Phase I/II Study of SyB L-0501RI in Combination With Rituximab to Treat Lymphoma

For previously untreated patients with Lg-B-NHL or MCL

Inclusion criteria

Patients who satisfy all of the conditions listed below:

▪ Patients who satisfy all of the following criteria A) to D): A) Patients who are histopathologically confirmed to have one of the following subtypes of CD20 (cluster of differentiation 20)-positive Lg-B-NHL or MCL (excluding transformed lymphoma) by lymph node biopsy or evaluable tissue biopsy (World Health Organization [WHO] histological classification [4th edition]).

• Small lymphocytic lymphoma
• Splenic marginal zone lymphoma
• Lymphoplasmacytic lymphoma
• Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT)
• Nodal marginal zone lymphoma
• Follicular lymphoma (Grade 1, 2, 3a)
• MCL B) Patients who have at least one measurable lesion (>1.5 cm in major axis on computed tomography [CT]).

C) Patients without a history of treatment for lymphoma. D) Patients with at least one of the following clinical signs or symptoms (with the exception of MCL patients).

• Bulky disease >7 cm in major axis on CT (excluding lesions in the spleen)
• B symptoms

• Unexplained fever exceeding 38.0ºC
• Night sweats
• Weight loss of more than 10% within 6 months before registration
• Elevated serum lactate dehydrogenase (LDH) or β2-microglobulin level
• Involvement of at least 3 regional lymph nodes >3 cm in major axis on CT
• Symptomatic splenomegaly
• Compressive symptoms
• Pleural effusion and/or ascites

• Patients aged between 20 and 79 years (at the time of registration).
• Patients who are expected to survive for at least 3 months.
• Patients with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 to 2.
• Patients with adequate functional reserve of major organs (bone marrow, heart, lungs, liver, kidneys, etc.).

• Neutrophil count: ≥1,500/mm^3
• Platelet count: ≥75,000/mm^3
• Aspartate aminotransferase (AST) [glutamic oxaloacetic transaminase [GOT]): ≤3.0 times the institution's upper limit of normal (ULN)
• Alanine aminotransferase (ALT) [glutamic pyruvic transaminase (GPT)]: ≤3.0 times the institution's ULN
• Total bilirubin: <2.0 mg/dL
• Serum creatinine: <2.0 mg/dL
• Percutaneous arterial oxygen saturation (SpO2): ≥95% or Partial arterial oxygen pressure (PaO2): ≥65 mmHg
• No abnormal findings requiring treatment on electrocardiogram (ECG)
• Left ventricular ejection fraction (LVEF) on echocardiography: ≥55%
• Patients who have provided written informed consent to participate in this study.

Exclusion criteria

Patients who meet any of the following conditions will be excluded:

• MCL patients aged ≤65 years (at the time of registration).
• Patients who have a history of treatment for Lg-B-NHL or MCL (chemotherapy, radiotherapy, antibody therapy or antitumor steroid therapy).
• Patients who have previously received hematopoietic stem cell transplantation.
• Patients with invasion to central nervous system (CNS) or clinical symptoms suspected of CNS invasion.
• Patients with serious active infection (requiring antibiotic, antifungal, or antiviral IV injection).
• Patients with serious complications (such as hepatic failure and renal failure).
• Patients with concurrent or previous, serious cardiac disease (e.g., myocardial infarction, ischemic heart disease); however, patients with arrhythmias are allowed to be enrolled if it does not require treatment at the time of registration.
• Patients with serious gastrointestinal symptoms (such as high-grade or severe nausea/vomiting or diarrhea).
• Patients with malignant pleural effusion, pericardial effusion, or ascites.
• Patients positive for hepatitis B surface (HBs) antigen, hepatitis C virus (HCV) antibody, or human immunodeficiency virus (HIV) antibody (patients with positive hepatitis B virus [HBV]-DNA quantitative test results if they are negative for HBs antigen and positive for HBs antibody or hepatitis B core [HBc] antibody).
• Patients with serious bleeding tendencies (such as disseminated intravascular coagulation [DIC]).
• Patients with a fever of 38.0ºC or higher (with the exception of fever developing as a B symptom).
• Patients with concurrent or previous interstitial pneumonia, pulmonary fibrosis, or chronic obstructive pulmonary disease.
• Patients with active multiple primary cancers or patients with a history of other malignancy within the past 5 years, with the exception of basal cell carcinoma or squamous cell carcinoma of the skin or carcinoma in situ of the cervix or digestive organs.
• Patients with concurrent or previous autoimmune hemolytic anemia.
• Patients who have previously received bendamustine hydrochloride.
• Patients who have received a cytokine preparation, such as granulocyte colony- stimulating factor (G-CSF) or erythropoietin, or blood transfusions within 2 weeks before a screening test for this study.
• Patients who have received other investigational products or unapproved drugs within 3 months before registration for this study.
• Patients with a history of allergy to medications similar to SyB L-0501RI (e.g., alkylating agents and purine-nucleoside derivatives).
• Patients who cannot tolerate rituximab.
• Pregnant, possibly pregnant, or lactating women.
• Patients, whether male or female, who do not agree to use contraception.

Duration:

Male patients; during the treatment period and for 6 months after treatment Female patients with no menstruation; during the treatment period Female patients with menstruation; during the treatment period and for 3 months after treatment

• Patients with drug addiction, narcotic addiction, or alcohol dependence.
• Patients who are unable to take pre-treatment medication due to drug allergies or the like.
• Patients who are otherwise judged by the investigator or subinvestigator to be unsuitable as a subject.

For patients with recurrent or refractory DLBCL

Inclusion criteria

Patients who satisfy all of the conditions listed below:

▪ Patients who satisfy both of the following criteria A and B: A) Patients who are histopathologically confirmed to have CD20-positive DLBCL (excluding transformed lymphoma) by lymph node biopsy or evaluable tissue biopsy (WHO histological classification [4th edition]).

B) Patients with recurrent or refractory DLBCL who have had disease progression after standard rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) therapy or R-CHOP-like therapy as first-line treatment.

• Patients aged between 20 and 79 years (at the time of registration).
• Patients who are expected to survive for at least 3 months.
• Patients with an ECOG PS of 0 to 2.
• Patients with adequate functional reserve of major organs (bone marrow, heart, lungs, liver, kidneys, etc.).

• Neutrophil count: ≥1,500/mm^3
• Platelet count: ≥75,000/mm^3
• AST (GOT): ≤3.0 times the institution's ULN
• ALT (GPT): ≤3.0 times the institution's ULN
• Total bilirubin: <2.0 mg/dL
• Serum creatinine: <2.0 mg/dL
• SpO2: ≥95% or PaO2: ≥65 mmHg
• No abnormal findings requiring treatment on ECG
• LVEF on echocardiography: ≥55%
• Patients who have provided written informed consent to participate in this study.

Exclusion criteria

Patients who meet any of the following conditions will be excluded:

• Patients with an off-treatment interval of less than 3 weeks between the last day of preceding treatment (chemotherapy, radiotherapy, antibody therapy, or antitumor steroid therapy) for DLBCL and the day of registration for this study.
• Patients who are judged by the investigator or subinvestigator to be suitable for autologous peripheral blood stem cell transplantation.
• Patients who have previously received allogeneic hematopoietic stem cell transplantation.
• Patients who have previously received radioimmunotherapy
• Patients with invasion to CNS or clinical symptoms suspected of CNS invasion.
• Patients with serious active infection (requiring antibiotic, antifungal, or antiviral IV injection).
• Patients with serious complications (such as hepatic failure and renal failure).
• Patients with concurrent or previous, serious cardiac disease (e.g., myocardial infarction, ischemic heart disease); however, patients with arrhythmias are allowed to be enrolled if it does not require treatment at the time of registration.
• Patients with serious gastrointestinal symptoms (such as high-grade or severe nausea/vomiting or diarrhea).
• Patients with malignant pleural effusion, pericardial effusion, or ascites.
• Patients positive for HBs antigen, HCV antibody, or HIV antibody (patients with positive HBV-DNA quantitative test results if they are negative for HBs antigen and positive for HBs antibody or HBc antibody).
• Patients with serious bleeding tendencies (such as DIC).
• Patients with a fever of 38.0ºC or higher (with the exception of fever developing as a B symptom).
• Patients with concurrent or previous interstitial pneumonia, pulmonary fibrosis, or chronic obstructive pulmonary disease.
• Patients with active multiple primary cancers or patients with a history of other malignancy within the past 5 years, with the exception of basal cell carcinoma or squamous cell carcinoma of the skin or carcinoma in situ of the cervix or digestive organs.
• Patients with concurrent or previous autoimmune hemolytic anemia.
• Patients who have previously received bendamustine hydrochloride.
• Patients who have received a cytokine preparation, such as G-CSF or erythropoietin, or blood transfusions within 2 weeks before a screening test for this study.
• Patients who have received other investigational products or unapproved drugs within 3 months before registration for this study.
• Patients with a history of allergy to medications similar to SyB L-0501RI (e.g., alkylating agents and purine-nucleoside derivatives).
• Patients who cannot tolerate rituximab.
• Pregnant, possibly pregnant, or lactating women.
• Patients, whether male or female, who do not agree to use contraception.

Duration:

Male patients; during the treatment period and for 6 months after treatment Female patients with no menstruation; during the treatment period Female patients with menstruation; during the treatment period and for 3 months after treatment

• Patients with drug addiction, narcotic addiction, or alcohol dependence.
• Patients who are unable to take pre-treatment medication due to drug allergies or the like.
• Patients who are otherwise judged by the investigator or subinvestigator to be unsuitable as a subject.