Exposure-response relationship of AMG 386 in combination with weekly paclitaxel in recurrent ovarian cancer and its implication for dose selection.
OBJECTIVE
To characterize exposure-response relationships of AMG 386 in a phase 2 study in advanced ovarian cancer for the facilitation of dose selection in future studies.


METHODS
A population pharmacokinetic model of AMG 386 (N = 141) was developed and applied in an exposure-response analysis using data from patients (N = 160) with recurrent ovarian cancer who received paclitaxel plus AMG 386 (3 or 10 mg/kg once weekly) or placebo. Reduction in the risk of progression or death with increasing exposure (steady-state area under the concentration-versus-time curve [AUC(ss)]) was assessed using Cox regression analyses. Confounding factors were tested in multivariate analysis. Alternative AMG 386 doses were explored with Monte Carlo simulations using population pharmacokinetic and parametric survival models.


RESULTS
There was a trend toward increased PFS with increased AUC(ss) (hazard ratio [HR] for each one-unit increment in AUC(ss), 0.97; P = 0.097), suggesting that the maximum effect on prolonging PFS was not achieved at the highest dose tested (10 mg/kg). Among patients with AUC(ss) ≥ 9.6 mg h/mL, PFS was 8.1 months versus 5.7 months for AUC(ss) < 9.6 mg h/mL and 4.6 months for placebo. No relationship between AUC(ss) and grade ≥ 3 adverse events was observed. Simulations predicted that AMG 386 15 mg/kg once weekly would result in an AUC(ss) ≥ 9.6 mg h/mL in > 90% of patients with median PFS of 8.2 months versus 5.0 months for placebo (HR [15 mg/kg vs. placebo], 0.56).


CONCLUSIONS
Increased exposure to AMG 386 was associated with improved clinical outcomes in recurrent ovarian cancer, supporting the evaluation of a higher dose in future studies.
Amgen Inc., One Amgen Center Drive, Mailstop 28-3-B, Thousand Oaks, CA 91320, USA.
Jian-Feng
JF
Lu
Erik
E
Rasmussen
Beth Y
BY
Karlan
Ignace B
IB
Vergote
Lynn
L
Navale
Mita
M
Kuchimanchi
Rebeca
R
Melara
Daniel E
DE
Stepan
David M
DM
Weinreich
Yu-Nien
YN
Sun
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019540:Area Under Curve; D003198:Computer Simulation; D015986:Confounding Factors, Epidemiologic; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008954:Models, Biological; D009010:Monte Carlo Method; D009364:Neoplasm Recurrence, Local; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology; D017239:Paclitaxel / Q000008:administration & dosage; D016016:Proportional Hazards Models; D011446:Prospective Studies; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage; D012044:Regression Analysis; D016896:Treatment Outcome
D011993:Recombinant Fusion Proteins; D017239:Paclitaxel; C551398:trebananib