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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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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References