Phase II and pharmacokinetic trial of rebeccamycin analog in advanced biliary cancers.
OBJECTIVE
Advanced cancers of the bile duct and gallbladder carry an ominous prognosis. Rebeccamycin analogue (RA) is a novel antitumor antibiotic where phase I trials suggested clinical efficacy in patients with biliary cancers.


METHODS
The primary objective was to determine the response rate to RA in patients with advanced gallbladder and bile duct tumors. Secondary endpoints were survival and pharmacokinetic characterization. RA was given at a dose 165 mg/(m(2) day) x 5 days every 3 weeks.


RESULTS
Forty-six patients were enrolled. Nine patients were removed from study before their first planned imaging study for response. Two patients had partial responses and 16 had stable disease. On an intent-to-treat analysis the median survival was 6.3 months. A >20% drop in CA19.9 was seen in 43% of patients with initial high levels. Grade 4 neutropenia and thrombocytopenia were seen in 35 and 5% of patients, respectively. Febrile neutropenia occurred in 16% of patients. The pharmacokinetic profile of this trial closely resembles those of prior phase I trials. Measured biliary concentrations of RA were as much as 100x greater than simultaneous plasma concentration.


CONCLUSIONS
Although RA has a response rate of 5% in advanced biliary cancers, it is associated with significant numbers of patients experiencing prolonged stable disease. Biliary concentrations of RA are significantly greater than plasma concentrations.
Dowlati
Afshin
A
University Hospitals Case Medical Center, 11100 Euclid Avenue, Cleveland, OH 44106, USA. afshin.dowlati@case.edu
Posey
James
J
Ramanathan
Ramesh K
RK
Rath
Linda
L
Fu
Pingfu
P
Chak
Amitabh
A
Krishnamurthi
Smitha
S
Brell
Joanna
J
Ingalls
Stephen
S
Hoppel
Charles L
CL
Ivy
Percy
P
Remick
Scot C
SC
D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001650:Bile Duct Neoplasms / Q000188:drug therapy* / Q000401:mortality; D018395:CA-19-9 Antigen / Q000097:blood; D002227:Carbazoles / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005260:Female; D005334:Fever / Q000139:chemically induced; D005706:Gallbladder Neoplasms / Q000188:drug therapy* / Q000401:mortality; D005960:Glucosides / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009503:Neutropenia / Q000139:chemically induced; D015996:Survival Rate; D013921:Thrombocytopenia / Q000139:chemically induced
D000970:Antineoplastic Agents; D018395:CA-19-9 Antigen; D002227:Carbazoles; D005960:Glucosides; C093269:becatecarin