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

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).

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

• Experimental: IO-R-CVP
  Inotuzumab Ozogamicin plus Rituximab and CVP (Cyclophosphamide, vincristine & prednisolone).
  Interventions:

  • Drug: Cyclophosphamide
  • Drug: Vincristine
  • Drug: Prednisolone
  • Drug: Rituximab
  • Drug: Inotuzumab Ozogamicin
• Active Comparator: Gem-R-CVP
  Gemcitabine plus Rituximab and CVP (Cyclophosphamide, Vincristine and Prednisolone).
  Interventions:

  • Drug: Cyclophosphamide
  • Drug: Vincristine
  • Drug: Prednisolone
  • Drug: Rituximab
  • Drug: Gemcitabine

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

• Pfizer
• Cancer Research UK