Abstract
Purpose: The methoxymorpholinyl doxorubicin analogue PNU 152243 was brought into clinical studies because of preclinical observations of its non- cross-resistance in mdr tumor cells, dose-limiting neutropenia, lack of cardiotoxicity, and antitumor activity after oral administration. Methods: PNU 152243 was given orally every 4 weeks to 21 adults with a variety of solid tumors at doses ranging from 59 to 940 μg/m2. Antiemetic prophylaxis with 5-HT3 antagonists and steroids, given i.v. on day 1 and orally on days 2-8, was required beginning with the dose of 118 μg/m2. The plasma pharmacokinetics of PNU 152243 were determined by an HPLC method with fluorescence detection. The in vitro myelotoxic effects on granulocyte macrophage-colony forming cells (GM-CFC) of the plasma from 11 patients, obtained 4 and 6 h after treatment at all dose levels, were also assessed. Results: Neutropenia was the main hematologic toxic effect and the maximum tolerated dose (MTD) for myelotoxicity was 940 μg/m2, with neutropenia grade 3-4 in two of three patients: Dose-dependent nausea and vomiting were dose-limiting and the MTD for gastrointestinal toxicity was fixed at 820 μg/m2, with grade 4 vomiting in one of two patients. Other frequent toxic effects were diarrhea and fatigue. Peak levels of PNU 152243 were achieved 4 h after dosing. Dose-dependent Cmax and AUCExp, and significant interpatient variability of the main pharmacokinetic parameters were found. Very low levels of the 13-dihydrometabolite PNU 155051 were detected only at the highest doses. The hematotoxicity tests showed a
| Original language | English |
|---|---|
| Pages (from-to) | 403-410 |
| Number of pages | 8 |
| Journal | Cancer Chemotherapy and Pharmacology |
| Volume | 44 |
| Issue number | 5 |
| DOIs | |
| Publication status | Published - 1999 |
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Keywords
- Anthracycline analogs
- Hematotoxicology
- Methoxymorpholinyl doxorubicin
- Oral chemotherapy
- Phase I
ASJC Scopus subject areas
- Cancer Research
- Pharmacology
- Oncology
Cite this
Phase I clinical and pharmacological study of oral methoxymorpholinyl doxorubicin (PNU 152243). / Sessa, Cristiana; Zucchetti, Massimo; Ghielmini, Michele; Bauer, Jean; D'Incalci, Maurizio; De Jong, Jolanda; Naegele, Huguette; Rossi, Simona; Pacciarini, Maria Adele; Domenigoni, Letizia; Cavalli, Franco.
In: Cancer Chemotherapy and Pharmacology, Vol. 44, No. 5, 1999, p. 403-410.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Phase I clinical and pharmacological study of oral methoxymorpholinyl doxorubicin (PNU 152243)
AU - Sessa, Cristiana
AU - Zucchetti, Massimo
AU - Ghielmini, Michele
AU - Bauer, Jean
AU - D'Incalci, Maurizio
AU - De Jong, Jolanda
AU - Naegele, Huguette
AU - Rossi, Simona
AU - Pacciarini, Maria Adele
AU - Domenigoni, Letizia
AU - Cavalli, Franco
PY - 1999
Y1 - 1999
N2 - Purpose: The methoxymorpholinyl doxorubicin analogue PNU 152243 was brought into clinical studies because of preclinical observations of its non- cross-resistance in mdr tumor cells, dose-limiting neutropenia, lack of cardiotoxicity, and antitumor activity after oral administration. Methods: PNU 152243 was given orally every 4 weeks to 21 adults with a variety of solid tumors at doses ranging from 59 to 940 μg/m2. Antiemetic prophylaxis with 5-HT3 antagonists and steroids, given i.v. on day 1 and orally on days 2-8, was required beginning with the dose of 118 μg/m2. The plasma pharmacokinetics of PNU 152243 were determined by an HPLC method with fluorescence detection. The in vitro myelotoxic effects on granulocyte macrophage-colony forming cells (GM-CFC) of the plasma from 11 patients, obtained 4 and 6 h after treatment at all dose levels, were also assessed. Results: Neutropenia was the main hematologic toxic effect and the maximum tolerated dose (MTD) for myelotoxicity was 940 μg/m2, with neutropenia grade 3-4 in two of three patients: Dose-dependent nausea and vomiting were dose-limiting and the MTD for gastrointestinal toxicity was fixed at 820 μg/m2, with grade 4 vomiting in one of two patients. Other frequent toxic effects were diarrhea and fatigue. Peak levels of PNU 152243 were achieved 4 h after dosing. Dose-dependent Cmax and AUCExp, and significant interpatient variability of the main pharmacokinetic parameters were found. Very low levels of the 13-dihydrometabolite PNU 155051 were detected only at the highest doses. The hematotoxicity tests showed a
AB - Purpose: The methoxymorpholinyl doxorubicin analogue PNU 152243 was brought into clinical studies because of preclinical observations of its non- cross-resistance in mdr tumor cells, dose-limiting neutropenia, lack of cardiotoxicity, and antitumor activity after oral administration. Methods: PNU 152243 was given orally every 4 weeks to 21 adults with a variety of solid tumors at doses ranging from 59 to 940 μg/m2. Antiemetic prophylaxis with 5-HT3 antagonists and steroids, given i.v. on day 1 and orally on days 2-8, was required beginning with the dose of 118 μg/m2. The plasma pharmacokinetics of PNU 152243 were determined by an HPLC method with fluorescence detection. The in vitro myelotoxic effects on granulocyte macrophage-colony forming cells (GM-CFC) of the plasma from 11 patients, obtained 4 and 6 h after treatment at all dose levels, were also assessed. Results: Neutropenia was the main hematologic toxic effect and the maximum tolerated dose (MTD) for myelotoxicity was 940 μg/m2, with neutropenia grade 3-4 in two of three patients: Dose-dependent nausea and vomiting were dose-limiting and the MTD for gastrointestinal toxicity was fixed at 820 μg/m2, with grade 4 vomiting in one of two patients. Other frequent toxic effects were diarrhea and fatigue. Peak levels of PNU 152243 were achieved 4 h after dosing. Dose-dependent Cmax and AUCExp, and significant interpatient variability of the main pharmacokinetic parameters were found. Very low levels of the 13-dihydrometabolite PNU 155051 were detected only at the highest doses. The hematotoxicity tests showed a
KW - Anthracycline analogs
KW - Hematotoxicology
KW - Methoxymorpholinyl doxorubicin
KW - Oral chemotherapy
KW - Phase I
UR - http://www.scopus.com/inward/record.url?scp=0032834824&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0032834824&partnerID=8YFLogxK
U2 - 10.1007/s002800050996
DO - 10.1007/s002800050996
M3 - Article
C2 - 10501914
AN - SCOPUS:0032834824
VL - 44
SP - 403
EP - 410
JO - Cancer Chemotherapy and Pharmacology
JF - Cancer Chemotherapy and Pharmacology
SN - 0344-5704
IS - 5
ER -