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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT01073163




Registration number
NCT01073163
Ethics application status
Date submitted
19/02/2010
Date registered
23/02/2010
Date last updated
24/04/2014

Titles & IDs
Public title
Study to Assess the Effect of Treatment With Bendamustine in Combination With Rituximab on QT Interval in Patients With Advanced Indolent Non-Hodgkin's Lymphoma (NHL) or Mantle Cell Lymphoma (MCL)
Scientific title
A Study to Assess the Effect of Treatment With Bendamustine in Combination With Rituximab on QT Interval in Patients With Advanced Indolent Non-Hodgkin's Lymphoma (NHL) or Mantle Cell Lymphoma (MCL)
Secondary ID [1] 0 0
C18083/3070
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Non-Hodgkin's Lymphoma 0 0
Mantle Cell Lymphoma 0 0
Condition category
Condition code
Cancer 0 0 0 0
Lymphoma (non Hodgkin's lymphoma) - High grade lymphoma
Cancer 0 0 0 0
Lymphoma (non Hodgkin's lymphoma) - Low grade lymphoma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Bendamustine
Treatment: Drugs - Rituximab

Experimental: Bendamustine with Rituximab - Participants were administered bendamustine intravenous (IV) infusion at 90 mg/m^2 on Days 1 and 2 of each 28-day cycle, and rituximab IV infusion at 375 mg/m^2 on Day 1 of each 28-day cycle.


Treatment: Drugs: Bendamustine
Bendamustine at 90 mg/m^2 IV on Days 1 and 2 of a 28-day cycle.

Treatment: Drugs: Rituximab
Rituximab at 375 mg/m^2 IV on Day 1 of a 28-day cycle.

Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Mean Change From Baseline in QT Interval as Corrected by the Fridericia Method (QTcF) at End of Infusion - On Day 2 of Cycle 1, three electrocardiograms (ECGs) were collected 15 minutes prior to any study drug administration. The baseline ECG interval value was obtained by averaging these 3 ECGs, and was compared to the average of the 3 ECGs taken on treatment with bendamustine at the end of the infusion.
Timepoint [1] 0 0
Baseline ECGs (Day 2 of Cycle 1): 15 minutes prior to bendamustine infusion. Postinfusion ECGs (Day 2 of Cycle 1): at the end of the 30-minute infusion.
Secondary outcome [1] 0 0
Mean Change From Baseline in QTcF at 1 Hour Postinfusion - On Day 2 of Cycle 1, three ECGs were collected 15 minutes prior to any study drug administration. The baseline ECG interval value was obtained by averaging these 3 ECGs, and was compared to the average of the 3 ECGs taken on treatment with bendamustine 1 hour postinfusion.
Timepoint [1] 0 0
Baseline ECGs (Day 2 of Cycle 1): 15 minutes prior to bendamustine infusion. Postinfusion ECGs (Day 2 of Cycle 1): 1 hour postinfusion.
Secondary outcome [2] 0 0
Number of Participants With QTcF New Outlier Events at End of Infusion and 1 Hour Postinfusion - Participants were considered to have an outlier ECG value based on the most extreme value across each of the time points. "New" means not present at baseline and becomes present on at least 1 on-treatment ECG time point. A participant had a new outlier event (500) if the maximum QTcF was >500 ms while their baseline was <=500 ms, or had an outlier event (480) if the maximum QTcF was >480 ms while their baseline was <= 480 ms. QTcF in the 30-60 ms or >60 ms categories were also considered outliers.
Timepoint [2] 0 0
Baseline ECGs (Day 2 of Cycle 1): 15 minutes prior to bendamustine infusion. Postinfusion ECGs (Day 2 of Cycle 1): at the end of the 30-minute infusion and 1 hour postinfusion.
Secondary outcome [3] 0 0
Number of Participants With New Onset ECG Waveform Morphological Changes - The core ECG laboratory cardiologist assessed all leads in the ECGs and defined morphological changes. Changes from baseline (looking at each of the 3 ECGs at Day 2 Cycle 1 individually and the ECGs at all on-treatment time points individually) were noted for the following events: atrial fibrillation or flutter; second degree heart block; third degree heart block; complete right bundle branch block; complete left bundle branch block; ST segment depression; T wave abnormalities (negative T waves only); myocardial infarction pattern; any new abnormal U waves.
Timepoint [3] 0 0
Baseline ECGs (Day 2 of Cycle 1): 15 minutes prior to bendamustine infusion. Postinfusion ECGs (Day 2 of Cycle 1): at the end of the 30-minute infusion and 1 hour postinfusion.
Secondary outcome [4] 0 0
Number of Participants With Treatment-Emergent Cardiac Disorders - Number of participants with cardiac disorders overall, with severity from grades 1 (mild) to grade 4 (severe), according to the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 (grade 1=mild, grade 2=moderate, grade 3=severe, grade 4=life-threatening, grade 5= death). Participants may have reported more than 1 event.
Timepoint [4] 0 0
Adverse events were collected throughout the study and up to 30 days after the last dose of study drug. The median number of 28-day cycles was 6.0. The median duration of the treatment period was 143 days.
Secondary outcome [5] 0 0
Change From Baseline in QTcF at Maximum Concentration (Cmax) of Bendamustine and Its Metabolites (M3 and M4) - Results from a pharmacokinetic-pharmacodynamic model to show the relationship of the overall predicted change from Baseline in QTcF at the average Cmax of bendamustine and its metabolites M3 and M4.
Timepoint [5] 0 0
Baseline ECGs (Day 2 of Cycle 1): 15 minutes prior to bendamustine infusion. Postinfusion ECGs (Day 2 of Cycle 1): at the end of the 30-minute infusion and 1 hour postinfusion.
Secondary outcome [6] 0 0
Model-predicted Bayesian Bendamustine Clearance in the Presence of Rituximab - Boxplots of model-predicted Bayesian bendamustine clearance (CL) values in the presence of rituximab were generated based on the administered bendamustine doses, rate of infusion, and sample times.
Timepoint [6] 0 0
Day 1 of Cycle 1: prior to start of bendamustine infusion, immediately postinfusion, 15 minutes and 30 minutes postinfusion. Day 2 of Cycle 1: 15 minutes prior to start of bendamustine infusion, 15 minutes, 30 minutes, 1, 3, and 5 hours postinfusion.
Secondary outcome [7] 0 0
Rituximab Concentrations at 0.5 Hours, 24 Hours, and 7 Days Postinfusion
Timepoint [7] 0 0
Day 1 of Cycle 1: prior to start of rituximab infusion, immediately postinfusion. Day 2 of Cycle 1: 15 minutes prior to the start of the bendamustine infusion. Day 7 and Day 14: anytime. Day 1 of Cycle 2: prior to start of rituximab infusion.
Secondary outcome [8] 0 0
Percentage of Participants With Complete Response (CR) - Complete response, as defined by the International Working Group (IWG) Revised Response Criteria For Malignant Lymphoma. Results are presented for participants with non-Hodgkin lymphoma and mantle cell lymphoma as well as all participants.
Timepoint [8] 0 0
The median number of 28-day cycles was 6.0. The median duration of the treatment period was 143 days.
Secondary outcome [9] 0 0
Percentage of Participants With Overall Response - Overall Response was comprised of those participants who had Complete Response (CR) plus those who had Partial Response (PR), as defined by the International Working Group (IWG) Revised Response Criteria For Malignant Lymphoma. Results are presented for participants with non-Hodgkin lymphoma and mantle cell lymphoma as well as all participants.
Timepoint [9] 0 0
The median number of 28-day cycles was 6.0. The median duration of the treatment period was 143 days.
Secondary outcome [10] 0 0
Overview of Adverse Events - Adverse event (AE)=any untoward medical occurrence in a patient administered study drug that develops or worsens in severity during the conduct of a clinical study of a pharmaceutical product and does not necessarily have a causal relationship to the study drug. Treatment-related AEs=those that began or worsened after treatment with study drug. AE severity was graded according to the National Cancer Institute's Common Terminology Criteria for AEs (grade 1=mild, grade 2=moderate, grade 3=severe, grade 4=life-threatening, grade 5= death). Relationship of an AE to study drug was categorized as definite, probable, possible, unlikely, or not related. Serious AE (SAE)=one that occurred at any dose that resulted in any of the following outcomes or actions: death; a life-threatening adverse event; inpatient hospitalization or prolongation of existing hospitalization; a persistent or significant disability/incapacity; a congenital anomaly/birth defect; or an otherwise important medical event.
Timepoint [10] 0 0
Adverse events were collected throughout the study and up to 30 days after the last dose of study drug. The median number of 28-day cycles was 6.0. The median duration of the treatment period was 143 days.
Secondary outcome [11] 0 0
Eastern Cooperative Oncology Group (ECOG) Performance Status at Endpoint - The investigator assessed each patient's ECOG performance status according to the ECOG scale at screening, on Day 1 of each treatment cycle, and at the end-of-treatment visit. Scale scores were: 0=fully active, able to carry on all pre-disease performance without restriction; 1=restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature; 2=ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours; 3=capable of only limited self-care, confined to bed or chair more than 50% of waking hours; 4=completely disabled. Cannot carry on any self-care. Totally confined to bed or chair; 5=dead. Any change in score to a higher value signifies worsening, and any change to a lower value signifies improvement.
Timepoint [11] 0 0
End of study. The median number of 28-day cycles was 6.0. The median duration of the treatment period was 143 days.
Secondary outcome [12] 0 0
Worst Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 Grades for Hematology Laboratory Tests Results Overall - Grade 1=Mild, 2=Moderate, 3=Severe/medically significant, 4=Life-threatening. Overall is defined as the worst postbaseline grade value for each patient and laboratory test across all cycles. Only postbaseline grades are summarized. If absolute neutrophil count (ANC) and neutrophils absolute (ABS) were both measured, the worse grade value from the two was summarized. Otherwise the worst ANC grade value or the worst neutrophils ABS grade value was summarized. WBC=white blood cell; LLN=lower limit of normal
Timepoint [12] 0 0
Adverse events were collected throughout the study and up to 30 days after the last dose of study drug. The median number of 28-day cycles was 6.0. The median duration of the treatment period was 143 days.

Eligibility
Key inclusion criteria
Key

- Histopathologic confirmation of one of the following CD20+ B-cell non-Hodgkin's
lymphomas. Tissue diagnostic procedures must be performed within 6 months of study
entry and with biopsy material available for review:

- follicular lymphoma (grade 1 or 2)

- immunoplasmacytoma/immunocytoma (Waldenstrom's macroglobulinemia)

- splenic marginal zone B-cell lymphoma

- extra-nodal marginal zone lymphoma of mucosa associated lymphoid tumor (MALT)
type

- nodal marginal zone B-cell lymphoma

- mantle cell lymphoma

- Meets one of the following need-for-treatment criteria (with the exception of mantle
cell lymphoma for which treatment is indicated):

- presence of at least one of the following B-symptoms:

1. fever (>38ºC) of unclear etiology

2. night sweats

3. weight loss of greater than 10% within the prior 6 months

- large tumor mass (bulky disease)

- presence of lymphoma-related complications, including narrowing of ureters or
bile ducts, tumor-related compression of a vital organ, lymphoma induced pain,
cytopenias related to lymphoma/leukemia, splenomegaly, pleural effusions, or
ascites

- hyperviscosity syndrome due to monoclonal gammopathy

- CD20-positive B cells in lymph node biopsy or other lymphoma pathology specimen

- No prior treatment. Patients on "watch and wait" may enter the study if a recent
biopsy (obtained within the last 6 months) is available.

- Adequate hematologic function (unless abnormalities related to lymphoma infiltration
of the bone marrow or hypersplenism due to lymphoma) as follows:

- hemoglobin of >= 10.0 g/dL

- absolute neutrophil count (ANC) >=1.5*10^9/L

- platelet count >=100*10^9/L

- Bidimensionally measurable disease (field not previously radiated)

- Able to provide written informed consent

- Eastern Cooperative Oncology Group (ECOG) performance status <=2

- Estimated life expectancy >=6 months

- Serum creatinine of <=2.0 mg/dL or creatinine clearance >=50 mL/min

- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =2.5* upper limit
of normal (ULN), and alkaline phosphatase and total bilirubin within normal limits

- Left ventricular ejection fraction (LVEF) >=50% by multiple gated acquisition scan
(MUGA) or cardiac echocardiogram (ECHO), prior for any patient to be treated with
rituximab/cyclophosphamide/doxorubicin/vincristine/prednisolone (R-CHOP)

- A medically accepted method of contraception to be used by women of childbearing
potential (not surgically sterile or at least 12 months naturally postmenopausal)

- Men capable of producing offspring and not surgically sterile must practice abstinence
or use a barrier method of birth control

Key
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- Chronic lymphocytic leukemia, small lymphocytic lymphoma (SLL), or grade 3 follicular
lymphoma

- Transformed disease. Bone marrow blasts are permitted, however, transformed disease
indicating leukemic involvement is not permitted

- Central nervous system (CNS) lymphomatous involvement or leptomeningeal lymphoma

- Prior radiation for non-Hodgkin's lymphoma (NHL), except for a single course of
locally delimited radiation therapy with a radiation field not exceeding 2 adjacent
lymph node regions

- Active malignancy, other than NHL, within the past 3 years except for localized
prostate cancer treated with hormone therapy, cervical carcinoma in situ, breast
cancer in situ, or non-melanoma skin cancer following definitive treatment

- New York Heart Association (NYHA) Class III or IV heart failure, arrhythmias or
unstable angina, electrocardiographic evidence of active ischemia or active conduction
system abnormalities, or myocardial infarction within the last 6 months. (Prior to
study entry, ECG abnormalities at screening must be documented by the investigator as
not medically relevant)

- Known human immunodeficiency virus (HIV) positivity

- Active hepatitis B or hepatitis C infection (Hepatitis B surface antigen testing
required)

- Women who are pregnant or lactating

- Corticosteroids for treatment of lymphoma within 28 days of study entry. Chronically
administered low-dose corticosteroids (e.g., prednisone =20 mg/day) for indications
other than lymphoma or lymphoma-related complications are permitted

- Any serious uncontrolled, medical or psychological disorder that would impair the
ability of the patient to receive therapy

- Any condition which places the patient at unacceptable risk or confounds the ability
of the investigators to interpret study data

- Any other investigational agent within 28 days of study entry

- Known hypersensitivity to bendamustine, mannitol, or other study-related drugs

- The patient has Ann Arbor stage I disease

- The patient has a history of congenital long QT syndrome

- The patient has a history of cardiac disease with significant potential for QT
prolongation

- The patient has screening electrocardiography (ECG) on Day 1 of Cycle 1 with QTcF
interval >450 ms that is confirmed by a second ECG. If the QTcF interval is >450 ms on
both ECGs, the ECGs will be sent to eResearch Technology, Inc. (ERT), the Central ECG
Reader vendor, for an overread (with 24-hour turn around time) and ERT will make a
final decision on enrollment

- The patient has serum potassium or magnesium less than the lower limit of normal

Study design
Purpose of the study
Treatment
Allocation to intervention
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 3
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
ACT,SA,TAS,VIC
Recruitment hospital [1] 0 0
The Canberra Hospital - Garran
Recruitment hospital [2] 0 0
Royal Adelaide Hospital - Adelaide
Recruitment hospital [3] 0 0
The Queen Elizabeth Hospital - Woodville
Recruitment hospital [4] 0 0
Royal Hobart Hospital - Hobart
Recruitment hospital [5] 0 0
The Alfred Hospital - Melbourne
Recruitment postcode(s) [1] 0 0
- Garran
Recruitment postcode(s) [2] 0 0
- Adelaide
Recruitment postcode(s) [3] 0 0
- Woodville
Recruitment postcode(s) [4] 0 0
- Hobart
Recruitment postcode(s) [5] 0 0
- Melbourne
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Arizona
Country [2] 0 0
United States of America
State/province [2] 0 0
Arkansas
Country [3] 0 0
United States of America
State/province [3] 0 0
California
Country [4] 0 0
United States of America
State/province [4] 0 0
Colorado
Country [5] 0 0
United States of America
State/province [5] 0 0
Connecticut
Country [6] 0 0
United States of America
State/province [6] 0 0
Florida
Country [7] 0 0
United States of America
State/province [7] 0 0
Georgia
Country [8] 0 0
United States of America
State/province [8] 0 0
Indiana
Country [9] 0 0
United States of America
State/province [9] 0 0
Iowa
Country [10] 0 0
United States of America
State/province [10] 0 0
Kansas
Country [11] 0 0
United States of America
State/province [11] 0 0
Kentucky
Country [12] 0 0
United States of America
State/province [12] 0 0
Louisiana
Country [13] 0 0
United States of America
State/province [13] 0 0
Maine
Country [14] 0 0
United States of America
State/province [14] 0 0
Missouri
Country [15] 0 0
United States of America
State/province [15] 0 0
New Mexico
Country [16] 0 0
United States of America
State/province [16] 0 0
New York
Country [17] 0 0
United States of America
State/province [17] 0 0
Oregon
Country [18] 0 0
United States of America
State/province [18] 0 0
Pennsylvania
Country [19] 0 0
United States of America
State/province [19] 0 0
South Carolina
Country [20] 0 0
United States of America
State/province [20] 0 0
Tennessee
Country [21] 0 0
United States of America
State/province [21] 0 0
Texas
Country [22] 0 0
United States of America
State/province [22] 0 0
Virginia
Country [23] 0 0
United States of America
State/province [23] 0 0
Washington
Country [24] 0 0
United States of America
State/province [24] 0 0
West Virginia
Country [25] 0 0
Canada
State/province [25] 0 0
Nova Scotia
Country [26] 0 0
Canada
State/province [26] 0 0
Ontario

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
Cephalon
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
The primary objective of this study is to assess the effect of treatment with bendamustine on
cardiac repolarization as reflected by the rate-corrected QT interval by the Fridericia
method (QTcF).
Trial website
https://clinicaltrials.gov/show/NCT01073163
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Sponsor's Medical Expert
Address 0 0
Cephalon
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

Summary results
Other publications