Clinical trial NCT01596621: A Study of Bendamustine in the Treatment of Chinese Participants With Indolent Non-Hodgkin Lymphoma Refractory to Rituximab Treatment
Official title: An Open-Label Study to Evaluate Bendamustine Hydrochloride in the Treatment of Chinese Patients With Indolent Non-Hodgkin Lymphoma (NHL) Refractory to Rituximab Treatment
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Non-Hodgkin Lymphoma
Keywords: Bendamustine hydrochloride
CEP-18083
Treanda®
Non-Hodgkin Lymphoma
Lead sponsor: Teva Branded Pharmaceutical Products R&D, Inc.
Sponsor class: INDUSTRY
First posted: 2012-05-11
Enrollment: 102
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The primary objective of the study is to determine the overall response rate (ORR), which includes complete response (CR) and partial response (PR), to bendamustine treatment in participants with indolent non-Hodgkin lymphoma (NHL) that has progressed after rituximab or a rituximab-containing therapy.

Detailed description: This is a multicenter, nonrandomized, open-label, single-agent clinical study conducted in China, and is designed to investigate the use of bendamustine in the treatment of Chinese participants with relapsed, rituximab-refractory indolent NHL. The study consists of a screening period of up to 4 weeks, a treatment period of approximately 24 weeks (up to eight 21-day cycles), and a long-term follow-up period for up to 2 years after the last dose of study drug. Participants are expected to participate in this study for approximately 2.5 years.

Eligibility criteria: Inclusion Criteria:

- The participant has documented relapse from indolent B-cell NHL. Participants with the following subtypes of indolent NHL are eligible for this study: i) small lymphocytic lymphoma (peripheral B cell count \<5000 cells/cubic millimeters \[mm\^3\]) ii) lymphoplasmacytic lymphoma iii) splenic marginal zone B-cell lymphoma (±villous lymphocytes) iv) extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue type v) nodal marginal zone lymphoma (±monocytoid B-cells) vi) follicle center lymphoma vii) follicular (grade 1, 2, or 3a) lymphoma

- The participant has disease documented to have progressed despite rituximab treatment. The participant's disease is considered to be rituximab refractory if any of the following criteria are met at any time during the participant's treatment history (progression must be documented by computed tomography \[CT\] scan or magnetic resonance imaging \[MRI\] or biopsy) or if a participant has palpable lymph nodes that were well documented in size and, after rituximab treatment, palpable disease remains or comes back \[CT, MRI, or biopsy is preferred and performed whenever possible to document progressive disease (PD)\]: i) rituximab-only regimen: Participants who receive a full course of single-agent rituximab (at least 2 doses of 375 mg/m\^2 \[or a therapeutically-active dose\] weekly) and have no response (do not obtain a PR or better) to treatment or progress after a full regimen of rituximab was given.

ii) rituximab maintenance therapy or extended schedule: Participants who have a history of a full course of rituximab (at least 2 doses of 375 mg/m\^2 \[or a therapeutically-active dose\] as a single agent \[weekly\] or in combination with chemotherapy \[day 1 of each of 4 cycles\]) and are on a maintenance regimen, and progress before the next scheduled rituximab dose or after completing a maintenance rituximab regimen.

iii) rituximab-chemotherapy combination regimen: Participants who receive a full course of rituximab (at least 2 doses of 375 mg/m\^2 or a therapeutically-active dose \[on day 1 of each of 2 cycles\]) in combination with chemotherapy and have no response (do not obtain a PR or better) to treatment or progress after the last dose of rituximab in a regimen.

iv) full rituximab exposure treatment: Participants who have a history of a full course of rituximab treatment (at least 2 doses of 375 mg/m\^2 \[or a therapeutically-active dose\] as a single agent or in combination with chemotherapy) and, in a subsequent rituximab/chemotherapy combination regimen, have no response (do not obtain a PR or better) to treatment or progress after the last dose of rituximab in a given regimen, even if the subsequent regimen included less than 2 doses of rituximab. Participants could receive additional systemic treatment after the qualifying rituximab regimen.

* The participant has received treatment with at least 1, but no more than 3, previous chemotherapy regimens. A regimen is defined as a new treatment combination or agent. Retreatment with the identical regimen or agent does not count as a new regimen; however, change from cyclophosphamide, vincristine, and prednisolone (CVP) to cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) is counted as a new regimen. Rituximab, radioimmunotherapy, or other biologic treatments not combined with chemotherapy are not counted as a regimen.
* The participant has a bidimensionally measurable disease with at least 1 lesion measuring 2.0 centimeters (cm) or more in a single dimension. Participants who have previous involved-field irradiation can be included, provided the irradiated area is not the only source of measurable disease.
* The participant has a World Health Organization (WHO) performance status of 0, 1, or 2.
* The participant has absolute neutrophil count (ANC) 1000 cells/mm\^3 or more and platelet count 85000 cells/mm\^3 or more.
* The participant has a creatinine clearance of more than 30 mL/min as determined by the Cockcroft-Gault calculation.
* The participant has adequate hepatic function (no more than 2.5 times the upper limit of normal (ULN) for aspartate aminotransferase (AST) and alanine aminotransferase (ALT), and no more than 1.5 times the upper limit of the normal range (ULN) for total bilirubin). Participants with nonclinically significant elevations of bilirubin due to Gilbert's disease are eligible.
* The participant has had a bone marrow biopsy within 6 weeks before the 1st dose of bendamustine.
* Women of childbearing potential (not surgically sterile or 1 year postmenopausal) must use a medically accepted method of contraception and must agree to continue use of this method starting 2 weeks before the start of study drug treatment, during study drug treatment, and for 3 months after the end of study drug treatment. Acceptable methods of contraception include abstinence, barrier method with spermicide, intrauterine device (IUD), or steroidal contraceptive (oral, transdermal, implanted, and injected) in conjunction with a barrier method.
* Women of childbearing potential must have a negative serum or urine pregnancy test.
* Men not surgically sterile or who are capable of producing offspring must practice abstinence or use a barrier method of birth control, and must agree to continue use of this method starting 2 weeks before the start of study drug treatment, during study drug treatment, and for 3 months after the end of study drug treatment.
* The participant has an estimated life expectancy of at least 3 months.
* The participant (or participant's legal representative) provides written informed consent.

Exclusion Criteria:

* The participant has received previous radiotherapy, radioimmunotherapy, chemotherapy, or immunotherapy within 4 weeks before day 1 of cycle 1 or has failed to recover (to Common Terminology Criteria for Adverse Events \[CTCAE\] toxicity grade 1 or 2) from clinically significant nonhematologic adverse events due to any agents administered previously.
* The participant has received treatment with an investigational agent within 4 weeks of day 1 of cycle 1.
* The participant has received hematopoietic growth factors within 4 weeks of day 1 of cycle 1. However, participants receiving chronic erythropoietin treatment are eligible for inclusion in this study.
* The participant has a history of previous high-dose chemotherapy with allogeneic stem cell support (history of autologous stem cell support is permissible).
* The participant is receiving or has received treatment with therapeutic doses of systemic steroids within 4 weeks of day 1 of cycle 1. (Low doses of chronic steroids \[prednisone or equivalent\] up to 20 mg/day for non-neoplastic disorders or for indications other than lymphoma or lymphoma-related complications are permitted.)
* The participant has transformed disease.
* The participant has any history of central nervous system (CNS) or leptomeningeal lymphoma.
* The participant has, or has had within the past 5 years, an active malignancy other than the target cancer. The exceptions are prostate cancer (Gleason grade \<6 with prostate specific antigen \[PSA\] levels within the normal range), in situ cervical or breast carcinoma, and nonmelanoma skin cancer that have received definitive treatment.
* The participant is a pregnant or lactating woman. (Any women becoming pregnant during the study will be withdrawn from the study immediately.)
* The participant has a serious infection, medical condition, or psychiatric condition that, in the opinion of the investigator, might interfere with the achievement of the study objectives.
* The participant is known to be positive for human immunodeficiency virus (HIV), have active hepatitis B, or active hepatitis C (anti-hepatitis C virus \[HCV\] positive). Hepatitis B surface antigen must be tested. The determination of active disease is left up to the Investigator.
* The participant has a known hypersensitivity to mannitol.
* The participant has used bendamustine previously.

Primary outcomes:
measure: Overall Response Rate (ORR) (Assessed by Independent Review Committee [IRC])
timeFrame: From the date of the first administration of bendamustine to the first documentation of disease progression/relapse, new anticancer therapy, or death (regardless of cause), whichever occurred first (up to 2.5 Years)
Secondary outcomes:
measure: Duration of Response (DOR) (Assessed by IRC)
timeFrame: From the date of first documentation of response to the first documentation of disease progression, new anticancer therapy, or death (regardless of cause), whichever occurred first (up to 2.5 Years)
measure: Progression-Free Survival (Assessed by IRC)
timeFrame: From the date of the first administration of bendamustine to the first documentation of disease progression/relapse, new anticancer therapy, or death (regardless of cause), whichever occurred first (up to 2.5 Years)
measure: Maximum Observed Plasma Concentration (Cmax) of Bendamustine
timeFrame: Prior to the start of infusion on Day 1 for up to 24 hours after the end of infusion during Cycle 1 (each cycle is 21 days)
measure: Time to Reach Cmax (Tmax) of Bendamustine
timeFrame: Prior to the start of infusion on Day 1 for up to 24 hours after the end of infusion during Cycle 1 (each cycle is 21 days)
measure: Area Under the Plasma Concentration Versus Time Curve From Time 0 to the Time of the Last Measurable Drug Concentration (AUC0-t) of Bendamustine
timeFrame: Prior to the start of infusion on Day 1 for up to 24 hours after the end of infusion during Cycle 1 (each cycle is 21 days)
measure: Area Under the Plasma Concentration Versus Time Curve From Time 0 to Infinity (AUC0-∞) of Bendamustine
timeFrame: Prior to the start of infusion on Day 1 for up to 24 hours after the end of infusion during Cycle 1 (each cycle is 21 days)
measure: Rate Constant for Elimination (λz) of Bendamustine
timeFrame: Prior to the start of infusion on Day 1 for up to 24 hours after the end of infusion during Cycle 1 (each cycle is 21 days)
measure: Percentage of the AUC0-∞ Based on Extrapolation (%AUCext)
timeFrame: Prior to the start of infusion on Day 1 for up to 24 hours after the end of infusion during Cycle 1 (each cycle is 21 days)
measure: Half-Life (t½) of Bendamustine
timeFrame: Prior to the start of infusion on Day 1 for up to 24 hours after the end of infusion during Cycle 1 (each cycle is 21 days)
measure: Number of Participants With Adverse Events (AEs)
timeFrame: From first administration of bendamustine through 30 days after the last administration (up to 2.5 Years)
measure: World Health Organization (WHO) Performance Status
timeFrame: At the end of treatment (up to 2.5 years)
measure: Number of Participants Who Need At Least 1 Hematologic Supportive Care (Plasma, Blood Cells, or Cytokines)
timeFrame: From first administration of bendamustine up to the end of treatment (up to 2.5 Years)
measure: Number of Participants With Concomitant Medication Usage
timeFrame: From first administration of bendamustine up to the end of treatment (up to 2.5 Years)
Other outcomes:
Locations:
city: Beijing
country: China
facility: Teva Investigational Site 001
city: Beijing
country: China
facility: Teva Investigational Site 026
city: Beijing
country: China
facility: Teva Investigational Site 022
city: Beijing
country: China
facility: Teva Investigational Site 004
city: Beijing
country: China
facility: Teva Investigational Site 003
city: Beijing
country: China
facility: Teva Investigational Site 002
city: Beijing
country: China
facility: Teva Investigational Site 023
city: Beijing
country: China
facility: Teva Investigational Site 016
city: Beijing
country: China
facility: Teva Investigational Site 021
city: Changchun
country: China
facility: Teva Investigational Site 015
city: Chengdu
country: China
facility: Teva Investigational Site 010
city: Guangzhou
country: China
facility: Teva Investigational Site 008
city: Guangzhou
country: China
facility: Teva Investigational Site 007
city: Hangzhou
country: China
facility: Teva Investigational Site 011
city: Harbin
country: China
facility: Teva Investigational Site 019
city: Hefei
country: China
facility: Teva Investigational Site 025
city: Lanzhou
country: China
facility: Teva Investigational Site 024
city: Nanjing
country: China
facility: Teva Investigational Site 012
city: Nanjing
country: China
facility: Teva Investigational Site 013
city: Shanghai
country: China
facility: Teva Investigational Site 006
city: Shanghai
country: China
facility: Teva Investigational Site 005
city: Shenyang
country: China
facility: Teva Investigational Site 009
city: Shenyang
country: China
facility: Teva Investigational Site 027
city: Suzhou
country: China
facility: Teva Investigational Site 020
city: Tianjin
country: China
facility: Teva Investigational Site 014
city: Xi'an
country: China
facility: Teva Investigational Site 018
city: Zhengzhou
country: China
facility: Teva Investigational Site 017
Study officials:
affiliation: Teva Branded Pharmaceutical Products R&D, Inc.
name: Teva Medical Expert, MD
role: STUDY_DIRECTOR
References:
citation: Shi YK, Hong XN, Yang JL, Xu W, Huang HQ, Xiao XB, Zhu J, Zhou DB, Han XH, Wu JQ, Zhang MZ, Jin J, Ke XY, Li W, Wu DP, Yang SM, Du X, Jia YQ, Liu AC, Liu DH, Shen ZX, Zhang LS, James L, Hellriegel E. Bendamustine treatment of Chinese patients with relapsed indolent non-Hodgkin lymphoma: a multicenter, open-label, single-arm, phase 3 study. Chin Med J (Engl). 2021 May 6;134(11):1299-1309. doi: 10.1097/CM9.0000000000001463.