Trastuzumab Fab-HER2 complex 1N8Z

US-based Oncothyreon and Array BioPharma have started a phase 1b trial of ONT-380 (ARRY-380) in combination with Xeloda (capecitabine) and/or Herceptin (trastuzumab) for the treatment of patients with metastatic HER2+ breast cancer.

ONT-380 is an orally active, reversible and selective small-molecule HER2 inhibitor invented by Array and is currently being developed by Oncothyreon in collaboration with Array.

Around 50 patients will be enrolled in the dose-escalation trial, which is being carried out in patients who have been previously treated with Herceptin (trastuzumab) and Kadcyla (ado-trastuzumab emtansine or TDM-1) for metastatic breast cancer.

The primary objective of the trial is to determine the maximum-tolerated and/or recommended phase 2 dose (MTD/RP2D) of ONT-380 in combination with the approved dose of either Xeloda or Herceptin or both, while the secondary objectives include assessment of the safety and preliminary anti-tumour activity of the combinations.

The trial includes an expansion arm at the MTD/RP2D of ONT-380 in combination with both Xeloda and Herceptin, with the option to include expansion arms in combination with either agent alone.

According to the company, patients with treated stable central nervous system (CNS) metastases are eligible for the dose escalation portions of the trial.

However, patients with CNS metastases which are either asymptomatic and untreated or progressive following local therapy may be included in the expansion cohorts. The trial is expected to enrol approximately 50 patients.

Oncothyreon chief medical officer Diana Hausman said: "The treatment or prevention of CNS metastases is perhaps the greatest unmet medical need for patients with HER2+ metastatic breast cancer. ONT-380 has demonstrated preclinical activity in an animal model of brain metastases from HER2+ breast cancer.

"This trial is intended to identify clinically relevant combination therapy to advance the evaluation of the activity of ONT-380 in patients with CNS metastases."

"The trial is expected to enrol approximately 50 patients."

ONT-380 was well tolerated and showed significant dose-related tumour growth inhibition that was superior to Herceptin and Tykerb (lapatinib) in multiple preclinical tumour models.

In these models, ONT-380 showed synergistic or additive tumour growth inhibition when dosed in combination with the standard-of-care therapeutics Herceptin or Taxotere (docetaxel ).

Compared to Tykerb and the investigational drug neratinib, ONT-380 has shown superior activity, based on overall survival in an intracranial HER2+ breast cancer xenograft model.

The company said that a phase 1 trial of ONT-380, with both dose-escalation and expansion components, has been completed in 50 patients, 43 of whom had HER2+ metastatic breast cancer.

Apart from the phase 1b trial of ONT-380 in combination with Xeloda and/or Herceptin, the company also intends to begin a phase 1b trial of ONT-380 in combination with Kadcyla (ado-trastuzumab emtansine or TDM-1) in patients with metastatic HER2+ breast cancer.

The trial is being conducted under the sponsorship of the Dana-Farber Cancer Institute, Boston, Massachusetts.

Image: Ribbon diagram of the Fab fragment of trastuzumab, a monoclonal antibody, bound to the extracellular domain of HER2. Photo: courtesy of Fvasconcellos.