CLL Trials in the UK Professor Peter Hillmen updated by CLLSA

CLL Trials in the UK

This section has been updated by the CLLSA from the original which was written by Professor Peter Hillmen Consultant Haematologist at Leeds Teaching Hospitals, NHS Trust. Peter is Chairman of the CLL Trials Group of the National Cancer Research Institute.

The article has been written for patients and their carers and assumes almost no prior medical knowledge

Introduction

Until relatively recently research into the understanding of chronic lymphocytic leukaemia (CLL) and therapy of the disease has been somewhat pedestrian compared to other haematological malignancies, such as acute myeloid leukaemia. The principle reasons for this impression were that there was little understanding of the biology of CLL and there was a lack of novel therapeutic agents. This has all changed in dramatic fashion over the last decade. This change has been led by remarkable advances in our understanding of the pathophysiology of CLL as well as new insights into the reasons why CLL becomes resistant to therapy in some patients. Simultaneously with these advances we have witnessed the development of several potential novel therapies for CLL. Together these advances are revolutionising the way we look at, and treat, CLL. There is a need to change the therapeutic and diagnostic perception of CLL to a more proactive view.

We have moved from the times when the only treatment intent was palliation to a time when real efforts at achieving meaningful improvements in survival can be expected. There is the hope that in the not to distant future we may even talk of cure (or at least indefinite control) of CLL in more than just a small minority of patients. CLL is now arguably one of the most rapidly moving disorders, in terms of our understanding, in oncology generally. Along with these advances come many challenges including how do we test the variety of therapeutic options for patients and therefore navigate our way to the most effective treatment for individual patients? How do haematologists who do not have a particular specialist interest in CLL maintain and update their knowledge in order to deliver the best therapy for their patients? In addition, how do we make available these advances in our understanding of the biology of CLL to all patients in the United Kingdom? The new treatments for CLL are not inexpensive both in terms of financial implications to the NHS as well as in terms of potential side effects for individual patients.

The answer to all of these questions must be, at least in part, by continuing our strong commitment to well designed clinical trials. However there are significant obstacles placed in our way with increasing bureaucracy, increasing costs of running trials and the not inconsiderable cost of the newer agents even within clinical trials.

Trial Organisation in the United Kingdom

Haematology in the United Kingdom has an enviable reputation worldwide for it’s portfolio of clinical trials. The trials were originally organised under the auspices of the Adult Leukaemia Working Party (ALWP) of the Medical Research Council (MRC). This was a group of haematologists from all regions of the UK who met regularly and organised some very successful clinical trials over a period of 3 or more decades. The reorganisation of cancer services in the UK at the beginning of the 21st century (driven by the “Cancer Plan”) identified that clinical trials were an important component of cancer care and led to the development of a new body called the National Cancer Research Institute (NCRI) with the responsibility of overseeing clinical trials for all cancers in the U.K. The ALWP of the MRC was subsumed into the Haematological Oncology Clinical Study Group (CSG) of the NCRI. The CLL trials in the U.K. are the responsibility of the CLL sub-group of the Haematological Oncology CSG of the NCRI.

Types of Clinical Trials

Clinical trials can be classified in several different ways. There are four general types of trials: Phase I, II, III and IV trials. These different phases of trials have different aims and designs as listed in the Table below: 

Type of trial Drug/therapy Aims Design Patient eligibility Size

Phase I

New drug – often with no previous experience in the disease

To find the maximum tolerated dose.Hope to show early signs of efficacy

Usually 6 to 8 cohorts of patients (usually 3 to 6 patients per cohort) with increasing doses in each cohort

Usually patients whose CLL is refractory to normal therapies

Up to 42 patients in total

Phase II

Drugs that have been through Phase I trials

To test the dose/schedule derived from Phase I trials in a larger number of patients.

Can be a single arm trial (i.e. all patients get the same therapy) or randomized (i.e. “standard therapy” versus “standard therapy” + Drug X)

Usually previously treated patients. Not necessarily refractory to other therapies

Up to 50 is typical

Phase III

Drugs or combinations that appear effective in Phase II trials or in other disease settings

To test whether a “newer” treatment is better than the current standard

Always randomized between the new regime and the standard

Usually previously untreated patients

300 to 1000 is typical

Phase IV

Established regime

Confirmatory testing of a drug/ regime that has proved successful in Phase III

Trials Randomized trial. (this type are rarely performed unless requested by the Regulatory Authorities)

Usually previously untreated patients

1000+ patients

 

In addition, trials can be organised by single Investigators (an individual haematologist), collaborative groups (such as the CLL sub-group of the NCRI) or the Pharmaceutical Industry. The Pharmaceutical Industry usually perform trials in order to test out a new drug that they are developing with the aim of obtaining a product licence for it’s sale. In fact, increasingly the Collaborative Group studies also require support from the Pharmaceutical Industry due to the requirement to use newer therapies and also because of the inadequate funding of Clinical Trials in the U.K. by the Grant-giving bodies and the government.

Logistics of running trials in the United Kingdom

The effort required before a trial can be started is not trivial. The following steps have to be taken before the first patient can be entered into a proposed trial 

 

1.            Trial design: First of all we have to decide what question needs to be addressed and in which patients. Then we need the input of an expert statistician as we need to calculate the expected improvement that we might see with the “newer therapy” and then calculate how many patients will be needed to be entered into the study to have a reasonable chance of answering the question (trials that are too small are unethical as patients are exposed to a new therapy which may carry some additional risks with little prospect of getting an answer to the question).

2.            Funding the drug costs: After the design of the study has been established we need to negotiate with the Pharmaceutical industry as the trials will inevitably involve new therapies which are usually not licensed for the indication. Therefore the NHS will not (and should not pay for the drug) – we therefore need support of free drug at the very least.

3.            Funding the trial logistics: The trial needs to be co-coordinated in accordance to the current European Union and Good Clinical Practice Guidelines. This ensures that patients within the trial are cared for safely (for example, any drug-related adverse events must be acted upon immediately to ensure that a similar problem does not occur in subsequent patients.). There needs to be proper data collection performed in the trial so that the results are accurate and reliable. This requires Trial Coordinators and ideally a Clinical Trials Research Unit and thus more funding. We then need to approach the official grant-giving bodies (Medical Research Council, Leukaemia Research Fund, Cancer Research (UK) – now the MRC and CRUK are combined as the Clinical Trials Advisory and Awards Committee [CTAAC]) to obtain a grant to fund the running of the trial.

4.            Protocol writing: The final protocol then needs to be completed and reviewed by other experts in the field – this is likely to include CLL experts from abroad. Each study requires a Sponsor, such as a University or Hospital, which takes responsibility for the correct running of the trial.

5.            Ethics Committee Approval: At this stage the trial protocol can be submitted Central Ethics Approval for the UK. Here it is reviewed and usually modifications in the trial design, protocol or patient information are required to ensure patient safety and confidentiality are maintained. After central ethics approval is obtained each hospital that will recruit patients into the trial must obtain local ethics approval.

6.            Trust Approval: Finally we need to obtain the Trust (hospitals) approval that we can perform the trial in a particular hospital (mainly to ensure that we are not spending NHS money on clinical trials).

7.            Patient Accrual: At this point we can approach the patient.

At any point along this development pathway we can hit an insurmountable barrier requiring at best a subtle change in direction and at worst the abandonment of the trial completely! I can say from personal experience that this can be a very painful, protracted and frustrating process – at times it seems that the system is deliberately obstructive! Anyway we brush ourselves off and start again.

 

Trials  in the UK

There are many CLL trials taking place in the UK and a list of non-commercial and commercial trials being conducted under the auspices of the NCRI in this listing of Current UK Trials updated November 2018

You can access more information about UK CLL clinical trials status & listing at:

 

Commercially sponsored trials

There are a large number of novel therapeutic agents in Phase I, II and III trials in U.K. and beyond. These are run by the Pharmaceutical Industry and typically are international studies. In the U.K. these trials are performed in a small number (usually 3 to 8 sites) of large “CLL centres”. They offer novel therapeutic options for patients with refractory disease and although there may only be a relatively small chance of success there is always hope!

Conclusion

There is a very active CLL trials group in the United Kingdom which has a track record of performing innovative clinical trials. Clinical trials are the bed-rock of evidence-based medicine and are essential if we are to continue the progress currently being made in CLL and other diseases. The most important people in the trials are the patients as they are trusting us to develop sensible well-designed trials which give them the best possible care and hopefully advance our understanding of CLL for future generations of patients.

If you wish to take part in a clinical trial please discuss the possibility with your clinician or nurse specialist. A suitable trial may not be available at your normal hospital but it may be possible for you to travel to a location where a trial is available.