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|Ref Type||Journal Article|
|Authors||Mita M, Gordon M, Rosen L, Kapoor N, Choy G, Redkar S, Taverna P, Oganesian A, Sahai A, Azab M, Bristow R, Tolcher AW|
|Title||Phase 1B study of amuvatinib in combination with five standard cancer therapies in adults with advanced solid tumors.|
|Journal||Cancer chemotherapy and pharmacology|
|Abstract Text||Amuvatinib is an oral multi-kinase inhibitor that suppresses RAD51, inhibits mutant c-KIT and platelet-derived growth factor receptor alpha, and has synergistic activity with DNA-damaging agents and topoisomerase inhibitors such as etoposide, doxorubicin, and topotecan. We conducted a phase 1B study to estimate the maximum tolerated dose (MTD) levels of amuvatinib with standard chemotherapy regimens and to define the safety profiles of specific amuvatinib + standard regimens.Five therapies each co-administered with amuvatinib 100-800 mg/day every 21 days were evaluated in treatment-naïve or moderately pre-treated subjects: paclitaxel IV followed by carboplatin IV; carboplatin IV followed by etoposide; topotecan IV; docetaxel IV; and erlotinib by mouth.Among 97 treated subjects, no treatment arm reached the MTD. Dose-limiting toxicities included febrile neutropenia and diarrhea. No pharmacokinetic interactions of amuvatinib with any cancer regimens occurred. Of 12/97 (12 %) partial responses overall, 11 were seen in the amuvatinib and paclitaxel/carboplatin or carboplatin/etoposide arms and most commonly in the neuroendocrine (NE), non-small cell lung cancer (NSCLC), and small cell lung cancer (SCLC) tumors. Forty-four subjects (45 %) had stable disease. Adverse events reflected combination treatment and were primarily non-hematologic (fatigue, alopecia, diarrhea, nausea, anorexia) and hematologic (neutropenia, anemia, thrombocytopenia, leukopenia). Pharmacodynamic effects as measured by decreased levels of RAD51 and increased residual DNA damage (53BP1 foci) were seen in skin punch biopsies.Amuvatinib was well tolerated, modulated RAD51, and showed antitumor activity when combined with paclitaxel/carboplatin and carboplatin/etoposide in NE, NSCLC, and SCLC tumors.|
|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|
|Amuvatinib||MP470|HPK56||AXL Inhibitor 27 FLT3 Inhibitor 55 KIT Inhibitor 51 MET Inhibitor 51 PDGFR-alpha Inhibitor 9 RET Inhibitor 39||Amuvatinib (MP470) is a multi-kinase inhibitor, with activity against KIT, MET, AXL, RET, FLT3, and PDGFR-alpha, that also inhibits Rad51 induction, which may enhance the efficacy of chemotherapeutic agents (PMID: 17325667, PMID: 21903282, PMID: 20563581, PMID: 24849582 ).|
|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|
|Unknown unknown||Advanced Solid Tumor||not applicable||Amuvatinib + Carboplatin + Paclitaxel||Phase I||Actionable||In a Phase I clinical trial, Amuvatinib (MP470) in combination with chemotherapeutic agents, demonstrated safety and some efficacy in patients with advanced solid tumors (PMID: 24849582).||24849582|