Randomized, Double-Blind, Placebo-Controlled, Dose and Schedule-Finding Study of AMG 531 In Chemotherapy-Induced Thrombocytopenia (CIT): Results of a Phase I/II Study.

AMG 531 is a peptibody that increases platelet production by stimulating thrombopoietin (TPO) receptors. Prior studies (Vadhan-Raj et al, JCO 2003) have shown the importance of schedule of recombinant TPO to overcome thrombocytopenia (TCP) caused by high dose chemotherapy (CT). RHyper-CVAD alternating with RArac-MTX is a highly effective regimen in the treatment of aggressive non-Hodgkin's lymphoma (NHL), including Mantle-cell lymphoma, with severe TCP as dose-limiting toxicity (86% grade 4 TCP in cycle-2). The objectives of this study were to evaluate the clinical safety and preliminary efficacy of AMG 531 in CIT. Cohorts of 12 evaluable patients were enrolled sequentially at each of the 3 dose levels (1, 3, or 10 mcg/kg). Patients at each dose level were randomized 1:1 into Arm A (pre/post dosing) or Arm B (post-dosing only). All pts received CT alone in cycle-1. In cycle-2, all pts received blinded study drug (2:1 AMG 531 or placebo). The study drug was administered SC as 2 doses given on days -5 and 5 (pre and post doses-Arm A), or on days 5 and 7 (only post-chemotherapy doses-Arm B). In subsequent cycles of CT (maximum total 6 cycles), all pts, including placebo group, received open-label AMG 531 by the same schedule. Of the 50 pts enrolled, 41 received at least one dose of AMG 531 and are evaluable for toxicity and 36 received the treatment with the study drug as per protocol and are evaluable for response. Treatment with AMG 531 was generally well tolerated, with some pts experiencing mild to moderate headache, myalgia, bone pain, and thrombocytosis and venous thromboembolism [4 pts; 2 deep vein thrombosis (DVT) and 2 pulmonary embolism (PE); both at 10 mcg/kg]. Four of the 9 pts who did not receive the study drug also experienced DVT (3 pts) or PE (1 pt). The platelet nadir was significantly higher and the duration of TCP was shorter, with a reduced need for the PLT transfusions on Arm A (pre and post-dosing) compared to placebo as shown in the table below. There was reduced TCP on Arm B (post-dosing) as compared to placebo, but not statistically significant. There were also fewer patients with bleeding episodes (all grades) on Arm A vs placebo (1/12 pts vs 6/12 pts, p = 0.07, Fisher's exact test) in the blinded-cycle.

Using general-linear model, there was a difference in schedule (p=0.0466) and difference in doses (p=0.0162) on duration of TCP, and the lower doses (1 or 3 mcg/kg) appeared to have a better biologic activity than higher dose (10mcg/kg) as compared to the placebo.

AMG 531 was generally well tolerated and significantly reduced severe thrombocytopenia when administered both before and after (pre and post dosing) CT in NHL pts. Future larger studies are needed to establish the safety and efficacy of AMG 531 in CIT.

Vadhan-Raj:Amgen: Honoraria, Research Funding. Off Label Use: AMG 531 (Romiplostim) for chemotherapy-induced thrombocytopenia.