Dataset Information

Exposure-response relationship of AMG 386 in combination with weekly paclitaxel in recurrent ovarian cancer and its implication for dose selection.

ABSTRACT:

Purpose

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.

SUBMITTER: Lu JF

PROVIDER: S-EPMC3337406 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature

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Publications

Exposure-response relationship of AMG 386 in combination with weekly paclitaxel in recurrent ovarian cancer and its implication for dose selection.

Lu Jian-Feng JF Rasmussen Erik E Karlan Beth Y BY Vergote Ignace B IB Navale Lynn L Kuchimanchi Mita M Melara Rebeca R Stepan Daniel E DE Weinreich David M DM Sun Yu-Nien YN

Cancer chemotherapy and pharmacology 20120101 5

<h4>Purpose</h4>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.<h4>Methods</h4>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 wit ...[more]

PMID: 22210018

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Project description:BackgroundPaclitaxel treatment produces significant peripheral neuropathy, but the time course of neuropathy development and outcomes are unclear. Dose reduction is the only strategy to prevent neurotoxicity, however, the impact of dose-reduction on neuropathy outcomes remains unknown. This study aimed to prospectively evaluated neuropathy development from weekly paclitaxel treatment and evaluate the impact of dose-reduction on post-treatment neuropathy outcomes.Patients and methodsBreast cancer patients receiving paclitaxel (80mg/m2 ) weekly for 12-weeks were prospectively assessed using patient reported (Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity; FACTGOG-Ntx), clinical (Total Neuropathy Score clinical version; TNSc) and neurophysiological measures up to 12-months post completion. The impact of dose-reduction on post-treatment (3.6 ± 0.1 months) clinical and patient reported outcomes was evaluated in 105 weekly paclitaxel-treated patients.ResultsSignificant neuropathy was present by 6-weeks across patient-reported, clinical, and objective neurophysiological assessments, increasing in prevalence and severity over the treatment course. Limited recovery occurred, with significant neuropathy being maintained up to 12 months (p < .05). Patients who received dose reduction had worse patient reported (FACT-GOG-Ntx: 40.2 ± .1.4) and clinical neuropathy outcomes (TNSc: 4.3 ± 0.4) compared to those who received the full dose (FACT-GOG-Ntx: 45.9 ± 0.9; TNSc: 3.3 ± 0.3, p < .05). Patients who ceased treatment early demonstrated the worse deficits (TNSc: 5.0 ± 0.6; FACT-GOG-Ntx: 37.3 ± 2.7) compared to those who received the complete dose (TNSc: 3.5 ± 0.3; FACT-GOG-Ntx: 45.3 ± 0.9, p < .05).ConclusionWeekly paclitaxel produces symptomatic and objective neuropathy early in the treatment course which can persist. Dose reduction does not necessarily lead to more favorable neuropathy outcomes, with individual risk factors likely important in addition to cumulative dose.Implications for practiceWeekly paclitaxel schedules are extensively used in breast cancer. Patients may develop symptomatic and objective neuropathy early in the treatment course, with these individuals requiring closer monitoring. Furthermore, neuropathy is a long-term sequela that may impact quality of life and require appropriate supportive services. Results suggest that dose reduction does not necessarily lead to better neuropathy outcomes. Understanding schedule-specific toxicity and risk factors for neuropathy will be critical to determining individualized treatment strategies and improving quality of life in breast cancer survivors.

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Dataset Information

Exposure-response relationship of AMG 386 in combination with weekly paclitaxel in recurrent ovarian cancer and its implication for dose selection.

Purpose

Methods

Results

Conclusions

Publications

Exposure-response relationship of AMG 386 in combination with weekly paclitaxel in recurrent ovarian cancer and its implication for dose selection.

Similar Datasets

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