| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic Lymphocytic Leukaemia (CLL). |
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| E.1.1.1 | Medical condition in easily understood language |
| Chronic Lymphocytic Leukaemia (CLL). |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 17.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10008958 |
| E.1.2 | Term | Chronic lymphocytic leukaemia |
| 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 |
| The principle research question this trial aims to answer is does ibrutinib given in combination with rituximab (IR) improve the length of time that patients are progression free when compared to fludarabine, cyclophosphamide and rituximab (FCR) in patients with previously untreated chronic lymphocytic leukaemia (CLL). |
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| E.2.2 | Secondary objectives of the trial |
To assess and compare for each treatment group:
• Overall survival
• Proportion of participants with undetectable minimal residual disease (MRD) (as defined by IWCLL criteria)
• Response to therapy (as defined by IWCLL criteria)
• Safety and toxicity
• Health related quality of life
• Cost-effectiveness
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
• At least 18 years old.
• Maximum age of 75 years old.
• B-CLL with a characteristic immunophenotype, including small lymphocytic lymphoma
• Binet’s Stages C, B or Progressive Stage A
• Requiring therapy by the IWCLL criteria in that they must have at least one of the following:
1. Evidence of progressive marrow failure as manifested by the development of, or worsening of, anaemia and/or thrombocytopenia.
2. Massive (i.e. 6 cm below the left costal margin) or progressive or symptomatic splenomegaly
3. Massive nodes (i.e. 10 cm in longest diameter) or progressive or symptomatic lymphadenopathy.
4. Progressive lymphocytosis with an increase of more than 50% over a 2-month period or lymphocyte doubling time (LDT) of less than 6 months as long as the lymphocyte count is over 30x109/L
5. A minimum of any one of the following disease-related symptoms must be present:
(a) Unintentional weight loss more than or equal to 10% within the previous 6 months.
(b) Significant fatigue (i.e. Eastern Cooperative Oncology Group PS 2 or worse; cannot work or unable to perform usual activities)
(c) Fevers of greater than 38.0°C for 2 or more weeks without other evidence of infection.
(d) Night sweats for more than 1 month without evidence of infection.
• Considered fit for treatment with FCR as determined by the treating clinician.
• World Health Organisation (WHO) performance status (PS) of 0, 1 or 2
• Able to provide written informed consent
• Biochemical values must be within the following limits within 14 days prior to randomization and at baseline:
- Alanine aminotransferase (ALT) 3 x upper limit of normal (ULN). Aspartate aminotransferase (AST) 3 x ULN.
- Total bilirubin ≤1.5 x ULN, unless bilirubin rise is due to Gilbert’s syndrome or of non hepatic origin
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| E.4 | Principal exclusion criteria |
• Prior therapy for CLL
• History or current evidence of Richter’s transformation
• Major surgery within 4 weeks prior to randomisation
• Active infection.
• >20% P53 deletion, determined by FISH
• Past history of anaphylaxis following exposure to rat or mouse derived CDR-grafted humanised monoclonal antibodies.
• Concomitant warfarin or equivalent vitamin K inhibitor
• Pregnancy, lactation or women of child-bearing potential unwilling to use medically approved contraception whilst receiving treatment and for 12 months after treatment with rituximab has finished, or 30 days after treatment with ibrutinib has finished, whichever is latest. Women must agree to not donate eggs (ova, oocytes) for the purposes of assisted reproduction.
• Men whose partners are capable of having children but who are not willing to use appropriate medically approved contraception whilst receiving treatment and for 12 months after treatment with rituximab has finished, or 3 months after treatment with ibrutinib has finished, whichever is latest, unless they are surgically sterile.
• CNS involvement with CLL.
• Symptomatic cardiac failure not controlled by therapy, or unstable angina not adequately controlled by current therapy (in patients with a significant cardiac history the left ventricular function should be assessed and patients with severe impairment should be excluded)
• Respiratory impairment (bronchiectasis or moderate COPD)
• Other severe, concurrent diseases or mental disorders that could interfere with their ability to participate in the study.
• Inability to swallow oral medication
• Disease significantly affecting gastrointestinal function and/or inhibiting small intestine absorption (malabsorption syndrome, resection of the small bowel, poorly controlled inflammatory bowel disease etc)
• Known HIV positive
• Positive serology for Hepatitis B (HB) defined as a positive test for HBsAg. In addition, if negative for HBsAg but HBcAb positive (regardless of HBsAb status), a HB DNA test will be performed and if positive the subject will be excluded.*
• Positive serology for Hepatitis C (HC) defined as a positive test for HCAb, in which case reflexively perform a HC RIBA immunoblot assay on the same sample to confirm the result.
• History of prior malignancy, with the exception of the following:
- Malignancy treated with curative intent and with no evidence of active disease present for more than 3 years prior to screening and felt to be at low risk for recurrence by treating physician
- Adequately treated non-melanomatous skin cancer or lentigo maligna melanoma without current evidence of disease.
- Adequately treated cervical carcinoma in situ without current evidence of disease.
• Persisting severe pancytopenia (neutrophils <0.5 x 109/l or platelets <50 x 109/l) unless due to direct marrow infiltration by CLL
• Current treatment with prednisolone of >10mg/day.
• Active haemolysis (patients with haemolysis controlled with prednisolone at a dose 10mg or less per day can be entered into the trial)Patients with a creatinine clearance of less than 30ml/min (either measured or derived by the Cockcroft Gault formula or alternative locally approved formula).
• History of stroke or intracranial hemorrhage within 6 months prior to enrollment.
• Requirement for treatment with a strong CYP3A4/5 inhibitor or inducer
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Progression free survival: Time from randomisation to first documented evidence of disease progression (as defined by IWCLL criteria) or death from any cause. Participants who do not progress will be censored at the last date they were known to be alive and progression free. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| An interim analysis will be carried out on the primary endpoint when half the required number of events have been observed (191) in the FCR and IR arms combined (likely to be after the trial has closed to recruitment). Final analysis on both primary and secondary endpoints will be performed when at least 382 events are observed and there is sufficient follow-up data. This will be approximately 4 years after the trial closes to recruitment. Survival analyses will also be updated as appropriate. |
|
| E.5.2 | Secondary end point(s) |
1. Overall survival: Time from randomisation to date of death from any cause. Participants not known to have died will be censored at the date they were last known to be alive.
2. Minimal residual disease: A negative MRD is defined as the presence of <0.01% CLL cells in the bone marrow. MRD will be assessed for negativity at 3 months post-therapy, 12 months post-randomisation and then at each follow-up visit where MRD is assessed (annually for the FCR arm and 6 monthly for the IR arm from 12 months post-randomisation).
3. Response: Response criteria are defined by the standard IWCLL criteria. Response to therapy will be assessed at 3 months post-therapy with FCR or R and then again for participants randomised to IR at the end of therapy with ibrutinib.
4. Safety and toxicity: Reported based on adverse events, as graded by CTCAE V4.03 , and determined by routine clinical assessments at each centre.
5. Quality of life: The EORTC QLQC30 and EORTC QLQCLL16 will be used to measure participant assessed QoL prior to randomisation, at the end of treatment with FCR and R, and then at 6 monthly visits.
6. Cost-effectiveness: The SF12 and EQ5D will be used to produce quality adjusted life years (QALYs). NHS resource use and participants’ out of pocket expenses will be collected via the Case Record Forms, as well as health economics patient questionnaires. These will be collected prior to randomisation, at the end of treatment with FCR and R, and then at 6 monthly visits.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Overall survival: Time from randomisation to date of death.
2. Minimal residual disease: Assessed for negativity at 3 months post-therapy, 12 months post-randomisation and then at each follow-up visit where MRD is assessed (annually for the FCR arm and 6 monthly for the IR arm from 12 months post-randomisation).
3. Response: Assessed 3 months post-therapy with FCR or R and then again at the end of therapy with ibrutinib.
4. Safety and toxicity: Reported on an ongoing basis and based on adverse events as determined by routine clinical assessments at each centre.
5. Quality of life: Prior to randomisation, at the end of treatment with FCR and R, and then at approximately 6 monthly intervals.
6. Cost-effectiveness: Prior to randomisation and then at 6 monthly intervals.
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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 | 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 | Yes |
| 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 | 70 |
| 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 | No |
| 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 date of the collection of the last participant's last data item. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 10 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 30 |
| E.8.9.2 | In all countries concerned by the trial years | 10 |
| 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 | 29 |
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