Clinical activity of patupilone in patients with pretreated advanced/metastatic colon cancer: results of a phase I dose escalation trial.
BACKGROUND
New agents that are active in patients with metastatic colorectal cancer are needed. Patupilone (EPO906; epothilone B) is a novel microtubule-stabilising agent.


METHODS
Patients with advanced colon cancer who progressed after prior treatment regimens received intravenous patupilone (6.5-10.0 mg m(-2)) once every 3 weeks by a 20-min infusion (20MI), 24-h continuous infusion (CI-1D) or 5-day intermittent 16-h infusion (16HI-5D). Adverse events (AEs), dose-limiting toxicities (DLTs), pharmacokinetics and anti-tumour activity were assessed.


RESULTS
Sixty patients were enrolled. The maximum tolerated dose (MTD) was not reached in the 20MI arm (n=31), as no DLTs were observed. Three patients in the CI-1D arm (n=26) experienced 1 DLT each at 7.5, 8.0 and 9.0 mg m(-2), but MTD was not reached. However, the prolonged 16HI-5D arm was terminated at 6.5 mg m(-2) after two of the three patients developed a DLT. Diarrhoea was the most common AE and DLT, with increased severity at the higher doses (9.0 and 10.0 mg m(-2)). Grade 3 or 4 diarrhoea was observed in 11 (35%) of the patients in the 20MI arm, 4 (15%) of the patients in the CI-1D arm and 2 (67%) of the patients in the 16HI-5D arm. Patupilone activity was observed in the 20MI arm with a disease control rate of 58%, including four confirmed partial responses. The disease control rate in CI-1D arm was 39%.


CONCLUSIONS
Patupilone given once every 3 weeks as a 20-min infusion had promising anti-tumour activity and manageable safety profile at doses that demonstrated therapeutic efficacy.
Charles University Medical School and Teaching Hospital, Sokolská 581, Hradec Králové, Czech Republic. bohuslav.melichar@fnol.cz
B
B
Melichar
E
E
Casado
J
J
Bridgewater
J
J
Bennouna
M
M
Campone
P
P
Vitek
J-P
JP
Delord
J
J
Cerman
R
R
Salazar
J
J
Dvorak
C
C
Sguotti
P
P
Urban
K
K
Viraswami-Appanna
E
E
Tan
J
J
Tabernero
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D034261:Epothilones / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous / Q000379:methods; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009362:Neoplasm Metastasis; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D034261:Epothilones; C093788:epothilone B