CLL Trials in the U.K.

This article has been written exclusively for the CLL Support Association by Dr Peter Hillmen, Consultant Haematologist at Leeds Teaching Hospitals, NHS Trust. Peter is Chairman of the CLL Trials Group of the National Cancer Research Institute. This is a complete and up-to-date view of the UK CLL trials scene and contains information that is very difficult to find elsewhere. We are very grateful that Peter has taken the time to write this article for the association which I am sure will be very useful to anyone approaching or considering treatment.

September 2006

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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 5 or so years. 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 revolutionizing 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 are now moving 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 organized 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 organized some very successful clinical trials over a period of 3 or more decades. The recent reorganization of cancer services in the UK (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 has now been 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:

To find the maximum tolerated dose.

In addition, trials can be organized 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 licenced 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.

Phase III CLL Trials in the United Kingdom
There have now been five Phase III CLL trials performed by the old MRC sub-group (CLL1 to 5). The first 3 trials were performed up until 1997 when there were relatively few therapies available for CLL. The LRF CLL4 trial, which recruited patients between February 1999 and October 2004, has been the most successful of the UK CLL trials to date (see below). The MRC CLL5 trial is still recruiting.

LRF CLL4: This was a randomized Phase III trial which eventually recruited a total of 783 patients with previously untreated CLL between February 1999 and October 2004. Patients were randomized between either chlorambucil (the “standard” therapy) or fludarabine +/- cyclophosphamide. This trial has demonstrated much higher response rates and progression-free survival (the time until the CLL becomes active again) for the combination of fludarabine with cyclophosphamide. The trial has also yielded a phenomenonal amount of biological information about CLL and it’s treatment. The results of LRF CLL4 promise to have a great impact on the treatment of patients with CLL in the UK and beyond. On the basis of this trial the FC combination is now likely to become the standard first-line therapy upon which future trials will build.

MRC CLL5: The MRC CLL5 trial is a randomized Phase III trial which is testing the effectiveness of autologous stem cell transplantation in CLL. This trial is being run in collaboration with several other countries in Europe and should complete recruitment within the foreseeable future.

Phase II CLL Trials in the United Kingdom
In addition to the randomized Phase III trials the NCRI CLL sub-group organizes a series of Phase II trials designed, in part, to inform the development of the larger Phase III trials. The following is a summary of the various Phase II trials currently being run by the CLL sub-group.

CLL201 (FCM-R): This is a randomized Phase II trial comparing the combination of fludarabine+cyclophosphamide+mitoxantrone (FCM) with FCM combined with rituximab (MabThera). The trial is open in 17 Centres in the U.K. and will recruit up to 56 patients. To date 35 patients have been entered in CLL201. The trial is supported by Roche Products Ltd. with free drug and a grant from to support the running of the trial.

CLL202 (CamFlud): This was a single arm Phase II trial testing the use of sub-cutaneous (rather than intravenous) alemtuzumab (MabCampath) in patients with CLL that was refractory to fludarabine. The study recruited a total of 51 patients and the final results will be presented in December 2006 at the American Society of Hematology Meeting. An interim analysis of this trial after the treatment of 34 patients demonstrated a similar efficacy for sub-cutaneous to intravenous therapy. This trial was supported by Schering Health Care Ltd. with free drug and a grant to support the running of the trial.

CLL203 (Poor risk Stage A): This trial is currently the subject of discussion. The aim is to test whether by using the new biological markers in CLL we can identify patients with disease that is likely to progress early and therefore who may benefit from “targeted” therapy at diagnosis (rather than to wait for progression as is the current practice).

CLL204 (mini-allogeneic stem cell transplant): This trial is to collect information on patients who receive stem cell (bone marrow) transplants from their brother or sister (or an unrelated transplant). The trial is part of a larger mini-allogeneic stem cell transplant trial for a wide variety of haematological malignancies. However the trial has a CLL specific module to standardize which tests are performed prior to transplant as well as the monitoring of minimal residual disease following the transplant.

CLL205 (T-PLL): This is a trial of subcutaneous alemtuzumab (MabCampath) for T-prolymphocytic leukaemia (T-PLL). This is a rare form of chronic leukaemia (completely different to CLL but falls under our remit). This trial is supported by Schering Health Care Ltd. with free drug and a grant to support the running of the trial.

CLL206 (CamPred): This is a trial for patients with poor risk CLL identified as there is a loss of the short arm of chromosome 17 from the patient’s CLL cells. This indicates the loss of a critical gene, called p53, which is important for the effectiveness of conventional chemotherapy (fludarabine and chlorambucil). The loss of p53 explains why the patient’s CLL has not responded to fludarabine and indicates that we should use therapies that independent of p53, such as high doses of steroids and alemtuzumab (MabCampath). The trial combines these drugs and the preliminary results are very promising. At present the trial only aims to recruit 14 patients but we are currently negotiating to increase this number. This trial is supported by Schering Health Care Ltd. with free drug and a grant to support the running of the trial.

CLL207 (MRD eradication): This trial is for patients who have responded to conventional therapy, such as FC, but have detectable CLL when we use a very sensitive test that will pick up as low as a single CLL cell in 10,000 normal cells. Patients must be between 6 and 24 months since completing chemotherapy and remain in a good remission. Patients will then be treated with subcutaneous alemtuzumab (MabCampath) in an attempt to eradicate the residual CLL. This trial is due to open to recruitment in September 2006. This trial is also supported by Schering Health Care Ltd. with free drug and a grant to support the running of the trial.

The next Phase III trials in the United Kingdom
CLL6: The saga of the design of CLL6 is painful and raises some real concerns over the future of CLL trials in the U.K. The NCRI CLL sub-group designed a trial which was generally accepted by our International colleagues (CLL experts) to be forward-thinking and well-designed. The CLL6 was to test several things: First we were to test whether we should stratify patients by the biological characteristics of their CLL. This question built on our work from LRF CLL4. In other words, should we treat patients with “Good Risk” CLL differently from those with “Standard Risk” disease and from those with “Poor Risk” disease? Secondly, we were to test the best therapy to induce remissions and whether consolidation therapy was advantageous in “Standard Risk” CLL. One of the attractive features of the trial was that all patients would receive rituximab in combination with fludarabine-based chemotherapy – this is not yet approved for CLL but preliminary data from other groups suggests that the addition of rituximab will be beneficial (the German CLL Study Group have completed the randomized trial of adding rituximab to FC but we don’t yet have the results).

We had managed to negotiate free rituximab for over 750 patients within the CLL6 study and free alemtuzumab for consolidation and for poor risk CLL. Unfortunately we failed to obtain funding for running the trial from the MRC. One of the disturbing reasons given for not funding the trial was that it was very expensive due to the prolonged follow-up of patients in the trial! If this is a reason for not funding a trial then we may never get another Phase III CLL trial funded as by necessity, and perhaps because of the success of previous studies, prolonged follow-up is always needed (thankfully).

So we are now back to the drawing board with the design of CLL6!

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.

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