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

A Phase 1 Study of TRU-016 in Combination With Rituximab and Bendamustine in Subjects With Relapsed Indolent Lymphoma

This was a Phase 1 multicenter study of bendamustine, rituximab and TRU-016 (BRT) in subjects with relapsed indolent B-cell lymphoma. This was a multiple-dose escalation study to determine the maximum-tolerated dose (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 originally planned Phase 2 portion, an open-label, randomized study to evaluate the efficacy of BRT compared with BR, was not conducted.

Study Overview

• Status: Completed
• Conditions: B-cell Small Lymphocytic Lymphoma Recurrent
• Intervention / Treatment: Drug: TRU-016; Drug: Bendamustine; Drug: Rituximab

Detailed Description

This study was planned to be conducted in 2 parts: a Phase 1b component designed to determine a safe dosing regimen, and a Phase 2 component designed to evaluate the efficacy of BRT compared to BR in subjects with relapsed indolent lymphoma. The Phase 2 component was not conducted.

This was an open-label, non randomized, multiple-dose escalation study to determine the MTD of BRT and to determine a safe dosing regimen for the combination in subjects with relapsed indolent lymphoma.

The study consisted of a screening period lasting up to 21 days, a treatment period lasting up to 6 cycles (28 days each), and a 60-day follow-up period. Up to 12 subjects (2 cohorts of 6 subjects each) were planned for enrollment. Two dose levels (10 and 20 mg/kg) of TRU-016 combined with rituximab 375 mg/m2 and bendamustine 90 mg/m2 were evaluated during up to 6 cycles (28 days each). TRU-016 was administered by intravenous (IV) infusion on Days 1 and 15 of each cycle. Rituximab was administered by IV infusion on Day 2 of each cycle. Bendamustine was administered by IV infusion on Days 1 and 2 of each cycle. Subjects received study treatment for up to 6 cycles.

• Study Type: Interventional
• Enrollment (Actual): 12
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • Site Reference ID/Investigator# 61543
  • Georgia
    • Augusta, Georgia, United States, 30912
      • Site Reference ID/Investigator# 61542
  • Nebraska
    • Omaha, Nebraska, United States, 68114
      • Site Reference ID/Investigator# 61523
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • Site Reference ID/Investigator# 61522
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599-7305
      • Site Reference ID/Investigator# 61544
  • Washington
    • Seattle, Washington, United States, 98109-1023
      • Site Reference ID/Investigator# 61524

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 99 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 partial response (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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: TRU-016+bendamustine+rituximab; Two dose levels (10 and 20 mg/kg) of TRU 016 combined with rituximab 375 mg/m2 and bendamustine 90 mg/m2 were evaluated during up to 6 cycles (28 days each). TRU-016 was administered by intravenous (IV) infusion on Days 1 and 15 of each cycle. Rituximab was administered by IV infusion on Day 2 of each cycle. Bendamustine was administered by IV infusion on Days 1 and 2 of each cycle. Subjects received study treatment for up to 6 cycles.

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; Other Names: otlertuzumab; Drug: Bendamustine; Bendamustine by IV administration on Days 1 and 2 of each 28 day cycle.; Other Names: Treanda; Drug: Rituximab; Rituximab by IV administration at 375 mg/m^2 on Day 2 of each 28 day cycle.; Other Names: rituxan

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Response	Response was assessed by the investigator on the basis of clinical, radiological, and pathological (i.e., bone marrow) criteria, using the IWG criteria (Cheson et al 2007). A CR is a complete disappearance of all detectable clinical evidence of disease and disease-related symptoms if present before therapy. A PR is at least a 50% decrease in sum of the product of the diameters (SPD) of up to 6 of the largest dominant nodes or nodal masses, no increase should be observed in the size of other nodes, liver or spleen, and no new sites of disease should be observed.	Day 15 and Day 28 of even-numbered cycles

Collaborators and Investigators

• Sponsor: Aptevo Therapeutics
• Investigators: Study Director: Scott Stromatt, MD, Aptevo Therapeutics

Publications and helpful links

General Publications

• Gopal AK, Tarantolo SR, Bellam N, Green DJ, Griffin M, Feldman T, Mato AR, Eisenfeld AJ, Stromatt SC, Goy A. Phase 1b study of otlertuzumab (TRU-016), an anti-CD37 monospecific ADAPTIR therapeutic protein, in combination with rituximab and bendamustine in relapsed indolent lymphoma patients. Invest New Drugs. 2014 Dec;32(6):1213-25. doi: 10.1007/s10637-014-0125-2. Epub 2014 Jun 15.

Study record dates

Study Major Dates

• Study Start: May 1, 2011
• Primary Completion (Actual): April 1, 2013
• Study Completion (Actual): June 1, 2013

Study Registration Dates

• First Submitted: March 15, 2011
• First Submitted That Met QC Criteria: March 16, 2011
• First Posted (Estimate): March 17, 2011

Study Record Updates

• Last Update Posted (Actual): June 28, 2017
• Last Update Submitted That Met QC Criteria: June 26, 2017
• Last Verified: June 1, 2017

More Information

Terms related to this study

• Keywords: follicular lymphoma; non-Hodgkin's lymphoma; marginal zone lymphoma; small lymphocytic lymphoma; indolent lymphoma
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Leukemia, Lymphoid; Leukemia; Leukemia, B-Cell; Lymphoma; Leukemia, Lymphocytic, Chronic, B-Cell; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antirheumatic Agents; Antineoplastic Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Antineoplastic Agents, Immunological; Bendamustine Hydrochloride; Rituximab
• Other Study ID Numbers: 16011

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO