A Study of TRU-016 in Combination With Rituximab and Bendamustine in Subjects With Relapsed Indolent Lymphoma

• the incidence of dose limiting toxicities during cycle 1 of each dose cohort to determine Maximum Tolerated Dose of TRU-016 (Phase 1 only) [ Time Frame: Cycle 1 (28 days) ] [ Designated as safety issue: Yes ]
• efficacy as measured by the Complete Response Rate of TRU-016 in combination with rituximab and bendamustine (Phase 2 portion only) [ Time Frame: approximately 6 months ] [ Designated as safety issue: No ]

• safety of TRU-016 in combination with rituximab and bendamustine [ Time Frame: approximately 6 months ] [ Designated as safety issue: Yes ]
  safety including the incidence of treatment-emergent adverse events and drug related adverse events, change from baseline in clinical laboratory results, vital signs and physical exams, and incidence of TRU-016 anti-drug antibodies.
• efficacy of TRU-016 in combination with bendamustine and rituximab [ Time Frame: approximately 6 months ] [ Designated as safety issue: No ]
  secondary efficacy endpoints as measured by the Objective Response Rate (percentage of subjects with a Complete Response or a Partial Response); Progressions Free Survival; Overall Survival and Duration of Objective Response
• determine pharmacokinetics and pharmacodynamics [ Time Frame: approximately 6 months ] [ Designated as safety issue: No ]
  PK (maximum serum concentration, area under the curve, clearance, distribution and half-life) and PD (change from baseline levels of T cells, B cells and NK cells, change from baseline in levels of CD37 expression/saturation, change from baseline in cytokines and chemokines and changes from baseline of quantitative immunoglobulins) of TRU-016 in combination with bendamustine and rituximab

This is a Phase 1b/2 multicenter, open-label study of bendamustine, rituximab and TRU-016 (BRT) in up to approximately 88 subjects with relapsed indolent B-cell lymphoma. The study will be conducted in 2 parts, Phase 1b and Phase 2. Phase 1b is an open-label, non-randomized, multiple-dose escalation study to determine the MTD of TRU-016 given in combination with rituximab and bendamustine and to determine a safe dosing regimen for the combination in up to 12 subjects with relapsed indolent lymphoma.

The Phase 2 portion is an open-label, randomized study to evaluate the efficacy of BRT compared with BR. Approximately 76 subjects will be randomized in a 1:1 ratio to one of the 2 treatment groups. The dose level of TRU-016 for Phase 2 will be selected on the basis of safety data after 2 cycles of treatment in Phase 1b.

• Drug: TRU-016
  100 mg TRU-016 lyophilized solution for infusion at 10 or 20 mg/kg (or 6 mg/kg, if necessary) on Days 1 and 15 of each 28 day cycle
• Drug: bendamustine + rituximab
  Rituximab by IV administration at 375 mg/m^2 on Day 2, and bendamustine by IV on Days 1 and 2 of each 28 day cycle.

• Experimental: TRU-016+bendamustine+rituximab
  Intervention: Drug: TRU-016
• Active Comparator: bendamustine+rituximab
  Phase 2 portion only
  Intervention: Drug: bendamustine + rituximab

Inclusion Criteria

1. Age 18 years or older
2. Histologically confirmed diagnosis of indolent non-Hodgkin's B-cell lymphoma (ie, follicular lymphoma, small lymphocytic lymphoma, and marginal zone lymphoma) that has relapsed (relapsed is defined as confirmed progressive disease [PD] after receiving the most recent prior therapy, or failure to achieve at least a PR while receiving the most recent prior therapy)
3. At least one prior line of therapy for indolent lymphoma
4. Bi-dimensionally measurable disease with at least one lesion measuring >=1.5 cm in a single dimension
5. Eastern Cooperative Oncology Group (ECOG) performance status of <= 2
6. Creatinine clearance of >40 mL/min as calculated by the

Cockcroft-Gault method as follows:

(140 - age) * (weight in kg [* 0.85 if female] / 72 * serum creatinine level) 7. Adequate hepatic function, indicated as follows:

• aspartate aminotransferase (AST) of <2.5 x upper limit of normal (ULN)
• alanine aminotransferase (ALT) of <2.5 x ULN
• total bilirubin of <= 1.5 x ULN 8. Absolute neutrophil count (ANC) >=1000/mm3 (1000/µL) 9. Platelet count >= 100,000/mm3 10. Female subjects of child-bearing potential and male subjects must use an acceptable form of birth control for the duration of their study participation and for 6 months after completing study drug dosing; acceptable forms of birth control, unless dictated otherwise by local regulatory authorities 11. For women of childbearing potential, a negative serum pregnancy test result obtained during the screening period and a negative urine pregnancy test result within 24 hours before first administration of study drug 12. Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information

Exclusion Criteria

1. Diagnosis of grade 3b follicular lymphoma or transformed lymphoma of any grade
2. Previously received TRU-016
3. Prior treatment with rituximab if subject discontinued rituximab due to unresolved toxicity

4. Refractory to bendamustine, defined as follows:

   • progression within 6 months of last dose of bendamustine
   • failed to achieve at least a PR while receiving bendamustine
   • discontinued bendamustine due to toxicity
   • received bendamustine within 6 months prior to first dose of study drug
5. Received chemotherapy, radiotherapy, or immunotherapy including investigational agents within 28 days prior to the first dose of study drug
6. Received therapeutic corticosteroids at doses equivalent to >10 mg prednisone per day for longer than 5 days within 14 days prior to the first dose of study drug, except if needed as a pre-medication
7. Received filgrastim or equivalent within 14 days prior to screening (ie, collection of samples for laboratory tests) or pegfilgrastim within 28 days prior to screening (ie, collection of samples for laboratory tests)
8. Prior allogeneic bone marrow transplant
9. Prior autologous bone marrow transplant within 12 months prior to the first dose of study drug
10. Received blood or platelet infusion within 7 days prior to screening (ie, collection of samples for laboratory tests)
11. Previous or concurrent additional malignancy except non-invasive, non-melanomatous skin cancer or in situ carcinoma of the cervix, or other solid tumors if the subject has been disease-free for a minimum of 2 years prior to the first dose of study drug
12. Known central nervous system or leptomeningeal lymphoma

13. Any significant concurrent medical diseases or conditions, including but not limited to the following:

    • Clinically significant pulmonary dysfunction requiring oxygen therapy
    • An active infection (viral, bacterial, or fungal) requiring systemic therapy; subjects receiving prophylactic therapy are eligible
14. Known allergy to mannitol
15. History of positive serology for human immunodeficiency virus (HIV)
16. Positive serology for hepatitis B (surface antigen or core antibody) Note: If a positive test result for hepatitis B core antibody is due to immunoglobulin treatment, the subject may be enrolled if the hepatitis B viral deoxyribonucleic acid (DNA) is negative.
17. Positive serology for hepatitis C
18. Pregnant or breastfeeding
19. Other severe, acute, or chronic medical or psychiatric condition, laboratory abnormality, or difficulty complying with protocol requirements that may increase the risk associated with study participation or study drug administration or may interfere with safety
20. Any condition that, in the investigator's opinion, makes the subject unsuitable for study participation