Reference Detail

Ref Type

Journal Article

PMID

(24849582)

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	Vol	Issue	Date	Pages	Journal Short Title
Cancer chemotherapy and pharmacology	74	1	2014 Jul	195-204	Cancer Chemother Pharmacol

URL

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.

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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
Amuvatinib	Amuvatinib	0	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
Amuvatinib		MP470\|HPK56\|MP-470	AXL Inhibitor 30 FLT3 Inhibitor 66 KIT Inhibitor 57 MET Inhibitor 59 PDGFR-alpha Inhibitor 9 RET Inhibitor 52	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