Efficacy and Safety Study of SyB L-0501 in Combination With Rituximab in Patients With Untreated, Low-grade B Cell Non-Hodgkin's Lymphoma and Mantle Cell Lymphoma

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to assess the efficacy and safety of SyB L-0501 (two-day consecutive 90 mg/m2/day IV drip infusions) in combination with rituximab (375 mg/m2 IV drip infusion) on untreated, low-grade B cell non-Hodgkin's lymphoma and mantle cell lymphoma where hematopoietic stem cell transplantation is not indicated.

Official Title
-----------------
Phase II Clinical Study of SyB L-0501 in Combination With Rituximab in Patients With Untreated, Low-grade B-cell Non-Hodgkin's Lymphoma and Mantle Cell Lymphoma (Multicenter, Open-label).

Conditions
-----------------
Low-grade B Cell Non-Hodgkin's Lymphoma, Mantle Cell Lymphoma Where Hematopoietic Stem Cell Transplantation is Not Indicated

Intervention / Treatment
-----------------
* Drug: SyB L-0501
* Drug: rituximab


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients who are histopathologically confirmed to have the following cluster of differentiation 20 (CD20) positive low-grade B cell non-Hodgkin's lymphoma or mantle cell lymphoma by lymph node biopsy or evaluable tissue biopsy within 6 months before the registration WHO Classification of Tumors (fourth edition): Small lymphocytic lymphoma Splenic marginal zone B-cell lymphoma Lymphoplasmacytic lymphoma Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) Nodal marginal zone B-cell lymphoma Follicular lymphoma (Grade 1, 2, 3a) Mantle cell lymphoma Patients with a measurable lesion ( > 1.5 cm in major axis on CT) Patients without a medical history Patients with at least 1 of the following clinical symptoms or signs (excluding mantle cell lymphoma): Bulky disease measuring > 7 cm in major axis on CT (excluding spleen) B symptoms Fever exceeding 38.0ºC of unknown cause Night sweats Weight decrease exceeding 10% within 6 months before patient registration Elevated serum LDH or beta 2 microglobulin Three or more regional lymph nodes of > 3 cm in major axis on CT Symptomatic splenomegaly Intracranial pressure Pleural effusion/ascites retention Patients expected to live for at least 3 months Patients aged between 20 and 79 years (at the time of registration) Patients whose Eastern Cooperative Oncology Group (ECOG) performance status (P.S.) is 0～2 Patients with adequately maintained major organ function (bone marrow, heart, lungs, liver, kidneys) Neutrophil count: not less than 1,500 /mm3 Platelet count: not less than 75,000 /mm3 Aspartate aminotransferase (AST)[Glutamic oxaloacetic transaminase (GOT)]: not more than 3 times the standard upper limit for the site Alanine aminotransferase (ALT)[Glutamic pyruvic transaminase (GPT)]: not more than 3 times the standard upper limit for the site Total bilirubin: not more than 1.5 times the standard upper limit for the site Serum creatinine: not more than 1.5 times the standard upper limit for the site Arterial partial pressure of oxygen (PaO2): not less than 65 mmHg Electrocardiogram shows no abnormal findings that require treatment Echocardiogram of left ventricular ejection fraction (LVEF): not less than 55% Patients whose informed consent has been obtained in person Exclusion Criteria: Patients who fall under any one of the following criteria are to be excluded Patients whose transformation has been confirmed histopathologically Mantle cell lymphoma patients aged 65 years or younger Patients who were administered or received transfusion of cytokine formulations such as G-CSF (granulocyte colony stimulating factor) and erythropoietin within 14 days before pre-registration test Patients with severe active infectious disorders (receiving antibiotics, antifungals, or antivirus IV injection) Patients with serious complications (such as hepatic or renal failure) Patients with severe complications of cardiac disease (examples: myocardial infarction, ischemic heart disease) or its previous history within 2 years before patient registration, and patients with arrhythmia requiring a treatment Patients with serious gastrointestinal conditions (persistent or severe nausea/vomiting or diarrhea) Patients who are positive for hepatitis B surface (HBs) antigen, hepatitis C virus (HCV) antibody or HIV antibody [if HBs or hepatitis B core (HBc) positive, patients whose hepatitis B virus (HBV)-DNA test results indicate positive] Patients with serious bleeding tendencies [such as disseminated intravascular coagulation (DIC)] Patients having or suspected of having symptoms indicative of the central nervous system (CNS) involvement Patients with interstitial pneumonitis, pulmonary fibrosis, pulmonary emphysema complications requiring treatment or its medical history. Patients with active multiple primary cancer Patients who received chemotherapy, radiotherapy, antibody therapy and antitumor steroid therapy in the past Patients with complications or medical history of autoimmune haemolytic anaemia Patients who were administered investigative or unapproved drugs within 3 months before patient registration Patients with addiction to drugs or narcotics, or alcoholism Patients who have previously received hematopoietic stem cell transplantation Patients who are or may be pregnant, lactating patients Patients, whether male or female, who do not agree to use contraception Patients otherwise judged by the investigator or the sub-investigator to be unsuitable for inclusion in the study

Ages Eligible for Study
-----------------
Minimum Age: 20 Years
Maximum Age: 79 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SyB L-0501＋rituximab<br> | Drug: SyB L-0501<br>* A dose of 90 mg/m^2/day of SyB L-0501 is administered on Day 1 and Day 2 as an IV drip infusion, followed by 26-day observation. This is 1 cycle (28 days), which will be repeated for a maximum of 6 times.<br>Drug: rituximab<br>* A dose of 375 mg/m^2 of rituximab is administered on Day 1 (Day 0 in Cycle 1 only) as an IV drip infusion, followed by 26-day observation. This is 1 cycle (28 days), which will be repeated for a maximum of 6 times. From Cycle 2, rituximab will be coadministered with SyB L-0501 on Day 1. However, if the investigator or sub-investigator judges that the coadministration is difficult, rituximab may be administered on Day 0.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete Response Rate (CR + CRu) Based on International Workshop to Standardize Response Criteria for Non-Hodgkin's Lymphomas (1999)(IWRC) | The criteria for CR and CRu based on IWRC are shown below. CR: Fulfills all of the following Disappearance of all detectable disease LN* > 1.5 cm must decrease to ≤ 1.5 cm CRu: Fulfills all of the following LN >1.5 cm; SPD** decrease >75% indeterminate bone marrow LN: lymph nodes or nodal masses ** SPD: sum of the products of the greatest diameters | Up to 30 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (Antitumor Effect: PR or Better) Based on International Workshop to Standardize Response Criteria for Non-Hodgkin's Lymphomas (1999)(IWRC) | The criteria for PR based on IWRC are shown below. PR: SPD regressed > 50% | Up to 30 weeks | 
| Complete Response Rate (CR) Based on Revised Response Criteria for Malignant Lymphoma (2007)(Revised RC) | The criteria for CR based on the Revised RC are shown below. Definition: Disappearance of all evidence of disease Nodal Masses: [18F]fluorodeoxyglucose (FDG)-avid or PET positive prior to therapy; mass of any size permitted if PET negative. Variably FDG-avid or PET negative; regression to normal size on CT. Spleen, Liver: Not palpable, nodules disappeared Bone Marrow: Infiltrate cleared on repeat biopsy; if indeterminate by morphology, immunohistochemistry should be negative. | Up to 30 weeks | 
| Overall Response Rate (PR or Better) Based on Revised Response Criteria for Malignant Lymphoma (2007)(Revised RC) | The criteria for PR based on the Revised RC are shown below. Definition: Regression of measurable disease and no new sites Nodal Masses: 50% or more decrease in SPD of up to 6 largest dominant masses; no increase in size of other nodes FDG-avid or PET positive prior to therapy; one or more PET positive at previously involved site Variably FDG-avid or PET negative; regression on CT Spleen, Liver: 50% or more decrease in SPD of nodules (for single nodule in greatest transverse diameter); no increase in size of liver or spleen Bone Marrow: Irrelevant if positive prior to therapy; cell type should be specified. | Up to 30 weeks | 
| Complete Response Rate Based on WHO Handbook for Reporting Results of Cancer Treatment (1979) | The criteria for Complete response based on WHO Handbook for Reporting Results of Cancer Treatment (1979) are shown below. Measurable disease: The disappearance of all known disease, determined by 2 observations not less than 4 weeks apart. Unmeasurable disease: Complete disappearance of all known disease for at least 4 weeks. Bone metastases: Complete disappearance of all lesions on X-ray or scan for at least 4 weeks. | Up to 30 weeks | 
| Overall Response Rate (PR or Better) Based on WHO Handbook for Reporting Results of Cancer Treatment (1979) | The criteria for Overall response rate (PR or better) based on WHO Handbook for Reporting Results of Cancer Treatment (1979) are shown below. Definition of PR: Measurable disease: 50% or more decrease in total tumor size of the lesions which have been measured to determine the effect of therapy by 2 observations not less than 4 weeks apart. In addition there can be no appearance of new lesions or progression of any lesion. Unmeasurable disease: Estimated decrease in tumor size of 50% or more for at least 4 weeks. Bone metastases: Partial decrease in size of lytic lesions, recalcification of lytic lesions, or decreased density of blastic lesions for at least 4 weeks. | Up to 30 weeks | 
| Progression-Free Survival (PFS) | PFS is the period from registration date to the earliest onset date of any progression event calculated using the Kaplan-Meier estimator. The median and the 95% confidence interval (CI) were calculated using Greenwood's formula. Progression event was defined as progression (includes recurrence/relapse), initiation of post-study treatment, confirmation of other malignant tumor, or death due to any given cause. The date of progression was determined based on overall response assessed using IWRC, Revised RC, and WHO, and assessment by the primary physicians (excluding overall response). | Up to 30 weeks | 
| Duration of Response (DOR) | DOR is the period from the date of achieving CR, CRu or PR in the responders to the earliest onset date of any progression events calculated using the Kaplan-Meier estimator. The median and the 95% CI were calculated using Greenwood's formula. The date of achieving CR, CRu or PR was determined based on the overall response assessed using IWRC. The date of progression was determined based on overall response assessed using IWRC, Revised RC and WHO, and assessment by the primary physicians (excluding overall response). Progression event was defined as progression (includes recurrence/relapse), initiation of post-study treatment, confirmation of other malignant tumor, or death due to any given cause. | Up to 30 weeks | 
| Overall Survival (OS) | Death due to any given cause was defined as an event. OS was calculated using the Kaplan-Meier estimator. The median and the 95% CI were calculated using Greenwood's formula. | Up to 30 weeks | 
| Number of Subjects With Adverse Event, Related Adverse Event, Serious Adverse Event, and Discontinuation Due to Adverse Event | Adverse events were evaluated using Common Terminology Criteria for Adverse Events (CTCAE) v4.0, Japan Clinical Oncology Group/Japan Society of Clinical Oncology (JCOG/JSCO) version, and were encoded using Medical Dictionary for Regulatory Activities (MedDRA) Ver.16.1. | up to 30 weeks | 
| Laboratory Test Abnormalities (Biochemical Tests) | Abnormalities in laboratory test values in overall study period were analyzed. Severity of abnormalities were evaluated using CTCAE. Grade 1 : mild Grade 2 : moderate Grade 3 : severe or medically significant but not immediately life-threatening Grade 4 : life threatening or disabling Grade 5 : death related to AE | up to 30 weeks | 
| Laboratory Test Abnormalities (Hematology Tests) | Abnormalities in laboratory test values in overall study period were analyzed. Severity of abnormalities were evaluated using CTCAE. Grade 1 : mild Grade 2 : moderate Grade 3 : severe or medically significant but not immediately life-threatening Grade 4 : life threatening or disabling Grade 5 : death related to AE | up to 30 weeks |