Abstract OT2-07-09: A phase Ib study of neratinib, pertuzumab, and trastuzumab with paclitaxel in patients with metastatic and locally advanced breast cancer
Authors: Al-Awadhi A , Kono M , Marx A , Moseley T , Willey J , Sun H , Fu M , Whitman GJ , Valero V , Ueno NT , Lim B 
Published: May 2019

Abstract
Background: Neratinib, a potent irreversible pan-ErbB tyrosine kinase inhibitor that blocks signal transduction through HER1, HER2, and HER4, has demonstrated activity against metastatic HER2-positive breast cancer (HER2+ BC) in patients pretreated with trastuzumab. The FDA recently approved neratinib as an adjuvant treatment for HER2+ BC patients who have received trastuzumab for at least 1 year. Preclinical data demonstrate that trastuzumab-resistant BC cells remain sensitive to neratinib. Also, neratinib enhances responses to trastuzumab possibly by increasing trastuzumab's internalization, immune-mediated action, and other mechanisms. Taken together, these findings provide the rationale for adding neratinib to the standard of care combination of trastuzumab and pertuzumab with paclitaxel to enhance anti-HER2 efficacy in advanced HER2+ BC. Here, we report on the phase Ib portion of an ongoing phase Ib/II trial of this drug combination.
Trial Design: Patients with metastatic or locally advanced HER2+ BC will be enrolled in the phase Ib portion of the trial. Neratinib is given orally in 3-week cycles. The initial neratinib dose of 80 mg daily is increased to 120, 160, and 200 mg daily after safety assessments of each dose level. Other agents are administered as per the standard of care. Patients continue therapy with per-protocol dose escalation and de-escalation according to toxicity until the maximum tolerated dose (MTD) of neratinib is reached. The target maximum dose-limiting toxicity rate is 20%. All patients receive 4 cycles of the combination therapy. If patients do not have disease progression or excessive toxicity, they may receive 2-4 additional cycles at the treating physician's discretion. During therapy, patients undergo blood tests every week and have clinical visits and restaging scans every 3 weeks. Because gastrointestinal toxicity, mainly diarrhea, is anticipated, patients receive prophylactic antidiarrheal medication (e.g., loperamide, budesonide) beginning with the first dose of neratinib.
Eligibility Criteria: Eligible patients must have histologically confirmed metastatic or locally advanced HER2+ BC (BC may be inflammatory or non-inflammatory and have any hormone receptor status); an ECOG performance status score of 0 or 1; and adequate hematologic and organ function, including adequate cardiac function (as indicated by a left ventricle ejection fraction of ≥50%).
Specific Aims:
1- To determine the MTD of neratinib in combination with paclitaxel, pertuzumab, and trastuzumab.
2- Pharmacodynamic markers will be measured on biologic specimens. Neratinib-induced changes in pEGFR and/or HER2 expression will be analyzed and compared between dose levels.
Statistical Methods: The Bayesian modified toxicity probability interval is used to determine dose adjustment.
Accrual: The target enrollment for the phase Ib cohort is 20 patients. The trial has enrolled 3 patients since its activation in January 2018. This trial is supported by Puma Biotechnology, Aggressive Breast Cancer Research Program Grant.
Citation Format: Al-Awadhi A, Kono M, Marx A, Moseley T, Willey J, Sun H, Fu M, Whitman GJ, Valero V, Ueno NT, Lim B. A phase Ib study of neratinib, pertuzumab, and trastuzumab with paclitaxel in patients with metastatic and locally advanced breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT2-07-09.