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A Randomised Phase II Trial of Inotuzumab Ozogamicin Plus Rituximab & CVP (IO-R-CVP) vs Gemcitabine Plus Rituximab & CVP (Gem-R-CVP) for the First Line Treatment of Patients With DLBCL Who Are Not Suitable for Anthracycline Containing Chemotherapy

Phase 2
18 Years
Not Enrolling
Diffuse Large B Cell Lymphoma

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Trial Information

A Randomised Phase II Trial of Inotuzumab Ozogamicin Plus Rituximab & CVP (IO-R-CVP) vs Gemcitabine Plus Rituximab & CVP (Gem-R-CVP) for the First Line Treatment of Patients With DLBCL Who Are Not Suitable for Anthracycline Containing Chemotherapy

The incidence of DLBCL is increasing and with an expanding elderly population, the incidence
will continue to rise. Given that about 40% of cases of DLBCL occur in patients aged over 70
and the number of co-mobilities increases with age, research to investigate the optimal
treatment of DLBCL in this group of patients is needed. R-CHOP remains the standard of care
for the majority of patients with DLBCL, anthracycline use is precluded in a proportion of
these patients by a high risk of developing cardiotoxicity, especially congestive cardiac
failure. Currently there is no standard of care for patients who are unfit for anthracycline
treatment. It has been routine to omit the doxorubicin from R-CHOP, giving R-CVP instead.
However the outcome for patients treated with R-CVP is poor and attempts have been made to
replace the doxorubicin with alternative agents. The trial will compare an experimental arm
consisting of Inotuzumab Ozogamicin added to the standard immunochemotherapy regimen of
rituximab, cyclophosphamide, vincristine and prednisolone (R-CVP) with the control arm of
gemcitabine added to the same combination (Gem-R-CVP).

Inclusion Criteria

Inclusion criteria for registration:

- Informed written consent for the trial

- Histologically proven diffuse large B cell lymphoma (DLBCL) according to the current
World Health Organisation (WHO) classification including all morphological variants.
The B cell nature of the proliferation must be verified by demonstration of CD20

- Bulky Stage IA (lymph node or lymph node mass ≥ 10cm in maximum diameter), stage IB,
stage II, stage III and stage IV disease

- Measurable disease

- Age 18 ≥ years

- Adequate contraceptive precautions for all patients of childbearing potential

- No active malignant disease other than non-melanotic skin cancer or carcinoma in-situ
of the uterine cervix in the last 5 years

- No previous chemotherapy, radiotherapy or other investigational drug for this
indication - previous corticosteroids up to a dose equivalent to prednisolone
1mg/kg/day for up to 14 days are permitted prior to registration EITHER

- Unsuitable for anthracycline-containing chemotherapy due to impaired cardiac function
defined by an ejection fraction of ≤ 50% OR Left ventricle ejection fraction > 50%
but in the presence of significant co-morbidities (diabetes mellitus, hypertension or
ischaemic heart disease) precluding anthracycline-containing chemotherapy as
determined by treating physician. Co-morbidities must be documented on the
registration form and CIRS score recorded

- Adequate bone marrow function (Platelets > 100x109/l, WBC > 3.0x109/l, Neutrophils >
1.5x109/l) at time of study entry unless attributed to bone marrow infiltration by

- Life expectancy > 3 months

Inclusion Criteria for randomisation:-

- ECOG performance status 0-2 after steroid pre-phase

- Continue to meet all inclusion criteria detailed in inclusion registration section.

Exclusion criteria for registration:

- Symptomatic central nervous system or meningeal involvement by DLBCL

- Previous diagnosis of low grade lymphoma. A concurrent (synchronous) diagnosis of low
grade lymphoma (e.g. on bone marrow trephine) is permitted

- Non-bulky stage IA disease

- History of chronic liver disease or suspected alcohol abuse

- Serum bilirubin greater than upper limit of normal unless attributable to lymphoma or
Gilberts syndrome

- Glomerular filtration rate (GFR) < 30ml/min. GFR calculated by Cockroft-Gault (not

- Positive test results for chronic hepatitis B or C infection (defined as positive
HBsAg/HCsAg and/or HBcAb/HCcAb). Antibodies to Hepatitis B surface antigen (anti-HBs)
due to a history of past vaccination is acceptable

- Known history of HIV seropositive status

- Medical or psychiatric conditions compromising the patient's ability to give informed

- Women who are pregnant or lactating

- LVEF > 50% in the absence of significant co-morbidities that preclude anthracycline

- Patients with a history of severe allergic/anaphylactic reaction to any humanised
monoclonal antibody

- Patients with serious active infection

Exclusion criteria for randomisation:-

- ECOG performance status 3 or 4 after steroid pre-phase

- Meets one or more of the exclusion criteria detailed in exclusion registration

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:

Progression free survival rate and will be analysed using Kaplan-Meier survival analysis. PFS time will be measured from date of randomisation until progression or death.

Outcome Time Frame:

At 2 years following date of randomisation.

Safety Issue:


Principal Investigator

Andrew McMillan

Investigator Role:

Principal Investigator

Investigator Affiliation:

Nottingham University Hospitals NHS Trust


United Kingdom: Medicines and Healthcare Products Regulatory Agency

Study ID:

UCL 11/0475



Start Date:

June 2013

Completion Date:

December 2017

Related Keywords:

  • Diffuse Large B Cell Lymphoma
  • Diffuse large b cell lymphoma
  • Inotuzumab Ozogamicin
  • Gemcitabine
  • Rituximab
  • Cyclophosphamide
  • Vincristine
  • Prednisolone
  • Lymphoma
  • Lymphoma, B-Cell
  • Lymphoma, Large B-Cell, Diffuse