Phase I and pharmacological study of pazopanib in combination with oral topotecan in patients with advanced solid tumours.
BACKGROUND
This phase I study evaluated the safety, tolerability, maximum tolerated dose (MTD) and pharmacokinetics of two dosing schedules of oral topotecan in combination with pazopanib in patients with advanced solid tumours.


METHODS
Stage I of this study was to determine whether there was an impact of pazopanib on topotecan exposure. In stage II, the MTD and safety profile of oral topotecan given weekly on days 1, 8 and 15 in a 28-day cycle; or daily-times-five on days 1-5 in a 21-day cycle, both in combination with daily pazopanib, were explored.


RESULTS
In total, 67 patients were enroled. Pazopanib co-administration caused a substantial increase in exposure to total topotecan (1.7-fold) compared with topotecan alone, which is considered clinically relevant. Topotecan had no effect on pazopanib concentrations. Safety findings were consistent with the known profile of both agents. There were three drug-related deaths, liver failure, tumour haemorrhage and myelosuppression. Two patients experienced dose-limiting toxicities (DLTs; hand-foot syndrome, myelosuppression and diarrhoea) on the weekly topotecan schedule and four patients experienced DLTs (myelosuppression) on the daily-times-five topotecan schedule. When combined with pazopanib, 800 mg daily, the recommended doses for oral topotecan are: 8 mg weekly and 2.5 mg daily-times-five. Seven of eight patients with partial response had platinum-resistant ovarian cancer. In addition, 54% of patients had stable disease with 22% stable for 6 months.


CONCLUSIONS
Total topotecan exposure is 1.7-fold higher when co-administered with pazopanib. Both schedules of administration were tolerated and would permit further evaluation, especially the weekly schedule.
Department of Clinical Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.|Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
B Milojkovic
BM
Kerklaan
Department of Medical Oncology, University Medical Center Utrecht, Utrecht, The Netherlands.
M P J
MP
Lolkema
Department of Clinical Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.|Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
L A
LA
Devriese
Department of Medical Oncology, University Medical Center Utrecht, Utrecht, The Netherlands.
E E
EE
Voest
Department of Clinical Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
A
A
Nol-Boekel
Department of Clinical Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
M
M
Mergui-Roelvink
Department of Medical Oncology, University Medical Center Utrecht, Utrecht, The Netherlands.
M
M
Langenberg
Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
K
K
Mykulowycz
GlaxoSmithKline, Research Triangle Park, North Carolina, USA.
J
J
Stoebenau
GlaxoSmithKline, Research Triangle Park, North Carolina, USA.
S
S
Lane
GlaxoSmithKline, Research Triangle Park, North Carolina, USA.
P
P
Legenne
GlaxoSmithKline, Research Triangle Park, North Carolina, USA.
P
P
Wissel
GlaxoSmithKline, Research Triangle Park, North Carolina, USA.
D A
DA
Smith
Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
B J
BJ
Giantonio
Department of Clinical Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.|Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.|Science Faculty, Utrecht Institute of Pharmaceutical Sciences (UIPS), Utrecht University, Utrecht, The Netherlands.
J H M
JH
Schellens
Department of Medical Oncology, University Medical Center Utrecht, Utrecht, The Netherlands.
P O
PO
Witteveen
D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity; D005260:Female; D006801:Humans; D007191:Indazoles; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011743:Pyrimidines / Q000008:administration & dosage; D013449:Sulfonamides / Q000008:administration & dosage; D019772:Topotecan / Q000008:administration & dosage; D016896:Treatment Outcome; D055815:Young Adult
D007191:Indazoles; D011743:Pyrimidines; D013449:Sulfonamides; D019772:Topotecan; C516667:pazopanib