A phase I open-label dose-escalation study of oral BIBF 1120 combined with standard paclitaxel and carboplatin in patients with advanced gynecological malignancies.
BACKGROUND
The purpose of the phase I dose-escalation study was to evaluate the maximum tolerated dose (MTD) of BIBF 1120, an oral triple angiokinase inhibitor of vascular endothelial growth factor, platelet derived growth factor and fibroblast growth factor receptors, combined with paclitaxel and carboplatin.


METHODS
Patients with advanced gynecological malignancies received BIBF 1120 twice-daily (b.i.d.) continuously at 100, 150, 200 or 250 mg, combined with paclitaxel (175 mg/m(2)) and carboplatin (area under the curve 5 min.mg/ml) every 3 weeks. The MTD, safety, pharmacokinetics (PK) and clinical activity were evaluated.


RESULTS
Twenty-two patients were treated. Three experienced dose-limiting toxic effects in the first treatment cycle: 1 of 13 at 200 mg b.i.d. BIBF 1120 [diarrhea, common terminology criteria for adverse events (CTCAE) grade 3]; two of two at 250 mg b.i.d. BIBF 1120 (elevated alanine aminotransferase and aspartate aminotransferase, CTCAE grade 3/4). The MTD was defined as 200 mg b.i.d. Principal adverse events were gastrointestinal disorders. No clinically relevant drug-drug interaction was observed after 20 days treatment with 200 mg b.i.d. BIBF 1120 on the PK of paclitaxel or carboplatin and vice versa.


CONCLUSIONS
The MTD of BIBF 1120 in a 20-day continuous dosing regimen with standard-dose paclitaxel and carboplatin was 200 mg b.i.d. This combination had an acceptable safety profile and no clinically relevant drug-drug interactions. Further evaluation of this combination is warranted in this indication.
du Bois
A
A
Department of Gynecology and Gynecologic Oncology, Dr. Horst Schmidt Klinik (HSK), Wiesbaden. Electronic address: prof.dubois@googlemail.com.
Huober
J
J
Department of Gynecology and Obstetrics, Tübingen University, Tübingen.
Stopfer
P
P
Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach.
Pfisterer
J
J
Department of Gynecology and Obstetrics, Kiel University, Kiel.
Wimberger
P
P
Department of Gynecology and Obstetrics, Essen University, Essen.
Loibl
S
S
Department of Gynecology and Obstetrics, Johann-Wolfgang-Goethe University, Frankfurt, Germany.
Reichardt
V L
VL
Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach.
Harter
P
P
Department of Gynecology and Gynecologic Oncology, Dr. Horst Schmidt Klinik (HSK), Wiesbaden.
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016190:Carboplatin / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D005260:Female; D005833:Genital Neoplasms, Female / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy* / Q000378:metabolism; D017239:Paclitaxel / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D016896:Treatment Outcome
D007211:Indoles; D016190:Carboplatin; C530716:nintedanib; D017239:Paclitaxel