Alvespimycin is a second-generation Hsp90 inhibitor that has demonstrated the potential to disrupt the activity of multiple oncogenes and cell signaling pathways implicated in tumor growth, including HER2, a key signaling pathway in breast cancer.
The trial was designed to identify the recommended Phase II dose through the evaluation of toxicity and activity in patients with solid tumors. Patients were enrolled in three dose cohorts. The dosing schedule for alvespimycin was a one-hour weekly intravenous infusion of 60, 80 or 100mg/m2 administered along with the standard dose of Herceptin (trastuzumab). Patients were assessed every four weeks for toxicity and every eight weeks for response. Disease response was assessed by RECIST and by tumor markers, if available.
Of the 27 heavily-pretreated patients enrolled in the trial, 24 patients had HER2-positive breast cancer (with the majority of patients having had multiple trastuzumab-containing regimens prior to this study) and three patients had ovarian cancer (HER2 status unknown).
Clinical benefit was observed in 42% of evaluable patients (eight of 19 evaluable) with HER2-positive metastatic breast cancer. During the trial, one patient showed complete resolution of lung metastases by CT/PET with significant improvement in dypsnea (shortness of breath), one patient showed 10% reduction in tumor mass with change consistent with tumor necrosis. There was one partial response and five patients had extended stable disease.
Robert Johnson, Jr., Kosan's president and CEO, said: “Our strategy is to pursue potentially a broad and fast-to-market development pathway for alvespimycin in HER2-positive metastatic breast cancer. We are expanding the Phase I trial to include an alvespimycin plus trastuzumab plus paclitaxel regimen to establish a safety profile of this triplet regimen and to lay the groundwork for a potential larger Phase II/III trial. We expect to start our Phase II monotherapy trial in newly diagnosed HER2-positive patients later this year.”