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).

1. Bulky disease \>7 cm in major axis on CT (excluding lesions in the spleen)
2. B symptoms

   * Unexplained fever exceeding 38.0ºC
   * Night sweats
   * Weight loss of more than 10% within 6 months before registration
3. Elevated serum lactate dehydrogenase (LDH) or β2-microglobulin level
4. Involvement of at least 3 regional lymph nodes \>3 cm in major axis on CT
5. Symptomatic splenomegaly
6. Compressive symptoms
7. 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.