 2014
• Sponsor: Tongji University
• Collaborators: Sun Yat-sen University; Shanghai Chest Hospital; RenJi Hospital; Guangdong Provincial People's Hospital; Peking Union Medical College Hospital
• Information provided by (Responsible Party): Caicun Zhou, Tongji University

Tracking Information

• First Submitted Date: April 1, 2009
• First Posted Date: April 2, 2009
• Last Update Posted Date: September 25, 2014
• Study Start Date: August 2008
• Actual Primary Completion Date: July 2010 (Final data collection date for primary outcome measure)
• Current Primary Outcome Measures (submitted: August 4, 2009): Progression free survival [ Time Frame: 12 months ]
• Original Primary Outcome Measures (submitted: April 1, 2009): progression free survival [ Time Frame: 12 months ]

Current Secondary Outcome Measures (submitted: May 18, 2011)

• OS [ Time Frame: 24 months ]
• ORR [ Time Frame: 24 months ]
• Time to Progression [ Time Frame: 24 months ]
• lung cancer symptoms and health-related quality of life (HRQoL) [ Time Frame: 24 months ]
• explore the biological markers (tumor tissue) [ Time Frame: 24 months ]

• Original Secondary Outcome Measures (submitted: April 1, 2009): OS, ORR, TTP, lung cancer symptoms and health-related quality of life (HRQoL), and explore the biological markers (tumor tissue) [ Time Frame: 24 months ]
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Erlotinib Versus Gemcitabine/Carboplatin in Chemo-naive Stage IIIB/IV Non-Small Cell Lung Cancer Patients With Epidermal Growth Factor Receptor (EGFR) Exon 19 or 21 Mutation
• Official Title: A Randomized, Open-label, Multi-center Phase III Study of Erlotinib Versus Gemcitabine/Carboplatin in Chemo-naive Stage IIIB/IV Non-Small Cell Lung Cancer Patients With EGFR Exon 19 or 21 Mutation (Optimal)
• Brief Summary: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) such as erlotinib have proved effective in second or third line therapy for advanced non-small cell lung cancer(NSCLC).It is well tolerated without the side effects usually associated with chemotherapy. The mutations in EGFR exons 19 or 21 have been reported to be associated with efficacy of EGFR TKIs.Based on the encouraging preliminary results from the Spanish lung cancer group' prospective study reported that the efficacy of Tarceva as first line treatment for metastatic NSCLC patients with EGFR mutation would delay disease progression,prolong overall survival and be well tolerated, medium Progression-free survival(PFS) was around 12 months and OS reach 24 months，our study is designed to compare PFS between the patients with mutant EGFR treated by gemcitabine/carboplatin and those by erlotinib in the first-line setting. We assumed 11 months of PFS on Tarceva arm versus 6 months on chemotherapy arm with a=0.025(alpha-spend for an interim analysis), 80% power and 12 months enrolment period, 12 months FU duration to calculate the sample size. The sample size is 69 pairs. Considering about 10% drop-out rate, the final sample size is 152 patients.So, chemo-naive staged IIIb/IV patients with EGFR mutations in exon 19 or 21 will be enrolled into this open-label, randomized,multicenter phase III study.

Detailed Description

Primary Outcome Measures:

Progression-free survival(PFS) Secondary Outcome Measures: Overall response rate(ORR), overall survival(OS), quality of life(QOL),etc.

Estimated Enrollment: 160 Study Start Date: August 2008 Estimated Study Completion Date: August 2010

The patients will be randomized into the following two arms:

Arm A: erlotinib 150mg once per day up to disease progression or intolerable toxicity.

Arm B: Gemcitabine (1000mg/m2, IV,d1 and d8) plus Carboplatin (AUC=5, IV d1) repeated every 3 weeks up to 4 cycles.

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Non-small Cell Lung Cancer

Intervention

• Drug: erlotinib
  erlotinib 150 mg oral, once a day
  Other Name: Tarceva
• Drug: gemcitabine/carboplatin
  gemcitabine 1000mg/m2 on d1,8 with carboplatin AUC=5 on d1 intravenously, every 3 weeks, up to 4 cycles
  Other Name: Gemzar

Study Arms

• Experimental: erlotinib
  Arm 1 receive erlotinib 150 mg oral, once a day until progression or unacceptable toxicity
  Intervention: Drug: erlotinib
• Active Comparator: gemcitabine/carboplatin
  gemcitabine 1000mg/m2 on d1,8 with carboplatin AUC=5 on d1 intravenously, every 3 weeks, up to 4 cycles
  Intervention: Drug: gemcitabine/carboplatin

Publications *

• Zhou C, Wu YL, Chen G, Feng J, Liu XQ, Wang C, Zhang S, Wang J, Zhou S, Ren S, Lu S, Zhang L, Hu C, Hu C, Luo Y, Chen L, Ye M, Huang J, Zhi X, Zhang Y, Xiu Q, Ma J, Zhang L, You C. Final overall survival results from a randomised, phase III study of erlotinib versus chemotherapy as first-line treatment of EGFR mutation-positive advanced non-small-cell lung cancer (OPTIMAL, CTONG-0802). Ann Oncol. 2015 Sep;26(9):1877-1883. doi: 10.1093/annonc/mdv276. Epub 2015 Jul 3.
• Zhou C, Wu YL, Chen G, Feng J, Liu XQ, Wang C, Zhang S, Wang J, Zhou S, Ren S, Lu S, Zhang L, Hu C, Hu C, Luo Y, Chen L, Ye M, Huang J, Zhi X, Zhang Y, Xiu Q, Ma J, Zhang L, You C. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 2011 Aug;12(8):735-42. doi: 10.1016/S1470-2045(11)70184-X. Epub 2011 Jul 23.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: September 23, 2014): 165
• Original Estimated Enrollment (submitted: April 1, 2009): 160
• Actual Study Completion Date: July 2012
• Actual Primary Completion Date: July 2010 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Stage IIIB (cytological confirmed with malignant pleural effusion or pericardial effusion) or histopathological or cytological confirmed stage IV NSCLC or relapsed after complete resection .
2. EGFR exon19 deletions or exon 21 L858R mutation by the DNA direct PCR sequencing using fresh tumor sample or paraffin embed tumor sample.
3. Measurable lesions as defined by RECIST criteria .
4. Palliative radiotherapy allowed if it was finished 3 weeks after the first drug administration, but the target lesions should not be included in the radiotherapy field.
5. Patients with operation are allowed if the operation is 4 weeks before the first drug administration
6. Men or women of at least 18 years of age.
7. ECOG Performance status of 0 to 2.
8. Estimated life expectancy of at least 12 weeks.
9. Patient compliance and geographic proximity that allow adequate follow-up.

10. Adequate organ function tested 7 days before the first drug administration:

    hemoglobin ≥9 g/dL,absolute neutrophil count (ANC) ≥1.5*109/L, platelets ≥100 *109/L,bilirubin ≤1.5ULN, alkaline phosphatase (AP), aspartate transaminase (AST) and alanine transaminase (ALT) ≤2.5 upper limited number(ULN) (AP, AST, ALT ≤5ULN is acceptable if liver has tumor involvement).INR≤1.5, APTT in the normal range( 1.2DLN-1.2ULN),creatinine ≤1.5ULN.

11. Informed consent from the patient.

Exclusion Criteria:

1. Have received systemic anti-cancer therapy, including Cytotoxic drugs, targeted therapy, experimental treatment, adjuvant or neo-adjuvant therapy(except the disease relapse 6 months after the final drug)
2. Wild type EGFR.
3. Uncontrolled pericardial or pleural effusions prior to study entry.
4. History of cardiovascular disease: Congestive Heart Failure > grade II in NYHA. Unstable angina patients (have angina symptoms in rest) or a new occurrence of angina (began in the last 3 months) or myocardial infarction happens in the last 6 months
5. Brain metastasis (controlled brain metastasis and steroid free need is excluded).
6. HIV infection
7. Active infection, >grade 2 in Common Terminology Criteria for Adverse Events(CTCAE) version 3.
8. A history of operation or serious traumatic 3 weeks before the first drug administration
9. Patient with other malignant tumor except NSCLC 5 years previous to study entry. Excluding cervical carcinoma in situ, cured basal cell carcinoma, bladder epithelial tumor [including Ta and Tis]
10. Mixed with small cell lung cancer
11. Unable to swallow drugs.
12. Malabsorption
13. Pregnant or child breast feeding women
14. Childbearing patients will not use a reliable method of contraception before the study entry, during process of the study and within 30 days after discontinuation of the study. Reliable contraceptive methods will be determined by principal investigator or a designated officer.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: China

Administrative Information

• NCT Number: NCT00874419
• Other Study ID Numbers: ML20981
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Caicun Zhou, Tongji University
• Original Responsible Party: Caicun Zhou, Tongji University Affiliated Shanghai Pulmonary Hospital
• Current Study Sponsor: Tongji University
• Original Study Sponsor: Same as current

Collaborators

• Sun Yat-sen University
• Shanghai Chest Hospital
• RenJi Hospital
• Guangdong Provincial People's Hospital
• Peking Union Medical College Hospital

Investigators

• Principal Investigator: Caicun Zhou, MD & PhD; Tongji University

• PRS Account: Tongji University
• Verification Date: September 2014