At the 2009 Annual Meeting of the American Society of Hematology, we presented data summarizing the Phase I portion of a multi-center, international Phase I/II open-label, non-randomized dose-finding clinical trial evaluating SB-743921 in patients with non-Hodgkin or Hodgkin Lymphoma who have progressed or relapsed on standard therapy. The primary objectives of this clinical trial were to determine the dose-limiting toxicities (DLTs) and the maximum-tolerated dose (MTD) of SB-743921 administered as a 1-hour infusion on days 1 and 15 of a 28-day cycle, first without and then with prophylactic granulopoietic factor support (i.e., granulocyte colony-stimulating factor or G-CSF) and to assess the safety and tolerability of SB-743921 on this schedule. The secondary objectives were to characterize the pharmacokinetics of SB-743921 administered on this schedule and to evaluate the effect of SB-743921 on biomarkers of cell proliferation in patients with accessible tumors.

The authors concluded that the MTD of SB-743921 given on this schedule with G-CSF support was 9 mg/m2. The main DLT of SB-743921 on this schedule with G-CSF support was thrombocytopenia and neutropenia. The authors noted that a greater dose-density was achieved with SB-743921 given on a once every two week schedule without prophylactic G-CSF (i.e., 6 mg/m2 = 0.43 mg/m2/day) than a once every 21 days schedule (i.e., 4 mg/m2 = 0.19 mg/m2/day). Dose-density with G-CSF on the once every two week schedule was equal to 0.64 mg/m2. Grade 3 or 4 toxicities other than myelosuppression were infrequent; in particular, there was no evidence of neuropathy or alopecia greater than Grade 1. An efficacy signal was observed at doses at or above 6 mg/m2 in Hodgkin Lymphoma patients. Of the 55 patients evaluable for efficacy, four partial responses (three patients with Hodgkin Lymphoma and one with indolent non-Hodgkin Lymphoma) were observed. The duration of the response in the patients with a partial response was between 8 weeks and 28 weeks. Best response as a percentage reduction in the sum of the product of diameters for the dominant lesion ranged from 53% to 71%. The small numbers of patients in each of the non-Hodgkin Lymphoma subtypes limited the assessment of activity in those populations. The authors concluded that further evaluation of SB-743921 in selected Hodgkin Lymphoma populations as a single agent, and in combination with other promising drug candidates, is warranted.

At the American Society of Clinical Oncology (ASCO) annual meeting in May 2006, data was presented from an open-label, non-randomized, dose-finding, first-in-humans Phase I clinical trial of SB-743921in patients with advanced solid tumors. The authors concluded that SB-743921 appeared to have an acceptable tolerability profile on a once-every-21-day schedule. The MTD in the first-in-humans trial was 4 mg/m2 every 21 days, although dosing reached 8 mg/m2. The DLTs reported at that time were prolonged neutropenia, febrile neutropenia (with or without infection), elevated transaminases, hyperbilirubinemia and hyponatremia. Neurotoxicities, mucositis, thrombocytopenia, alopecia and nausea/vomiting requiring pre-medication were not observed.