| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic Lymphocytic Leukaemia |
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| E.1.1.1 | Medical condition in easily understood language |
| An overproduction of abnormal white blood cells (lymphocytes) in the lymphatic system and bone marrow causing swollen lymph nodes and a decrease in the number of white and red cells and platlets made. |
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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 | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10008993 |
| E.1.2 | Term | Chronic lymphoid leukaemia |
| E.1.2 | System Organ Class | 100000004864 |
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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 assess whether progression free survival (PFS) time (i.e. the length of time during and after medication or treatment during which the disease being treated does not get worse) using ofatumumab plus bendamustine is longer than that using ofatumumab plus chlorambucil.
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| E.2.2 | Secondary objectives of the trial |
To compare between the two treatment groups:
a. Response including MRD negativity
b. Duration of response
c. Overall survival
d. Time to treatment failure
e. Toxicity
f. Treatment dose administered
g. Quality of life
h. Health economic analysis
i. Co-morbidity assessment
j. Frailty assessment
k. Predictive value of biomarkers
In addition, treatment outcome will be analysed across biological subgroups defined by co-morbidity/frailty scores and laboratory biomarkers.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. CLL/Small Lymphocytic Leukamia (SLL) requiring treatment by NCI/IWCLL 2008 criteria. At least one of the following criteria:
a. Evidence of progressive marrow failure as manifested by the development of, or worsening of, anaemia and/or thrombocytopenia.
b. Massive (i.e. 6 cm below the left costal margin) or progressive or symptomatic splenomegaly.
c. Massive (i.e. 10 cm in longest diameter) or progressive or symptomatic lymphadenopathy.
d. Progressive lymphocytosis with an increase of more than 50% over a 2-month period or lymphocyte doubling time (LDT) of less than 6 months from a baseline value of at least 30x10^9/l and not due to causes other than CLL
e. Constitutional symptoms defines as at 10% unintentional weight loss within the previous 6 months; significant fatigue preventing usual activities, or fever of at least 38oc for at least 2 weeks or night sweats for at least one month in the absence of infection
2. No prior cytotoxic or targeted therapy for CLL (prior localised radiotherapy is allowed).
3. Full-dose R-FC considered inappropriate for at least one of the following reasons
a. Age 75 or greater
b. WHO performance status 2 or 3
c. Cardiac impairment (NYHA class II)
d. Respiratory impairment (bronchiectasis or moderate COPD)
e. Renal impairment (estimated Glomerular Filtration Rate (eGFR) 10-30 ml/min)
f. Any other significant co-morbidity or factor that makes R-FC inappropriate
4. Considered able to tolerate Chl at the dose used in the LRF CLL4 trial (10mg/m2 d1-7)
5. Written informed consent
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| E.4 | Principal exclusion criteria |
1. Neutrophil count less than 1.0 x 109/l or platelet count less than 50 x 109/l unless due to CLL
2. Uncontrolled auto-immune haemolytic anaemia or thrombocytopenia
3. Active infection
4. Seropositivity for HIV, HCV or HBV (surface antigen and core antibody)
5. Severe renal impairment (eGFR less than 10ml/min)
6. Serum bilirubin more than 1.5 the upper limit of normal unless due to CLL or Gilbert’s syndrome.
7. Serum ALT or AST more than 2.5 the upper limit of normal unless due to CLL
8. Ongoing alcohol or drug addiction.
9. History of prior allogeneic bone marrow or solid organ transplantation.
10. Concurrent treatment with glucocorticoids equivalent to more than prednisolone 20mg od
11. Prior treatment with monoclonal antibody therapy within the last 3 months
12. Yellow fever vaccination within 4 weeks prior to treatment start
13. Known hypersensitivity to ofatumumab, bendamustine, chlorambucil or any of their excipients
14. CNS involvement with CLL
15. History of Richter transformation
16. Concomitant malignancies within the last 3 years except successfully treated non-melanoma skin cancer or carcinoma in situ
17. Major surgery within 28 days prior to randomisation
18. WHO performance status 4
19. Severe cardiac disease including unstable angina, acute myocardial infarction within six months prior to study entry, congestive heart failure (NYHA III-IV) and arrhythmias (excluding extrasystoles or minor conduction abnormalities) unless controlled by therapy.
20. Any serious underlying medical or psychological conditions, which could impair the ability of the patient to participate in the trial or compromise ability to give informed consent
21. Treatment within a clinical trial within 30 days prior to trial entry.
22. Adult patient under tutelage (not competent to sign informed consent).
23. Pregnant or lactating women.
24. Women of childbearing potential, including women whose last menstrual period was less than one year prior to screening, unable or unwilling to use adequate contraception from study start to one year after the last dose of protocol therapy. Adequate contraception is defined as hormonal birth control, intrauterine device, double barrier method or total abstinence.
25. Male subjects unable or unwilling to use adequate contraception methods from study start to one year after the last dose of protocol therapy.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Progression-free survival (progression or death from any cause). |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
a. Response including Minimum Residual Disease (MRD) negativity
b. Duration of response
c. Overall survival
d. Time to treatment failure
e. Toxicity
f. Treatment dose administered
g. Quality of life
h. Health economic analysis
i. Co-morbidity assessment
j. Frailty assessment
k. Predictive value of biomarkers
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|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
a. Response including Minimum Residual Disease (MRD) negativity - cycles 4,7 & 10; 2 & 6 months post treatment; end of trial
b. Duration of response - cycles 4,7 & 10; 2 & 6 months post treatment; end of trial
c. Overall survival - end of trial
d. Time to treatment failure - cycles 4,7 & 10; 2 & 6 months post treatment; end of trial
e. Toxicity - every visit until 6 months post treatment
f. Treatment dose administered - end of treatment
g. Quality of life - every 3 months until end of trial
h. Health economic analysis - every 3 months until end of trial
i. Co-morbidity assessment - baseline; cycles 4, 7 & 10; 2 months post treatment; disease progression
j. Frailty assessment - baseline
k. Predictive value of biomarkers - baseline; months 6, 12, 18, 24, 30, 36, 42; progression |
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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 | No |
| 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 | Yes |
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| 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 | Yes |
| 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 | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| 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 | 120 |
| 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
|
| The last visit of the last patient will define the end of the trial. This will be followed by the completion of a study report. |
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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 | 8 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | 30 |
| E.8.9.2 | In all countries concerned by the trial years | 8 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 30 |
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