Annex M
Technical Note
CLINICAL EXPERIENCE
WITH BATIMASTAT
IN MALIGNANT
ASCITES
Following a successful Phase II, 40 patient
study in malignant ascites, British Biotech began a 150 patient
Phase III randomised controlled trial of batimastat versus no
drug treatment in November 1994. Malignant ascites is a serious,
late stage complication of ovarian and other intra-abdominal cancers
and is unresponsive to current therapy, being normally relieved
by repeated drainage of ascitic fluid. Batimastat, an inhibitor
of matrix metalloproteinases (MMPs), has shown beneficial effect
on the rate of fluid reaccumulation in Phase I/II and Phase II
studies. In the Phase III trial, which has recently been suspended,
a majority of the patients receiving batimastat reported pain
and discomfort following intra-peritoneal administration of the
drug. Previous experience with batimastat administered by the
same route to a total of more than 85 malignant ascites patients
in a variety of Phase I/II and Phase II trials had shown the drug
to be well tolerated and pain and discomfort following dosing
to be minimal. The incidence of side effects encountered in the
Phase III malignant ascites trial has therefore been significantly
different from previous experience with batimastat in this condition.
This has led to a detailed analysis of the formulation used in
the Phase III trial.
MANUFACTURING PROCESS
New chemical entities under development by British
Biotech are manufactured for large scale clinical trials and eventual
commercial use by external contractors using British Biotech's
proprietary routes of synthesis to closely defined specifications
approved by regulatory agencies. A number of changes to the batimastat
production process have been made to improve the efficiency of
manufacturing as production is increased in scale. All material
used in the clinical trials has been made to a closely defined
specification using Good Manufacturing Practice guidelines. Despite
meeting current ICH guidelines, batimastat made by the larger
scale process has been significantly more irritant to the peritoneum
than material produced by the earlier smaller scale process.
After extensive investigation the problem has
been identified with changes made to the final step in the manufacturing
process. Alterations have now been made to the large scale manufacturing
process and to the product specification which will avoid this
problem by reverting to the previously successful method of production.
Fresh clinical supplies of batimastat made by this revised process
are now being manufactured.
BATIMASTAT PROGRAMME
IN MALIGNANT
PLEURAL EFFUSION
British Biotech is also investigating the potential
for batismastat in the treatment of malignant pleural effusion,
a similar condition to malignant ascites but occurring in the
chest cavity. This is a significantly more common condition than
malignant ascites, being a relatively frequent complication of
primary and secondary lung cancer. A UK Phase I/II studyof batimastat
administered by direct injection into the chest cavity is nearing
completion in 24 pleural effusion patients. This trial is being
supplied with batimastat unaffected by the manufacturing problem
described above. Tolerability of batimastat in the pleural effusion
patients has been good and the clinical programme is continuing.
Full results of this study are being presented at the American
Society of Clinical Oncology (ASCO) in May in Los Angeles. Increased
emphasis will be given to this indication for batimastat and multicentre
dose ranging efficacy studies will be conducted in parallel in
Europe and the USA during 1995.
OTHER MMP INHIBITORS
UNDER DEVELOPMENT
Batimastat is the first matrix metalloproteinase
inhibitor world-wide undergoing clinical trials in cancer patients.
The manufacturing problem outlined above is unrelated to the biochemical
action of batimastat as an inhibitor of matrix metalloproteinase.
In addition, British Biotech has a number of
other matrix metalloproteinases inhibitors under development including
BB-2516, an oral anti-cancer drug, currently in Phase I volunteer
studies and a second oral agent with different activities in pre-clinical
development for arthritis. None of these development programmes
are affected by the delay to the batimastat malignant ascites
trials announced today.
BACKGROUND
British Biotech plc, founded in 1986, combines
approaches in molecular biology and synthetic chemistry to develop
new therapeutic agents primarily for the treatment of cancer.
In addition, the company is pursuing research in inflammatory,
vascular and viral diseases. The company has recently established
a new subsidiary, Neures, to investigate the role of metalloproteinase
inhibitors in neuro-inflammatory diseases. British Biotech, based
in Oxford, England, is listed on the London Stock Exchange and
quoted on NASDAQ under the symbol BBIOY. A US subsidiary, British
Biotech Inc, was established in Annapolis, Maryland, in December
1993.
British Biotech plc
Marimastat gives positive
interim results in cancer patient trials Highlights
British Biotech announces positive interim findings
from its Phase II trials of marimastat (BB-2516) in advanced human
cancer. Marimastat is British Biotech's oral anti-cancer drug
and potentially its most important product. It is currently being
evaluated in eight common and/or poorly treated cancers. Today's
results are from studies in patients with one of four different
tumour types in which disease progression can be measured by monitoring
cancer antigens.
— There was an absolute fall or no
rise in the level of cancer antigen in 33 per cent of patients.
A further 26 per cent of patients showed a reduction in the rate
of rise of cancer antigen.
— After four weeks of marimastat, 43
per cent of patients have met the criteria for potential benefit
and have continued with treatment beyond the initial 28 day period.
— Marimastat appears to have broadly
similar activity in colorectal, ovarian, pancreatic and prostatic
cancer.
— Marimastat concentrations in the
blood of patients were much higher than appear to be necessary
for therapeutic effect and some dose-related side-effects have
been seen. As a result, new lower doses are being tested.
Commenting on the results, Dr Peter Lewis, British
Biotech's Research and Development Director, said: "This
is the first evidence from human trials that marimastat may have
an effect on the progression of human cancer. Results to date
are most encouraging, particularly since they appear to be similar
across all four cancer types. However, these are interim findings
and firm conclusions as to the potential value of the drug in
the treatment of cancer must await the completion of clinical
testing. In particular, I would emphasize that, until we obtain
more information on its use, marimastat cannot be made available
to patients outside the company's clinical trial programme."
British Biotech plc
Marimastat gives positive
interim results in cancer patient trials
British Biotech announces that marimastat (BB-2516),
its novel anti-cancer drug, has shown early evidence of activity
in small-scale trials of advanced human cancer. It is currently
being evaluated in eight common and/or poorly treated cancers.
Today's results are interim findings from studies in patients
with one of four different cancer types in which disease progression
can be measured by monitoring cancer specific antigens: colorectal,
ovarian, pancreatic and prostatic cancer. In each of these trials,
marimastat treatment has shown a positive biological effect on
blood concentrations of cancer specific antigens which are recognised
as surrogate markers of tumour progression or regression. Of patients
evaluated after four weeks of therapy,43 per cent have shown sufficient
benefit to continue treatment with marimastat.
Marimastat is the first oral matrix metalloproteinase
inhibitor to be tested in cancer patient trials. This new drug
acts on tumours in an entirely different way to any existing anti-cancer
therapy and is thought to reduce the ability of malignant cancers
to expand and spread in the body. Since the mechanism of spread
is common to all solid malignant tumours, British Biotech is evaluating
marimastat in a wide variety of cancer types in a series of pilot
studies which began in March 1995.
RESULTS FROM
TRIALS IN
COLORECTAL, OVARIAN,
PANCREATIC AND
PROSTATIC CANCER
The first results, which are announced today,
are from trials using cancer specific antigens as surrogate measures
of tumour progression. Cancer specific antigens are proteins released
into the blood by tumours and variations in their concentrations
correlate with the progression of disease. Specific cancer antigens
have been used to monitor the response to therapy in separate
trials in colorectal, ovarian, pancreatic and prostatic cancer.
To be eligible for these trials, patients must have advanced inoperable
cancer with a documented rise of greater than 25 per cent in the
level of the relevant cancer antigen in the 28 day screening period
prior to starting marimastat treatment. In addition, patients
must not be under treatment with any other drug or therapy.
Following the screening period, patients are
generally treated for a period of 28 days, but the clinical trial
designs allow the physician to continue treatment for longer periods
with marimastat if a positive drug effect is seen, measured either
by reference to blood levels of the cancer antigen or by clinical
benefit or both. The criteria for a positive drug effect are defined
prospectively in each protocol. All of these trials are continuing.
Interim findings
Interim data have now been evaluated on an initial
94 patients who have completed 28 days of dosing in these cancer
antigen trials. A total of 167 patients have so far enrolled in
these trials and more complete data from these studies will be
reported in 1996.
At the end of 28 days of treatment with marimastat
at doses of 25, 50 or 75 mg taken twice a day, a total of 31 patients
(33 per cent) showed a "biological effect" on cancer
antigen concentrations. Biological effect is defined as an absolute
fall or no rise in the level of cancer antigen concentrations.
A further 24 patients(26 per cent) showed a "partial biological
effect", defined as a rise in cancer antigen levels of less
than 25 per cent during the 28 days of therapy. For comparison,
the average rise in cancer antigen concentrations in the 28 day
screening period before therapy was 114 per cent for all patients
and 91 per cent for this group of 55 patients.
These biological effects of marimastat treatment
were seen in patients with each of the four tumour types being
studied: colorectal, ovarian, pancreatic and prostatic cancer.
When viewed by cancer type, the effect rate is broadly similar,
although activity appears to be slightly higher in ovarian cancer.
A more precise assessment of tumour sensitivity to marimastat
must await data from a larger number of patients. In addition,
there were no significant differences between the effectiveness
of the three marimastat doses studied, suggesting that all doses
were above the level required for maximal efficacy.
These results on cancer specific antigens indicate
a potential benefit of marimastat on disease progression.
Continuation of marimastat treatment
In all of the cancer antigen trials other than
the US colorectal study, patients who responded to the initial
28 days of treatment by showing a complete or partial biological
effect or who showed a clinical improvement in their disease were
offered an opportunity to continue on marimastat treatment. Of
the 91 patients in these trials who have completed 28 days of
initial treatment and who have been evaluated for continuation,
39(43 per cent) have entered the continuation protocol. The continuation
rate is an indication of the percentage of patients with advanced
cancers of these types who have benefited from marimastat in the
judgement of their oncologist.
Tolerability and side effects of marimastat treatment
In general, marimastat has been well tolerated
when taken for 28 days. Only four out of 117 patients in the antigen
trials discontinued treatment due to side effects during this
period. The side effects observed have been musculo-skeletal in
nature, with pain and tenderness in the joints, particularly in
the shoulder or the hand. These effects respond to analgesics
and physiotherapy and are reversible on interrupting therapy.
The incidence is dose and time-related. After 56 days of treatment,
one patient out of 33 at 25 mg twice daily and 12 patients out
of 27 at 50 mg twice a day experienced musculo-skeletal pain sufficiently
severe to require dose reduction, physiotherapy or interruption
of drug.
Optimal dose and blood concentrations of marimastat
The first results from these trials revealed
that the concentrations of marimastat in the blood of cancer patients
were much higher than predicted. The average "trough"
level in patients receiving 25 mg twice daily was more than four
times the predicted value. These higher than expected drug concentrations
may be related to the fact that the cancer patients are much older
than the healthy volunteers who took part in the Phase I trials.
Cancer patients may also have impaired liver and/or kidney function
either as a direct result of their disease or as a result of previous
chemotherapy. Such impaired liver or kidney function is likely
to result in reduced metabolism and clearance of marimastat.
As a consequence of these preliminary results,
lower doses or marimastat are now being tested. Patients are already
receiving doses of 10 mg, twice daily, and doses of 5 mg and possibly
2 mg will also be studied. In addition, once-a-day dosing will
be explored, starting with a dose of 25 mg. Following testing
of these lower doses, it should be possible to define a "minimum
effective dose" which is likely to be the dose selected for
pivotal Phase III trials.
OTHER CANCER
STUDIES
In addition to the cancer antigen studies described
above, three other types of Phase II cancer studies are under
way:
— Studies in lung cancer patients where
the progress of the disease can be measured objectively by periodic
chest x-ray. In this study, marimastat is being examined for its
ability to stabilise progressive disease.
— A placebo-controlled study in bone
cancer secondary to breast or prostatic primary cancer. In this
study, marismastat is being assessed by measuring bone pain and
biochemical markers of bone destruction.
— Studies investigating the effect
of marimastat on cancer by microscopic examination of repeated
biopsies of the tumour. These studies include separate trials
in gastric cancer and melanoma.
These studies started more recently than the
cancer antigen studies and data are not yet available on them.
INDIVIDUAL CASE
RECORDS
Among patients treated with marimastat, there
are a number of anecdotal cases showing evidence of the activity
of the drug, particularly in pancreatic and gastric cancer.
FULL RESULTS
FROM PHASE
II MARIMASTAT TRIALS
A total of 11 Phase II studies with marimastat
are under way in eight different types of cancer. To date, a total
of 221 patients have commenced marimastat treatment in these trials.
All trials are continuing to recruit new patients. Full results
will be released on their completion in 1996. British Biotech
expects to be able to start a Phase III programme in the second
half of 1996.
AVAILABILITY OF
MARIMASTAT
Today's announcement, which releases interim
data at a very early stage, is being made in order to inform shareholders
of the progress of the company's principal compound. It is emphasised
that these are not complete results and that marimastat is still
at the clinical research stage. Every effort is being made to
expedite evaluation of the drug. However, at present the company
is not in a position to supply marimastat to patients other than
those participating in the clinical studies.
TECHNICAL NOTE
A technical note for Analysts giving further
information on cancer specific antigens, clinical trial design
and more detailed information on today's results is available
from the company on request.
British Biotech plc
POSITIVE MARIMASTAT RESULTS INCLUDE CLINICAL
OUTCOME DATA HIGHLIGHTS
British Biotech announces further positive data
from Phase II trials of marimastat, its oral anti-cancer drug,
in advanced human cancer.
— Positive interim results presented
in November 1995 have been confirmed in larger patient numbers.
— A dose response has been shown in
the cancer antigen trials and an optimum dose has been selected
for definitive trials.
— Cancer antigen responses to marimastat
correlate with clinical outcome as measured by
— progression of pancreatic cancer as assessed
by CT scan;
— survival in pancreatic cancer; and
— progression-free survival in ovarian
cancer.
— No severe drug related toxicity has
been experienced; localised musculo-skeletal pain or discomfort
is the only side effect which has been associated with marimastat
therapy.
— A randomised controlled clinical
trial comparing marimastat to cytotoxic drugs in pancreatic cancer
will begin shortly. Several comparative trials in other cancers
will start in 1996.
Commenting on these results, Dr Peter Lewis,
British Biotech's Research and Development Director, said: "Clinical
results on several hundred patients treated with marimastat confirm
and extend our interim findings of November 1995. An appropriate
dose, based on antigen data, of the drug has been identified and
its tolerability and side efect profile defined. We now have initial
evidence of a clinical response to marimastat in pancreatic and
ovarian cancer. Most importantly the effect of marimastat on cancer
antigens correlates both with slower progression of disease and
survival in pancreatic and ovarian cancer. Marimastat can now
be progressed to definitive clinical trials."
British Biotech plc
POSITIVE MARIMASTAT RESULTS INCLUDE CLINICAL
OUTCOME DATA
British Biotech announces that marimastat, its
oral anti-cancer drug, has shown further evidence of activity
in Phase II trials in advanced human cancer. Marimastat is currently
being evaluated in 10 common and/or poorly treated cancers. Today's
results are findings from human trials in colorectal, ovarian,
pancreatic and prostatic cancer and are being released to coincide
with presentations being made at the American Society of Clinical
Oncology (ASCO) by US clinical investigators. In each of these
studies, significant progress has been made. First, the interim
findings on the effect of marimastat on blood markers (known as
cancer antigens) released in November 1995 have been confirmed
in a larger number of patients. Secondly, a statistically significant
dose response has been seen, with an optimum dose established
of 10 mg twice a day. Thirdly, in ovarian and pancreatic cancer,
a statistically better clinical outcome was observed in patients
who responded to marimastat treatment as indicated by changes
in cancer antigens.
On the basis of these encouraging results, British
Biotech is planning a programme of larger definitive trials comparing
marimastat with existing cancer drugs or placebo. The first of
these, in 300 patients with pancreatic cancer, will begin shortly.
RESULTS FROM
TRIALS IN
COLORECTAL, OVARIAN,
PANCREATIC AND
PROSTATIC CANCER
The results being announced today are from trials
measuring blood levels of cancer specific antigens as surrogate
measures of tumour progression. Cancer specific antigens are proteins
released into the blood by tumours and variations in their concentrations
correlate with the progression or regression of disease. Cancer
specific antigens have been used by British Biotech to monitor
the response to therapy in separate trials in colorectal, ovarian,
pancreatic and prostatic cancer. In addition, in pancreatic cancer,
it has been possible to evaluate clinical outcome by the use of
repeated CT scans and, in pancreatic and ovarian cancers, by observing
the time to disease progression requiring chemotherapy or time
to death.
In November 1995, interim data were announced
on 94 patients. A total of 365 patients have now enrolled in cancer
antigen trials and data can today be reported on 232 patients
who have completed an initial 28 days of dosing. These additional
clinical results confirm and extend the positive cancer antigen
trial results presented in November 1995.
Biological responses to marimastat
At the end of 28 days of treatment with marimastat,
patients were evaluated for response by reference to the degree
of change in blood cancer antigen concentrations. Those patients
in whom marimastat induced an absolute fall or no rise in the
level of cancer antigen concentrations are defined as showing
a "biological effect". Patients showing a rise in cancer
antigen levels of less than 25 per cent during the 28 days of
therapy are defined as showing a "partial biological effect".
Eight dose levels have now been studied in these
trials. Patients received doses of 75 mg, 50 mg, 25 mg,10 mg and
5 mg twice daily and, in addition, once-a-day dosing was explored
at 25 mg, 10 mg and 5 mg. At each of the once-a-day doses and
at 5 mg twice a day, approximately 30 per cent of patients showed
a biological or partial biological response. At dose levels of
10 mg twice a day, these responses rose to 56 per cent with small
further rises at higher doses, reaching 63 per cent, at 50 mg
twice a day. This overall dose response was clear cut and statistically
significant. A similar dose response was observed across all four
tumour types studied, with no significant difference between 10
mg twice a day and higher doses. A dose of 10 mg twice a day has
therefore been selected as the lowest dose that shows maximal
effect and the primary dose to be used in Phase III registration
trials.
Measurements of clinical outcome
As permitted in these trials, a relatively large
number of patients have received marimastat treatment over several
months and it is now possible to correlate the biological response
to the drug, as defined by cancer antigens in the manner described
above, with clinical outcome in pancreatic and ovarian cancers.
In these studies, statistically significant positive correlations
have been observed between the 28 day biological responses to
marimastat and improvements in clinical outcome using three criteria:
— progression of pancreatic cancer
assessed by CT scan;
— survival in pancreatic cancer; and
— progression-free survival (defined
as the time to either chemotherapy or death) in ovarian cancer.
These correlations indicate that patients showing
a cancer antigen response to marimastat treatment may have a better
outcome that those not showing the same level of response.
For example, in pancreatic cancer patients,
there was evidence of tumour progression as assessed by CT scan
in only six out of 22 (27 per cent) biological responders to marimastat
compared with 15 out of 26 (58%) poor biological responders. Comparing
survival rates, median (50 per cent) survival in marimastat responders
was greater than 200 days, whereas in poor responders it was approximately
125 days. In ovarian cancer, median time to chemotherapy or death
in marimastat responders was 166 days compared to only 67 days
in poor responders. All of these comparisons are statistically
significant.
Tolerability and side effects of marimastat treatment
In general, marimastat has been well tolerated
when taken for several months at the lower doses tested. No severe
drug-related toxicity has been observed. Musculo-skeletal side
effects manifested by pain and tenderness in the joints, particularly
in the shoulder or hand, are the only drug-related side effects
identified. The rate of onset is gradual and has been confirmed
to be dose and time-related. These side effects respond to analgesics
and physiotherapy. After five months of treatment, the proportion
of patients reducing or interrupting marimastat treatment is about
one-third at 10 mg twice a day. Symptoms disappear quickly on
stopping treatment. Given the ease with which the syndrome can
be identified, continuation with marimastat treatment in patients
who find this musculo-skeletal side effect a problem is possible
after a short "dosing holiday". The long-term treatment
of a number of patients is now being managed in this way.
REGISTRATION TRIAL
PROGRAMME
As a result of the encouraging findings described
above, British Biotech is planning a series of definitive trials
of marimastat in rapidly progressing and poorly treated cancers.
Survival and progression-free interval will be the primary endpoints
in these trials which will compare the efficacy of marimastat
with that of currently approved therapies or, where no current
therapy is effective, with the effect of a placebo.
The first definitive trial will be a 300-patient
international study in pancreatic cancer and this is expected
to begin shortly. This trial will compare three doses of marimastat
with the cytotoxic drugs, gemeitabine or 5FU. Further registration
trials are being planned in cancer of the lung, ovary and prostate.
Additionally, the use of marimastat in combination
with cytotoxic therapy will be investigated in clinical trials,
following encouraging pre-clinical data presented at the European
Association for Cancer Research meetings earlier this year. These
pre-clinical studies suggested additive anti-tumour effects between
the use of cytotoxic chemotherapy and marimastat treatment. A
preliminary drug interaction trial studying a combination of carboplatin
and marimastat is expected to start shortly in the United Kingdom.
OTHER CLINICAL
TRIALS
Other Phase II trials in patients with advanced
cancer are continuing, with primary endpoints other than biological
responses as measured by cancer antigens. In Europe, disease progression
studies are under way in gastric, pancreatic and oesophageal tumours
and in secondary bone cancers. In the United States, studies are
continuing in lung and head and neck cancer and, in Canada, a
joint study with the National Cancer Institute of Canada is progressing
in patients with malignant melanoma. As at 19 April 1996, 149
patients had been recruited into these studies. Results from these
trials are expected to be available towards the end of 1996.
AVAILABILITY OF
MARIMASTAT
Today's announcement coincides with scientific
presentations at ASCO and is being made to inform shareholders
of the progress of British Biotech's most important drug development
programme. It is emphasised that marimastat is still at the clinical
research stage and that safety and efficacy awaits to be demonstrated
in definitive trials. Every effort is being made to expedite evaluation
of the drug and to bring marimastat into clinical use. However,
until definitive evidence of efficacy is available, the company
is unable to supply marimastat for the treatment of cancer patients
other than to those participating in the clinical trial programme.
Memorandum to Keith McCullagh
from Andrew Millar
INTERIM CLINICAL
DATA
Following on from our discussions on Tuesday
and Wednesday in which I disclosed to you that from November of
last year I was in possession of clinical data that had an important
potential bearing on the company's direction, I write to confirm
the following:
Marimastat:
During November, it became apparent to me from
routine surveillance of serious adverse events that the majority
of deaths in the pancreatic cancer study (128) were occurring
on marimastat. This was not superficially surprising as 75 per
cent of patients receive marimastat compared to 25 per cent on
gemcitabine, on the other hand, because the study was not blinded
between marimastat and gemcitabine I asked the project teams in
the US and UK to report to me the actual death rates on both treatments
in order to investigate any possible safety concerns. I attach
the memo from Dr Henrik Rasmussen dated 26th November 1996. At
that time there were 56 patients recruited on marimastat, 16 of
whom had died and 18 on gemcitabine, one of whom had died. This
obviously raised some concerns. Henrik, Dr Lloyd Curtis, Dr Terry
Rugg and I discussed this in detail. Firstly we observed that
numbers were very small indeed and no significant conclusions
could be drawn at that time, even though the direction of the
trends caused concern. We concluded that the deaths on marimastat
were occurring at a very short time after entry into the study,
before any possible therapeutic effect and perhaps patients would
only show a possible benefit after taking the agent for longer
periods. We had no evidence from any other studies at that time
that there was a particular safety concern with marimastat and
we all agreed that the study should be continued with the situation
under close review.
I informed Dr Peter Lewis of the situation at
the first opportunity; I cannot pinpoint the date but it would
have been either at an unscheduled meeting before December 9th
or else at our weekly meeting which was held on December 9th.
He agreed with my conclusions and indicated that he would take
appropriate cautious action from the company's point of view which
was one of my concerns. I gave him this bit of information at
the same time as the information on lexipafant (see below). He
instructed me not to tell you and to keep the information between
ourselves. He told me that we would both be for the "high
jump" if it was disclosed that I had knowledge of this clinical
data. I disagreed with this view, but recognised his authority
and trusted him to undertake appropriate action.
I watched the situation closely and decided
that I needed to look at the different dose groups on marimastat.
I directed Dr Alan Cornish to unblind the study and I attach the
worksheets for 31 January, 12 March and 29 April. I informed Peter
of each of these analyses by way of an unfiled hand written note
either at our weekly meetings or at other unscheduled convenient
opportunities. As you can see from the worksheets, the situation
with regard to deaths became no worse and equalised during the
first few months of this year. Currently there are 8/26 (30 per
cent) deaths on gemcitabine and 26/95 (27 per cent) deaths on
marimastat and I have just discontinued reviewing the situation.
At each of my meetings with Peter, he impressed upon me his view
of the importance of withholding this information and the lexipafant
data from you and gave various reasons for this. While the situation
became less concerning from a clinical point of view, I became
suspicious as to why he was so insistent, particularly as the
company was following a very optimistic course.
Lexipafant:
In November of last year, it became apparent
that the event rate in the US pancreatitis study 215 was lower
than we had expected with deaths running well below 10 per cent.
At that time, we had fully analysed the UK data which showed a
consistent but not absolutely compelling drug effect on mortality,
in that the significant analysis was stratified. On the other
hand, all the clinicians involved in the study had reviewed the
data and agreed that there was strong evidence of a therapeutic
effect in reducing mortality. It seemed essential to know whether
lexipafant was performing similarly in the high ITU usage USA
clinical situation compared to the UK. I directed Alan Cornish
to inform me of the distribution of deaths at that time. We had
very incomplete information in house with regard to dosing. I
attach his worksheets of 27 November and 31 January. On 27 November
the numbers were clearly too small to make any judgements but
you can see that there were4 deaths at 100 mg/24 hours, 2 deaths
at 10 mg/24 hours and 1 death on placebo, which represents a trend
inconsistent with great optimism. There were 5 deaths for which
we could not ascertain the dosage allocation. As more information
became available as recorded on the worksheets of 31st January
and beyond, the death rates became 12 at 10 mg/24 hours, 7 at
100 mg/24 hours and 5 on placebo. Clearly too small to draw any
conclusions, but not consistent with the probable treatment effect
we had observed in the UK study. I informed Peter Lewis of these
data at meetings held on a weekly basis between us with the response
which I indicate above. It was and remains my judgement that these
data were material to the direction of the company and I trusted
Peter to take appropriate action with regard to corporate matters.
In undertaking all of these data reviews I kept
all blinded information absolutely secret from the investigators,
project physicians, CRAs, statisticians and databasers.
Memorandum to Keith McCullagh
from Andrew Millar
MARIMASTAT PROGRAMME
Keith, this is in response to your request for
a summary of the current marimastat programme. In the text to
this memo I provide summary titles of each protocol. I attach
more detailed summaries as an appendix, but as you can see, this
is a very substantial document.
Overview
The marimastat programme is large by any standards
in cancer. It has grown from the original "phase III clinical
strategy" memo of 23 June 1995 in which 1,000 patients in
total were recommended and the subsequent memo of 23 January 1996
entitled provisional marimastat clinical plans. In both of these
documents it was stated that while the proposed clinical studies
were selected on the basis of rapid completion, there were reasons
to think that large bulk, refractory, late state disease may not
be the best in which to demonstrate efficacy. We have tried to
balance these factors within the programme and SCLC and the ovarian
cancer studies do represent relatively low burden disease situations,
but still may not be optimal. It appears that current corporate
strategies assume a high probability of success for these trials.
However, it is necessary to plan for a finite risk of failure.
I recommend a corporate direction which includes the possiblity
that marimastat may be an effective therapy, but efficacy may
not be demonstrated until after the turn of the century. This
takes account of my assessment that all studies are being performed
as rapidly as possible and speed cannot be increased.
From the limited view point of the clinical
department there are two things which we can and are doing.
Proceed with an attempt to secure an early conditional
registration in one or two late stage cancers. Negotiate with
collaborative groups to start large scale clinical trials in breast
and colorectal cancer.
PHASE III STUDIES
Common objective:
To provide data for registration in a manner
consistent with our presentation to the FDA at our end of phase
II meeting. That is:
It is our belief that a statistically significant
effect on survival in only one study has a reasonable chance of
being sufficient to gain registration; however, this was not accepted
by the FDA, although in conversation at the meeting they did indicate
that registration would depend on the data and it is still our
belief that one study would probably suffice.
It is also our belief that two positive studies
from two separate indications would be sufficient for registration.
Again the FDA did not formally accept this, but we judge that
they will accept this when presented with the data.
It may be that a registration is possible if
a study shows equivalence to an accepted therapy. For example,
the pancreatic study might conceivably have a result where there
is overall equivalence to gemcitabine and a dose response within
the marimastat groups. This may be sufficient for registration,
but this cannot be pre-judged and will depend on exactly how the
statistical analyses emerge.
The studies are as follows:
A randomised open comparison of the effect of
gemcitabine versus three doses of marimastat on survival in patients
with newly diagnosed, histologically proven, inoperable pancreatic
cancer (double blind between doses of marimastat).
Current status: 283 patients recruited out of
400
Estimated end of recruitment August/September
Estimated end of study (last CRF in house): March
1999
Estimated report date: May 1999
A randomised double blind comparison of the
effect of marimastat versus placebo on disease free interval in
patients with ovarian cancer who have responded to second line
chemotherapy.
Current status: Recruitment of 300 patients due
to start by July
Estimated end of recruitment: 2H98
Estimated end of study (last CRF in house): 2000
Estimated report date: 2H2000
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