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A Randomised, Open Label, Multi-centre, Phase III Study to Investigate the Efficacy of Bendamustine Compared to Treatment of Physician's Choice in the Treatment of Subjects With Indolent Non-Hodgkin's Lymphoma (NHL) Refractory to Rituximab

Phase 3
18 Years
Open (Enrolling)
Indolent B-cell NHL

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Trial Information

A Randomised, Open Label, Multi-centre, Phase III Study to Investigate the Efficacy of Bendamustine Compared to Treatment of Physician's Choice in the Treatment of Subjects With Indolent Non-Hodgkin's Lymphoma (NHL) Refractory to Rituximab

To test whether bendamustine will improve progression-free survival in subjects with
indolent B-cell NHL that did not respond (stable disease or progressive disease) to
rituximab or a rituximab-containing regimen during or within 6 months of the last rituximab
treatment compared to treatment of physican's choice.

Inclusion Criteria:

1. Indolent B-cell lymphoma: grades 1-3a follicular, small lymphocytic,
lymphoplasmacytic, and marginal zone lymphoma; stages III-IV, or bulky disease stage
II (i.e. as any single mass > 5 cm in any direction) defined according to WHO
Classification, 2008

2. CT imaging in screening phase (based on local evaluation) showing 2 or more clearly
demarcated lesions with a largest diameter ≥ 1.5 cm, or 1 clearly demarcated lesion
with a largest diameter ≥ 2.0 cm. CT imaging performed at screening will be
considered the baseline image

3. Indolent B-cell NHL that remains stable or unresponsive during or within 6 months of
treatment with rituximab or a rituximab-containing regimen:

- Maintaining stable disease or failure to achieve PR to rituximab-based therapy.
(CT imaging will support this finding, and will be performed at least 30 days
after the last dose of rituximab-based therapy) or,

- Disease progression while on rituximab-based therapy (e.g., includes 4 weekly
courses of rituximab given at 6 week intervals) or,

- Disease progression in subjects with stable disease or better response to
rituximab-based therapy < 6 months of the last dose of rituximab Note: Subjects
must have received at least 4 infusions of rituximab (either as monotherapy or
in combination with any chemotherapy).

4. Screening laboratory values:

- Platelets ≥ 75,000/µL (7 x 109 cells/L)

- Absolute neutrophil count (ANC) ≥ 1,000/µL (1.0 x 109 cells/L)

- ALT, AST and alkaline phosphatase ≤ 2.5 ULN and total bilirubin ≤ 1.5 xULN
(isolated predominantly indirect hyperbilirubinaemia due to Gilbert's syndrome
is acceptable for inclusion)

5. ECOG Performance Status of 0, 1, or 2

6. Age ≥ 18 years

7. Life expectancy of at least 3 months

8. Signed written informed consent prior to performing any study-specific procedures

Main exclusion criteria:

1. Grade 3b follicular lymphoma or evidence that the indolent lymphoma has transformed
to aggressive lymphoma as verified by biopsy confirmation [e.g. constitutional
symptoms, poor performance status, fast growing tumour or increasing lactate
dehydrogenase (LDH) level]

2. Previous allogeneic stem cell transplant

3. Previous external beam radiation therapy to the pelvis. Previous external beam
radiation therapy for bony disease to the cranium, mediastinum, and axilla or to more
than 3 vertebral bodies

4. More than 10 mg prednisolone daily at the time of randomisation

5. Prior bendamustine treatment within 1 year of randomisation not resulting in a CR or
PR for at least 6 months

6. Known CNS involvement of indolent lymphoma

7. Other past or current malignancy. Subjects who have been free of malignancy for at
least 5 years, or have a history of definitively treated non-melanoma skin cancer, or
successfully treated in situ carcinoma, are eligible

8. Chronic or current active infectious disease requiring systemic antibiotics,
antifungal, or antiviral treatment such as, but not limited to, chronic renal
infection, chronic chest infection with bronchiectasis, tuberculosis and active
Hepatitis C

9. Clinically significant cardiac disease including unstable angina, acute myocardial
infarction within 6 months of screening, congestive heart failure, and arrhythmia
requiring therapy, with the exception of extrasystoles or minor conduction
abnormalities. Subjects with well controlled congestive heart failure and atrial
arrhythmias need not be excluded but should be discussed with the study Medical

10. Significant concurrent, uncontrolled medical condition including, but not limited to,
renal, hepatic, haematological, gastrointestinal, endocrine, pulmonary, neurological,
cerebral or psychiatric disease

11. History of significant cerebrovascular disease or event with significant symptoms or

12. Current active liver or biliary disease (with the exception of Gilbert's syndrome or
asymptomatic gallstones, liver metastases or otherwise stable chronic liver disease
per investigator assessment)

13. Jaundice

14. Known HIV, Hepatitis B or Hepatitis C positive

15. Creatinine clearance ≤ 10 mL/min (measured or estimated using Cockcroft and Gault

16. Treatment with any known non-marketed drug substance or experimental therapy within
5-terminal half-lives or 4 weeks prior to screening, whichever is longer or currently
participating in any other interventional clinical study unless the sole purpose of
the study is for collection of survival data

17. Known or suspected inability to comply with study protocol

18. Lactating women, women with a positive pregnancy test at screening or women (of
childbearing potential) as well as men with partners of childbearing potential, who
are not willing to use adequate contraception from study start through last treatment
dose and for 6 months following cessation of treatment. Female contraception must be
individually recommended by an expert. Adequate contraception is defined as
abstinence, oral contraceptive, either combined or progestogen alone, injectable
progestogen, implants of levonorgestrel, estrogenic vaginal ring, percutaneous
contraceptive patches, intrauterine device (IUD) or intrauterine system (IUS), male
partner sterilization (vasectomy with documentation of azoospermia) prior to the
female subject's entry into the study, and this male is the sole partner for that
subject, or double barrier method: condom and an occlusive cap (diaphragm or
cervical/vault caps) with a vaginal spermicidal agent

20.Major surgery less than 30 days prior to start of treatment. 21.Known hypersensitivity
to the active substance or any excipients that cannot be controlled by appropriate

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Progression-free survival

Outcome Description:

Screening of 14 days, prior to ramdomisation. 8 cycles of 21 days, then follow up every 3 months after end of last cycle until disease progression, then every 6 months.

Outcome Time Frame:

8 cycles of 21 days, then follow up every 3 months

Safety Issue:



Spain: Agencia Española de Medicamentos y Productos Sanitarios

Study ID:




Start Date:

February 2011

Completion Date:

July 2015

Related Keywords:

  • Indolent B-cell NHL
  • Indolent B-cell NHL, bendamustine, rituximab, progression-free survival
  • Lymphoma
  • Lymphoma, Non-Hodgkin