Clinical trial NCT02098954: Erlotinib Combined With Chemotherapy in TKI Resistant Non-Small Cell Lung Cancers
Official title: Second Line Erlitinib Combination With Gemcitabine Cisplatinum in Non-small Cell Lung Cancer Patients Who Harbored EGFR Sensitive Mutation Developed Resistance After First Line TKI Treatment
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Carcinoma, Non-Small Cell Lung
EGFR Gene Mutation
Keywords: TKI
resistance
erlotinib
combined chemotherapy
Lead sponsor: Hunan Province Tumor Hospital
Sponsor class: OTHER
First posted: 2014-03-28
Enrollment: 40
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: Numerous evidences verified that erlotinib could dramatically improve the PFS and OS of non-small cell lung cancers who harbor EGFR sensitive mutations, however, primary or secondary resistance will be developed after TKI treatment, doctors do plenty of researches to overcome TKI resistance. FAST ACT-2 study present that, first line erlotinib combined with chemotherapy could improved mOS to more than 30 months in NSCLCs who harbor EGFR sensitive mutations, several study shows that sensitive mutations still exist after TKI resistance, because of the next generation TKIs(such as BIBW2992) are not avaliable at present, agents for met amplification(such as Crizotinib) are so expensive that many Chinese patients could not support. Thus, the investigators hypothesis that, after first line TKI treatment, the patients who developed TKI resistance could still benefit from second line TKI combined with chemotherapy.

Detailed description: The investigators will enroll patients diagnosed with advanced non-squamous,non-small cell lung cancer, patients with EGFR TKI sensitive mutations and developed TKI resistance in first line treatment. After enrollment, the investigators will do biopsy again before second line treatment to find out the potential mechanism of TKI resistance, do EGFR mutation test for both sensitive and resistant mutation in exon 18, 19, 20 and 21; do KRAS, BRAF and PI3K mutation test, do FISH for MET and HER-2, the investigators do all these test to evaluated both primary and secondary resistance, the investigators do all these tests to get an overview for EGFR mutation status of each patient who develop TKI resistance. For second line treatment, patients will received a 28 days gemcitabine platinum combined with erlotinib scheme, after 4 cycle of combined chemotherapy, patients will receive erlotinib for further treatment until progression disease. For the patients who have stable brain metastases, combined chemotherapy should begin after local treatment, such as whole brain radiotherapy or sterotactic radiosurgery.

the main endpoint of this study is mean PFS, second endpoints of this study consist of mean OS, 8 week ORR.

Eligibility criteria: Inclusion Criteria:

* advanced non-small cell lung cancer, stage IIIB/IV
* non-squamous
* EGFR sensitive mutations, such as exon 19 del, or exon 21 L858R
* received first line TKIs treatment and developed TKI resistance
* ECOG 0-2

Exclusion Criteria:

* squamous non-small cell lung cancer
* patients have unstable brain metastasis, predict survival less than 8 weeks
* spinal-cord compression without evidence of stabilisation or treatment
* women who were pregnant or lactating; women with a positive or no available pregnancy test result at baseline
* patients have any unstable illness that could not receive further treatment

Primary outcomes:
measure: mean progression free survival(mPFS)
timeFrame: after patients receive treatment, mPFS should be measured before the third cycle of chemotherapy, after the fourth cycle, mPFS should be measured every 3 months up to two years
Secondary outcomes:
measure: mean overall survival(mOS)
timeFrame: every 3 months up to 3 years, or until all the survival data is obtained
measure: 8 week overall response rate(8 week ORR)
timeFrame: 8 week ORR should be measured after enrollment, the exact time point should be the ninth week after combined chemotherapy
Other outcomes:
Locations:
city: Changsha
country: China
facility: Hunan Province Tumor Hospital
state: Hunan
Study officials:
affiliation: Hunan Province Tumor Hospital
name: Nong Yang, MD
role: STUDY_CHAIR
References:
citation: Wu YL, Lee JS, Thongprasert S, Yu CJ, Zhang L, Ladrera G, Srimuninnimit V, Sriuranpong V, Sandoval-Tan J, Zhu Y, Liao M, Zhou C, Pan H, Lee V, Chen YM, Sun Y, Margono B, Fuerte F, Chang GC, Seetalarom K, Wang J, Cheng A, Syahruddin E, Qian X, Ho J, Kurnianda J, Liu HE, Jin K, Truman M, Bara I, Mok T. Intercalated combination of chemotherapy and erlotinib for patients with advanced stage non-small-cell lung cancer (FASTACT-2): a randomised, double-blind trial. Lancet Oncol. 2013 Jul;14(8):777-86. doi: 10.1016/S1470-2045(13)70254-7. Epub 2013 Jun 17.
citation: Suda K, Mizuuchi H, Maehara Y, Mitsudomi T. Acquired resistance mechanisms to tyrosine kinase inhibitors in lung cancer with activating epidermal growth factor receptor mutation--diversity, ductility, and destiny. Cancer Metastasis Rev. 2012 Dec;31(3-4):807-14. doi: 10.1007/s10555-012-9391-7.