IciCLLe: Assessment of the Mechanism of Action of Ibrutinib (PCI-32765) in B-cell Receptor Pathway Inhibition in CLL

ISRCTN	ISRCTN12695354
DOI	https://doi.org/10.1186/ISRCTN12695354
ClinicalTrials.gov (NCT)	Nil known
Clinical Trials Information System (CTIS)	2012-003608-11
Integrated Research Application System (IRAS)	136775
Protocol serial number	15429
Sponsor	University of Birmingham (UK)
Funders	Blood Cancer UK, Pharmacyclics, F. Hoffmann-La Roche

Submission date: 03/04/2014
Registration date: 03/04/2014
Last edited: 24/04/2023

Recruitment status: No longer recruiting
Overall study status: Completed
Condition category: Cancer

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Plain English summary of protocol

http://www.cancerresearchuk.org/cancer-help/trials/a-study-looking-ibrutinib-chronic-lymphocytic-leukaemia-iciclle

Contact information

Dr Francesca Yates
Scientific

Haematology Team
Cancer Research UK Clinical Trials Unit
University of Birmingham
Birmingham
B15 2TT
United Kingdom

Phone	+44 (0)121 371 7867
Email	IcICLLe@trials.bham.ac.uk

Study information

Primary study design	Interventional
Study design	Non-randomised; Interventional; Design type: Treatment
Secondary study design	Non randomised study
Scientific title	IciCLLe: Assessment of the Mechanism of Action of Ibrutinib (PCI-32765) in B-cell Receptor Pathway Inhibition in CLL
Study acronym	IciCLLe
Study objectives	Current hypothesis as of 24/04/2023: The aim of this feasibility study is to confirm the mechanism of action of ibrutinib. Results will then inform the design of a randomized phase II/III trial using response as the primary outcome measure to determine whether ibrutinib shows sufficient evidence of activity in these cohorts of patients. In October 2015 the Extension Study was added to the IcICLLe protocol. The IcICLLe extension study will test the safety and efficacy of ibrutinib combined with obinutuzumab in CLL. A major aim of treatment in CLL is to eradicate detectable minimal residual disease (MRD). Ibrutinib is a major step forward in the treatment of CLL but results in an immediate lymphocytosis that persists in most patients for at least several months. However the combination of ibrutinib with rituximab, a relatively ineffective monotherapy in CLL, seems to abrogate the lymphocytosis. Obinutuzumab is a second-generation anti-CD20 monoclonal antibody that appears to be highly effective in CLL resulting in a rapid eradication of peripheral blood lymphocytosis and the eradication of MRD in a proportion of patients. Currently we only have data in untreated CLL for obinutuzumab vs. rituximab. Therefore the combination of obinutuzumab with ibrutinib is likely to be extremely effective. It may also inform possible future Phase III trials to test a more effective anti-CD20 antibody in combination with ibrutinib. IcICLLe Extension Study Up to 20 relapsed/refractory patients originally recruited to the IcICLLe study will transition to the extension study (cohort (B) iii). At least 20 relapsed/refractory CLL patients not previously treated in the IcICLLe study (i.e., ibrutinib naïve, cohort (B) ii) will be recruited so that the total sample size in the extension study is no more than 40 patients. _____ Previous hypothesis: The aim of this feasibility study is to confirm the mechanism of action of Ibrutinib. Results will then inform the design of a randomized phase II/III trial using response as the primary outcome measure to determine whether Ibrutinib shows sufficient evidence of activity in these cohorts of patients.
Ethics approval(s)	14/YH/0034; First MREC approval date 20/02/2014
Health condition(s) or problem(s) studied	Topic: Cancer; Subtopic: Haematological Oncology; Disease: Leukaemia (chronic)
Intervention	Current intervention as of 24/04/2023: Main study: Ibrutinib 420 mg (3 x 140-mg capsules) taken orally once daily continuously until disease progression Extension study: Ibrutinib 420 mg (3 x 140-mg capsules) taken orally once daily continuously. Obinutuzumab 1000 mg (6 cycles, cycle 1 consisting of three doses over first 15 days of cycle 1, cycles 2-6 one dose every 28 days) by intravenous infusion. _____ Previous intervention: Ibrutinib, B-Cell receptor pathway inhibitor; Follow Up Length: 60 month(s); Study Entry : Registration only
Intervention type	Drug
Phase	Phase II
Drug / device / biological / vaccine name(s)	Ibrutinib, obinutuzumab
Primary outcome measure(s)	Current primary outcome measure as of 24/04/2023: For main trial and extension: Proportion of patients achieving MRD-negative remission by IWCLL criteria (depletion of CLL below 0.01% in the peripheral blood and bone marrow) in a) the initial phase of the study at or before the 6-month assessment and b) the Extension Study at or before the 9-month assessment. Independent decisions will be made for each study (initial and extension). _____ Previous primary outcome measure: Assess the impact on Ibrutinib on: o CLL cell levels as a percentage of total leucocytes in the b; Timepoint(s): Baseline, Day1, Week 1, Week 2, month 1, Month 2, Month 6, month 9, Month 12.
Key secondary outcome measure(s)	Current secondary outcome measures as of 24/04/2023: Main trial: 1. Best disease response to treatment: Complete Remission (CR); Complete Remission with incomplete marrow recovery (Cri) or Partial Remission (PR) with leucocytosis, assessed according to the IWCLL Response Criteria (revised 2008) (Appendix 1) at or before the 6-month assessment. Independent decisions will be made for each study (initial and extension 1 and 2 year progression free survival for relapsed/refractory and treatment naïve patients defined as time from date of registration to date of progression (per the 2008 IWCLL criteria) or death from any cause. 2. Overall survival for relapsed/refractory and treatment naïve patients, defined as the time from date of registration to the date of death from any cause, at 2 years and 5 years 3. Toxicity of ibrutinib assessed throughout the trial 4. CLL cell levels as a percentage of total leucocytes in the bone marrow (BM) assessed using flow cytometry in months 1 and 6. 5. CLL cell levels as absolute counts in the peripheral blood (PB) assessed using flow cytometry frequently in the first month, 3-monthly to month 12 then 6-monthly. 6. The proportion of patients with >5%, 0.5-5%, <0.5% CLL cells in cell cycle (expressing Ki67) in the peripheral blood and bone marrow at or before the 6-month assessment 7. Change in the expression levels of CD10, CD103, CD11c, CD185, CD196, CD20, CD200, CD22, CD23, CD25, CD27, CD305, CD31, CD38, CD39, CD43, CD49d, CD5, CD79b, CD81, CD95, IgD, IgG, or IgM on CLL cells relative to baseline by more than 50% and at least 500 arbitrary units in median fluorescence intensity monitored throughout the study Extension: 1. Best disease response to treatment: Complete Remission (CR); Complete Remission with incomplete marrow recovery (Cri) or Partial Remission (PR) with leucocytosis, assessed according to the IWCLL Response Criteria (revised 2008) (Appendix 1) at or before the 9-month assessment. Independent decisions will be made for each study (initial and extension 1 and 2 year progression-free survival for relapsed/refractory and treatment naïve patients defined as time from date of registration to date of progression (per the 2008 IWCLL criteria) or death from any cause. 2. Overall survival for relapsed/refractory and treatment naïve patients, defined as the time from date of registration to the date of death from any cause, at 2 years and 5 years 3. Toxicity of ibrutinib and obinutuzumab assessed throughout the trial 4. CLL cell levels as a percentage of total leucocytes in the bone marrow (BM) assessed using flow cytometry in months 1 and 9. 5. CLL cell levels as absolute counts in the peripheral blood (PB) assessed using flow cytometry frequently in the first month, 3-monthly to month 12 then 6-monthly. 6. The proportion of patients with >5%, 0.5-5%, <0.5% CLL cells in cell cycle (expressing Ki67) in the peripheral blood and bone marrow at or before the 9-month assessment 7. Change in the expression levels of CD10, CD103, CD11c, CD185, CD196, CD20, CD200, CD22, CD23, CD25, CD27, CD305, CD31, CD38, CD39, CD43, CD49d, CD5, CD79b, CD81, CD95, IgD, IgG, or IgM on CLL cells relative to baseline by more than 50% and at least 500 arbitrary units in median fluorescence intensity monitored throughout the study _____ Previous secondary outcome measures: 1. One and two year progression free survival for relapsed/refractory and treatment naïve patients define; Timepoint(s): 1 and 2 years 2. Two and five year overall survival for relapsed/refractory and treatment naïve patients, defined as the; Timepoint(s): 1 and 5 years 3. Best disease response: Complete Remission (CR); Complete Remission with incomplete marrow recovery; Timepoint(s): Week 1, week 2, Month 1, Month 2, Month 6. 4. Biological response (complete, partial or nodal) at 1, 6 and 12 months, assessed according to the; Timepoint(s): 1, 6, 12 months
Completion date	31/12/2023

Eligibility

Participant type(s)	Patient
Age group	Adult
Lower age limit	18 Years
Sex	All
Target sample size at registration	40
Key inclusion criteria	Current inclusion criteria as of 24/04/2023: Cohort A (Treatment-naive) 1. Progressive Stage A, Stage B or Stage C CLL 2. CLL requiring therapy by the IWCLL criteria 3. ECOG performance status (PS) of 0, 1, or 2 4. Life expectancy of at least 6 months 5. Age >=18 years 6. Prepared to undergo the stipulated investigations within the trial (including bone marrow examinations) 7. Able to give informed consent 8. Adequate hepatic function, defined as serum aspartate transaminase (AST) or alanine transaminase (ALT) <2.5 x upper limit of normal (ULN), and total bilirubin ≤1.5 x ULN unless due to Gilbert’s syndrome 9. Adequate renal function, defined as estimated creatinine clearance ≥30 mL/min using the Cockcroft-Gault equation Cohorts (B)i and (B)ii: Relapsed/refractory (initial phase 20 patients, extension phase between 20-40 patients) 1. B-CLL requiring therapy according to the IWCLL guidelines. The leukaemia cells should co-express CD19, CD5, and CD23 and each clone should have restricted to expression of either kappa or lambda immunoglobulin light chains. The levels of surface immunoglobulin, CD20, and CD79b should be low. If there is atypically strong surface immunoglobulin, CD20, or CD79b expression, or other atypical features, it may not be possible to perform the MRD monitoring required to evaluate the primary endpoint. 2. Refractory CLL defined as any of the following: 2.1. Failure to achieve a response (CR or PR by IWCLL Criteria) to a purine analogue alone or in combination with chemotherapy 2.2. Relapse within 6 months of responding to a purine analogue alone or in combination with chemotherapy 2.3. Relapse within 24 months of responding to fludarabine, cyclophosphamide and rituximab (FCR) 2.4. Patients with CLL with deletion of chromosome 17p who have failed at least one previous therapy. 3. ECOG performance status (PS) of 0, 1, or 2 4. Life expectancy of at least 6 months 5. Prepared to undergo the stipulated investigations within the trial (including bone marrow examinations) 6. Age >= 18 7. Able to give informed consent 8. Ability to comply with study protocol procedures 9. Adequate hepatic function, defined as serum aspartate transaminase (AST) or alanine transaminase (ALT) <2.5 x ULN, and total bilirubin ≤1.5 x ULN unless due to Gilbert’s syndrome 10. Adequate renal function, defined as estimated creatinine clearance ≥30 mL/min using the Cockcroft-Gault equation 11. Minimum platelet count of ≥50 x 10^9/L 12. Absolute neutrophil count (ANC) ≥ 1.0 x 10^9/L (unless due to direct marrow infiltration by CLL (to be confirmed via bone marrow biopsy) Cohort (B)iii: Ibrutinib treated patients (extension phase only – up to 20 patients) 1. Patients enrolled on IcICLLe trial as relapsed/refractory patients who have received treatment with ibrutinib on the IcICLLe trial for at least 6 months _____ Previous inclusion criteria: Cohort A (Treatment naive) 1. Progressive Stage A, Stage B or Stage C CLL 2. CLL requiring therapy by the IWCLL criteria 3. ECOG performance status (PS) of 0, 1, or 2 4. Life expectancy of at least 6 months 5. Age =18 6. Prepared to undergo the stipulated investigations within the trial (including bone marrow examinations) 7. Able to give informed consent Cohort B (Relapsed/Refractory) 1. CLL requiring therapy 2. Refractory CLL defined as any of the following: 3. Failure to achieve a response (CR or PR by IWCLL Criteria) to a purine analogue alone or in combination with chemotherapy, or: 4. Relapse within 6 months of responding to a purine analogue alone or in combination with chemotherapy, or: 5. Relapse within 24 months of responding to a fludarabine, cyclophosphamide and rituximab (FCR), or: 6. Patients with CLL with deletion of chromosome 17p who have failed at least one previous therapy. 7. ECOG performance status (PS) of 0, 1, or 2 (see appendix 6) 8. Life expectancy of at least 6 months 9. Prepared to undergo the stipulated investigations within the trial (including bone marrow examinations) 10. Age = 18 11. Able to give informed consent Target Gender: Male & Female ; Lower Age Limit 18 years
Key exclusion criteria	Current exclusion criteria as of 24/04/2023: All participants: 1. Unwilling to undergo the protocol assessments including the bone marrow assessments 2. Active infection at the time of registration), history of chronic or recurrent infection 3. Other severe, concurrent (particularly cardiac or pulmonary) diseases or mental disorders that could interfere with their ability to participate in the study 4. Use of prior investigational agents within 6 weeks 5. Pregnancy or lactation 6. Unwilling to use appropriate contraception during and for 12 months following treatment 7. CNS involvement with CLL 8. Mantle cell lymphoma 9. Known HIV positive 10. Active or prior Hepatitis B or C 11. Active secondary malignancy excluding basal cell carcinoma 12. Persisting severe panocytopenia (neutrophils <1.0 x10^9/L) or transfusion dependent anaemia unless due to direct marrow infiltration by CLL (to be confirmed via bone marrow biopsy) 13. Active haemolysis (not controlled with prednisolone at 20 mg or less) 14. Patients requiring or who have received anticoagulation treatment with warfarin or vitamin K antagonists within 1 week of the first dose of ibrutinib 15. Patients requiring concomitant use of strong CYP3A4/5 inhibitors 16. Patients with evidence or history of transformation and/or PLL 17. Major surgery within 4 weeks prior to registration 18. Currently active, clinically significant cardiovascular disease, such as uncontrolled arrhythmia or Class 3 or 4 congestive heart failure or a history of myocardial infarction, unstable angina, or acute coronary syndrome within 6 months prior to registration History of stroke or intracranial haemorrhage within 6 months prior to registration 19. History of severe allergic or anaphylactic reactions to humanised or murine monoclonal antibodies. Known sensitivity or allergy to murine products. 20. Vaccination with a live vaccine a minimum of 28 days prior to registration. 21. Patients with Progressive Multifocal Leukoencephalopathy (PML). 22. No known allergy to obinutuzumab or excipients Cohort (B)i and (B)ii: Relapsed/refractory (initial phase – 20 patients, extension phase between 20-40 patients) 1. Previous treatment with ibrutinib or an alternative inhibitor of B-Cell receptor pathway _____ Previous exclusion criteria: Both cohorts A and B 1. Unwilling to undergo the protocol assessments including the bone marrow assessments 2. Active infection 3. Other severe, concurrent (particularly cardiac or pulmonary) diseases or mental disorders that could interfere with their ability to participate in the study 4. Use of prior investigational agents within 6 weeks 5. Pregnancy or lactation 6. Unwilling to use appropriate contraception during and for 12 months following treatment 7. CNS involvement with CLL 8. Mantle cell lymphoma 9. Known HIV positive 10. Active or prior Hepatitis B or C 11. Active secondary malignancy excluding basal cell carcinoma 12. 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) 13. Active haemolysis (not controlled with Prednisolone at 10 mg or less) 14. Patients requiring or who have received anticoagulation treatment with warfarin or vitamin K antagonists within 1 week of the first dose of ibrutinib 15. Patients requiring concomitant use of strong CYP3A4/5 inhibitors 16. Patients with evidence or history of transformation and/or PLL Cohort A (Treatment naive) 1. Previous treatment for CLL. This does not include steroids. Cohort B (Relapsed/Refractory) 1. Previous treatment with ibrutinib or an alternative inhibitor of BCell receptor pathway
Date of first enrolment	24/04/2014
Date of final enrolment	20/10/2017

Locations

Countries of recruitment

United Kingdom
England

Study participating centre

Institute for Cancer Studies

Birmingham
B15 2TT
United Kingdom

Results and Publications

Individual participant data (IPD) Intention to share	No
IPD sharing plan summary	Not expected to be made available
IPD sharing plan	IPD will not be available.

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
Abstract results	IcICLLe results presented at European Hematology Association conference	21/05/2015	13/04/2023	No	No
Abstract results	IcICLLe results presented at NCRI Cancer Conference	01/11/2015	13/04/2023	No	No
HRA research summary			28/06/2023	No	No
Protocol file	version 12.0	22/08/2022	24/04/2023	No	No
Study website	Study website	11/11/2025	11/11/2025	No	Yes

Additional files

ISRCTN12695354_Protocol_v12.0_22Aug2022.pdf: Protocol file

Editorial Notes

24/04/2023: The following changes have been made:
1. The IRAS number has been added.
2. The study hypothesis has been changed.
3. The intervention has been changed.
4. The trial phase has been added.
5. The primary outcome measure has been changed.
6. The secondary outcome measures have been changed
7. The overall trial end date has been changed from 01/04/2015 to 31/12/2023.
8. The participant inclusion criteria have been changed.
9. The participant exclusion criteria have been changed.
10. The recruitment end date has been changed from 01/04/2015 to 20/10/2017.
11. The main funder name has been changed from Leukaemia and Lymphoma Research to the charity's current name of Blood Cancer UK.
12. F. Hoffmann-La Roche has been added to the funders.
13. The publication and dissemination plan has been added.
14. The intention to publish date has been added.
15. The IPD sharing statement and summary have been added.
16. Protocol file uploaded.
13/04/2023: The following changes have been made:
1. The study website has been added.
2. Abstract links added.
3. The scientific contact has been changed.
24/07/2020: No publications found.
28/02/2018: No publications found in PubMed.