On June 4, 2014 Kadmon reported the initiation of a Phase 1b/2a study of KD019, the Company’s orally bioavailable small molecule kinase inhibitor of Src, HER2, EGFR and VEGFR2/KDR, in combination with trastuzumab (Herceptin) for the treatment HER2+ breast cancer metastasized to the brain (Press release Kadmon, JUN 4, 2014, View Source [SID:1234500709]).

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Activation of Src kinase has emerged as a key resistance mechanism in trastuzumab treated HER2-positive breast cancer. Additionally, Src activity has been shown to play a critical role in brain metastases of HER2-positive breast cancers. Subjects with HER2-positive breast cancer frequently develop brain metastases, despite control of systemic disease by trastuzumab or other HER2 inhibitors. These brain metastases are largely unresponsive to pharmaceutical treatment as none of the currently approved HER2 inhibitors effectively cross the blood-brain barrier (BBB) resulting in limited drug exposure in the brain. In preclinical studies, unlike the available HER2/EGFR inhibitor Iapatinib (Tykerb), KD019 demonstrated the ability to cross the BBB in vivo while also inhibiting HER2/EGFR as well as Src.

The primary objective of this multicenter, multiple ascending dose, open-label, Phase 1b/2a study is to assess the safety, tolerability and efficacy of KD019 when given in combination with trastuzumab to subjects with HER2-positive metastatic breast cancer who have received prior trastuzumab therapy. The study is expected to enroll up to 38 patients. In the Phase 1b portion of the study, KD019 will be orally administered in successive dose cohorts at 150, 250, and 300 mg doses once daily until the maximum tolerated dose is established for the Phase 2a expansion group. Patients in the Phase 1b portion of the study may be enrolled with or without brain metastases. The Phase 2a portion of the study will be limited to subjects with HER2-postive breast cancer with brain metastases progressing after radiation therapy.

"Brain metastases are common in patients with breast cancer who are treated with HER2 inhibitors, as the blood-brain barrier blocks exposure of the disease within the brain to available therapies," said Samuel D. Waksal, Ph.D., Chairman and CEO of Kadmon. "KD019 is not only an effective penetrant of the blood-brain barrier, as demonstrated preclinically, but also targets several pathways critical to tumor growth, metastasis and treatment resistance, including HER2, EGFR and Src. We believe KD019 may serve the dual purpose of both checking trastuzumab resistance systemically and targeting tumor growth within the brain."