Efficacy and Safety Study of SyB L-0501 for Patients With Chronic Lymphocytic Leukemia

Study Overview
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Brief Summary
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The purpose of this study is to investigate safety and efficacy of SyB L-0501 after 2-day intravenous infusion at a dose of 100 mg/m2/day to patients with chronic lymphocytic leukemia.

Official Title
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A Multicenter, Open-label Phase II Study of SyB L-0501 in Patients With Chronic Lymphocytic Lymphoma

Conditions
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Chronic Lymphocytic Leukemia

Intervention / Treatment
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* Drug: SyB L-0501


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Patients meeting all of the following criteria are to be included in the study: Patients aged between 20 and 80 years (at the time of registration) Patients who have provided written consent in person for participation in this study Patients with Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 to 2 Patients who are expected to survive for at least 3 months Patients who are naive to or not suitable for fludarabine therapy Patients who are documented with chronic lymphocytic leukemia on the basis of International Workshop on Chronic Lymphocytic Leukaemia guideline (IWCLL) guideline: The presence of ≥ 5000/mm3 monoclonal mature B-lymphocytes in the peripheral blood ≤ 55 % atypical lymphocytes, prolymphocyte-like cells, and lymphoblasts with prominent nucleoli For monoclonal mature B-lymphocytes, at least one of the B-cell specific differentiation antigens (Cluster of differentiation (CD) 19, CD 20, and CD 23) and CD 5 is positive by flow cytometry Patients in Stage C or stage B with active disease based on Binet staging system (at the time of registration) Decision to start treatment should be made upon IWCLL guideline criteria. Active disease is defined to meet at least one of the following criteria. Progression and/or worsening of anemia and/or thrombocytopenia caused by decreased bone marrow function. Massive (6 cm below the left costal margin) or progressive or symptomatic splenomegaly Massive nodes (≥10 cm in longest diameter) or progressive or symptomatic lymphadenopathy Progressive lymphocytosis with an increase of > 50% over a 2-month period, or lymphocyte doubling time of less than 6 months Autoimmune anemia and/or thrombocytopenia poorly responsive to corticosteroids or other standard therapy B symptoms Weight loss > 10% within the previous 6 months Fevers of greater than 38.0° C for 2 or more weeks without other evidence of infection Night sweats Patients with 2 or less regimens of previous chemotherapy including antibody therapy. Corticosteroid monotherapy is not counted. Patients with adequately maintained organ functions (e.g., bone marrow, heart, lung, liver, and kidney functions) Neutrophil count: ≥ 1,000 /mm3 Aspartate aminotransferase(AST) Glutamic oxaloacetic transaminase(GOT): ≤ 3.0 times the upper limit of normal range at each site Alanine aminotransferase (ALT) Glutamic pyruvic transaminase(GPT): ≤ 3.0 times the upper limit of normal range at each site Total bilirubin: ≤ 1.5 times the upper limit of normal range at each site Serum creatinine: ≤ 1.5 times the upper limit of normal range at each site Partial pressure of O2 (PaO2): ≥ 65 mmHg No abnormalities which require treatment are detected on ECG Left ventricular ejection fraction (LVEF) (echocardiography): ≥ 55% Exclusion Criteria: Patients who fall under any one of the following criteria are to be excluded Patients who have been without treatment for less than 4 weeks after prior treatment. For patients treated with antibody therapy or underwent hematopoietic stem cell transplantation, for 3 months after prior treatment Patients who enrolled other clinical studies within 4 weeks before registration for this study Patients who received allogeneic stem cell transplantation in the past Patients with defective p53 (17p-) confirmed by chromosome analysis (Fluorescence in situ hybridization (Fish) method) Patients who are clinically diagnosed with Richter's syndrome Patients with infiltration to the central nervous system (CNS) or patients with clinical symptoms of suspected infiltration to the CNS Patients with multiple primary cancers or patients with a history of other malignant tumors within past 5 years, except for basal cell or squamous cell skin cancer, or carcinoma in situ of the cervix or gastrointestinal tract Patients with serious bleeding tendencies (e.g., disseminated intravascular coagulation (DIC)) Patients with, or confirmed in the past to have had, interstitial lung disease or pulmonary fibrosis Patients with, or confirmed in the past to have had, autoimmune hemolytic anemia responds to corticosteroid therapy Patients with any of the following complications serious cardiac disease (e.g., myocardial infarction, ischemic heart disease, or arrhythmia requiring treatment) serious, active infections (requiring intravenous administration of antibiotics, antifungal drugs, or antiviral drugs) hepatic or renal dysfunction accumulation of pleural effusion, pericardial effusion, or peritoneal effusion uncontrollable serious gastrointestinal disease, endocrine disorder, or mental illness Patients who received SyB L-0501 in the past Patients with allergies to mannitol Patients who need cytokine preparations such as erythropoietin or granulocyte colony stimulating factor (G-CSF) or blood transfusions at registration for this study Patients positive for HIV antibody or Hepatitis C virus (HCV) antibody Patients positive for Hepatitis B surface (HBs) antigen. Patients with negative results will also be checked for Hepatitis B core (HBc) antibody and HBs antibody. If either of the test results is positive, measure Hepatitis B virus (HBV)-DNA and exclude the patients with results above sensitivity Patients with clinical symptom of cytomegalovirus (CMV) infection, except asymptomatic patients with CMV positive Patients who are pregnant, who may possibly be pregnant, or lactating Patients who do not agree to practice contraception. Male: During investigational product administration and until 6 months after final administration Female: During investigational product administration and until 4 months after final administration Patients with drug addiction, narcotics addiction, and/or alcohol dependency Patients otherwise judged by the investigator or sub-investigator to be unsuitable for inclusion in this study

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 80 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SyB L-0501<br> | Drug: SyB L-0501<br>* SyB L-0501 is administered at 100 mg/m2/day by intravenous infusion on Day 1 and Day 2 followed by 26 days of monitoring. This is considered to be one cycle and may be repeated up to 6 cycles. Dose administration can be delayed or discontinued from the second cycle as necessary according to adverse events and the results of monitoring during the previous cycle, but dose reduction is permitted from the 3rd cycle.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response Rate [Complete Remission (CR) +Complete Remission / Incomplete (CRi) + Nodular Partial Remission (nPR) + Partial Remission (PR)] Based on International Workshop on Chronic Lymphocytic Leukemia (IWCLL) Guideline | The criteria for CR, CRi, nPR and PR based on IWCLL guideline are shown below. For the criteria for nPR and PR, please refer to the description of NCI-WG response rate (CR+nPR+PR). CR: Assessment should be made at least 8 weeks after completion of administration. Absence of significant lymphadenopathy (lymph nodes greater than 1.5 cm in diameter) No hepatomegaly or splenomegaly Absence of B symptoms Meet the following laboratory test values; lymphocyte count in peripheral blood: <4.0×10^9/L neutrophil count: >1.5×10^9/L platelet count: 100×10^9/L hemoglobin: 11.0 g/dL without transfusions less than 30% of nucleated cells are lymphocytes (confirmed by bone marrow aspiration and no lymphoid nodules). No new lesion emergence CRi: Fulfills all of the following criteria Delayed anemia, thrombocytopenia, or neutropenia is observed. Fulfills all CR criteria other than 4). Delayed symptoms are all judged to be caused by drug. | Up to 30 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| National Cancer Institute-sponsored Working Group (NCI-WG) Response Rate (CR+nPR+PR) Based on IWCLL Guideline | The criteria for nPR and PR based on IWCLL guideline are shown below. nPR: Fulfills all CR criteria other than residual lymphoid nodules confirmed by bone marrow examination. PR: Fulfills two or more items from Group A and one or more items from Group B for a minimal duration of 8 weeks. Group A; 50% or greater reduction in lymphocyte count in peripheral blood from baseline 50% or greater reduction (size reduction) in Sum of the products of the greatest diameters (SPD) and no new lesion emergence or no new enlarged lymph node A decrease in the size of the liver and/or spleen by 50% more A decrease in marrow infiltration or lymphoid nodules by 50% more Group B; 1) Neutrophil count >1.5×10^9/L or 50% improvement from baseline 2) Platelet count >100×10^9/L or 50% improvement from baseline 3) Hemoglobin 11.0 g/dL or 50% improvement from baseline without transfusions | Up to 30 months | 
| Complete Remission Rate (CR+CRi) Based on IWCLL Guideline |  | Up to 30 months | 
| Progression-free Survival (PFS) | The period from the first day of the study drug administration (Day1) to progressive disease (PD), recurrence/relapse, or death. | Up to 30 months | 
| Duration of Remission | The period from the day of CR or PR confirmation to recurrence/relapse. | Up to 30 months | 
| Overall Survival (OS) | The period from the date of patient registration to the date of death. | Up to 30 months | 
| Adverse Events | All undesirable medical events experienced by the subject treated with the investigational product (including abnormal changes in laboratory values) are treated as adverse events and evaluated for safety. | Up to 30 months | 
| Number of Subjects With Clinically Significant Laboratory Test Values of Grade 3 or More | Abnormalities in laboratory test values in overall study period were analyzed. Severity of abnormalities were evaluated using Common Terminology Criteria for Adverse Events (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 adverse event | Up to 30 months | 
| Number of Subjects With Clinically Significant Physical Examination Values | Number of subjects with abnormal or severe values of vital signs, electrocardiogram, and physical examination including ECOG performance status | Up to 30 months |