A randomised phase 2 trial of IM versus HCQ/IM for patients with CML in MCyR with residual disease by Q-PCR

Lead Research Organisation: University of Glasgow
Department Name: College of Medical, Veterinary &Life Sci

Abstract

Patients who developed chronic myeloid leukaemia (CML) are currently treated with drugs called tyrosine kinase inhibitors (TKI), which bind to and inhibit the function of BCR/ABL, the abnormal protein found exclusively in CML cells. In the majority of cases these drugs convert CML from a rapidly progressive and fatal disease to a chronic condition where quality of life is maintained for at least 10 years on continuous drug therapy. However continuous drug therapy is expensive and associated with significant side effects for patients. Since BCR/ABL is the major survival and proliferative factor driving the development and progression of CML, when this protein is switched off by TKI the majority of CML cells die. The cells which fail to die in response to these drugs are either stem or bone marrow founder cells (CML in early phase) or cells showing other forms of drug resistance (CML in advanced phase). It is critical to find ways to kill CML stem cells as these cells are responsible for producing all the other cells that constitute the disease and without killing these cells CML cannot be cured. Our long term aims are to find combinations of drugs that can cure CML in early phase and to improve responses in advanced phase. We have recently shown that when CML cells, including stem cells, are exposed to TKI they induce a process called ?autophagy? in which, in simple terms, the cells begin to break down their own intracellular constituents to produce energy. By producing energy in this way they are able to survive the drug exposure. In preliminary studies (Journal of Clinical Investigation, in press) we have shown that the drug hydroxychloroquine (HCQ), which inhibits the process of autophagy, potentiates the effect of TKI in inducing death of CML cells, including stem cells. In this proposal we aim to lead a Phase 2 trial in which patients who have been on imatinib (standard TKI for CML) for 12 months, are tolerating it well and have experienced a partial response to treatment, will be randomised to either continue imatinib therapy or to take imatinib in combination with HCQ. The combination treatment will last 12 months and the study will investigate the safety of combining imatinib with HCQ and test whether the combination is more effective than imatinib alone.

Technical Summary

Imatinib mesylate (IM) is standard therapy for CML. The main limitations of IM and second generation tyrosine kinase inhibitors (TKI) are development of resistance and instrinsic refractoriness of CML stem cells to these agents. Therefore, new therapeutic approaches that more effectively target CML stem cells and prevent the outgrowth of TKI-resistant cells are required. Our preliminary data (JCI in press) lead us to believe that autophagy is a major cause of TKI-resistance in CML stem cells. We have shown that IM induces autophagy in BCR/ABL+ cells, including primary CML stem cells. Suppression of autophagy in BCR/ABL+ cells using pharmcological inhibitors or siRNA-mediated knockdown of essential autophagy genes enhances cell death induced by IM in primary CML cells, demonstrating that induction of autophagy has a pro-survival effect. Critically, the combination of TKI with inhibitors of autophagy (chloroquine and bafilomycin A1) results in near complete elimination of phenotypically and functionally defined CML stem cells, including CFC and LTC-IC. Together, these findings suggest that autophagy inhibitors will enhance the therapeutic effects of TKI in the treatment of CML. Hydroxychloroquine (HCQ), a less toxic derivative of chloroquine, has been widely used in rheumatology over many years, often at the same time as multiple other drugs. IM now has a 10 year clinical experience and is well tolerated. Here we propose to lead a randomised phase 2 trial with a safety run-in across 3 UK centres in which we will investigate the safety of combining IM with HCQ and compare the efficacy of the combination vesus IM alone in reducing levels of residual disease in CML chronic phase patients who have achieved MCyR after 12 months IM monotherapy but have residual disease as shown by Q-PCR. Patients will be recruited over 24 months, combination treatment will be for 12 months with a further 12 months follow-up.

Publications

10 25 50
 
Description training of basic pHd and clinical research fellows
Geographic Reach Local/Municipal/Regional 
Policy Influence Type Influenced training of practitioners or researchers
 
Description CRUK
Amount £19,000 (GBP)
Organisation Cancer Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 03/2012 
End 02/2013
 
Description MRC Clinical Trial Grant (A randomised phase 2 trial of IM versus HCQ/IM with CML in MCyR with residual disease by Q-PCR)
Amount £833,326 (GBP)
Funding ID G0900882 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 09/2010 
End 09/2013
 
Description Novartis
Amount £60,000 (GBP)
Organisation Novartis 
Sector Private
Country Global
Start 01/2011 
End 01/2013
 
Description SULSA
Amount £100,000 (GBP)
Funding ID MSD23_G_Holyoake-Chan 
Organisation Scottish Universities Life Sciences Alliance 
Sector Academic/University
Country United Kingdom
Start 10/2012 
End 09/2016
 
Description Bruno Calabretta 
Organisation Thomas Jefferson University
Department Department of Cancer Biology
Country United States 
Sector Academic/University 
PI Contribution published JCI paper together
Collaborator Contribution ENHANCED RESEARCH
Impact JCi paper Kay Kendall grant MRC grant MRC DGT sponsorship
Start Year 2007
 
Description CRUK 
Organisation Beatson Institute for Cancer Research
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution We are the leaders of partnership
Collaborator Contribution Providing LC3-GFP mouse to cross to BCR-ABL double transgenic mouse. Ed Chan is providing expertise relating to ULK-1
Impact Nothing as yet
Start Year 2012
 
Description David Marin 
Organisation Imperial College London
Department Centre for Haematology
Country United Kingdom 
Sector Academic/University 
PI Contribution PUBLISHED JCI PAPER
Collaborator Contribution enhanced science and clinical trial
Impact JCI paper Kay Kendall grant MRC grant MRC DGT sponsorship
Start Year 2007
 
Description Paolo Salmoni 
Organisation Medical Research Council (MRC)
Department MRC Toxicology Unit
Country United Kingdom 
Sector Public 
PI Contribution we published the JCI paper together
Collaborator Contribution enhanced science
Impact JCI paper Kay kendall grant MRC grant MRC DGT
Start Year 2007
 
Description Richard Clark 
Organisation University of Liverpool
Department Department of Molecular and Clinical Cancer Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution published JCI paper
Collaborator Contribution enhanced science and clinical trial
Impact JCI paper Kay Kendall grant MRC grant MRC DGT sponsorship CHOICEs TRIAL
Start Year 2007
 
Description SULSA 
Organisation Scottish Universities Life Sciences Alliance
Country United Kingdom 
Sector Academic/University 
PI Contribution We are the leaders of the partnership
Collaborator Contribution Ed Chan is providing expertise relating to ULK-1
Impact Still awaitng
Start Year 2012
 
Description autophagy work 
Organisation Thomas Jefferson University
Country United States 
Sector Academic/University 
PI Contribution We have generated a new grant entitled "A randomised phase 2 trial of IM versus HCQ/IM for patients with CML in MCyR with residual disease by Q-PCR" MRC Ref: G0900882
Collaborator Contribution Collaborated on a paper - Pub med reference 19363292
Impact 19363292
Start Year 2009
 
Description autophagy work 
Organisation University College London
Department UCL Cancer Institute
Country United Kingdom 
Sector Academic/University 
PI Contribution We have generated a new grant entitled "A randomised phase 2 trial of IM versus HCQ/IM for patients with CML in MCyR with residual disease by Q-PCR" MRC Ref: G0900882
Collaborator Contribution Collaborated on paper - Pubmed reference 19363292
Impact 19363292
Start Year 2009
 
Title Imatinib and Hydroxychloroquine 
Description Imatinib Mesylate With or Without Hydroxychloroquine in Treating Patients With Chronic Myeloid Leukemia NCT01227135 
Type Therapeutic Intervention - Drug
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2008
Development Status Under active development/distribution
Clinical Trial? Yes
UKCRN/ISCTN Identifier ISRCTN61568166
Impact Trial ongoing. No impacts available yet 
URL http://www.controlled-trials.com/ISRCTN61568166
 
Description AAAS Vancouver 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Participants in your research and patient groups
Results and Impact Talk

Improved collaborations
Year(s) Of Engagement Activity 2012
 
Description ASH San Diego 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Participants in your research and patient groups
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Year(s) Of Engagement Activity 2011
 
Description BUSCC University Stem Cell seminars birmingham 
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Part Of Official Scheme? No
Geographic Reach National
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Description BUSCC University Stem cell seminar Birmingham 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Participants in your research and patient groups
Results and Impact Talk

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Description Beatson Institute for Cancer Research Glasgow 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
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Description Beatson Institute for Cancer Research, Glasgow 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Participants in your research and patient groups
Results and Impact talk

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Year(s) Of Engagement Activity 2011
 
Description British Society of Haematology 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach National
Primary Audience Participants in your research and patient groups
Results and Impact Talk

Improved collaborations
Year(s) Of Engagement Activity 2012
 
Description CML Professionals Meeting Newcastle 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach National
Primary Audience Participants in your research and patient groups
Results and Impact CML Professionals Meeting

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Year(s) Of Engagement Activity 2012
 
Description EHA Amsterdam 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Participants in your research and patient groups
Results and Impact Talk

Improved collaborations
Year(s) Of Engagement Activity 2012
 
Description EHA London 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Participants in your research and patient groups
Results and Impact Talk

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Year(s) Of Engagement Activity 2011
 
Description EHA meeting London 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Participants in your research and patient groups
Results and Impact Talk

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Year(s) Of Engagement Activity 2011
 
Description ESH 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Participants in your research and patient groups
Results and Impact 500 audience, CML research and clinical run by ESH

improved collaborations
Year(s) Of Engagement Activity 2008
 
Description ESH Baltimore 
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Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Participants in your research and patient groups
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Improved collaborations
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Description ESH Portugal 
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Geographic Reach International
Primary Audience Health professionals
Results and Impact Talk with discussion

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Year(s) Of Engagement Activity 2013
 
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Results and Impact Talk

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Year(s) Of Engagement Activity 2011
 
Description ESH Vienna 
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Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Participants in your research and patient groups
Results and Impact Talk

Improved collaborations
Year(s) Of Engagement Activity 2012
 
Description Erasmus Haematology Lecture 
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Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Participants in your research and patient groups
Results and Impact Talk

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Year(s) Of Engagement Activity 2013
 
Description ISEH Amsterdam 
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Primary Audience Participants in your research and patient groups
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Year(s) Of Engagement Activity 2012
 
Description NCMLSG Seminar Stockholm 
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Geographic Reach International
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Year(s) Of Engagement Activity 2011
 
Description NCMLSG Stockholm 
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Year(s) Of Engagement Activity 2011
 
Description Paterson Institute Manchester 
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Description Paterson Institute Manchester 
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Results and Impact talk

improved collaborations
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Description TSCRC Dundee 
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Description TSCRC Dundee 
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Description UCSF Cancer Centre, San Francisco 
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Year(s) Of Engagement Activity 2011
 
Description UCSF Cancer Centre, San Francisco 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Participants in your research and patient groups
Results and Impact Talk

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Year(s) Of Engagement Activity 2011
 
Description UKNSCN 4th Annual science meeting York 
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Description UKNSCN York 
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Description open days for new paul O'Gorman Leukaemia Research centre 
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Geographic Reach Regional
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Results and Impact 9/10 and 22 May 2008. Audience of around 100 at each, short speeches, poster presentations, demon strations in the laboratory

press were present - Sunday Times, Herald articles guest of honour Richard Rockefeller
Year(s) Of Engagement Activity 2008
 
Description retiral lecture 
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Part Of Official Scheme? No
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Primary Audience Health professionals
Results and Impact audience around 80, local cytogenetics department for retiral of member of staff

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Year(s) Of Engagement Activity 2008