Chemistry Reference
In-Depth Information
prophylactically.
27
Most toxicities appear to be diminished with fractionated
dosing (3
3mgm
2
over one week) with no apparent loss in activity.
28
5.7 Clinical Trials
A Phase 1 clinical trial was conducted in patients with relapsed AML, for which
there was no approved treatment. Although there was very significant myelo-
suppression consistent with the depletion of CD33-positive cells, formal dose-
limiting toxicity was not reached.
29
A dose of 9mgm
2
was chosen as the final
dose, based on the observed near saturation of circulating blasts.
30
There were a
significant number of responders starting at a dose of only 1mgm
2
of con-
jugate, indicating that further clinical trials were warranted.
A total of 277 patients were treated in three similar Phase 2 clinical trials, all
of which were open-label, single-arm studies.
31
The responders fell into two
groups of about equal size, corresponding to patients with or without full
recovery of platelets (4100 000 mL
1
), which were designated CR and CRp. To
qualify for the CRp group a patient had to be transfusion independent, and
these two groups were almost identical in their responses other than having
lower platelet levels. The combined remission rate was 26% and the medium
recurrence-free survival in this heavily pre-treated patient population was 5.5
months. Based on these data, gemtuzumab ozogamicin was approved by the
FDA in May 2000 for use in patients with CD33-positive AML in first relapse
who are 60 years of age or older and are not candidates for cytotoxic che-
motherapy. The most significant advantage of gemtuzumab ozogamicin is the
ability to use it for patients who are not likely to survive the toxicities of tra-
ditional chemotherapy. This is reflected in the fact that many gemtuzumab
ozogamicin patients are treated on an out-patient basis, which reduces hospi-
talization costs
32
and which is virtually unheard of for traditional chemother-
apy for AML due to the need to monitor for toxicities.
Gemtuzumab ozogamicin has been used in many different experimental
settings in oncology research centers. In the studies in Japan that were similar
to the studies used to approve gemtuzumab ozogamicin in the US, particularly
striking results were obtained, with 4/40 patients surviving for over 44
months.
33
Gemtuzumab ozogamicin appears to be particularly active in APL
(M4 sub-group of AML),
34
and has shown activity in AML patients with
myeloid sarcoma,
35
as well as in CD33-positive ALL.
36,37
Fractionated dosing
appears to be promising.
28
Gemtuzumab ozogamicin has also been examined in
pediatric AML.
38
Although gemtuzumab ozogamicin is active as a single agent as initial therapy
in AML,
39
it appears to be more promising as part of combination che-
motherapy, with many of the possible combinations having been explored at the
MD Anderson Cancer Center. These include topotecan/Ara-C,
40
all-trans-reti-
noic acid,
23
interleukin 11,
41
liposomal daunorubicin/Ara-C/cyclosporine,
42
daunorubicin/Ara-C/thioguanine,
43
daunorubicin/Ara-C,
43
fludarabine/Ara-C/
G-CSF/idarubicin,
43
fludarabine/Ara-C/cyclosporine,
44
oblimersen,
45
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