Abstract P5-19-14: A phase 1b study of trebananib plus paclitaxel and trastuzumab or capecitabine and lapatinib in patients with HER2+ locally recurrent or metastatic breast cancer
Authors: Kaufman Peter A , Freyer Gilles , Kemeny Margaret , Goncalves Anthony , Jerusalem Guy , Stopeck Alison , Vrindavanam Nandagopal , Dalenc Florence , Nanayakkara Nuwan , Wu Benjamin , Pickett-Gies Cheryl A , Wildiers Hans 
Published: May 2015

Abstract
Background: The angiopoietin axis is distinct and critical for angiogenesis. Trebananib suppresses tumor angiogenesis by binding to angiopoietin-1 and -2 (Ang1/2), thereby inhibiting their interaction with the Tie2 receptor. This interim analysis evaluated the tolerability and efficacy of trebananib plus paclitaxel and trastuzumab or capecitabine and lapatinib in HER2+ locally recurrent or metastatic breast cancer (MBC).
Methods: Patients (pts) in cohorts A1 and A3 (no prior 1st-line trastuzumab, lapatinib, or chemotherapy for MBC) received trebananib (A1, 10 mg/kg; A3, 30 mg/kg) IV QW plus paclitaxel 80 mg/m2 IV QW and trastuzumab 8 mg/kg loading dose, then 6 mg/kg Q3W. Pts in cohorts B1 and B3 (history of failed 1st-line MBC treatment, no prior lapatinib or capecitabine) received trebananib (B1, 10 mg/kg; B3, 30 mg/kg) IV QW plus capecitabine 1000 mg/m2 PO Q12 h, days 1-14 Q21D and lapatinib 1250 mg PO QD. Cohorts were expanded to n = 20 if ≤1 of 6 or ≤2 of 9 pts had dose-limiting toxicities (DLTs). Cohort B3 was closed early due to poor enrollment. Endpoints were treatment-emergent adverse events (AEs) and DLTs (primary); and efficacy, pharmacokinetics (PK), and incidence of anti-trebananib antibodies (secondary).
Results: All pts received ≥1 dose of trebananib. Across all cohorts, two DLTs occurred (A1: grade 3 transient ischemic attack, n = 1; A3: grade 3 increased gamma-glutamyltransferase, n = 1). Across A1 and A3, AEs &gt;50% were peripheral edema, diarrhea, alopecia, fatigue, nausea, nail disorder, and rash; AEs grade ≥3 in &gt;10% of pts were peripheral/sensory neuropathy and dyspnea. No pt in A1 or A3 died during treatment. Across B1 and B3, AEs &gt;50% were diarrhea, nausea, palmar-plantar erythrodysesthesia syndrome (PPES), and peripheral edema; AEs grade ≥3 in &gt;10% of pts were diarrhea, PPES, and neutropenia. One pt in B1 died from sepsis considered to be possibly related to administration of trebananib and capecitabine. Peripheral edema was a frequently reported AE for cohorts A1, A3, B1, and B3 (n = 13, 15, 10, 3); most were grade 1 and 2 and appeared to be manageable. No AEs of gastrointestinal perforation, ascites, or proteinuria were reported. Efficacy endpoints are summarized in Table 1. No apparent PK drug-drug interaction was observed. No pt developed neutralizing binding antibodies during treatment.
Table 1 1ST LINE-TREATMENT≥2ND-LINE TREATMENT† A1 (n = 20)A3 (n = 20)B1 (n = 20)TUMOR RESPONSE* Evaluable pts, n201714Best response, n Complete response030Partial response16127Stable disease325Progressive disease001Not assessed101Objective response rate, %808850PROGRESSION-FREE SURVIVAL Median, months14.518.58.695% CI6.9–20.610.4–21.93.7–14.4DURATION OF RESPONSE* Evaluable pts, n16157Median, months12.616.68.395% CI4.3–20.28.2–not estimable4.1–16.8*Tumor response was assessed only in pts with measurable disease at baseline †&gt;Efficacy results for B3 are not reported due to the small sample size (n = 5)
Conclusion: Interim results from this phase 1b study of pts with HER2+ locally recurrent or MBC suggest that adding trebananib to paclitaxel and trastuzumab or capecitabine and lapatinib is tolerable and may improve antitumor activity.
Citation Format: Peter A Kaufman, Gilles Freyer, Margaret Kemeny, Anthony Goncalves, Guy Jerusalem, Alison Stopeck, Nandagopal Vrindavanam, Florence Dalenc, Nuwan Nanayakkara, Benjamin Wu, Cheryl A Pickett-Gies, Hans Wildiers. A phase 1b study of trebananib plus paclitaxel and trastuzumab or capecitabine and lapatinib in patients with HER2+ locally recurrent or metastatic breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-19-14.