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

Diffuse Large B Cell Lymphoma Clinical Trial

— INCA  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01679119
• Other study ID #: UCL 11/0475
• Status: Completed
• Phase: Phase 2
• Start date: October 2013
• Est. completion date: March 2022

Study information

• Verified date: May 2022
• Source: University College, London
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 129
• Est. completion date: March 2022
• Est. primary completion date: March 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Diffuse Large B Cell Lymphoma
• Lymphoma
• Lymphoma, B-Cell
• Lymphoma, Large B-Cell, Diffuse

Intervention

Drug:
• Cyclophosphamide
Cyclophosphamide 750mg/m2 IV, given day 1
• Vincristine
Vincristine 1.4mg/m2(max 2mg)IV given day 1
• Prednisolone
Prednisolone 100mg OD Oral given days 1-5
• Rituximab
Rituximab 375mg/m2 IV given day 1
• Inotuzumab Ozogamicin
Inotuzumab Ozogamicin 0.8mg/m2 IV given on day 2
• 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.)

Locations

Country	Name	City	State
United Kingdom	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

Sponsors (3)

Lead Sponsor	Collaborator
University College, London	Cancer Research UK, Pfizer

Country where clinical trial is conducted

United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Progression free survival	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.	At 2 years following date of randomisation.
Secondary	Overall response rate	At the end of treatment	Approximately 6 months after treatment start
Secondary	Overall Survival	Date of registration until death.	5 years from date of registration
Secondary	Treatment toxicity	During treatment and follow up visits	7 months from beginning of treatment
Secondary	Quality of life of patients during and after treatment	QoL questionnaires (EORTC QLQ-C30; Quality of life of cancer patients; 30 questions) to be completed by patient at time points listed below	Baseline, during treatment and 6 month and 2 year follow up
Secondary	Activities of Daily Living of patients during and after treatment	Activities of Daily Living questionnaire (ADL) to be completed by patient at time points listed below (6 questions about ability to undertake self-care)	Baseline, during treatment and 6 month and 2 year follow up
Secondary	Instrumental Activities of Daily Living of patients during and after treatment	Instrumental Activities of Daily Living questionnaire (IADL) to be completed by patient at time points listed below (8 questions about ability to undertake daily activities/self-care)	Baseline, during treatment and 6 month and 2 year follow up
Secondary	Performance status post treatment	Performance status to be measured by investigator at time points listed below	Baseline, every 21 days for 8 cycles, 5 1/2 months at the end of treatment and then up to 3 years after the end of treatment.
Secondary	Co-morbidities of patients	Details of co-morbidities to be recorded at point of randomisation by investigator	Baseline