Oncothyreon Inc. a biotechnology company specializing in the development of innovative therapeutic products for the treatment of cancer, and biopharmaceutical company, Array BioPharma Inc. announced the initiation of a phase 1b trial of ONT-380 (ARRY-380) in combination with Kadcyla (ado-trastuzumab emtansine or TDM-1) in patients with metastatic HER2+ breast cancer.  ONT-380 is an orally active, reversible and selective small-molecule HER2 inhibitor invented by Array and being developed by Oncothyreon in collaboration with Array.

The trial (ClinicalTrials.gov Identifier NCT01983501) is a dose-escalation study in up to 48 patients who have been previously treated with Herceptin (trastuzumab) and a taxane for metastatic breast cancer.  The primary objective is to determine the maximum-tolerated and/or recommended phase 2 dose (MTD/RP2D) of ONT-380 in combination with the approved dose of Kadcyla.  Secondary objectives include an evaluation of the safety and preliminary anti-tumor activity of the combination.  Following determination of the MTD/RP2D, the study includes an expansion arm at the MTD/RP2D as well as an optional second expansion arm in patients with central nervous system metastases.

"ONT-380 and Kadcyla are both directed at HER2, but with differing mechanisms of action," said Diana Hausman, chief medical officer of Oncothyreon. "The strategy of combining two agents targeting HER2 has previously proven useful in HER2+ breast cancer, and we believe the combination of ONT-380 and Kadcyla is particularly relevant to evaluate as the treatment of metastatic HER2+ breast cancer continues to evolve."

ONT-380 is an orally active, reversible and selective HER2 inhibitor. In multiple preclinical tumor models, ONT-380 was well tolerated and demonstrated significant dose-related tumor growth inhibition that was superior to Herceptin and Tykerb (lapatinib). Additionally, in these models, ONT-380 demonstrated synergistic or additive tumor growth inhibition when dosed in combination with the standard-of-care therapeutics Herceptin or Taxotere (docetaxel). ONT-380 has also demonstrated superior activity, based on overall survival, compared to Tykerb and to the investigational drug, neratinib, in an intracranial HER2+ breast cancer xenograft model.

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. All HER2+ breast cancer patients had progressed on a Herceptin-containing regimen. In addition, over 80% had been treated with Tykerb, with many having progressed on therapy. In this study, ONT-380 demonstrated an acceptable safety profile; treatment-related adverse events were primarily Grade 1. Because ONT-380 is selective for HER2 and does not inhibit EGFR, there was a low incidence and severity of treatment-related diarrhea, rash and fatigue. Additionally, there were no treatment-related cardiac events or Grade 4 treatment-related adverse events reported. The maximum tolerated dose of ONT-380 established in this phase 1 trial was 600 mg twice daily (BID). Twenty-two HER2+ breast cancer patients with measurable disease were treated with ONT-380 at doses greater than or equal to 600 mg BID. In this heavily pretreated patient population, there was a clinical benefit rate (partial response [n = 3] plus stable disease for at least 6 months [n = 3]) of 27%. Notably, two of the patients with partial responses during treatment with ONT-380 had confirmed progressions while on prior Tykerb- and Herceptin-containing regimens.

n addition to the phase 1b trial of ONT-380 in combination with Kadcyla described above, Oncothyreon recently initiated a second phase 1b trial of ONT-380 in combination with Herceptin and/or Xeloda (capecitabine) in patients with metastatic HER2+ breast cancer.  The Dana-Farber Cancer Institute, Boston, Massachusetts, is also currently conducting an investigator-sponsored trial of ONT-380 in combination with Herceptin in patients with brain metastases from HER2+ breast cancer.

Array BioPharma Inc. is a biopharmaceutical company focused on the discovery, development and commercialization of targeted small molecule drugs to treat patients afflicted with cancer.