Phase I clinical trial of topotecan and pegylated liposomal doxorubicin.
BACKGROUND
The objective of this study was to determine the feasibility and maximum tolerated dose (MTD) of combination topotecan and pegylated liposomal doxorubicin (PLD) administered in 4- or 3-week cycles in patients with advanced or refractory solid tumors.


METHODS
Patients were treated with intravenous topotecan (0.75-1.25 mg/m2) for 3 days followed by PLD (25-40 mg/m2) on Day 4. The following dose combinations (topotecan/PLD, mg/m2) were explored: 0.75/40, 1.0/40, and 1.25/40 every 28 days; and 1.0/25 and 1.0/30 every 21 days.


RESULTS
Thirty-two patients were enrolled, and all had received prior chemotherapy. Most (84 percent) patients had ovarian cancer. A total of 157 cycles (median, 4 cycles; range, 1-19 cycles) of chemotherapy were administered. Dose-limiting toxicities were Grade 4 neutropenia and death at dose level 3 (1.25/40 mg/m2 every 28 days), and neutropenic fever, Grade 3 stomatitis, and Grade 3 peripheral neuropathy (all in one patient) at dose level 5 (1/30 mg/m2 every 21 days). Myelosuppression was the most common serious toxicity. Twenty-six patients were evaluable for response and 7 (27 percent) had partial responses. All responses were seen in patients with ovarian cancer.


CONCLUSIONS
This combination is feasible and well tolerated; encouraging activity was observed in heavily pretreated patients with ovarian cancer. The recommended regimens for a Phase II study are topotecan 1.0 mg/m2 on Days 1-3 followed by PLD 40 mg/m2 on Day 4 of a 28-day cycle, and topotecan 1.0 mg/m2 on Days 1-3 and PLD 30 mg/m2 on Day 4 of a 21-day cycle.
Garcia
Agustin A
AA
Division of Medical Oncology, University of Southern California Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA 90048, USA. agustin.garcia@cshs.org
Roman
Lynda
L
Muderspach
Laila
L
O'meara
Anne
A
Facio
Grace
G
Edwards
Susan
S
Burnett
Alexander
A
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D004317:Doxorubicin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000473:pathology; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D019772:Topotecan / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*
D000970:Antineoplastic Agents; C506643:liposomal doxorubicin; D011092:Polyethylene Glycols; D019772:Topotecan; D004317:Doxorubicin