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Ibrutinib

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In Phase I, starting dose of Ibrutinib will be 560 mg orally per day. 3 patients will be enrolled first. If none of these have DLTs, 3 new patients will be enrolled at the next higher Ibrutinib dose level (840 mg orally per day). If 1 of these 3 patients have a DLT, expand this arm to 6 patients. If 2 or more of these 6 patients have a DLT, enroll 3 patients in lower dose lever (420 mg).

If no patients in 560 mg arm have DLTs, this arm will be opened in Phase I to see how this higher dose is tolerated.

If 2 or more patients in 560 mg arm have DLTs, this arm will be opened in Phase I to see how this lower dose is tolerated.

Maximum tolerated dose from Phase I will be used here in Phase II.

8 mg/kg loading dose (first dose), followed by 6 mg/kg every 3 weeks, administered intravenously (IV)

Ibrutinib 560 mg

Ibrutinib 840 mg

Ibrutinib 420 mg

Joyce O'Shaughnessy, MD

This is a Phase I/II, open-label dose-escalation study designed to evaluate the maximum tolerated dose (MTD) and dose-limiting side effects of ibrutinib (560 or 840 or 420 mg daily oral dose), given in combination with trastuzumab administered through the vein, in patients with HER2-amplified Metastatic Breast Cancer that has gotten worse after prior therapy with ado-trastuzumab emtansine (T-DM1).

Ado-trastuzumab emtansine (T-DM1) is approved by the FDA for patients with HER2-positive metastatic breast cancer (MBC) previously treated with a taxane and trastuzumab, and is currently listed as the preferred second-line therapy in the NCCN guidelines (NCCN 2014). While the benefit of continued HER2 inhibition has been conclusively established for disease that has progressed on a trastuzumab-containing regimen, there are currently no data regarding the efficacy of HER2- targeted therapies following progression on T-DM1.

With the population of T-DM1-treated patients steadily growing, clinical trials are needed to investigate novel therapies in this setting,to meet the medical need for effective, evidence-based therapies for these patients.

The oral small-molecule Bruton's Tyrosine Kinase (BTK) inhibitor ibrutinib has also demonstrated the ability to inhibit erythroblastosis virus oncogene B (ErbB)/HER receptor family kinases in preclinical studies at clinically relevant concentrations, with an equivalent or greater potency than other HER2-directed tyrosine kinase inhibitors (TKIs) with demonstrated activity in HER2-positive MBC, including lapatinib, neratinib, and afatinib. Of note, in preclinical HER2-positive cell model systems the growth inhibitory ability of ibrutinib was substantially greater in HER2-amplified breast cancer cells versus those that simply overexpressed the HER2 protein.

Ibrutinib is currently approved for use in patients with Chronic lymphocytic leukemia (CLL) or Mantle cell lymphoma (MCL), and has an established safety record from clinical trials in these patient populations. Thus there is a reasonable rationale to investigate ibrutinib in patients with HER2- amplified MBC, in the setting of T-DM1-pretreated disease. Previous studies have demonstrated that combined targeting of HER2 with multiple HER2-directed agents is more effective that single agent therapy and therefore this study will explore the safety and efficacy of ibrutinib in combination with trastuzumab.

This is a Phase I/II, open-label, unblinded, nonrandomized, standard 3+3 dose-escalation study designed to evaluate the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of ibrutinib (560 or 840 or 420 mg QD) given orally in combination with trastuzumab (8 mg/kg loading dose followed by 6 mg/kg q3w) administered intravenously (IV) in patients with HER2-amplified MBC that has progressed on prior therapy with ado-trastuzumab emtansine.

Once the recommended phase II dose of ibrutinib plus trastuzumab has been determined (no more than 1 of 6 patients with dose-limiting toxicity) in the required 6 to 18 patients over the 3 possible dose levels, additional patients will be enrolled on the phase II part of the study at the recommended phase II dose of ibrutinib plus trastuzumab, for a maximum of 51 patients total.

This is a Phase I/II, open-label, unblinded, nonrandomized, standard 3+3 dose-escalation study designed to evaluate the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of ibrutinib (560 or 840 or 420 mg QD) given orally in combination with trastuzumab (8 mg/kg loading dose followed by 6 mg/kg q3w) administered intravenously (IV) in patients with HER2-amplified MBC.

Once the recommended phase II dose of ibrutinib plus trastuzumab has been determined (no more than 1 of 6 patients with dose-limiting toxicity) in the required 6 to 18 patients over the 3 possible dose levels, additional patients will be enrolled on the phase II part of the study at the recommended phase II dose of ibrutinib plus trastuzumab, for a maximum of 51 patients total.

Trial of Ibrutinib Plus Trastuzumab in HER2-amplified Metastatic Breast Cancer

Phase I/II Trial of Ibrutinib Plus Trastuzumab in HER2-amplified Metastatic Breast Cancer

Changes in Th1- and Th2-related cytokine gene expression in whole blood, from Baseline to Week 12 to End of Treatment with ibrutinib plus trastuzumab, using NanoString human immunology gene panel.

Highest dose of ibrutinib from Phase 1 (420, 560, or 840 mg by mouth daily) that had fewer than two dose-limiting toxicities in its respective cohort

To define the clinical benefit rate (CBR = CR \[complete response\] + PR \[partial response\] + SD \[stable disease\] \> 6 months) of ibrutinib plus trastuzumab in patients with HER2-amplified, T-DM1-pretreated MBC

To determine the objective response rate (ORR = CR + PR) associated with ibrutinib plus trastuzumab.

To assess median overall survival (OS) associated with ibrutinib plus trastuzumab.

To assess median progression-free survival (PFS) associated with ibrutinib plus trastuzumab

Number of Adverse Events and Serious Adverse Events from informed consent signature to 30 days after last dose of study drug, using Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.03: June 14, 2010)

maximum (or peak) serum concentration that Ibrutinib achieves in Cycle 1 at indicated time points, and on Day 1 of cycle 3 for pharmacokinetic analysis

Area Under the Curve of Ibrutinib in 24 hours

Spots Global Cancer Trial Database for ibrutinib 840 mg