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 language | English (US) |
|---|---|
| Journal | Clinical Breast Cancer |
| DOIs | |
| State | Accepted/In press - Jan 1 2018 |
| Externally published | Yes |
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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 journal › Article
}
TY - JOUR
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
Y1 - 2018/1/1
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
UR - http://www.scopus.com/inward/record.url?scp=85056336575&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85056336575&partnerID=8YFLogxK
U2 - 10.1016/j.clbc.2018.09.012
DO - 10.1016/j.clbc.2018.09.012
M3 - Article
C2 - 30420181
AN - SCOPUS:85056336575
JO - Clinical Breast Cancer
JF - Clinical Breast Cancer
SN - 1526-8209
ER -