Phase I/II trial of sorafenib in combination with vinorelbine as first-line chemotherapy for metastatic breast cancer

Cristiano Ferrario, Ivan Strepponi, Khashayar Esfahani, Helen Charamis, Adrian Langleben, Emanuela Scarpi, Oriana Nanni, Wilson H. Miller, Lawrence C. Panasci

Research output: Contribution to journalArticle

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Abstract

Background: Preclinical models have reported a synergistic interaction between sorafenib and vinorelbine. We investigated the toxicity, efficacy, and pharmacokinetics interaction of this combination as first-line treatment for patients with metastatic breast cancer. Methods: Patients were HER2-negative and treated with vinorelbine 30 mg/m2 IV days 1,8 every 21 plus daily oral sorafenib. In the phase I portion (3+3 design) patients received sorafenib 200 mg BID (cohort 1) or 400 mg BID (cohort 2). In the phase II expansion, 21 more evaluable patients were planned to receive the maximum tolerated dose (MTD). Pharmacokinetic analysis was performed in 6 patients: blood concentrations were compared for each drug in the presence or absence of the other drug. Results: In cohort 1, one patient experienced a dose-limiting toxicity (DLT) (grade 3 pancreatitis), requiring the expansion of this cohort to 6 patients, without further documented DLTs. In cohort 2, one patient of six experienced a grade 4 DLT (asymptomatic rise in amylase not requiring drug discontinuation), establishing this dose level as the MTD (sorafenib 400 mg BID). After expansion at the MTD, a total of 27 patients (median age 57) were treated for a median of 8 cycles. One grade 5 febrile neutropenia occurred. With repeated cycles, 52% of patients required at least 1 dose reduction of either drug. One patient experienced a sustained grade 3 fatigue resulting in treatment discontinuation. The response rate was 30%. Median PFS was 5.7 months (95% CI 4.4-7.6), and clinical benefit (absence of disease progression at 6 months) was 48%. PK analysis showed a significant interaction between the two drugs, resulting in a higher Cmax of vinorelbine in the presence of sorafenib. Conclusion: The combination of sorafenib and vinorelbine at full doses is feasible but not devoid of toxicity, likely also due to a significant PK interaction.

Original languageEnglish
Article numbere0167906
JournalPLoS One
Volume11
Issue number12
DOIs
Publication statusPublished - Dec 1 2016

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Chemotherapy
breast neoplasms
drug therapy
Breast Neoplasms
Drug Therapy
Toxicity
Pharmacokinetics
Pharmaceutical Preparations
dosage
Maximum Tolerated Dose
drugs
toxicity
Amylases
pharmacokinetics
sorafenib
vinorelbine
Blood
Fatigue of materials
Febrile Neutropenia
neutropenia

ASJC Scopus subject areas

  • Medicine(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Ferrario, C., Strepponi, I., Esfahani, K., Charamis, H., Langleben, A., Scarpi, E., ... Panasci, L. C. (2016). Phase I/II trial of sorafenib in combination with vinorelbine as first-line chemotherapy for metastatic breast cancer. PLoS One, 11(12), [e0167906]. https://doi.org/10.1371/journal.pone.0167906

Phase I/II trial of sorafenib in combination with vinorelbine as first-line chemotherapy for metastatic breast cancer. / Ferrario, Cristiano; Strepponi, Ivan; Esfahani, Khashayar; Charamis, Helen; Langleben, Adrian; Scarpi, Emanuela; Nanni, Oriana; Miller, Wilson H.; Panasci, Lawrence C.

In: PLoS One, Vol. 11, No. 12, e0167906, 01.12.2016.

Research output: Contribution to journalArticle

Ferrario, C, Strepponi, I, Esfahani, K, Charamis, H, Langleben, A, Scarpi, E, Nanni, O, Miller, WH & Panasci, LC 2016, 'Phase I/II trial of sorafenib in combination with vinorelbine as first-line chemotherapy for metastatic breast cancer', PLoS One, vol. 11, no. 12, e0167906. https://doi.org/10.1371/journal.pone.0167906
Ferrario, Cristiano ; Strepponi, Ivan ; Esfahani, Khashayar ; Charamis, Helen ; Langleben, Adrian ; Scarpi, Emanuela ; Nanni, Oriana ; Miller, Wilson H. ; Panasci, Lawrence C. / Phase I/II trial of sorafenib in combination with vinorelbine as first-line chemotherapy for metastatic breast cancer. In: PLoS One. 2016 ; Vol. 11, No. 12.
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abstract = "Background: Preclinical models have reported a synergistic interaction between sorafenib and vinorelbine. We investigated the toxicity, efficacy, and pharmacokinetics interaction of this combination as first-line treatment for patients with metastatic breast cancer. Methods: Patients were HER2-negative and treated with vinorelbine 30 mg/m2 IV days 1,8 every 21 plus daily oral sorafenib. In the phase I portion (3+3 design) patients received sorafenib 200 mg BID (cohort 1) or 400 mg BID (cohort 2). In the phase II expansion, 21 more evaluable patients were planned to receive the maximum tolerated dose (MTD). Pharmacokinetic analysis was performed in 6 patients: blood concentrations were compared for each drug in the presence or absence of the other drug. Results: In cohort 1, one patient experienced a dose-limiting toxicity (DLT) (grade 3 pancreatitis), requiring the expansion of this cohort to 6 patients, without further documented DLTs. In cohort 2, one patient of six experienced a grade 4 DLT (asymptomatic rise in amylase not requiring drug discontinuation), establishing this dose level as the MTD (sorafenib 400 mg BID). After expansion at the MTD, a total of 27 patients (median age 57) were treated for a median of 8 cycles. One grade 5 febrile neutropenia occurred. With repeated cycles, 52{\%} of patients required at least 1 dose reduction of either drug. One patient experienced a sustained grade 3 fatigue resulting in treatment discontinuation. The response rate was 30{\%}. Median PFS was 5.7 months (95{\%} CI 4.4-7.6), and clinical benefit (absence of disease progression at 6 months) was 48{\%}. PK analysis showed a significant interaction between the two drugs, resulting in a higher Cmax of vinorelbine in the presence of sorafenib. Conclusion: The combination of sorafenib and vinorelbine at full doses is feasible but not devoid of toxicity, likely also due to a significant PK interaction.",
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AU - Charamis, Helen

AU - Langleben, Adrian

AU - Scarpi, Emanuela

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AB - Background: Preclinical models have reported a synergistic interaction between sorafenib and vinorelbine. We investigated the toxicity, efficacy, and pharmacokinetics interaction of this combination as first-line treatment for patients with metastatic breast cancer. Methods: Patients were HER2-negative and treated with vinorelbine 30 mg/m2 IV days 1,8 every 21 plus daily oral sorafenib. In the phase I portion (3+3 design) patients received sorafenib 200 mg BID (cohort 1) or 400 mg BID (cohort 2). In the phase II expansion, 21 more evaluable patients were planned to receive the maximum tolerated dose (MTD). Pharmacokinetic analysis was performed in 6 patients: blood concentrations were compared for each drug in the presence or absence of the other drug. Results: In cohort 1, one patient experienced a dose-limiting toxicity (DLT) (grade 3 pancreatitis), requiring the expansion of this cohort to 6 patients, without further documented DLTs. In cohort 2, one patient of six experienced a grade 4 DLT (asymptomatic rise in amylase not requiring drug discontinuation), establishing this dose level as the MTD (sorafenib 400 mg BID). After expansion at the MTD, a total of 27 patients (median age 57) were treated for a median of 8 cycles. One grade 5 febrile neutropenia occurred. With repeated cycles, 52% of patients required at least 1 dose reduction of either drug. One patient experienced a sustained grade 3 fatigue resulting in treatment discontinuation. The response rate was 30%. Median PFS was 5.7 months (95% CI 4.4-7.6), and clinical benefit (absence of disease progression at 6 months) was 48%. PK analysis showed a significant interaction between the two drugs, resulting in a higher Cmax of vinorelbine in the presence of sorafenib. Conclusion: The combination of sorafenib and vinorelbine at full doses is feasible but not devoid of toxicity, likely also due to a significant PK interaction.

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