23 research outputs found
Drug-administration sequence does not change pharmacodynamics and kinetics of irinotecan and cisplatin
Drug-administration sequence does not change pharmacodynamics and kinetics of irinotecan and cisplatin
Phase I study of irinotecan and raltitrexed in patients with advanced astrointestinal tract adenocarcinoma
To determine the dose-limiting toxicities (DLT) and maximum tolerated dose (MTD) of irinotecan and raltitrexed given as sequential short infusions every 3 weeks, 33 patients with pretreated gastrointestinal adenocarcinoma (31 colorectal, 2 oesophagogastric) entered this open label dose-escalation study. For the first five dose levels patients received irinotecan 175–350 mg m–2followed by raltitrexed 2.6 mg m–2. Level VI was irinotecan 350 mg m–2plus raltitrexed 3.0 mg m–2, level VII was irinotecan 400 mg m–2plus raltitrexed 2.6 mg m–2; 261 courses were administered. Only one patient at dose levels I–V experienced DLT. At level VI, 5/12 patients experienced DLT: one had grade 3 diarrhoea and lethargy, one had grade 4 diarrhoea and one had lethargy alone. Two others had lethargy caused by disease progression. There was no first-cycle neutropenia. At level VII, 3/6 patients experienced dose-limiting lethargy, one also had grade 3 diarrhoea. Dose intensity fell from over 90% for both drugs at level VI to 83% for irinotecan and 66% for raltitrexed at level VII. Lethargy was therefore the DLT, and level VII the MTD. Pharmacokinetic data showed no measurable drug interaction; 6/30 patients (20%) had objective responses. This combination is active with manageable toxicity. Recommended doses for further evaluation are irinotecan 350 mg m–2and raltitrexed 3.0 mg m–2. © 2000 Cancer Research Campaig
Drug-administration sequence does not change pharmacodynamics and kinetics of irinotecan and cisplatin
In this study, 11 patients with solid tumors were randomized to receive
irinotecan (CPT-11; 200 mg/m2) as a 90-min i.v. infusion, immediately
followed by cisplatin (CDDP; 80 mg/m2) as a 3-h i.v. infusion in the first
course and the reversed sequence in the second course or vice versa. No
significant differences in any toxicity were observed between the
treatment schedules (decrease in absolute neutrophil count, 74.7 +/- 18.3
versus 80.3 +/- 18.0%; P = 0.41). CPT-11 lactone clearance was similar to
single agent data and not significantly different between study courses
(60.4 +/- 17.1 versus 65.5 +/- 16.3 liter/h/m2; P = 0.66). The kinetic
profiles of the major CPT-11 metabolites SN-38, SN-38 glucuronide,
7-ethyl-10-[4-N-(5-aminopentanoic
acid)-1-piperidinolcarbonyloxycamptothecine (APC), and
7-ethyl-10-[4-N-(1-piperidino)-1-amino]carbonyloxycamptothecine (NPC) were
also sequence independent (P > or = 0.20). In addition, CPT-11 had no
influence on the clearance of nonprotein-bound CDDP (40.8 +/- 16.7 versus
50.3 +/- 18.6 liter/h/m2; P = 0.08) and the platinum DNA-adduct formation
in peripheral leukocytes in either sequence (1.94 +/- 2.20 versus 2.42 +/-
1.62 pg Pt/microg DNA; P = 0.41). These data indicate that the toxicity of
the combination CPT-11 and CDDP is schedule independent and that there is
no mutual pharmacokinetic interaction
Phase I study of docetaxel in combination with cyclophosphamide as first-line chemotherapy for metastatic breast cancer
This phase I was study conducted to establish the maximum tolerated dose, dose-limiting toxicity, and recommended dose of docetaxel in combination with cyclophosphamide as first-line chemotherapy for metastatic breast cancer. Twenty-six patients were treated with cyclophosphamide (600 mg m−2, intravenous bolus) followed by docetaxel (60, 75 or 85 mg m−2, 1-h intravenous infusion) every 3 weeks. The maximum tolerated dose was docetaxel 85 mg m−2 with cyclophosphamide 600 mg m−2, the dose-limiting toxicity being febrile neutropenia. Grade 4 neutropenia was experienced by all patients, but was generally brief. Otherwise, the combination was well tolerated with few acute and no chronic non-haematological toxicities of grade 3/4. Activity was observed at all dose levels and disease sites, and the overall response rate was 42% (95% confidence interval 22–61%). The pharmacokinetics of docetaxel were not modified by cyclophosphamide coadministration. These findings establish a recommended dose of docetaxel 75 mg m−2 in combination with cyclophosphamide 600 mg m−2 every three weeks for phase II evaluation