Study of SyB L-0501 to Treat Relapsed/Refractory Multiple Myeloma

Study Overview
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Brief Summary
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The purpose of this study is to determine the antitumor efficacy and safety of bendamustine (SyB L-0501: 90 mg/m^2/day) for a maximum of 6 cycles (1 cycle: intravenous administration for 2 consecutive days and 26-day observation period) in patients with relapsed/refractory multiple myeloma.

Official Title
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A Multicenter, Open-Label Phase II Study of SyB L-0501 in Patients With Relapsed/Refractory Multiple Myeloma

Conditions
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Relapsed/Refractory Multiple Myeloma

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 who are diagnosed with multiple myeloma on the basis of the response criteria of the International Myeloma Working Group (IMWG) and confirmed to meet one or more of the following criteria: (definition of progression according to the IMWG response criteria) 25% or more increase compared to baseline for the following values Serum M-protein level (however, the absolute value is 0.5 g/dL or higher) Urine M-protein level (however, absolute value is 200 mg/24 hours or higher) For lesions without measurable serum or urine M-protein values. involved/uninvolved free light chain (FLC) ratio (however, absolute value is 10 mg/dL or higher) Clear appearance of new bone lesions or soft tissue plasmacytoma or apparent growth in size of current bone lesions or soft tissue plasmacytoma Appearance of hypercalcemia (corrected calcium level ≥ 11.5 mg/dL and if determined to be caused solely by myelomas) Patients with measurable lesions (meets at least one of the following two criteria Serum M-protein [Immunoglobulin G (IgG)≥ 1.0 g/dL, Immunoglobulin A (IgA) ≥ 0.5 g/dL, Immunoglobulin D (IgD) ≥ 0.1 g/dL) Urine M-protein ≥ 200 mg/24 hours Patients who meet either one of the following items for all prior chemotherapy using proteasome inhibitors, Immunomodulatory Drugs (IMiDs) (thalidomide or lenalidomide) or alkylating agents. No response* Relapse/recurrence after response* Intolerance Not applicable (reason can be confirmed in the source document) because of predicted aggravation of complications (neurotoxicity, etc.) * Patients whose disease has progressed based on the IMWG response criteria after receiving the most recent therapy Patients who have undergone a washout period of more than 3 weeks after the end of the previous therapy and determined not to be under the effect of previous treatment (antitumor effectiveness). Patients who are expected to survive for at least 3 months Patients aged from 20 to 79 years at the time of interim registration Performance Status (P.S.) of 0 to 125. However, P.S. 2 due to pain from lytic bone lesions is acceptable Patients with adequately maintained organ functions (e.g., bone marrow, heart, lung, liver, and kidney functions) Neutrophil count:≥ 1,500 /mm^3 Platelet count:≥ 75,000 /mm^3 Albumin:≥ 2.5 g /dL Aspartate aminotransferase (AST) Glutamic oxaloacetic transaminase (GOT): < than 3.0 times the upper limit of normal range for the site Alanine aminotransferase (ALT) Glutamic pyruvic transaminase (GPT): < than 3.0 times the upper limit of normal range for the site Total bilirubin: < than 1.5 times the upper limit of normal range for the site Serum creatinine: < than 3.0 times the upper limit of normal range for the site Partial pressure of O2 (PaO2) ≥ 65 mmHg No abnormalities which require treatment are detected on ECG Left ventricular ejection fraction (LVEF)(echocardiography): ≥ 55% Patients who have provided written consent for participation in this study Exclusion Criteria: Patients with apparent infections (including viral infections) Patients with serious complications (hepatic or renal dysfunction, etc.) Patients with complications or medical history of serious cardiac disease (e.g., myocardial infarction, ischemic heart disease) within 2 years of the date of interim registration or patients with arrhythmias that require treatment Patients with serious gastrointestinal symptoms (e.g., severe nausea, vomiting, or diarrhea) Patients positive for Hepatitis B surface (HBs) antigen, Hepatitis C virus (HCV) antibody, or HIV antibody Patients with serious bleeding tendencies (e.g., disseminated intravascular coagulation: DIC) Patients with, or confirmed in the past to have had, interstitial pneumonia, pulmonary fibrosis, or pulmonary emphysema which requires treatment. Patients with a complication of apparent cardiac amyloidosis Patients with infiltration to the central nervous system (CNS) or patients with clinical symptoms of suspected infiltration to the CNS, Patients with active multiple primary cancer Patients with, or confirmed in the past to have had, autoimmune hemolytic anemia Patients who have received this investigational product in the past Patients who have received allogeneic stem cell transplants in the past. (patients who have received autologous stem cell transplantation are acceptable) Patients who received cytokine preparations such as erythropoietin or granulocyte colony stimulating factor (G-CSF) or blood transfusions within 1 week prior to the examination conducted before interim registration for this study Patients who received other investigational products or unapproved medications within 3 months before interim registration for this study Patients with prior allergies to medications that are similar to this investigational product (e.g., alkylating agents, or purine-nucleoside derivatives) or mannitol Patients with drug addiction, narcotics addiction, and/or alcohol dependency Patients who are pregnant, who may possibly be pregnant, or lactating Patients who do not agree to practice contraception for the following periods: 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 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: 79 Years

Sexes Eligible for Study
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All

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>* The administration of SyB L-0501 at 90 mg/m^2/day by 60-minute intravenous infusion for 2 consecutive days followed by 26 days of monitoring. This is considered to be one cycle and may be repeated up to 6 times. Dose reduction or discontinuation is permitted from the second cycle as necessary according to adverse events and the results of monitoring during the previous cycle.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response Rate [Stringent CR (sCR)+Complete Response (CR)+Very Good PR (VGPR)+Partial Response (PR)]Based on International Myeloma Working Group (IMWG) Criteria | The criteria for sCR, CR, VGPR, and PR based on IMWG are shown below. sCR: Fulfills CR criteria as well as all of the following conditions Normal free light chain (FLC) ratio(κ/λ) Disappearance of clonal cells in bone marrow by immunohistochemistry or immunofluorescence CR: Fulfills all of the following criteria Negative immunofixation of serum and urine M-protein <5% plasma cells in bone marrow Disappearance of any soft tissue plasmacytoma VGPR: Fulfills at least one of the following criteria Serum and urine M-protein detectable by immunofixation but not electrophoresis ≥90% reduction in serum M-protein and 24-hour M-protein excretion amount in urine <0.1 g/24 hour PR: Fulfills the following criteria ≥50% reduction in serum M-protein, and ≥90% reduction in urine M-protein, urine M-protein excretion amount is reduced to < 0.2 g/24hours | up to around 44 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response Rate (sCR+CR) Based on IMWG Criteria |  | up to around 44 weeks | 
| Complete Response (CR) Based on the Blade Criteria | The criteria for CR based on the Blade are shown below. CR requires all of the followings: Absence of the original monoclonal paraprotein in serum and urine by immunofixation, maintained for a minimum of 6 weeks <5% plasma cells in a bone marrow aspirate and also on trephine bone biopsy No increase in size or number of lytic bone lesions Disappearance of soft tissue plasmacytomas | up to around 44 weeks | 
| Response Rate (CR+PR) Based on the Blade Criteria | The criteria for PR based on the Blade are shown below. PR requires 1. or all of the others: Some, but not all, of the criteria for CR are fulfilled ≥50% reduction in the level of the serum monoclonal paraprotein, maintained for a minimum of 6 weeks Reduction in 24 h urinary light chain excretion either by ≥90% or to <200 mg, maintained for a minimum of 6 weeks For patients with non-secretory myeloma only, ≥50% reduction in plasma cells in a bone marrow aspirate and on trephine biopsy ≥50% reduction in the size of soft tissue plasmacytomas No increase in size or number of lytic bone lesions | up to around 44 weeks | 
| Progression-Free Survival (PFS) | Using the registration date as the start date, PFS with relapse/recurrence or progression, and death regardless of the cause as events are to be summarized using the Kaplan-Meier estimator and the 50% point according to the Greenwood's formula and the 95% confidence interval are to be calculated. | up to around 44 weeks | 
| Time to Treatment Failure (TTF) | Using the registration date as the start date, TTF with relapse/recurrence or progression, death regardless of the cause, and early discontinuation of treatment as events are to be summarized using the Kaplan-Meier estimator and the 50% point according to the Greenwood's formula and 95% confidence interval are to be calculated. | up to around 44 weeks | 
| Duration of Response (DOR) | From initial response (PR or higher), DOR with relapse/recurrence or progression, and death, regardless of cause, as events, are to be summarized using the Kaplan-Meier estimator and the 50% point according to the Greenwood's formula and 95% confidence interval are to be calculated. | up to around 44 weeks | 
| Overall Survival (OS) | Using the registration date as the start date, OS with death, regardless of the cause, as events, are to be summarized using the Kaplan-Meier estimator and the 50% point according to the Greenwood's formula and 95% confidence interval are to be calculated. | up to around 44 weeks | 
| Adverse Events | All adverse events occurring during the administration of the investigational product are to be examined for safety by cross tabulation lists and tables of incidence from the viewpoint of relationship with the drug, disease severity and medicine treated group. | up to around 44 weeks | 
| Number of Subjects With Abnormality (Grade ≥3) in Laboratory Test Values | 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 around 44 weeks | 
| Number of Abnormalities (Grade ≥3) in Laboratory Test Values | 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 around 44 weeks |