Title
An Open Label, Phase II Trial of Pre-operative Neratinib and Endocrine Therapy with Trastuzumab in Triple Positive Breast Cancers (BRE17-141)

Description
Patient will be treated with neratinib, an aromatase inhibitor and trastuzumab for 24 weeks prior to surgery, following an initial 3 weeks of neratinib alone, aromatase inhibitor alone or the combination of neratinib and an aromatase inhibitor. A breast biopsy will be performed prior to Day 1 of week 4 of treatment. Following surgery, patients will receive standard of care HER2-directed and endocrine therapy at the treating physician's discretion.

Objective
Primary Objective:
-To estimate the pathologic complete response (pCR) rate (defined as the lack of all signs of invasive cancer in the breast tissue [ypT0/Tis]) after 24 weeks of treatment, consisting of 3 weeks of initial treatment with neratinib alone, OR non-steroidal aromatase inhibitor (NSAI) alone, OR combined treatment with neratinib and NSAI, followed by 21 weeks of combined treatment with neratinib, NSAI, and trastuzumab in patients with triple positive breast cancers.

Secondary Objectives:
-To estimate the safety and tolerability of 24 weeks of treatment, consisting of 3 weeks of initial treatment with neratinib alone, OR non-steroidal aromatase inhibitor (NSAI) alone, OR combined treatment with neratinib and NSAI, followed by 21 weeks of combined treatment with neratinib, NSAI, and trastuzumab in patients with triple positive breast cancers.
-To estimate the pCR in the breast tissue and lymph nodes (ypT0/Tis ypN0) after 24 weeks of treatment, consisting of 3 weeks of initial treatment with neratinib alone, OR nonsteroidal aromatase inhibitor (NSAI) alone, OR combined treatment with neratinib and NSAI, followed by 21 weeks of combined treatment with neratinib, NSAI, and trastuzumab in patients with triple positive breast cancers.
-To estimate residual disease in the breast tissue after 24 weeks of treatment, consisting of 3 weeks of initial treatment with neratinib alone, OR non-steroidal aromatase inhibitor (NSAI) alone, OR combined treatment with neratinib and NSAI, followed by 21 weeks of combined treatment with neratinib, NSAI, and trastuzumab in patients with triple positive breast cancers using Residual Cancer Burden (MD Anderson).
-To estimate radiologic response using RECIST 1.1 in the breast tissue after 24 weeks of treatment, consisting of 3 weeks of initial treatment with neratinib alone, OR non-steroidal aromatase inhibitor (NSAI) alone, OR combined treatment with neratinib and NSAI, followed by 21 weeks of combined treatment with neratinib, NSAI, and trastuzumab in patients with triple positive breast cancers.
-To estimate the Overall Survival (OS) and Disease Free Survival (DFS).
-To estimate the relative dose intensity during 24 weeks of treatment.

Treatment Experimental: A
Weeks 1-3* patients receive either (a) Neratinib, (b) Letrozole or Anastrozole or (c) Neratinib + Letrozole or Anastrozole Weeks 4-24 patients receive Neratinib + Letrozole or Anastrozole and Trastuzumab
*Starting drug intervention varies for the first 3 weeks depending on arms: a, b, and c by randomization.
Drug: Neratinib
120mg for 7 days; 160mg for 7 days ; 240mg for 7 days. 240 mg (up to a maximum of 24 weeks) orally daily*.
Other Name: Nerlynx

Drug: Letrozole (L) or Anastrozole (A)
L: (2.5 mg) OR A: (1 mg) orally daily (up to a maximum of 24 weeks)*
Other Names:
Femara
Arimidex

Drug: Trastuzumab
All Arms 8mg/kg loading dose followed by 6mg/kg every 3 weeks administered every 3 weeks by IV starting wk 4. Trastuzumab biosimilars may be used per institutional guidelines.
Other Name: Herceptin

Key Eligibility For full study eligibility, see this study's ClinicalTrials.gov record.

Applicable Disease Sites
Breast

Participating Institutions
UW Health 1 S. Park Medical Center; UW Health Eastpark Medical Center; UW Health University Hospital