Phase I study of rubitecan and gemcitabine in patients with advanced malignancies.
BACKGROUND
Rubitecan (9-nitrocamptothecin, 9-NC, Orathecin) and gemcitabine have single-agent activity in pancreatic and ovarian carcinoma. We conducted a phase I trial to evaluate the maximum tolerated dose (MTD) and toxicities of this combination in advanced malignancies.


METHODS
Twenty-one patients with refractory or recurrent malignancies were enrolled in this dose escalation trial. Dose escalation proceeded from a starting level of rubitecan at 0.75 mg/m(2)/day administered orally on days 1-5 and 8-12 in combination with gemcitabine 1000 mg/m(2) administered intravenously on days 1 and 8 of a 21-day cycle.


RESULTS
The MTD was defined as rubitecan 1 mg/m(2) administered orally days 1-5 and 8-12, and gemcitabine 1000 mg/m(2) administered intravenously over 30 min days 1 and 8, given every 21 days. Dose-limiting toxicity was myelosuppression including neutropenia and thrombocytopenia. Other side effects included diarrhea, nausea, vomiting and fatigue. Five patients with stable disease were observed among 18 evaluable patients.


CONCLUSIONS
The recommended phase II dose is rubitecan 1 mg/m(2) given orally on days 1-5 and 8-12 in combination with gemcitabine 1000 mg/m(2) as a 30-min intravenous infusion on days 1 and 8 of a 21-day cycle.
Fracasso
P M
PM
Departments of Medicine and Obstetrics and Gynecology, Washington University School of Medicine, St Louis, MO 63110, USA. fracasso@im.wustl.edu
Rader
J S
JS
Govindan
R
R
Herzog
T J
TJ
Arquette
M A
MA
Denes
A
A
Mutch
D G
DG
Picus
J
J
Tan
B R
BR
Fears
C L
CL
Goodner
S A
SA
Sun
S L
SL
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000633:toxicity*; D001707:Biopsy, Needle; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007262:Infusions, Intravenous; D008207:Lymphatic Metastasis; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000473:pathology; D009367:Neoplasm Staging; D009369:Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D018570:Risk Assessment; D016019:Survival Analysis; D016896:Treatment Outcome; D000093542:Gemcitabine
D003841:Deoxycytidine; C079905:rubitecan; D002166:Camptothecin; D000093542:Gemcitabine