Clinical trial NCT02359162: Efficacy and Safety Study of P-Gemox vs.EPOCH as First-line Chemotherapy to Treat NK/T-cell Lymphoma With Early Stage
Official title: 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Lymphoma, Extranodal NK-T-Cell
Keywords: NK/T-cell lymphoma
induction chemotherapy
survival
Lead sponsor: Sun Yat-sen University
Sponsor class: OTHER
First posted: 2015-02-09
Enrollment: 50
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

1. 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)
2. 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.

Eligibility criteria: 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

Primary outcomes:
measure: progression free survival
timeFrame: up to end of follow-up-phase (approximately 3 years)
Secondary outcomes:
measure: complete remission rate
timeFrame: every 4 weeks,up to completion of treatment(approximately 6 months)
measure: overall survival
timeFrame: .up to end of follow-up-phase (approximately 3 years)
measure: safety, as measured by adverse events
timeFrame: up to end of follow-up-phase (approximately 3 years)
Other outcomes:
measure: serum Epstein-Barr virus(EBV) DNA copies
timeFrame: every 3 weeks,up to completion of treatment(approximately 6 months)
measure: serum β2-microglobulin
timeFrame: every 3 weeks,up to completion of treatment(approximately 6 months)
measure: serum interleukin 9
timeFrame: every 3 weeks,up to completion of treatment(approximately 6 months)
measure: serum interleukin 15
timeFrame: every 3 weeks,up to completion of treatment(approximately 6 months)
Locations:
city: GuangZhou
country: China
facility: Sun Yat-sen University Cancer Center
state: Guangdong
Study officials:
affiliation: Department of Hematological Oncology, Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China
name: Hua Wang, MD.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Wang H, Wuxiao ZJ, Zhu J, Wang Z, Wang KF, Li S, Chen X, Lu Y, Xia ZJ. Comparison of gemcitabine, oxaliplatin and L-asparaginase and etoposide, vincristine, doxorubicin, cyclophosphamide and prednisone as first-line chemotherapy in patients with stage IE to IIE extranodal natural killer/T-cell lymphoma: a multicenter retrospective study. Leuk Lymphoma. 2015 Apr;56(4):971-7. doi: 10.3109/10428194.2014.939964. Epub 2014 Aug 20.
citation: Wang L, Wang ZH, Chen XQ, Li YJ, Wang KF, Xia YF, Xia ZJ. First-line combination of gemcitabine, oxaliplatin, and L-asparaginase (GELOX) followed by involved-field radiation therapy for patients with stage IE/IIE extranodal natural killer/T-cell lymphoma. Cancer. 2013 Jan 15;119(2):348-55. doi: 10.1002/cncr.27752. Epub 2012 Jul 18.
citation: Huang H, Lin Z, Lin X, Cai Q, Xia Z, Jiang W. Long-term outcomes of patients with newly diagnosed extranodal natural killer/T-cell lymphoma treated by etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin regimen: a single-institution experience. Leuk Lymphoma. 2011 Jun;52(6):1041-8. doi: 10.3109/10428194.2011.561388.