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 |
A form of leukaemia in which there are an excess of mature but poorly functioning lymphocyte cells in the blood. |
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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 | 14.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10009310 |
E.1.2 | Term | CLL |
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 |
The aim of this clinical study is to investigate how the drug, called ibrutinib (previously PCI32765), affects the rate of growth, and the lifespan, of leukaemia cells in patients with Chronic Lymphocytic Leukaemia (CLL). The purpose of the trial is to gain a better understanding of how the drug works in order to use it in logical combinations with other drugs that treat CLL which will be tested in future clinical studies. We hope to achieve this by taking frequent blood samples from patient being treated with the drug and analysing them using methods called flow-cytometery and histology. |
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E.2.2 | Secondary objectives of the trial |
The amount of patients should a Complete Remission (CR) Complete Remission with incomplete marrow recovery (Cri) or Partial Remission (PR), to ibrutinib at 6 months, assessed according to the IWCLL Response Criteria The changes in CLL cell protein expression levels. At 6 and 12 months we will also be looking at where and how the drug is acting within the body by measuring the biological response in both the circulating CLL cells blood and in the CLL cells in the bone marrow. We will also study the CLL cells that are responsible for increasing the number of cancer cells. To determine the amount of patients for who their disease has not worsened at 1 and 2 years. To determine the amount of patients alive 1 and 5 years after the start of treatment. To assess the toxicity of the drug over 6 months of treatment.
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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 |
Kinetic Substudy To assess the tumour proliferation rate by measuring the in-vivo incorporation of denueterated glucose in the CLL cells. UK CLL biobank Blood, and salivia collected as part of the ethically approved UK CLL biobank project. A separate consent form will be used for consent to this study. |
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E.3 | Principal inclusion criteria |
Cohort A (Treatment naive) • Progressive Stage A, Stage B or Stage C CLL • CLL requiring therapy by the IWCLL criteria • ECOG performance status (PS) of 0, 1, or 2 • Life expectancy of at least 6 months • Age ≥16 • Age <65 years or ≥65 years with deletion 17p • Prepared to undergo the stipulated investigations within the trial (including bone marrow examinations) • Able to give informed consent
Cohort B (Relapsed/Refractory) • CLL requiring therapy • Refractory CLL defined as any of the following: • Failure to achieve a response (CR or PR by IWCLL Criteria) to a purine analogue alone or in combination with chemotherapy, or: • Relapse within 6 months of responding to a purine analogue alone or in combination with chemotherapy, or: • Relapse within 24 months of responding to a fludarabine, cyclophosphamide and rituximab (FCR), or: • Patients with CLL with deletion of chromosome 17p who have failed at least one previous therapy. • ECOG performance status (PS) of 0, 1, or 2 (see appendix 6) • Life expectancy of at least 6 months • Prepared to undergo the stipulated investigations within the trial (including bone marrow examinations) • Age ≥ 16 • Able to give informed consent
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E.4 | Principal exclusion criteria |
Both cohorts A and B • Unwilling to undergo the protocol assessments including the bone marrow assessments • Active infection • Other severe, concurrent (particularly cardiac or pulmonary) diseases or mental disorders that could interfere with their ability to participate in the study • Use of prior investigational agents within 6 weeks • Pregnancy or lactation • Unwilling to use appropriate contraception during and for 12 months following treatment • CNS involvement with CLL • Mantle cell lymphoma • Known HIV positive • Active or prior Hepatitis B or C • Active secondary malignancy excluding basal cell carcinoma • Persisting severe panocytopenia (nNeutrophils <0.5 x109/L) or transfusion dependent anaemia unless due to direct marrow infiltration by CLL (to be confirmed via bone marrow biopsy) • Active haemolysis (not controlled with Prednisolone at 10 mg or less) • Patients requiring or who have received anticoagulation treatment with warfarin or vitamin K antagonists within 1 week of the first dose of ibrutinib • Patients requiring concomitant use of strong CYP3A4/5 inhibitors • Patients with evidence or history of transformation and/or PLL Cohort A (Treatment naive) • Previous treatment for CLL. This does not include steroids.
Cohort B (Relapsed/Refractory) • Previous treatment with ibrutinib or an alternative inhibitor of B-Cell receptor pathway
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E.5 End points |
E.5.1 | Primary end point(s) |
• Assessment of the proliferating cells in the peripheral blood and bone marrow by flow cytometry and histology
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Baseline, day 1, day 2, week 1, Week 2, 1 month, 2 month, 6 month, 9 months and 12 months. |
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E.5.2 | Secondary end point(s) |
• Disease response, whether complete, CRi or partial, to ibrutinib at 6 months, according to the 2008 IWCLL Criteria • Changes in CLL cell levels and proliferating compartment • Biological response (complete, partial or nodal) at 6 and 12 months, according to the modified IWCLL Criteria. • 1 and 2 year progression free survival for relapsed/refractory and treatment naïve patients • 1 and 5 year overall survival for relapsed/refractory and treatment naïve patients • Toxicity of ibrutinib within 6 months
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
• Disease response IWCLL, at 6 months • Changes in CLL cell levels and proliferating compartment at 6 and 12 months • Biological response, modified IWCLL Criteria, at 6 and 12 months • Progression free survival at 1 and 2 years • Overall survival at 1 and 5 years • Toxicity of ibrutinib within 6 months
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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 | No |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
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 | No |
E.8.1.1 | Randomised | No |
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) | Information not present in EudraCT |
E.8.2.2 | Placebo | Information not present in EudraCT |
E.8.2.3 | Other | Information not present in EudraCT |
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 | 10 |
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
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For the purposes of the MHRA the end of trial will be 6 months after the last patient has completed protocol defined interventional treatment. For the purposes of main REC approval, the trial end date is deemed to be 6 months after last data capture following either death of all of the trial patients or 5 years of follow up from day 1 of trial treatment, whichever occurs latest. The trial office will notify the MHRA and REC when the trial has ended and provide a summary report within 12 months. |
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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 | 6 |
E.8.9.1 | In the Member State concerned months | 5 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 6 |
E.8.9.2 | In all countries concerned by the trial months | 5 |
E.8.9.2 | In all countries concerned by the trial days | 0 |