Abstract OT1-03-06: Phase IB/II clinical trial to evaluate safety and efficacy of tucatinib in combination with palbociclib and letrozole in patients with hormone receptor positive and HER2-positive metastatic breast cancer
Authors: Shagisultanova E , Diamond J , Stopeck A , Pusztai L , O'Regan R , Gradishar W , Brown-Glaberman U , Chalasani P , McSpadden T , Borakove M , Shedin T , Kabos P , Borges V 
Published: February 2018

Abstract
Breast cancers overexpressing HER2-oncogene and hormone receptors (HR) represent therapeutic challenge because of a bi-directional cross-talk between HR and HER2 pathways leading to tumor progression and drug resistance. There is a strong rationale for evaluation of novel targeted drug combinations in this breast cancer subtype.
We designed a phase IB /II clinical trial to test the combination of novel oral HER2 small molecule inhibitor tucatinib with CDK4/6 inhibitor palbociclib and aromatase inhibitor letrozole in patients with HR+/HER2+ metastatic breast cancer (NCT03054363). In addition to the rationale for the synergy of targeting HR, HER2 and CDK4/6 pathways simultaneously in this disease setting and its potential for anti-tumor efficacy, we propose this novel combination of three oral agents, if well tolerated, will be highly patient-centered as an effective non-chemotherapy based regimen for treatment of HR+/HER2+ breast cancer.
This multicenter clinical trial is conducted through the Academic Breast Cancer Consortium (ABRCC), with the University of Colorado Cancer Center as the lead site.
Target enrollment: 40 patients (20 patients in phase IB and 20 patients in phase II part).
Main inclusion criteria:
1. HR+/HER2+ locally advanced unresectable / metastatic breast cancer
2. Measurable or evaluable disease. Bone only disease is allowed.
3. Subjects without brain metastases are eligible; subjects with untreated asymptomatic CNS metastases not needing immediate local therapy, and subjects with stable brain metastases previously treated with radiation therapy or surgery are eligible
4. ECOG 0-1
5. Postmenopausal women, or premenopausal women on ovarian suppression
6. Prior treatments:
- At least two approved HER2-targeted agents (trastuzumab, pertuzumab, or TDM-1) at any time in the course of the disease
- At least 1 line of HER2-targeted therapy in the metastatic setting (with the exception of asymptomatic subjects with oligometastatic or bone / soft tissue only disease who, on investigator opinion, are appropriate for a front line single agent anti-endocrine therapy per NCCN guidelines)
- Up to 2 lines of prior endocrine therapy in the metastatic setting are allowed
7. Adequate organ and marrow function
Main exclusion criteria:
1. Previously treated progressing brain metastases
2. Brain metastases and contraindications to undergo contrast brain MRI
3. Toxicities of prior cancer therapies that have not resolved to grade 1 or less, except peripheral neuropathy, which must have resolved to grade 2 or less, and alopecia
4. Previous treatment with EGFR or HER2 tyrosine kinase inhibitors or CDK4/6 inhibitors
5. Systemic anti-cancer therapy or radiation within 2 weeks of the first dose of study drugs
6. Active bacterial, fungal or viral infections, hepatitis B, C, or HIV
7. Clinically significant cardio-vascular disease
Primary objectives:
- Phase IB: safety and tolerability of combination therapy
- Phase II: efficacy by PFS
Exploratory assessment of biomarkers of resistance and response will be performed in the blood and biopsy samples
Study contact: Elena Shagisultanova, MD, PhD, elena.shagisultanova@ucdenver.edu
Citation Format: Shagisultanova E, Diamond J, Stopeck A, Pusztai L, O'Regan R, Gradishar W, Brown-Glaberman U, Chalasani P, McSpadden T, Borakove M, Shedin T, Kabos P, Borges V. Phase IB/II clinical trial to evaluate safety and efficacy of tucatinib in combination with palbociclib and letrozole in patients with hormone receptor positive and HER2-positive metastatic breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT1-03-06.