Vinorelbine-ifosfamide Versus Gefitinib for EGFR Gene Mutation Negative Non-small Cell Lung Cancer Patients

Study Description

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Brief Summary:

In the National Comprehensive Cancer Network (NCCN) guideline for NSCLC, epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) is recommended as the third-line treatment for EGFR gene mutation negative NSCLC patients who failed to the first-line platinum doublet chemotherapy [i.e. paclitaxel-carboplatin (PC) or gemcitabine-cisplatin (GP)] and the second-line chemotherapy with docetaxel or pemetrexed. But as we know, if patients had no EGFR gene mutation, EGFR-TKI treatment is not effective. The overall survival is short and the objective response rate is low. As for EGFR gene wild type patients with good performance status, besides EGFR-TKI treatment, other first generation cytotoxic drugs i.e. vinorelbine or ifosfamide maybe an alternative treatment. So the purpose of this clinical trial is to compare the effectiveness and safety of vinorelbine-ifosfamide with gefitinib in advanced or metastatic EGFR gene mutation negative NSCLC patients.

Condition or disease	Intervention/treatment	Phase
Non-small Cell Lung Cancer; Effects of Chemotherapy	Drug: Gefitinib group; Drug: Vinorelbine, Ifosfamide, Mesna	Phase 2

Detailed Description:

Ifosfamide is a first generation cytotoxic drug to treat NSCLC. Phase Ⅱ studies demonstrated that single-agent ifosfamide administrated by various schedules produces response rates of 15-29%, with media survival times of 5-7 months. Ifosfamide has also been used in various combination regimens to treat NSCLC, including platinum based and non-platinum regimens. But in refractory NSCLC patients platinum and some third generation cytotoxic drugs have been used before. So in this study, ifosfamide is combined with vinorelbine. In previous study, Masters reported the objective response rate was 40% and the median survival duration was 50 weeks, with a 1-year survival rate of 48% with vinorelbine-ifosfamide regimen [Vinorelbine 15 mg/m2 on days 1-3, and ifosfamide 2.0g/m2 on days 1-3 with granulocyte-colony stimulating factor (G-CSF) support]. The dose limiting toxicity (DLT) of this regimen is myelosuppression. In our experience, the regimen of vinorelbine 25mg/m2 d1, d8 and ifosfamide 1.25g/m2 d1-d3 with Mesna uroprotection is safe in Chinese population and the objective response rate is about 7% (data not published).

Gefitinib is the first small molecule inhibitor that has directed activity towards EGFR and has shown appreciable response rates in phase Ⅱ trials of patients with previously treated advanced NSCLC. In the posterior analysis of Iressa Dose Evaluation in Advanced Lung Cancer (IDEAL) and IRESSA Survival Evaluation in Lung Cancer (ISEL) trials, the response rate with gefitinib ranges from 2.6% to 10% in wild-type EGFR gene NSCLC patients.

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	120 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	A Phase Ⅱ Randomized Clinical Trial Comparing Vinorelbine-ifosfamide With Gefitinib as Third-line Treatment in Advanced EGFR Gene Mutation Negative Non-small Cell Lung Cancer Patients
Study Start Date :	December 2012
Estimated Primary Completion Date :	December 2016
Estimated Study Completion Date :	December 2017

Arms and Interventions

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Arm	Intervention/treatment
Gefitinib; Gefitinib group Gefitinib (Iressa) 250mg once per day until progression disease or intolerant side effects	Drug: Gefitinib group; Gefitinib 250mg once per day until the progression disease or intolerant side effects; Other Name: Gefitinib (Iressa)
Vinorelbine-Ifosfamide; VI group Vinorelbine 25mg/m2 d1,d8;Ifosfamide 1.25g/m2 d1-d3(Usually Ifosfamide 2g d1-d3 with Mesna 400mg 0,4,8hours after Ifosfamide administration for 3 days);every 3 weeks;at least for 2-6 cycles depending on the progression disease or the patient's physical condition	Drug: Vinorelbine, Ifosfamide, Mesna; Vinorelbine 25mg/m2 d1,d8; Ifosfamide 1.25g/m1 d1-d3 (Usually 2g d1-d3); Mesna 400mg 0,4,8 hours after Ifosfamide administration for uroprotection d1-d3; Other Name: VI group

Outcome Measures

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Primary Outcome Measures :

1. Progression free survival [ Time Frame: up to 52 weeks (about one year) ]
   From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 52 weeks.

Secondary Outcome Measures :

1. Overall survival [ Time Frame: Up to 100 weeks ]
   From date of randomization until the date of death from any cause, assessed up to 100 weeks.
2. objective response rate [ Time Frame: up to 9 weeks ]
   The objective response rate includes the complete remission and partial remission rate.
3. the score of functional assessment of cancer treatment-lung (FACT-L) [ Time Frame: Up to 100 weeks ]
   FACL-L is assessed at different time points.(Date of randomization, 1 week after chemotherapy/EGFR-TKI, every cycle of chemotherapy/EGFR-TKI, every month of EGFR-TKI treatment/observation, up to 100 weeks)
4. Number of participants with adverse events [ Time Frame: Up to six months ]
   The adverse events are assessed by National Cancer Institute-Common Toxicity Criteria (Version 3.0) (NCI-CTC).

Eligibility Criteria

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Ages Eligible for Study:	18 Years to 70 Years (Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

• age range:18-70 years old
• life expectancy more than 12 weeks
• histologically or cytologically confirmed inoperable NSCLC (stage ⅢB/Ⅳ)
• ineligible for curative radiotherapy
• no prior radiotherapy for the target lesions
• Eastern Cooperative Oncology Group (ECOG) performance score of 0-2;
• prior treatments include first-line platinum doublet chemotherapy i.e. PC or GP and second-line chemotherapy with docetaxel or pemetrexed;
• No EGFR gene mutation detected by Scorpions-ARMS;
• at least one bidimensionally measurable or radiographically assessable lesion;
• adequate bone marrow reserve;
• adequate hepatic and renal function;

Exclusion Criteria:

• prior treatments including any of the following drugs:gefitinib,vinorelbine and ifosfamide;
• additional malignancies;
• uncontrolled systemic disease;
• any evidence of clinically active interstitial lung disease;
• newly diagnosed central nervous system (CNS) metastasis and not treated by radiotherapy or surgery;
• pregnancy or breast feeding phase;

Contacts and Locations

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Contacts

Contact: Mengzhao Wang, MD	010-69155039 ext +86	mengzhaowang@sina.com
Contact: Jing Zhao, MD	010-69158206 ext +86	pumchzj@sina.com

Locations

China, Beijing
Department of Respiratory Medicine, Peking Union Medical College Hospital	Recruiting
Beijing, Beijing, China, 100730
Contact: Mengzhao Wang, MD 010-69155039 ext +86 mengzhaowang@sina.com
Contact: Jing Zhao, MD 010-69158206 ext +86 pumchzj@sina.com
Sub-Investigator: Wei Zhong, MD
Sub-Investigator: Jinmei Luo, MD

Sponsors and Collaborators

Peking Union Medical College Hospital

Investigators

Principal Investigator:	Mengzhao Wang, MD	Department of Respiratory Medicine, Peking Unoin Medical College Hospital

More Information

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Publications of Results:

Thatcher N, Anderson H, Smith DB, Steward WP, Webb K, Hilton A, Rahman A. Ifosfamide by bolus as treatment for advanced non-small cell lung cancer. Cancer Chemother Pharmacol. 1986;18 Suppl 2:S30-3.

Holoye PY, Glisson BS, Lee JS, Dhingra HM, Murphy WK, Umsawasdi T, Levy JK, Jeffries D, Raber MN, Hong WK. Ifosfamide with mesna uroprotection in the management of lung cancer. Am J Clin Oncol. 1990 Apr;13(2):148-55.

Masters GA, Hoffman PC, Hsieh A, Drinkard LC, Mick R, Samuels BL, Guaspari A, Golomb HM, Vokes EE. Phase I study of vinorelbine and ifosfamide in advanced non-small-cell lung cancer. J Clin Oncol. 1997 Mar;15(3):884-92.

Bell DW, Lynch TJ, Haserlat SM, Harris PL, Okimoto RA, Brannigan BW, Sgroi DC, Muir B, Riemenschneider MJ, Iacona RB, Krebs AD, Johnson DH, Giaccone G, Herbst RS, Manegold C, Fukuoka M, Kris MG, Baselga J, Ochs JS, Haber DA. Epidermal growth factor receptor mutations and gene amplification in non-small-cell lung cancer: molecular analysis of the IDEAL/INTACT gefitinib trials. J Clin Oncol. 2005 Nov 1;23(31):8081-92. Epub 2005 Oct 3.

Hirsch FR, Varella-Garcia M, Bunn PA Jr, Franklin WA, Dziadziuszko R, Thatcher N, Chang A, Parikh P, Pereira JR, Ciuleanu T, von Pawel J, Watkins C, Flannery A, Ellison G, Donald E, Knight L, Parums D, Botwood N, Holloway B. Molecular predictors of outcome with gefitinib in a phase III placebo-controlled study in advanced non-small-cell lung cancer. J Clin Oncol. 2006 Nov 1;24(31):5034-42.

Responsible Party:	Peking Union Medical College Hospital
ClinicalTrials.gov Identifier:	NCT01749072 History of Changes
Other Study ID Numbers:	PUMCH-S464
First Posted:	December 13, 2012
Last Update Posted:	December 13, 2012
Last Verified:	December 2012

Keywords provided by Peking Union Medical College Hospital:

non small cell lung cancer; chemotherapy; gefitinib; vinorelbine; ifosfamide

Additional relevant MeSH terms:

Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases; Carcinoma, Bronchogenic; Bronchial Neoplasms; Vinorelbine; Vinblastine; Gefitinib; Isophosphamide mustard	Ifosfamide; Mesna; Antineoplastic Agents, Phytogenic; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Molecular Mechanisms of Pharmacological Action; Protein Kinase Inhibitors; Enzyme Inhibitors; Antineoplastic Agents, Alkylating; Alkylating Agents; Protective Agents; Physiological Effects of Drugs