Date: 2015-05-30
Type of information: Presentation of results at a congress
phase: 1b
Announcement: presentation of results at the American Society of Clinical Oncology (ASCO) annual meeting, in Chicago
Company: Oncothyreon (USA - WA)
Product: ONT-380
Action
mechanism: ONT-380 (previously known as ARRY-380) is a small molecule selective inhibitor of HER2, a growth factor receptor that is over-expressed in multiple cancers, including breast, ovarian, and stomach cancer. HER2 mediates cell growth, differentiation and survival, and tumors that overexpress HER2 are more aggressive and historically have been associated with poorer overall survival compared with HER2-negative cancers. In a Phase 1 single agent clinical study, ONT-380 administered orally twice a day demonstrated anti-tumor activity in heavily pre-treated HER2+ breast cancer patients with metastatic disease without treatment-related Grade 3 diarrhea and only minimal Grade 3 rash. This safety and tolerability profile is important given that HER2 inhibitors are typically used in combination with other agents that may be associated with significant side effects. Addition of ONT-380 to these regimens has the potential to increase efficacy without adding significantly to the side effect burden. Oncothyreon is currently conducting two Phase 1b trials of ONT-380 in women with HER2+ breast cancer. Oncothyreon has an exclusive license from Array BioPharma Inc. to manufacture, develop and commercialize ONT-380.
Disease: Her2 positive metastatic breast cancer
Therapeutic area: Cancer - Oncology
Country: USA
Trial
details: The Phase 1b trial of ONT-380 in combination with Xeloda® (capecitabine) and/or Herceptin® (trastuzumab) is a parallel dose escalation study in patients previously treated with Herceptin and Kadcyla® (ado-trastuzumab emtansine or TDM-1) for metastatic breast cancer. The purpose of this study is to determine the maximal tolerated dose (MTD) or recommended phase 2 dose (RP2D) of ONT-380 and to assess the safety and tolerability of ONT-380 combined with capecitabine alone, trastuzumab alone and with both capecitabine and trastuzumab in patients with HER2+ metastatic breast cancer. (NCT02025192)
Latest
news: * On December 8, 2015, Oncothyreon announced updated data from the company's ongoing trials of ONT-380, an orally active, reversible and selective small-molecule HER2 inhibitor being developed for the treatment of HER2-positive metastatic breast cancer. The presentation (Abstract P4-14-19) combines data for patients with response assessable brain metastases from two trials, the Phase 1b trial in combination with Kadcyla® and a Phase 1b trial of ONT-380 in combination with Herceptin and/or Xeloda® (capecitabine). The analysis includes patients with previously untreated CNS metastases as well as patients with progressive or new CNS metastases after prior treatment with radiation or surgery. Responses and clinical benefit in the CNS were seen for both groups and in all combinations tested. * On May 30, 2015, Oncothyreon announced the presentation of positive data from the company's ongoing trials of ONT-380, an orally active, reversible and selective small-molecule HER2 inhibitor for the treatment of breast cancer, at the American Society of Clinical Oncology (ASCO) 2015 Annual Meeting. The first presentation updated data from the Phase 1b trial of ONT-380 in combination with Xeloda® (capecitabine)and Herceptin® (trastuzumab) in third line treatment of HER2-positive metastatic breast cancer. The data support Oncothyreon's plans to initiate a blinded, randomized, placebo-controlled Phase 2 trial in this indication. The second presentation focused on the role of ONT-380 in the treatment of HER2-positive breast cancer central nervous system (CNS) metastases. The Phase 1b trial of ONT-380 in combination with Xeloda® (capecitabine) and/or Herceptin® (trastuzumab) is a parallel dose escalation study in patients previously treated with Herceptin and Kadcyla® (ado-trastuzumab emtansine or TDM-1) for metastatic breast cancer. Data were presented for 32 patients, including seven in the ONT-380 plus Xeloda cohort, 13 in the ONT-380 plus Herceptin cohort and 12 in the ONT-380 plus Xeloda and Herceptin cohort. Twenty-seven of the patients were evaluable for best overall response using RECIST 1.1 criteria. Considering the three cohorts together, a complete response (CR) was seen in two patients, a partial response (PR) in 12 patients, stable disease (SD) in nine patients and progressive disease (PD) in four patients. Patients included in the presentation on the role of ONT-380 in the treatment of CNS metastases were selected from the above trial and from an ongoing Phase 1b trial (NCT01983501) of ONT-380 in combination with Kadcyla® in patients who have been previously treated with Herceptin® and a taxane for metastatic breast cancer. Patients were included if their presenting CNS lesions were evaluable for response using RECIST 1.1 criteria and they had either untreated, asymptomatic lesions having never received radiotherapy or surgery to the CNS (n=8) or new or progressive lesions following prior CNS therapy (n=14). Best CNS response was a CR in one patient, a PR in four patients and SD in nine patients. No patient had progressive disease as a CNS best response. One patient was not evaluable for response having undergone surgery for a symptomatic CNS lesion; pathologic examination of the resected specimen found no evidence of viable tumor. Two patients were not evaluated because of progressive disease outside of the CNS, while five patients in the series remain too early to evaluate.
ONT-380 has been well tolerated in both Phase 1b trials. The most common adverse events included diarrhea, nausea, constipation, fatigue, dyspepsia, headache and vomiting. Most adverse events were grade 1 or 2 in severity. Laboratory abnormalities included asymptomatic elevated liver function tests, which were more common in patients also receiving Kadcyla®. No grade 3 diarrhea was seen in either trial at the recommended dose of ONT-380; anti-diarrheal prophylaxis was not a study requirement.
