A phase I and pharmacologic study of the MDR converter GF120918 in combination with doxorubicin in patients with advanced solid tumors.
BACKGROUND
Resistance to chemotherapy can partly be explained by the activity of membrane bound P-glycoprotein. Competitive inhibition of P-glycoprotein, by multidrug resistance (MDR) converters, may overcome this MDR. Previously studied MDR converters either have serious intrinsic side effects or considerably influence the pharmacokinetics of cytotoxic agents at concentrations theoretically required to convert MDR. GF120918 is a third-generation MDR converter with high affinity for P-glycoprotein and can be given orally. We performed a phase 1 study with escalating doses of GF120918 in combination with doxorubicin.


METHODS
The study group comprised 46 patients with advanced solid tumors. Doxorubicin was administered on day 1 (cycle 1), GF120918 on days 22-24 (cycle 2), and on days 29-33 with doxorubicin administered on day 31 (cycle 3). Pharmacokinetics of both GF120918 and doxorubicin were studied. The starting daily dose of GF120918 was 50 mg and was to be increased in subsequent cohorts until a steady state plasma level of 100 ng/ml was reached. The starting dose of doxorubicin was 50 mg/m2 and was to be increased after reaching the target dose level of GF120918.


RESULTS
In 37 of the 46 patients, full pharmacokinetic data from the three scheduled cycles were obtained. Pharmacokinetics of GF120918 showed a less than linear increase in Cmax with increasing doses, with considerable interpatient variation. The target steady-state plasma level for GF120918 was exceeded in 12 out of 19 patients who received 400 mg GF120918 alone twice daily and in 12 of 17 patients who received 400 mg GF120918 twice daily in combination with doxorubicin. GF120918 pharmacokinetics were not influenced by coadministration of doxorubicin. The doxorubicin AUC was only marginally influenced by GF120918 and only at the highest dose levels. In these patients there was a significant increase in the AUC of doxorubicinol in cycle 3 as compared to cycle 1. Hematologic toxicity mainly consisted of neutropenia and was more severe in cycle 3 than in cycle 1 (13 vs 5 patients with grade 4 neutropenia, P=0.003). Neutropenic fever was the dose-limiting toxicity at a doxorubicin dose of 75 mg/m2 with 400 mg GF120918 twice daily. The toxicity of GF120918 was limited to somnolence in eight patients and occasional gastrointestinal complaints.


CONCLUSIONS
GF120918 is an MDR converter with only minimal side effects at a dose level yielding concentrations able to convert the action of P-glycoprotein in vitro. A doxorubicin dose of 60 mg/m2 on day 3 in combination with 400 mg GF120918 twice daily on days 1-5 is an acceptable regimen for further clinical trials.
Planting
A S T
AS
Department of Medical Oncology, Erasmus Medical Center/Daniel den Hoed Cancer Center, P.O. Box 5201, 3008 AE, Rotterdam, The Netherlands. a.s.t.planting@erasmusmc.nl
Sonneveld
P
P
van der Gaast
A
A
Sparreboom
A
A
van der Burg
M E L
ME
Luyten
G P M
GP
de Leeuw
K
K
de Boer-Dennert
M
M
Wissel
P S
PS
Jewell
R C
RC
Paul
E M
EM
Purvis
N B
NB
Verweij
J
J
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000166:Acridines / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D004334:Drug Administration Schedule; D004347:Drug Interactions; D018432:Drug Resistance, Multiple; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy; D044005:Tetrahydroisoquinolines / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000166:Acridines; D000903:Antibiotics, Antineoplastic; D044005:Tetrahydroisoquinolines; D004317:Doxorubicin; C083501:Elacridar