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

Study Overview
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Brief Summary
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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
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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).

Official Title
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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

Conditions
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Diffuse Large B Cell Lymphoma

Intervention / Treatment
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* Drug: Cyclophosphamide
* Drug: Vincristine
* Drug: Prednisolone
* Drug: Rituximab
* Drug: Inotuzumab Ozogamicin
* Drug: Gemcitabine


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: IO-R-CVP<br>Inotuzumab Ozogamicin plus Rituximab and CVP (Cyclophosphamide, vincristine & prednisolone). | Drug: Cyclophosphamide<br>* Cyclophosphamide 750mg/m2 IV, given day 1<br>Drug: Vincristine<br>* Vincristine 1.4mg/m2(max 2mg)IV given day 1<br>Drug: Prednisolone<br>* Prednisolone 100mg OD Oral given days 1-5<br>Drug: Rituximab<br>* Rituximab 375mg/m2 IV given day 1<br>* Other names: MabThera;Drug: Inotuzumab Ozogamicin<br>* Inotuzumab Ozogamicin 0.8mg/m2 IV given on day 2<br>|
| Active Comparator: Gem-R-CVP<br>Gemcitabine plus Rituximab and CVP (Cyclophosphamide, Vincristine and Prednisolone). | Drug: Cyclophosphamide<br>* Cyclophosphamide 750mg/m2 IV, given day 1<br>Drug: Vincristine<br>* Vincristine 1.4mg/m2(max 2mg)IV given day 1<br>Drug: Prednisolone<br>* Prednisolone 100mg OD Oral given days 1-5<br>Drug: Rituximab<br>* Rituximab 375mg/m2 IV given day 1<br>* Other names: MabThera;Drug: Gemcitabine<br>* 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.)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall response rate | At the end of treatment | Approximately 6 months after treatment start | 
| Overall Survival | Date of registration until death. | 5 years from date of registration | 
| Treatment toxicity | During treatment and follow up visits | 7 months from beginning of treatment | 
| 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 | 
| 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 | 
| 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 | 
| 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. | 
| Co-morbidities of patients | Details of co-morbidities to be recorded at point of randomisation by investigator | Baseline | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Gemcitabine, Diffuse large b cell lymphoma, Inotuzumab Ozogamicin, Rituximab, Cyclophosphamide, Vincristine, Prednisolone