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|Authors||A.J. Olszanski, R. Gonzalez, P. Corrie, A.C. Pavlick, M. Middleton, P. Lorigan, R. Plummer, S. Skaria, C. Herbert, M. Gore, S. Agarwala, A. Daud, S. Zhang, B. Bahamon, L. Rangachari, E. Hoberman, M. Kneissl, D. Rasco|
|Title||Phase I study of the investigational, oral pan-RAF kinase inhibitor TAK- 580 (MLN2480) in patients with advanced solid tumors (ST) or melanoma (MEL): Final analysis|
|Abstract Text||Background: MAPK pathway mutations leading to signaling hyperactivation are common in many ST; as RAF kinases play a key role in MAPK signaling, they represent a valid target for therapy. As a pan-RAF inhibitor, TAK-580 is differentiated from approved BRAF-specific RAF inhibitors. Here we report the expanded cohort data from a single-agent, first-in-human study of TAK-580 (NCT01425008). Methods: Patients with advanced ST or inoperable stage III/IV MEL received TAK-580 Q2D or QW in 28-d cycles. Primary objectives were safety and maximum tolerated doses [MTD] of TAK-580; secondary objectives included preliminary antitumor activity, PK and PD effects. Safety and PK were compared between 2 MTD regimens (200 mg Q2D vs 600 mg QW). Preliminary antitumor activity of TAK-580 Q2D vs QW was evaluated in NRAS-mutation positive (mut) MEL. Activity and efficacy (PFS) were assessed in BRAF-mut MEL. Plasma PK were assessed pre- and post-dose between d1 and d28 of cycle 1 (C1). Tumor biopsies were taken at screening and post-dose on d21 or 22 of C1. Disease assessments were performed at baseline and every 2 cycles thereafter. Results: 80 patients received TAK-580 200 mg Q2D (60 MEL + 20 PK-evaluable ST) and 19 MEL patients received 600 mg QW. DLTs observed were: periorbital edema and maculopapular rash (280 mg Q2D); rash and hyperbilirubinemia (800 mg QW). For Q2D and QW, 41% and 32% of patients, respectively, had Gr ≥ 3 drug-related adverse events (AE); 19% and 11% discontinued due to AEs. Total weekly exposure (AUC168h) after TAK-580 600 mg QW was comparable to 3-fold AUC48h after 200 mg Q2D. Of 14 NRAS-mut MEL Q2D patients, 1 achieved PR (1.5 mos). In comparison, none of 17 NRAS-mut MEL QW patients had an objective response. 50% of the 16 BRAF-mut MEL Q2D patients achieved a PR with a median PFS of 4.6 mos (range 1.0–40.8). Conclusions: The safety and PK profiles of TAK-580 Q2D and QW at MTD were acceptable. QW dosing improved safety but not efficacy over Q2D dosing. PD results were consistent with the proposed mechanism of action of TAK-580 with observed RAF pathway inhibition. These data support the use of QW dosing in the assessment TAK-580 given in combination. Clinical trial identification: NCT01425008|
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