| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Diffuse large B cell lymphoma |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10012818 |
| E.1.2 | Term | Diffuse large B-cell lymphoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To compare the efficacy and safety of adding inotuzumab ozogamicin to R-CVP in the first line treatment of DLBCL in patients who are not able to receive anthracycline containing immunochemotherapy and whether efficacy and safety are sufficient to warrant further investigation. |
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| E.2.2 | Secondary objectives of the trial |
Overall response rate
Overall survival
Treatment toxicity according to CTCAE v4.03
Quality of life - measured by EORTC-QLQ-30 |
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
All patients will be asked to provide blood and tissue samples for translational studies which will investigate the frequency of different sub-groups of DLBCL (ABC vs GCB) and assess the frequency of NFκB mutations in elderly patients. In addition, the frequency and prognostic significance of EBV tumoural status and assess CD22 expression levels in tumour samples by RQ-PCR. A single 7ml EDTA blood sample will be collected for future germline DNA extraction as part of future ethically approved translational studies.
There is also a sub-study looking at a gene called FLT-3. Patients can decline to give these samples and still take part in the trial.
Levels of FLT-3 will be meausured in serial blood samples and may tell us how likely a patient is to develop infections after chemotherapy. Patients will need to provide 4 blood samples in total for this sub-study and every effort will be asked of sites to take the blood samples at the same time the patient's routine blood samples are taken. |
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| E.3 | Principal inclusion criteria |
Inclusion criteria for randomisation:-
a. Informed written consent for the trial
b. 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.
c. Bulky Stage IA (lymph node or lymph node mass ≥10cm in maximum diameter), stage IB, stage II, stage III and stage IV disease
d. ECOG performance status 0-2
e. Measurable disease
f. Age 18 ≥ years
g. Adequate contraceptive precautions for all patients of childbearing potential
h.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. Cases with second malignancy where eligibility is uncertain should be discussed in the first instance with the CTC.
i. 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
j. 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
k. 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
l. Life expectancy >3 months
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|
| E.4 | Principal exclusion criteria |
Exclusion criteria for randomisation:-
a. Symptomatic central nervous system or meningeal involvement by DLBCL
b. Previous diagnosis of low grade lymphoma which has been treated with a systemic therapy
c. Non-bulky stage IA disease
d. ECOG performance status 3-4
e. History of chronic liver disease or suspected alcohol abuse
f. Serum bilirubin greater than upper limit of normal unless attributable to Gilberts syndrome or haemolysis
g. Alanine and/or aspartate aminotransferase levels (ALT and/or AST) and alkaline phosphatase (ALP) greater than 2.5 times the upper limit of normal
h. Glomerular filtration rate (GFR) <30ml/min. GFR calculated by Cockroft-Gault (not eGFR).
i. 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
j. Known history of HIV seropositive status
k. Medical or psychiatric conditions compromising the patient’s ability to give informed consent
l. Women who are pregnant or lactating
m. LVEF >50% in the absence of significant co-morbidities that preclude anthracycline use
n. Patients with a history of severe allergic/anaphylactic reaction to any humanised monoclonal antibody
o. Patients with serious active infection
p. Patients with a history of Venoocclusive Disease (VOD) and Sinusoidal Obstructive Syndrome (SOS)
q. Patients with a screening of QTcF interval >470msec |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoint is 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.
|
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
After 3 cycles, End of all treatment, follow up (year 1: 3 monthly, year 2: 4 monthly, year 3: 6 monthly and annually thereafter).
CT scan to be performed at baseline, after 3 cycles, end of treatment, at 3 month and 1 year follow up visit. |
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| E.5.2 | Secondary end point(s) |
Secondary endpoints are overall response rate, overall survival, treatment toxicity, quality of life and performance status post treatment
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Overall response rate: CT scan to be done at baseline,after 3 cycles,end of treatment and at 3 month and 1 year follow up visit.Clinic visit after 3 cycles,end of treatment and follow up (year 1:3 monthly,year 2:4 monthly,year 3:6 monthly and annually thereafter). Overall survival:Clinic visit after 3 cycles,end of treatment,FU visits as detailed above and long term flagging with NHS. Treatment toxicity:Adverse event assessment at day 1 and day 8 of each cycle and FU visits as detailed above. QoL (EORTC QLQ-C30) and ADL/IADL to be done before randomisation,after 3 cycles, end of treatment and at 6 month and 2 year FU visit.
Performance status: ECOG to be done pre-registration,pre-randomisation,at day 1 and day 8 of each cycle,after 3 cycles,end of treatment and FU visits as detailed above |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 25 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
For regulatory purposes the end of the trial will occur when all patients have completed at least two years of follow-up post-treatment at which point the ‘declaration of end of trial’ form will be submitted to participating regulatory authorities and ethical committees, as required.
Following this, UCL CTC will advise sites on the procedure for closing the trial at the site. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 7 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 2 |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
| E.8.9.2 | In all countries concerned by the trial months | 11 |
| E.8.9.2 | In all countries concerned by the trial days | 2 |
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