Efficacy and Safety of YM155 in Relapsed/Refractory Non-Hodgkin’s Lymphoma Patients Enrolled in a Phase I Study.

Background: YM155 is a member of a novel class of compounds called survivin suppressants that target survivin. Survivin is a member of the inhibitor of apoptosis proteins (IAPs) family which is responsible for preservation of cell viability and regulation of mitosis in tumor cells. Survivin over-expression has been reported in a variety of tumor cells including lymphoma. A Phase I dose escalation study of YM155 was conducted to evaluate safety, tolerability and antitumor activity in patients with solid tumors or non-Hodgkin’s lymphoma (NHL).

Methods: Patients with solid tumors or NHL with no other treatments options were eligible for this Phase I study and received YM155 in escalating doses ranging from 1.8 – 6 mg/m²/day as a 168 hour (7 day) continuous infusion in a 21 day cycle. Patients could continue to receive YM155 until either disease progression or toxicity. 41 patients were enrolled into the study including 5 patients with NHL (2 diffuse large B-cell lymphoma [DLBCL], 1 each small lymphocytic B-cell, follicular [FL] and anaplastic large cell lymphoma). This report focuses solely on the patients with NHL. All 5 NHL patients had at least 2 prior treatment regimens (range: 2 – 7) including stem cell transplant in two patients (DLBCL, FL) and one patient who received 2 investigational therapies. Three patients were considered refractory to the treatment regimen given just prior to study entry (DLBCL, anaplastic large cell, FL).

Results: All 5 NHL patients were male with a mean age of 56 (range: 46 – 64). They were all dosed at the maximum tolerated dose (MTD) of 4.8 mg/m²/day. The most common adverse events reported, regardless of relationship to YM155, were URI (3/5) and arthralgia, fever, hypomagnesemia, mucositis peripheral edema and rash (2/5). The majority of adverse events were Grade 1 or 2 with 3 events reported as Grade 4: Klebsiella bacteremia, neutropenia and hypokalemia. Three patients (60%) (2 DLBCL and FL) had partial response (PR) to YM155 as assessed by independent review using both RECIST and 1999 Cheson criteria. One responder (DLBCL) had a PR after 2 cycles, completed a total of 5 cycles and proceeded to stem cell transplant. This patient has no evidence of disease at 3 years. A second responder (DLBCL) had a PR after 12 cycles and received a total of 26 cycles (∼ 1.5yrs) before disease progression. The third responder (FL) had a PR after 14 cycles, has maintained a prolonged PR for ∼ 2 years and continues to receive YM155 in a long-term extension study.

Conclusion: Based upon the objective responses, the tolerability and safety profile observed in this Phase I study in 5 NHL patients, a Phase II study in refractory DLBCL has been initiated.