Treatment of Patients With Diffuse Large B Cell Lymphoma Who Are Not Suitable for Anthracycline Containing Chemotherapy

NCT ID: NCT01679119

Last Updated: 2022-05-18

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 129 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-10-31
• Study Completion Date: 2022-03-31

Brief Summary

The purpose of this trial is to compare the efficacy and safety of Inotuzumab Ozogamicin in combination with R-CVP with that of R-G-CVP for the treatment of Diffuse Large B Cell Lymphoma (DLBCL) in a population of patients not suitable for anthracycline based chemotherapy.

There is no standard of care for the treatment of this group of patients. If demonstrated to be efficacious and safe to deliver this regimen will be further tested in a phase III trial to determine whether this should become the standard of care amongst patients with DLBCL not fit for anthracycline (R-CHOP).

Detailed Description

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).

Conditions

Diffuse Large B Cell Lymphoma

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

IO-R-CVP

Inotuzumab Ozogamicin plus Rituximab and CVP (Cyclophosphamide, vincristine \& prednisolone).

Group Type: EXPERIMENTAL

Cyclophosphamide

Intervention Type: DRUG

Cyclophosphamide 750mg/m2 IV, given day 1

Vincristine

Intervention Type: DRUG

Vincristine 1.4mg/m2(max 2mg)IV given day 1

Prednisolone

Intervention Type: DRUG

Prednisolone 100mg OD Oral given days 1-5

Rituximab

Intervention Type: DRUG

Rituximab 375mg/m2 IV given day 1

Inotuzumab Ozogamicin

Intervention Type: DRUG

Inotuzumab Ozogamicin 0.8mg/m2 IV given on day 2

Gem-R-CVP

Gemcitabine plus Rituximab and CVP (Cyclophosphamide, Vincristine and Prednisolone).

Group Type: ACTIVE_COMPARATOR

Cyclophosphamide

Intervention Type: DRUG

Cyclophosphamide 750mg/m2 IV, given day 1

Vincristine

Intervention Type: DRUG

Vincristine 1.4mg/m2(max 2mg)IV given day 1

Prednisolone

Intervention Type: DRUG

Prednisolone 100mg OD Oral given days 1-5

Rituximab

Intervention Type: DRUG

Rituximab 375mg/m2 IV given day 1

Gemcitabine

Intervention Type: DRUG

Gemcitabine up to 1g/m2 IV given day 1 and day 8 (Patients with ECOG PS 0-1: starting dose: 875mg/m2 (1st cycle). If tolerated can be escalated to 1g/m2 in cycle 2 and subsequent cycles. Patients with ECOG PS 2: starting dose 750mg/m2 (1st cycle). If tolerated can be escalated to 875mg/m2 in cycle 2 and then escalated to 1g/m2 in cycle 3 and subsequent cycles.)

Interventions

Cyclophosphamide

Cyclophosphamide 750mg/m2 IV, given day 1

Intervention Type: DRUG

Vincristine

Vincristine 1.4mg/m2(max 2mg)IV given day 1

Intervention Type: DRUG

Prednisolone

Prednisolone 100mg OD Oral given days 1-5

Intervention Type: DRUG

Rituximab

Rituximab 375mg/m2 IV given day 1

Intervention Type: DRUG

Inotuzumab Ozogamicin

Inotuzumab Ozogamicin 0.8mg/m2 IV given on day 2

Intervention Type: DRUG

Gemcitabine

Gemcitabine up to 1g/m2 IV given day 1 and day 8 (Patients with ECOG PS 0-1: starting dose: 875mg/m2 (1st cycle). If tolerated can be escalated to 1g/m2 in cycle 2 and subsequent cycles. Patients with ECOG PS 2: starting dose 750mg/m2 (1st cycle). If tolerated can be escalated to 875mg/m2 in cycle 2 and then escalated to 1g/m2 in cycle 3 and subsequent cycles.)

Intervention Type: DRUG

Other Intervention Names

MabThera

Eligibility Criteria

Inclusion Criteria

• 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 positivity. A concurrent (synchronous) diagnosis of low grade lymphoma (e.g. on bone marrow trephine or presence of both low grade and DLBCL in a lymph node biopsy) or previous diagnosis of low grade lymphoma which hasn't been treated with a systemic therapy is permitted
• Bulky Stage IA (lymph node or lymph node mass ≥ 10cm in maximum diameter), stage IB, stage II, stage III and stage IV disease
• ECOG performance status 0-2
• Measurable disease
• Age 18 ≥ years
• Adequate contraceptive precautions for all patients of childbearing potential
• History of malignant disease diagnosed at any time in the past with completed radical treatment and the risk of relapsing within the next 5 years is <10%. Patients previously treated should be free of sequelae of treatment which would compromise the delivery of study drugs as compared with other eligible patients.
• 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 randomisation 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 randomisation 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 DLBCL
• Life expectancy > 3 months

Exclusion Criteria

• Symptomatic central nervous system or meningeal involvement by DLBCL
• Previous diagnosis of low grade lymphoma which has been treated with a systemic therapy
• Non-bulky stage IA disease
• ECOG performance status 3-4
• History of chronic liver disease or suspected alcohol abuse
• Serum bilirubin greater than upper limit of normal unless attributable to Gilberts syndrome or haemolysis
• Alanine and/or aspartate aminotransferase levels (ALT and/or AST) and alkaline phosphatase (ALP) greater than 2.5 times the upper limit of normal
• Glomerular filtration rate (GFR) < 30ml/min. GFR calculated by Cockroft-Gault (not eGFR).
• Serological evidence of active hepatitis B or C infection whether acute or chronic (defined as positive anti-HCV serology; positive HBsAg). All positive HBcAb results should also be excluded on safety grounds regardless of HBsAg or HBV DNA status. Antibodies to Hepatitis B surface antigen (anti-HBs) due to a history of past vaccination is acceptable
• Known history of HIV seropositive status
• Patients with a history of Venoocclusive Disease (VOD) and Sinusoidal Obstructive Syndrome (SOS)
• Patients with a screening of QTcF interval >470msec
• Medical or psychiatric conditions compromising the patient's ability to give informed consent
• Women who are pregnant or lactating
• LVEF > 50% in the absence of significant co-morbidities that preclude anthracycline use
• Patients with a history of severe allergic/anaphylactic reaction to any humanised monoclonal antibody
• Patients with serious active infection

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Pfizer

INDUSTRY

Sponsor Role: collaborator

Cancer Research UK

OTHER

Sponsor Role: collaborator

University College, London

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Andrew McMillan

Role: PRINCIPAL_INVESTIGATOR

Nottingham University Hospitals NHS Trust

Locations

Stoke Mandeville Hospital (including Wycombe Hospital)

Aylesbury, , United Kingdom

North Hampshire Hospital

Basingstoke, , United Kingdom

Royal United Hospital

Bath, , United Kingdom

Royal Bournemouth Hospital

Bournemouth, , United Kingdom

Bristol Oncology Centre

Bristol, , United Kingdom

West Suffolk Hospital

Bury St Edmunds, , United Kingdom

Kent and Canterbury Hospital

Canterbury, , United Kingdom

Castle Hill Hospital

Cottingham, , United Kingdom

University Hospital, Coventry

Coventry, , United Kingdom

Darent Valley Hospital

Dartford, , United Kingdom

Royal Devon & Exeter Hospital

Exeter, , United Kingdom

Medway Maritime Hospital

Gillingham, , United Kingdom

Beatson West of Scotland Cancer Centre (including Gartnavel Royal Hospital)

Glasgow, , United Kingdom

James Paget University Hospital

Great Yarmouth, , United Kingdom

Northwick Park Hospital

Harrow, , United Kingdom

Kettering General Hospital

Kettering, , United Kingdom

St James's University Hospital

Leeds, , United Kingdom

Leicester Royal Infirmary

Leicester, , United Kingdom

Aintree University Hospital

Liverpool, , United Kingdom

Royal Liverpool University Hospital

Liverpool, , United Kingdom

Guy's Hospital (including St Thomas's Hospital)

London, , United Kingdom

Royal Free Hospital

London, , United Kingdom

University College London Hospital

London, , United Kingdom

Luton and Dunstable Hospital

Luton, , United Kingdom

Christie Hospital

Manchester, , United Kingdom

Freeman Hospital

Newcastle, , United Kingdom

North Tyneside Hosptial (including Wansbeck Hospital and Hexham General Hospital)

North Shields, , United Kingdom

Norfolk and Norwich University Hospital

Norwich, , United Kingdom

Nottingham City Hospital

Nottingham, , United Kingdom

Princess Royal University Hospital

Orpington, , United Kingdom

Churchill Hospital

Oxford, , United Kingdom

Derriford Hospital

Plymouth, , United Kingdom

Queen's Hospital

Romford, , United Kingdom

Southampton General Hospital

Southampton, , United Kingdom

Kings Mill Hospital

Sutton in Ashfield, , United Kingdom

Torbay Hospital

Torquay, , United Kingdom

Royal Cornwall Hospital

Truro, , United Kingdom

Royal Hampshire County Hospital

Winchester, , United Kingdom

Worcester Royal Hospital (including Kidderminster Hospital and Alexandra Hospital)

Worcester, , United Kingdom

Wythenshawe Hospital (including Trafford General Hospital)

Wythenshawe, , United Kingdom

Countries

United Kingdom

Other Identifiers

UCL 11/0475

Identifier Type: -

Identifier Source: org_study_id