Conditions: HER-2 Positive Breast Cancer Metastatic Malignant Neoplasm to Brain
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 17
Healthy volunteers: no

Brief summary:
Evaluate the safety and tolerability and determine the maximum tolerated dose (MTD) of the combination of tesevatinib and trastuzumab in subjects with HER2-positive metastatic breast cancer

Detailed description:
This is a multicenter, Phase 1b/2a, multiple ascending-dose, open-label study designed to assess the safety, tolerability, and efficacy of tesevatinib (KD019) in combination with trastuzumab in subjects with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. The study planned to include a Phase 2a expansion in which approximately 50 subjects would receive tesevatinib at the maximum tolerated dose (MTD) dose determined in Phase 1b.

The study employs a successive cohort dose-escalation designed to determine the MTD of tesevatinib in combination with trastuzumab. The MTD dose is defined as the dose level below in which : (a) 2 of 3 subjects (or 2 of 6 subjects if Grade ≥ 3 tesevatinib related treatment emergent adverse event \[TEAE\] experience in 1 of the first 3 subjects).

In the Phase 1b portion of the study, tesevatinib is to be administered orally (PO) to successive cohorts of subjects at 150 mg, 250 mg, 300 mg, 350 mg, and 400 mg once daily (QD).

The following 4 dossing cohorts are initiated during the study:

* Cohort 1: 150 mg tesevatinib PO QD
* Cohort 2: 250 mg tesevatinib PO QD
* Cohort 3: 300 mg tesevatinib PO QD
* Cohort 4: 350 mg tesevatinib PO QD

\[Note: the sponsor suspended the study before a cohort of subjects were enrolled at tesevatinib 400 mg PO QD.\]

Trastuzumab is administered intravenously (IV) at 8 mg/kg as an initial loading dose on Day 1 of Cycle 1, followed by 6 mg/kg IV every 3 weeks thereafter, beginning Day 1 of Cycle 2. Subjects entering the study already on trastuzumab are not to receive the initial loading dose and instead receive trastuzumab 6 mg/kg IV. The first doses of trastuzumab and tesevatinib are administered in the clinic on Study Day 1. Subsequent doses of tesevatinib are to be taken on an outpatient basis for the remainder of each 21-day cycle. During Cycle 1, subjects are to be returned to the clinic for weekly safety and tolerability assessments.

Tumor response, both in the central nervous system (CNS) and peripheral to the CNS, is to be assessed after the second cycle of treatment and then at the end of every 2 cycles of treatment thereafter. Subjects are to be treated until disease progression or the subject experienced unacceptable toxicity. Subjects who demonstrated tumor progression are to stop study drug and followed for survival. All subjects discontinuing tesevatinib therapy are to be followed for survival.

Safety assessments include adverse event monitoring, electrocardiograms (ECGs), laboratory testing, physical examinations, vital signs, and pregnancy testing.

An End-of-Treatment visit is to be conducted as soon as possible after the subject's last dose of study drug. This could occur at the visit when disease progression is diagnosed. Subjects are to be followed for disease progression and survival.

A follow-up visit planned for 30 days (± 5 days) after the last dose of study drug assessments is to include collection of AE (Adverse Event) and concomitant medication data. This visit could occur prior to 30 days if a new therapy is started within 30 days of last dose of study drug.

For long-term follow-up, subjects are to be contacted by telephone every 8 weeks to assess survival status and any subsequent anti-cancer treatment.

The duration of treatment for subjects with tesevatinib in combination with trastuzumab is planned until the subject experiences disease progression or unacceptable toxicity.

\[Note: Changes to the Planned Analysis: The study, planned to include a Phase 2a expansion in which approximately 50 subjects would have received tesevatinib at the MTD dose determined in Phase 1b, was terminated early. Although some patients had prolonged stable disease in the study, no clear treatment responses were observed. The sponsor decided to suspend the study while gathering additional data from other tesevatinib oncology studies. The study was subsequently terminated early because the sponsor stopped evaluations of tesevatinib as a treatment for HER2-positive metastatic breast cancer.\]

Arms:
arm 1: Tesevatinib in combination with Trastuzumab: tesevatinib 150 mg PO QD in combination with trastuzumab 8 mg/kg IV initially then 6 mg/kg IV every 3 weeks thereafter. arm 2: Tesevatinib in combination with Trastuzumab: tesevatinib 250 mg PO QD in combination with trastuzumab 8 mg/kg IV initially then 6 mg/kg IV every 3 weeks thereafter. arm 3: Tesevatinib in combination with Trastuzumab: tesevatinib 300 mg PO QD in combination with trastuzumab 8 mg/kg IV initially then 6 mg/kg IV every 3 weeks thereafter. arm 4: Tesevatinib in combination with Trastuzumab: tesevatinib 350 mg PO QD in combination with trastuzumab 8 mg/kg IV initially then 6 mg/kg IV every 3 weeks thereafter.

Interventions: intervention 1: Tesevatinib intervention 2: Trastuzumab
Intervention descriptions: intervention 1: None intervention 2: None

Protocol document: