Chemistry Reference
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respectively, were observed in the two studies, with diarrhoea being the dose-limit-
ing toxicity in both cases. All other toxicities observed at MTD were mild to mod-
erate, and no significant myelosuppression was found. The drug seemed to be
particularly active in patients with colorectal cancer, with additional responses in
patients with breast, ovarian, and NSCLC cancers, and carcinoid tumors, whose dis-
ease had progressed on several other therapies. Phase II trials with Epo B in color-
ectal cancer are currently ongoing (second-line treatment), and preliminary data
seem to indicate that the drug is active.
64
Subsequent of the initiation of clinical studies with Epo B, a variety of modified
analogs have also proceeded to clinical evaluation in humans. The most advanced
of these compounds is BMS-247550 (1), and the current state of the clinical phar-
macology for this compound has been summarized recently in an excellent review
by Lin et al.
128
(see also Ref. 39). (As for all other agents of this class, most of the
original information related to clinical trial results with BMS-247550 (1) is only
available in the form of meeting abstracts and posters). Briefly, clinical trials
with BMS-247550 (1) were initiated in early 2000, and several objective responses
to single-agent treatment with the compound were observed in these studies in
breast, ovarian, cervical, prostate, colon, lung, and renal cancers as well as in
squamous cell cancers of the head and neck, lymphoma, and angiosarcoma.
Dose-limiting toxicities included fatigue, prolonged neutropenia, and peripheral
neuropathy.
129
The compound was also shown to be orally bioavailable in
humans,
39
which thus confirms previous results from animal studies (vide supra).
71
Very importantly, BMS-247550 (1) has been demonstrated to induce microtubule
bundling in peripheral blood monocytes (PBMCs) of treated persons, and a good
correlation was observed between the magnitude of this effect and plasma areas under
the curve.
130
These findings validate the in vitro pharmacodynamic findings with
BMS-247550 (1) in the clinical setting.
Phase II trials with BMS-247550 (1) have produced objective responses for a
variety of tumor types, including tumors that had been refractory to treatment
with platinum-based drugs or taxanes.
39,128
Based on these highly promising
results, the compound has been advanced to phase III studies, which are cur-
rently ongoing in parallel with several phase II trials (including combination
studies).
39
Phase I clinical studies have recently been completed with Epo D, and phase II
trials with the compound are now ongoing together with an additional phase I study
[sponsored by Kosan Biosciences (as KOS-862)].
131,132
As for BMS-247550,
KOS-862 was demonstrated to induce microtubule bundling in patient PBMCs,
and several tumor responses have been noted in the phase I studies.
131
The most recent additions to the portfolio of epothilone-type clinical develop-
ment compounds are the semisynthetic derivatives BMS-310705 (23),
39,133
which
differs from Epo B by the presence of a primary amino group at C21, and C20-
desmethyl-C20-methylsulfanyl-Epo B (32, ABJ879).
122
As indicated above,
BMS-310705 (23) exhibits improved water-solubility over BMS-247550 (1), thus
allowing the use of clinical formulations not containing Cremophor-EL.
39
Accord-
ingly, no hypersensitivity reactions were observed in phase I studies with BMS-
310705 (23) in contrast to BMS-247550 (1) (in the absence of premedication).
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