Annex M
MEMORANDUM
| To: | Peter Lewis
| From: | Andy Millar |
| Paul Littlewood |
| |
| Peter Brown |
| |
| Peter McCann |
| |
| Greg Hockel |
| |
| Bob Blakie |
| |
| Neil Graham |
| |
| Russ Smith |
| |
| cc: | Keith McCullagh | Date:
| 13 October 1994 |
| James Noble |
| |
| Alan Drummond |
| |
| |
| |
RE: INTRA-PERITONEAL
ADVERSE EFFECTS
AND BATIMASTAT
It has been reported by Dr Mike Hawkins of Georgetown University
Hospital, Washington that patient No 005 in study D02/IVB/307
underwent laparotomy for small bowel obstruction on 9 October
1994.
This patient had advanced ovarian cancer without evidence
of widespread peritoneal disease apart from two nodules on the
stomach which were removed and no ascites at laparoscopy. It is
significant that during placement of the intra-peritoneal catheter
on 28 July 1994 prior to first administration of batimastat on
8 March 1994 that puncture of the gallbladder occurred "without
sequelae". Batimastat was administered at a dose of 1,200
mg/M2 at four weekly intervals. After the first dose, the patient
developed a pyrexia of 102F and had abdominal tenderness.
She had also developed abdominal distension and ascites was drained.
She went on to develop increasing abdominal distension and tenderness
after the third administration of batimastat which did not settle
with conservative resuscitation.
At laparotomy, the patient was found to have a large mass
of white "elephant skin" material 2-3 mm thick densely
adherent to multiple loops of small bowel in the right upper quadrant.
It was also adherent to the parietal peritoneum. The material
appeared to be some form of concretion of batimastat. Careful
dissection over 2-3 hours freed all the bowel which was found
to be "pristine", in particular it was free of any signs
of malignancy. There was one nodule in the transverse mesocolon
distal from the site of the concretion.
A sample of the material has been sent to British Biotech
for analysis for batimastat content, but the assumption is that
this represents a concretion of batimastat with inflammatory protein
or other substances. The placement of the intraperitoneal catheter
in the right upper quadrant and the finding of the white material
confined to the same area indicates that in this patient without
ascites batimastat was not distributed freely around the peritoneal
cavity and the vehicle and dextrose used to administer it presumably
was absorbed and left the batimastat to precipitate.
It is not possible to judge accurately the extent to which
the inadvertent gall bladder puncture contributed to the findings
in this patient. It is important to note that not only did this
patient not have ascites, but she has also received the largest
total amount of drug administered to a human to date.
The report from Dr Hawkins is pertinent to the report from
Professor Kerr in Birmingham where patient No 63 in study D02/IVB/309,
who had advanced ovarian adenocarcinoma with ascites was dosed
with batimastat on 18 August 1994 and was readmitted with vomiting
on 26 August 1994. Small bowel obstruction failed to resolve with
conservative management and laparatomy was performed on 16 September
1994. At laparotomy the bowel was found to be stuck together with
a dense "super-glue"-like exudate (consultant surgeon's
description). Histopathology revealed that the exudate showed
typical features of adenocarcinoma.
In Professor Smyth's first study there were two cases of
sub-acute intestinal obstruction which settled with conservative
management. It is not known whether these represented the natural
history of the disease, a fibrous reaction or other "tumour
agglutinating reaction" caused by the pharmacological effect
of batimastat, a physical irritant effect of batimastat or any
other mechanism.
Examination of the current preliminary data of patients in
study D02/IVB/309 (30 patient II ascites study) reveals that a
high proportion have reported abdominal pain, vomiting or bowel
disturbance. The dose here was 1 g/m2. These effects could be
due to tumour, a physical irritant effect of batimastat or sub-acute
bowel obstruction. It is probably not possible to determine which
without a controlled comparative study.
At present, the data in the non-ascitic abdomen are very
preliminary, however the findings in patient 005 are clear. A
reasonable explanation is that the volume of vehicle is inadequate
to disperse the drug adequately throughout the peritoneal cavity
and as the vehicle is rapidly absorbed through the normal peritoneum
batimastat precipitates. It is then combining with exudative protein
to form an adhesive concretion which is impairing normal gut motility.
If this is the mechanism then this might well occur in other patients
with normal peritoneal cavities if similar doses and methods of
delivery are used.
It is noteworthy that the AUC for this patient No 005's blood
levels has been relatively low compared to those for the ascites
patients in general and one other "non-ascites" patient
from Georgetown. This would be consistent with the batimastat
going in to a non-bioavailable form such as this apparent concretion.
The data are scanty at this stage, but it is my impression that
the blood levels in the non-ascites patients are lower than the
ascites patients and that we are not seeing dose proportionality.
This may indicate that the dry peritoneum's ability to keep batimastat
in a biologically available state is being exceeded.
The current blood levels appear high compared to the IC50
although free drug levels are not known. Dose reduction is a possibility
for overcoming the problem of concretions and still maintaining
adequate blood levels. Increasing the volume of vehicle and using
physical movement to achieve wider dispersion also seems attractive.
Methods for increasing dwell time (high molecular weight dextran)
should also be reconsidered.
These findings have implications for the current clinical
research programme:
1. We do not now have adequate data or confidence to broaden
the programme in the non-ascitic abdomen using the current dose
in the protocol of 1000 mg/m2. These studies, all in the US, should
be put on hold. We should inform the FDA and the clinical investigators
of this decision.
Action Greg Hockel and Peter McCann.
2. All patients in all clinical studies including the
ascites studies should be informed that there is a risk of gastro-intestinal
obstruction as an element of informed consent.
Action self (write letter to investigators), Peter Brown
and UK/US CRAs).
3. We should consider ways of acting in the best interests
of patient 005. For example determining what benefit she may have
received from administration of batimastat, eg discuss progression
and CA125 levels.
Action self (discuss with Mike Hawkins and James Barter).
Peter McCann and Paul Littlewood (consideration of legal situation).
4. Revise current protocol with Mike Hawkins to explore
lower doses and larger volumes of infusate.
5. Discuss situation with UK investigators involved with
dry abdomen studies and take similar action to US.
Action self and Peter Brown.
Implications for ascites phase III programme
The situation with respect to ascites is less clear at present,
but based on the current data the risk to patients is less than
for non-ascites patients, on the other hand if the drug is effective
and renders the abdomen dry then repeated administration might
produce the same effect. It therefore seems that the repeated
dosing proposed in the European and Australian protocols should
be looked at again.
The situation should become clearer with a little more time
as patients progress through study 309 and data comes in house
over the next few weeks (see attachment).
The dose of 1000 mg/m2 produces adequate blood levels (with
the caveat that free levels and tissue distribution have not yet
been determined). It is therefore possible that dose reduction
would increase tolerability and maintain efficacy particularly
if the main effect is topical. We already have lower dose levels
(500 and 250 mg/m2) in the European and Australian protocols.
It may be worth reconsidering a lower dose level in the UK study
although this may be time consuming. Unless the 309 data indicates
that the dose is definitely too high on the grounds of safety
there is no reason to change the dose of 1000 mg/m2. If the dose
does appear too high then we might need to do a further pilot
study at a lower dose. However, based on John Smyth's first 24
patients and current impressions this will not be the case.
It seems prudent to proceed cautiously in order not to risk
the malignant ascites project. The current situation will be reviewed
with John Smyth on November 2nd. I predict that around that time
it will become clear that it is appropriate to proceed with the
UK ascites study without much change, if any to the current format.
On the other hand, it seems imprudent at this stage to widen recruitment
to 60 different hospitals throughout Europe and Australia. In
the initial stages we should restrict the UK study to 10 or 15
centres to keep the data under control and reviewable.
Implications for the pleural effusion study
There seem to be no adverse implications for the treatment
of pleural effusion. Particulate matter and pleurodesis are part
of standard therapy and there are no problems akin to bowel obstruction
in the pleural cavity. Furthermore the possible need for dose
reduction in ascites is in no way disadvantageous. We will proceed
to expand this programme.
|
| Centre | Patient
| Start | 2 Month
| CRF in-house |
|
| 01 | 01 | 9 June
| 9 August | |
| Beattie | 02 | 7 July
| 7 September | |
| 03 | 14 July
| 14 September | |
| 04 | 15 July
| 15 September | |
| 05 | 18 August
| 18 October | |
| 06 | 18 August
| 18 October | |
| 07 | ? September
| ? November | |
| 08 | ? September
| ? November | |
| 02 | 20 | 6 May
| 6 July | YES* |
| Miles | 21 | 6 May
| 6 July | YES* |
| 22 | 9 May
| 9 July | YES* |
| 23 | 10 May
| 10 July | YES* |
| 24 | 9 June
| 9 August | |
| 25 | 2 August
| 2 October | |
| 26 | 22 September
| 22 November | |
| 03 | 30 | 8 September
| 8 November | |
| Carmich | 31 | 9 September
| 9 November | |
| 32 | 23 September
| 23 November | |
| 04 | 40 | 4 July
| 4 September | YES* |
| Coleman | 41 | 12 July
| 12 September | |
| 42 | 28 July
| 28 September | |
| 43 | 1 August
| 1 October | YES* |
| 44 | 25 August
| 25 October | |
| 05 | 50 | 20 May
| 20 July | |
| Perren | 51 | 28 July
| 28 September | YES* |
| 52 | 3 August
| 3 October | |
| 53 | 28 September
| 28 November | |
| 06 | 61 | 15 June
| 15 August | YES* |
| Kerr | 62 | 8 July
| 8 September | YES* |
| 63 | 13 August
| 13 October | YES* |
| 64 | 16 September
| 16 November | YES* |
| 65 | 29 September
| 29 November | |
| 66 | 6 October
| 6 December | |
| 07 | 70 | 4 October
| 4 December | |
| Green | 71 | 6 October
| 6 December | |
|
35 Patients entered.
11 CRFs In-House (10 of which are for patients who withdrew
before day 28).
10 Additional CRFs to be collected at sites now.
4 further CRFs by end October.
| 
