US-based Kadmon has started a Phase Ib/IIa trial of KD019, an orally bioavailable small molecule kinase inhibitor of Src, HER2, EGFR and VEGFR2/KDR, in combination with trastuzumab (Herceptin) to treat HER2+ breast cancer metastasized to the brain.

The company said that activation of Src kinase has emerged as a key resistance mechanism in trastuzumab treated HER2-positive breast cancer.

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In addition, Src activity has been shown to play a major role in brain metastases of HER2-positive breast cancers.

Despite control of systemic disease by trastuzumab or other HER2 inhibitors, patients with HER2-positive breast cancer frequently develop brain metastases, which 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.

"KD019 is not only an effective penetrant of the blood-brain barrier, as demonstrated preclinically, but also targets several pathways critical to tumour growth, metastasis and treatment resistance, including HER2, EGFR and Src."

Compared with the available HER2/EGFR inhibitor Iapatinib (Tykerb), KD019 has showed in the preclinical studies its ability to cross the BBB in vivo while also inhibiting HER2/EGFR as well as Src.

The trial’s primary objective is to evaluate 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.

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A total of 38 patients are expected to be enrolled in the multicentre, multiple ascending dose, open-label Phase Ib/IIa trial.

In the Phase Ib portion of the trial, KD019 will be orally administered in successive dose groups at 150mg, 250mg, and 300mg doses once-daily until the maximum tolerated dose is established for the Phase IIa expansion group.

Patients in the Phase Ib portion of the trial may be enrolled with or without brain metastases.

The Phase IIa portion of the trial will be limited to subjects with HER2-postive breast cancer with brain metastases progressing after radiation therapy.

Kadmon chairman and CEO Samuel Waksal said 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.

"KD019 is not only an effective penetrant of the blood-brain barrier, as demonstrated preclinically, but also targets several pathways critical to tumour growth, metastasis and treatment resistance, including HER2, EGFR and Src," Waksal said.

"We believe KD019 may serve the dual purpose of both checking trastuzumab resistance systemically and targeting tumour growth within the brain."