Efficacy and Safety Study of P-Gemox vs.EPOCH as First-line Chemotherapy to Treat NK/T-cell Lymphoma With Early Stage

Study Overview
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Brief Summary
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Purpose :To compare the efficacy and and safety of the P-Gemox chemotherapy regimen with those of the EPOCH regimen for stage IE to IIE ENKTL.

Detailed Description
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ENKTL is an aggressive type of NHL characterized by poor survival, for which the optimal treatment strategies have not been fully defined. Radiation therapy (RT) is widely administered for patients with localized nasal disease, and produces a complete response (CR) rate of up to 70%.However, local and systemic failures are observed frequently in patients who receive RT alone.Therefore, chemotherapy is needed in combination with RT to reduce the risk of recurrence. Unfortunately, ENKTL shows a poor response to the CHOP chemotherapy regimen (cyclophosphamide, doxorubicin, vincristine and prednisone) . EPOCH (etoposide, vincristine, doxorubicin, cyclophosphamide and prednisone) chemotherapy followed by involved field radiotherapy (IFRT) results in a CR rate of 75.0%. Recently, a chemotherapy regimen including gemcitabine,oxaliplatin and l-asparaginase (GELOX) has emerged, with promising results.Since 2003, a proportion of patients newly diagnosed with ENKTL were treated with the EPOCH chemotherapy regimen at some hospitals in China. From 2008, many hospitals in the southern part of China began to use the GELOX( Pegaspargase is used instead of l-asparaginase,P-Gemox).Our multicenter retrospective study showed the GELOX regimen produces a better long outcome with less toxicity than the EPOCH regimen for patients with early stage ENKTL.However,further prospective randomized clinical trials are needed to confirm the conclusion. Patients All patients should sign a written informed consent form before enrollment, and the study should be approved by the Sun Yat-sen University Cancer Center Ethics Board. Baseline of patients: Computed tomography (CT) scans of the chest, abdomen, and pelvis, magnetic resonance imaging studies of the head and neck, and bilateral bone marrow aspiration or biopsy. Positron emission tomography-CT scans (optional). Epstein-Barr virus (E B V) DNA blood levels, titer of EBV antibody (EA-IgA, VCA-IgA), β2-micro globulin (β2-MG) , IL-9 and IL-15 in the serum. Recheck before and after every course: Epstein-Barr virus (EBV) DNA blood levels, titer of EBV antibody (EA-IgA, VCA-IgA), β2-micro globulin (β2-MG), IL-9 and IL-15 in the serum. Recheck every two course: Computed tomography (CT) scans of the chest, abdomen, and pelvis, magnetic resonance imaging studies of the head and neck, and bilateral bone marrow aspiration or biopsy. Positron emission tomography-CT scans (optional) Treatment Protocol: The GELOX regimen consist of the following drugs: gemcitabine ：1250 mg/ m2 on days 1,ivdrip oxaliplatin ：85 mg/m2 on day 1, ivdrip pegaspargase : 2500 IU/m 2 daily on day 1,intramuscular. The treatment cycle is repeated every 14 days. The EPOCH regimen included a 24 h continuous infusion of etoposide (50 mg/m 2 /day), vincristine (0.4 mg/m 2 /day) and doxorubicin(10 mg/m 2 /day administered on days 1-4, followed by cyclophosphamide (750 mg/m2 /day) over 15 min intravenously on day 5 and prednisone (60 mg/m 2 /day) 60 mg/m 2 /day on days 1-5.The treatment cycle is repeated every 21 days. After at least two cycles of chemotherapy, patients who have achieved stable disease (SD) following two cycles, partial response (PR) after four cycles or complete response (CR) after six cycles of chemotherapy are referred to primary IFRT. ◦IFRT was delivered using 6-MeV linear accelerator using 3-dimensional conformable treatment planning. The IFRT dose was 56 grays (Gy) in 28 fractions, we define the clinical target volume of limited stage IE disease as the bilateral nasal cavity, bilateral ethmoid sinuses, and ipsilateral maxillary sinus; and the clinical target volume would extend to involved tissues for patients who had extensive stage IE disease. For patients who had stage IIE disease, the clinical target volume also, included the bilateral cervical lymph node area.

Official Title
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Comparison of Gemcitabine, Oxaliplatin and Pegaspargase and Etoposide, Vincristine, Doxorubicin, Cyclophosphamide and Prednisone as First-line Chemotherapy in Patients With NK/T-cell Lymphoma：a Prospective Randomized Phase III Study

Conditions
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Lymphoma, Extranodal NK-T-Cell

Intervention / Treatment
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* Drug: Gemcitabine
* Drug: Oxaliplatin
* Drug: Pegaspargase
* Drug: Etoposide
* Drug: Vincristine
* Drug: Doxorubicin
* Drug: Cyclophosphamide
* Drug: Prednisone
* Radiation: IMRT


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: newly diagnosed ENKTL age:18-69years Ann Arbor stage IE,or stage IIE with cervical lymph node involvement at lease one measurable lesion receive no chemotherapy or radiotherapy before Eastern CooperativeOncology Group performance status of 0 to 2. Adequate hematologic function (eg, white blood cell ≥ 3×10e9/l,neutrophils count ≥1.5×10e9/L, and platelet count≥ 100×10e9/L),renal function (eg, serum creatinine≤1.5 mg/dL and creatinine clearance ≥50 mL minute), and hepatic function (e.g, total bilirubin≤ 2 times the upper limit of normal and aspartate and alanine transaminase levels ≤ 3 times the upper limit of normal) Exclusion Criteria: mismatch the inclusion criteria systematic central nervous system involvement, previous or concomitant malignancies and any coexisting medical problems that could cause poor compliance with the study protocol. primary lesion not from the upper respiratory

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: P-Gemox<br>P-Gemox:gemcitabine :1250mg/m2 (ivdrip) on days 1, oxaliplatin :85 mg/m2 (ivdrip) on day 1, and pegaspargase : 2500 IU/m2 (intramuscular injection) on day 1.Cycle is repeated every 14 days. IMRT：IMRT is delivered using 6-8 MeV linear accelerator using intensity-modulated radiation treatment planning. The radiation dose is 50 grays (Gy) in 25 fractions. | Drug: Gemcitabine<br>* gemcitabine :1250mg/m2 (ivdrip) on days 1<br>Drug: Oxaliplatin<br>* oxaliplatin :85 mg/m2 (ivdrip) on day 1<br>Drug: Pegaspargase<br>* pegaspargase : 2500 IU/m2 (intramuscular injection)<br>Radiation: IMRT<br>* IMRT is delivered using 6-8 MeV linear accelerator using intensity-modulated radiation treatment planning. The radiation dose is 50 grays (Gy) in 25 fractions.<br>* Other names: Intensity-modulated radiation therapy;|
| Active Comparator: EPOCH<br>EPOCH:Patients received the EPOCH chemotherapy regimen every 3 weeks. The EPOCH regimen included a 24 h continuous infusion of etoposide (50 mg/m 2 /day), vincristine (0.4 mg/m 2 /day) and doxorubicin(10 mg/m 2 /day administered on days 1-4, followed by cyclophosphamide (750 mg/m2 /day) over 15 min intravenously on day 5 and prednisone (60 mg/m 2 /day) on days1- 5 orally. IMRT：IMRT is delivered using 6-8 MeV linear accelerator using intensity-modulated radiation treatment planning. The radiation dose is 50 grays (Gy) in 25 fractions. | Drug: Etoposide<br>* 50 mg/m 2 /day 24 h continuous infusion on days 1-4<br>Drug: Vincristine<br>* 0.4 mg/m 2 /day 24 h continuous infusion on days 1-4<br>Drug: Doxorubicin<br>* 10 mg/m 2 /day 24 h continuous infusion on days 1-4<br>Drug: Cyclophosphamide<br>* cyclophosphamide 750 mg/m2 /day over 15 min intravenously on day 5<br>Drug: Prednisone<br>* 60 mg/m 2 /day 60 mg/m 2 /day on days 1-5<br>Radiation: IMRT<br>* IMRT is delivered using 6-8 MeV linear accelerator using intensity-modulated radiation treatment planning. The radiation dose is 50 grays (Gy) in 25 fractions.<br>* Other names: Intensity-modulated radiation therapy;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| progression free survival | time from the date of enrollment to date of disease progression, or death of any cause, or date of lost follow-up, whichever comes first | up to end of follow-up-phase (approximately 3 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| complete remission rate | The criteria for the efficacy evaluation (overall response rate and complete remission) of the regimen is according to the following article: Cheson BD, Horning SJ, Coiffier B, et al. Report of an international workshop to standardize response criteria for non-Hodgkin's lymphomas. NCI Sponsored International Working Group. J Clin Oncol. 1999;17:1244. | every 4 weeks,up to completion of treatment(approximately 6 months) | 
| overall survival | overall survival (OS): time from the date of enrollment to date of death from any cause, or date of lost follow-up, whichever comes first | .up to end of follow-up-phase (approximately 3 years) | 
| safety, as measured by adverse events | including hematological safety and non-hematological safety.All the adverse events will be classified according to Common Terminology Criteria for Adverse Events v3.0 (CTCAE) | up to end of follow-up-phase (approximately 3 years) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NK/T-cell lymphoma, induction chemotherapy, survival