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Recruitment status Completed
Unique ID issued by UMIN UMIN000000712
Receipt No. R000000847
Scientific Title Phase II study of SMILE chemotherapy for stage IV or relapsed/refractory extranodal NK/T-cell lymphoma
Date of disclosure of the study information 2007/05/14
Last modified on 2011/11/09

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Basic information
Public title Phase II study of SMILE chemotherapy
for stage IV or relapsed/refractory extranodal NK/T-cell lymphoma
Acronym Phase II study of SMILE chemotherapy
for stage IV or relapsed/refractory extranodal NK/T-cell lymphoma
Scientific Title Phase II study of SMILE chemotherapy
for stage IV or relapsed/refractory extranodal NK/T-cell lymphoma
Scientific Title:Acronym Phase II study of SMILE chemotherapy
for stage IV or relapsed/refractory extranodal NK/T-cell lymphoma
Japan Asia(except Japan)

Condition extranodal NK/T-cell lymphoma, nasal type
Classification by specialty
Hematology and clinical oncology
Classification by malignancy Malignancy
Genomic information NO

Narrative objectives1 To establish a more effective therapy for extranodal NK/T-cell lymphoma, nasal type, with untreated stage IV or relapsed/refractory state, we plan a safety and efficacy study of SMILE (Steroid=dexamethasone, Methotrexate, Ifosfamide, L-asparaginase and Etoposide) regimen.
Basic objectives2 Safety,Efficacy
Basic objectives -Others
Trial characteristics_1 Confirmatory
Trial characteristics_2
Developmental phase Phase II

Primary outcomes overall response rate
Key secondary outcomes complete response rate (%CR), 1-year overall survival, response stratified by frontline/relapsed/refractory categorization, response stratified by the prior regimen of chemotherapy (CHOP-like vs. DeVIC-like), and the rate of adverse events

Study type Interventional

Study design
Basic design Single arm
Randomization Non-randomized
Randomization unit
Blinding Open -no one is blinded
Control Uncontrolled
Dynamic allocation
Institution consideration

No. of arms 1
Purpose of intervention Treatment
Type of intervention
Interventions/Control_1 Two cycles of SMILE chemotherapy consisting from steroid, methotrexate, ifosfamide, L-asparaginase, and etoposide.

Age-lower limit
15 years-old <=
Age-upper limit
69 years-old >=
Gender Male and Female
Key inclusion criteria 1) Histological or cytological diagnosis of extranodal NK/T-cell lymphoma, nasal type, according to the WHO classification. Diagnostic samples should be obtained by surgical or needle biopsy, bone marrow aspiration/biopsy, or peripheral blood cytology.
[Notes: Tumor cells must show immunophenotype of NK/T-cells. They should be CD56-positive and CD20-negative either by immunohistochemistry (IHC) or by flow-cytometry (FCM). For CD56-negative cases, they must be CD3epsilon-positive and CD20-negative by IHC/FCM, and positive for EBV either by Southern blotting or by in-situ hybridization (EBER). At least one cytotoxic molecule (perforin, granzyme B or TIA-1) must be positive.]
2) Disease state must be either of the following:
i) Newly diagnosed Ann Arbor stage IV cases before any chemotherapy
ii) First relapsed/recurrent cases after remission (complete or partial). No chemotherapy or radiotherapy are given within 21 days before registration.
iii) Refractory (either NC or PD) cases with first-line chemotherapy. No chemotherapy or radiotherapy are given within 21 days before registration.
3) Age 15-69 years
4) Performance status (ECOG) 0-2
5) At least one evaluable lesion
6) Patients who received corticosteroids alone are eligible for this study, but those under treatment must be discontinued before registration
7) Patients with sufficient hematopoietic (except for cases with bone marrow involvement or HPS), hepatic, renal, cardiac, and pulmonary function
8) Patient's written informed consent before registration.
Key exclusion criteria (1) History of hematopoietic stem cell transplant within 12 months
(2) History of allogeneic transplantation
(3) Clinical symptoms of CNS involvement (CSF cytology or brain MRI imaging are not required)
(4) Need for radiation more than 15 Gy including palliation at the time of registration
(5) History of serious adverse reaction(s) by agents including SMILE chemotherapy
(Example: allergy for L-asparaginase, delayed excretion of methotrexate, etc.)
(6) Pleural effusion or ascites except for those with little amount, which cannot be performed pleural or abdominal puncture
(7) Uncontrollable hypertension
(8) History of myocardial infarction or angina or cardiomyopathy
(9) HBs antigen positive
(10) HIV antibody positive
(11) Accompanying interstitial pneumonitis, pulmonary fibrosis, or severe emphysema (all apparently diagnosed by chest X-ray)
(12) Severe infections
(13) Liver cirrhosis, either biopsy proven or clinically diagnosed
(14) Active double cancer: overlapping cancer or asynchronous cancer within 5 years. Carcinoma in situ, intramucosal cancers, and other equivalent lesions are not included for the active double cancer.
(15) Women during pregnancy, lactation period or of childbearing potentials not using a reliable contraceptive method
(16) Use of major tranquilizer, antidepressant, or antimanic
(17) Severe psychosis
Target sample size 28

Research contact person
Name of lead principal investigator
1st name
Middle name
Last name Kazuo Oshimi
Organization Juntendo University
Division name Department of Hematology
Zip code
Address Hongo, Bunkyo-ku, Tokyo 113-8421, Japan

Public contact
Name of contact person
1st name
Middle name
Last name Motoko Yamaguchi
Organization Study Coordinator of SMILE-PII
Division name Department of Hematology and Oncology, Mie University Graduate School of Medicine
Zip code
Homepage URL

Institute NK-cell Tumor Study Group

Funding Source
Organization Ministry of Health, Labour and Welfare
Category of Funding Organization
Nationality of Funding Organization Japan

Other related organizations
Name of secondary funder(s)

IRB Contact (For public release)

Secondary IDs
Secondary IDs NO
Study ID_1
Org. issuing International ID_1
Study ID_2
Org. issuing International ID_2


Other administrative information
Date of disclosure of the study information
2007 Year 05 Month 14 Day

Related information
URL releasing protocol
Publication of results Published

URL related to results and publications
Number of participants that the trial has enrolled
Results Patients and Methods: Patients with newly diagnosed stage IV, relapsed, or refractory disease and a performance status of 0 to 2 were eligible. Two cycles of SMILE chemotherapy were administered as the protocol treatment. The primary end point was the overall response rate (ORR) after the protocol treatment. Results: A total of 38 eligible patients were enrolled. The median age was 47 years (range, 16 to 67 years), and the male:female ratio was 21:17. The disease status was newly diagnosed stage IV in 20 patients, first relapse in 14 patients, and primary refractory in four patients. The eligibility was revised to include lymphocyte counts of 500/microL or more because the first two patients died from infections. No treatment-related deaths were observed after the revision. The ORR and complete response rate after two cycles of SMILE chemotherapy were 79% (90% CI, 65% to 89%) and 45%, respectively. In the 28 patients who completed the protocol treatment, 19 underwent hematopoietic stem-cell transplantation. The 1-year overall survival rate was 55% (95% CI, 38% to 69%). Grade 4 neutropenia was observed in 92% of the patients. The most common grade 3 or 4 nonhematologic complication was infection (61%). Conclusion: SMILE chemotherapy is an effective treatment for newly diagnosed stage IV, relapsed or refractory ENKL. Myelosuppression and infection during the treatment should be carefully managed.
Results date posted
Results Delayed
Results Delay Reason
Date of the first journal publication of results
Baseline Characteristics
Participant flow
Adverse events
Outcome measures
Plan to share IPD
IPD sharing Plan description

Recruitment status Completed
Date of protocol fixation
2007 Year 05 Month 12 Day
Date of IRB
Anticipated trial start date
2007 Year 07 Month 01 Day
Last follow-up date
2011 Year 07 Month 01 Day
Date of closure to data entry
Date trial data considered complete
Date analysis concluded

Other related information

Management information
Registered date
2007 Year 05 Month 09 Day
Last modified on
2011 Year 11 Month 09 Day

Link to view the page

Research Plan
Registered date File name

Research case data specifications
Registered date File name

Research case data
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