Phase I combining a P-glycoprotein inhibitor, MS209, in combination with docetaxel in patients with advanced malignancies.
OBJECTIVE
The purpose of this study was to investigate the safety and tolerability of MS209, a potent inhibitor of P-glycoprotein, when given in combination with docetaxel and to determine whether MS209 affects docetaxel pharmacokinetics.


METHODS
Patients with advanced solid malignancies were eligible for this phase I trial. Docetaxel as 1-hour infusion was given alone during the first cycle. MS209 was introduced as of cycle 2 and given orally 30 minutes after docetaxel infusion. The dose escalation scheme followed a modified Fibonacci model with six steps (docetaxel, 60-100 mg/m2 and MS209, 300-1,200 mg per body).


RESULTS
A total of 30 patients were treated at five dose levels. Dose-limiting toxicities were febrile neutropenia, infection, stomatitis, dysphagia, and fatigue. The maximum tolerated dose was reached at level 5 (docetaxel, 80-MS: 1,200). Pharmacokinetic analysis failed to show a strong pharmacokinetic interaction between the two compounds, but at the highest dose levels, there is a trend to an increase of docetaxel AUC when this agent is given in combination with MS209.


CONCLUSIONS
MS209 can be given in combination with docetaxel, with limited effect on docetaxel toxicity or pharmacokinetics.
Diéras
Véronique
V
Department of Medical Oncology, Institut Curie, Paris, France. veronique.dieras@curie.net
Bonneterre
Jacques
J
Laurence
Valérie
V
Degardin
Marian
M
Pierga
Jean-Yves
JY
Bonneterre
Marie-Edith
ME
Marreaud
Sandrine
S
Lacombe
Denis
D
Fumoleau
Pierre
P
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019540:Area Under Curve; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D011446:Prospective Studies; D011804:Quinolines / Q000008:administration & dosage / Q000493:pharmacokinetics; D043823:Taxoids / Q000008:administration & dosage / Q000493:pharmacokinetics; D016896:Treatment Outcome
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D011804:Quinolines; D043823:Taxoids; C087719:dofequidar; D000077143:Docetaxel