Phase 1b Study of Trebananib Plus Paclitaxel and Trastuzumab in Patients With HER2-Positive Locally Recurrent or Metastatic Breast Cancer

Peter A. Kaufman, Hans Wildiers, Gilles Freyer, Margaret Kemeny, Anthony Gonçalves, Guy Jerusalem, Alison T Stopeck, Nandagopal Vrindavanam, Florence Dalenc, Nuwan Nanayakkara, Benjamin Wu, Cheryl A. Pickett

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Introduction: Trebananib, a peptide-Fc fusion protein, blocks angiogenesis by inhibiting binding of angiopoietin-1/2 to the receptor tyrosine kinase Tie2. Trebananib plus trastuzumab and paclitaxel was evaluated in human epidermal growth factor receptor 2–positive breast cancer in an open-label phase 1b clinical study. Patients and Methods: Women with human epidermal growth factor receptor 2–positive breast cancer received weekly paclitaxel (80 mg/m2), trastuzumab (8 mg/m2 then 6 mg/kg every 3 weeks), and intravenous trebananib (10 mg/kg or 30 mg/kg weekly) beginning week 2. The primary end point was the incidence of dose-limiting toxicities. Secondary end points included incidence of adverse events (AEs), pharmacokinetics, and tumor response (objective response and duration of response). Results: Forty women were enrolled; 2 experienced dose-limiting toxicities (grade 3 ocular transient ischemic attack [10 mg/kg cohort] and grade 3 elevation in γ-glutamyl transferase [30 mg/kg cohort]). The most common treatment-emergent AEs were peripheral edema (n = 28), diarrhea (n = 27), alopecia (n = 26), fatigue (n = 24), and nausea (n = 24). Maximum observed concentration and area under the concentration–time curve increased proportionally with the trebananib dose. Objective response was confirmed in 31 patients. In the 10 mg/kg cohort, 16 patients (80%) experienced partial response, and none experienced complete response. In the 30 mg/kg cohort, 12 patients (71%) experienced partial response and 3 (18%) experienced complete response. Median (95% confidence interval) duration of response in the 10 and 30 mg/kg cohorts was 12.6 (4.3-20.2) and 16.6 (8.2-not estimable) months, respectively. Conclusion: This phase 1b study showed that trebananib was tolerated with manageable AEs at a dose up to 30 mg/kg weekly. Trebananib demonstrated anticancer activity, as indicated by objective response and duration of response. Given the potential interactions between human epidermal growth factor receptor 2 (HER2) signaling and angiogenesis, we investigated the angiopoietin (Ang) 1/Ang2 inhibitor trebananib plus trastuzumab and paclitaxel in HER2-positive breast cancer. Forty women received trebananib (10 or 30 mg/kg) plus trastuzumab and paclitaxel. The combination demonstrated acceptable toxicity and antitumor response in HER2-positive locally recurrent/metastatic breast cancer.

Original languageEnglish (US)
JournalClinical Breast Cancer
DOIs
StateAccepted/In press - Jan 1 2018
Externally publishedYes

Fingerprint

Paclitaxel
Breast Neoplasms
Angiopoietin-1
Epidermal Growth Factor Receptor
Angiopoietin-2
human ERBB2 protein
Trastuzumab
trebananib
Transient Ischemic Attack
Alopecia
Incidence
Receptor Protein-Tyrosine Kinases
Transferases
Nausea
Area Under Curve
Fatigue
Diarrhea
Edema
Pharmacokinetics
Confidence Intervals

Keywords

  • AMG 386
  • Angiogenesis
  • Angiopoietin
  • HER2 positive

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Phase 1b Study of Trebananib Plus Paclitaxel and Trastuzumab in Patients With HER2-Positive Locally Recurrent or Metastatic Breast Cancer. / Kaufman, Peter A.; Wildiers, Hans; Freyer, Gilles; Kemeny, Margaret; Gonçalves, Anthony; Jerusalem, Guy; Stopeck, Alison T; Vrindavanam, Nandagopal; Dalenc, Florence; Nanayakkara, Nuwan; Wu, Benjamin; Pickett, Cheryl A.

In: Clinical Breast Cancer, 01.01.2018.

Research output: Contribution to journalArticle

Kaufman, PA, Wildiers, H, Freyer, G, Kemeny, M, Gonçalves, A, Jerusalem, G, Stopeck, AT, Vrindavanam, N, Dalenc, F, Nanayakkara, N, Wu, B & Pickett, CA 2018, 'Phase 1b Study of Trebananib Plus Paclitaxel and Trastuzumab in Patients With HER2-Positive Locally Recurrent or Metastatic Breast Cancer', Clinical Breast Cancer. https://doi.org/10.1016/j.clbc.2018.09.012
Kaufman, Peter A. ; Wildiers, Hans ; Freyer, Gilles ; Kemeny, Margaret ; Gonçalves, Anthony ; Jerusalem, Guy ; Stopeck, Alison T ; Vrindavanam, Nandagopal ; Dalenc, Florence ; Nanayakkara, Nuwan ; Wu, Benjamin ; Pickett, Cheryl A. / Phase 1b Study of Trebananib Plus Paclitaxel and Trastuzumab in Patients With HER2-Positive Locally Recurrent or Metastatic Breast Cancer. In: Clinical Breast Cancer. 2018.
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title = "Phase 1b Study of Trebananib Plus Paclitaxel and Trastuzumab in Patients With HER2-Positive Locally Recurrent or Metastatic Breast Cancer",
abstract = "Introduction: Trebananib, a peptide-Fc fusion protein, blocks angiogenesis by inhibiting binding of angiopoietin-1/2 to the receptor tyrosine kinase Tie2. Trebananib plus trastuzumab and paclitaxel was evaluated in human epidermal growth factor receptor 2–positive breast cancer in an open-label phase 1b clinical study. Patients and Methods: Women with human epidermal growth factor receptor 2–positive breast cancer received weekly paclitaxel (80 mg/m2), trastuzumab (8 mg/m2 then 6 mg/kg every 3 weeks), and intravenous trebananib (10 mg/kg or 30 mg/kg weekly) beginning week 2. The primary end point was the incidence of dose-limiting toxicities. Secondary end points included incidence of adverse events (AEs), pharmacokinetics, and tumor response (objective response and duration of response). Results: Forty women were enrolled; 2 experienced dose-limiting toxicities (grade 3 ocular transient ischemic attack [10 mg/kg cohort] and grade 3 elevation in γ-glutamyl transferase [30 mg/kg cohort]). The most common treatment-emergent AEs were peripheral edema (n = 28), diarrhea (n = 27), alopecia (n = 26), fatigue (n = 24), and nausea (n = 24). Maximum observed concentration and area under the concentration–time curve increased proportionally with the trebananib dose. Objective response was confirmed in 31 patients. In the 10 mg/kg cohort, 16 patients (80{\%}) experienced partial response, and none experienced complete response. In the 30 mg/kg cohort, 12 patients (71{\%}) experienced partial response and 3 (18{\%}) experienced complete response. Median (95{\%} confidence interval) duration of response in the 10 and 30 mg/kg cohorts was 12.6 (4.3-20.2) and 16.6 (8.2-not estimable) months, respectively. Conclusion: This phase 1b study showed that trebananib was tolerated with manageable AEs at a dose up to 30 mg/kg weekly. Trebananib demonstrated anticancer activity, as indicated by objective response and duration of response. Given the potential interactions between human epidermal growth factor receptor 2 (HER2) signaling and angiogenesis, we investigated the angiopoietin (Ang) 1/Ang2 inhibitor trebananib plus trastuzumab and paclitaxel in HER2-positive breast cancer. Forty women received trebananib (10 or 30 mg/kg) plus trastuzumab and paclitaxel. The combination demonstrated acceptable toxicity and antitumor response in HER2-positive locally recurrent/metastatic breast cancer.",
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T1 - Phase 1b Study of Trebananib Plus Paclitaxel and Trastuzumab in Patients With HER2-Positive Locally Recurrent or Metastatic Breast Cancer

AU - Kaufman, Peter A.

AU - Wildiers, Hans

AU - Freyer, Gilles

AU - Kemeny, Margaret

AU - Gonçalves, Anthony

AU - Jerusalem, Guy

AU - Stopeck, Alison T

AU - Vrindavanam, Nandagopal

AU - Dalenc, Florence

AU - Nanayakkara, Nuwan

AU - Wu, Benjamin

AU - Pickett, Cheryl A.

PY - 2018/1/1

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N2 - Introduction: Trebananib, a peptide-Fc fusion protein, blocks angiogenesis by inhibiting binding of angiopoietin-1/2 to the receptor tyrosine kinase Tie2. Trebananib plus trastuzumab and paclitaxel was evaluated in human epidermal growth factor receptor 2–positive breast cancer in an open-label phase 1b clinical study. Patients and Methods: Women with human epidermal growth factor receptor 2–positive breast cancer received weekly paclitaxel (80 mg/m2), trastuzumab (8 mg/m2 then 6 mg/kg every 3 weeks), and intravenous trebananib (10 mg/kg or 30 mg/kg weekly) beginning week 2. The primary end point was the incidence of dose-limiting toxicities. Secondary end points included incidence of adverse events (AEs), pharmacokinetics, and tumor response (objective response and duration of response). Results: Forty women were enrolled; 2 experienced dose-limiting toxicities (grade 3 ocular transient ischemic attack [10 mg/kg cohort] and grade 3 elevation in γ-glutamyl transferase [30 mg/kg cohort]). The most common treatment-emergent AEs were peripheral edema (n = 28), diarrhea (n = 27), alopecia (n = 26), fatigue (n = 24), and nausea (n = 24). Maximum observed concentration and area under the concentration–time curve increased proportionally with the trebananib dose. Objective response was confirmed in 31 patients. In the 10 mg/kg cohort, 16 patients (80%) experienced partial response, and none experienced complete response. In the 30 mg/kg cohort, 12 patients (71%) experienced partial response and 3 (18%) experienced complete response. Median (95% confidence interval) duration of response in the 10 and 30 mg/kg cohorts was 12.6 (4.3-20.2) and 16.6 (8.2-not estimable) months, respectively. Conclusion: This phase 1b study showed that trebananib was tolerated with manageable AEs at a dose up to 30 mg/kg weekly. Trebananib demonstrated anticancer activity, as indicated by objective response and duration of response. Given the potential interactions between human epidermal growth factor receptor 2 (HER2) signaling and angiogenesis, we investigated the angiopoietin (Ang) 1/Ang2 inhibitor trebananib plus trastuzumab and paclitaxel in HER2-positive breast cancer. Forty women received trebananib (10 or 30 mg/kg) plus trastuzumab and paclitaxel. The combination demonstrated acceptable toxicity and antitumor response in HER2-positive locally recurrent/metastatic breast cancer.

AB - Introduction: Trebananib, a peptide-Fc fusion protein, blocks angiogenesis by inhibiting binding of angiopoietin-1/2 to the receptor tyrosine kinase Tie2. Trebananib plus trastuzumab and paclitaxel was evaluated in human epidermal growth factor receptor 2–positive breast cancer in an open-label phase 1b clinical study. Patients and Methods: Women with human epidermal growth factor receptor 2–positive breast cancer received weekly paclitaxel (80 mg/m2), trastuzumab (8 mg/m2 then 6 mg/kg every 3 weeks), and intravenous trebananib (10 mg/kg or 30 mg/kg weekly) beginning week 2. The primary end point was the incidence of dose-limiting toxicities. Secondary end points included incidence of adverse events (AEs), pharmacokinetics, and tumor response (objective response and duration of response). Results: Forty women were enrolled; 2 experienced dose-limiting toxicities (grade 3 ocular transient ischemic attack [10 mg/kg cohort] and grade 3 elevation in γ-glutamyl transferase [30 mg/kg cohort]). The most common treatment-emergent AEs were peripheral edema (n = 28), diarrhea (n = 27), alopecia (n = 26), fatigue (n = 24), and nausea (n = 24). Maximum observed concentration and area under the concentration–time curve increased proportionally with the trebananib dose. Objective response was confirmed in 31 patients. In the 10 mg/kg cohort, 16 patients (80%) experienced partial response, and none experienced complete response. In the 30 mg/kg cohort, 12 patients (71%) experienced partial response and 3 (18%) experienced complete response. Median (95% confidence interval) duration of response in the 10 and 30 mg/kg cohorts was 12.6 (4.3-20.2) and 16.6 (8.2-not estimable) months, respectively. Conclusion: This phase 1b study showed that trebananib was tolerated with manageable AEs at a dose up to 30 mg/kg weekly. Trebananib demonstrated anticancer activity, as indicated by objective response and duration of response. Given the potential interactions between human epidermal growth factor receptor 2 (HER2) signaling and angiogenesis, we investigated the angiopoietin (Ang) 1/Ang2 inhibitor trebananib plus trastuzumab and paclitaxel in HER2-positive breast cancer. Forty women received trebananib (10 or 30 mg/kg) plus trastuzumab and paclitaxel. The combination demonstrated acceptable toxicity and antitumor response in HER2-positive locally recurrent/metastatic breast cancer.

KW - AMG 386

KW - Angiogenesis

KW - Angiopoietin

KW - HER2 positive

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