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RESEARCH PRODUCT
Antitumor activity of ipatasertib combined with chemotherapy: results from a phase Ib study in solid tumors
Manish R. PatelLuna MusibPaul ConklingAndrés CervantesPremal PatelKedan LinNicholas J. VogelzangAri David BaronJohanna C. BendellJ-c. SoriaMaha HussainDaniel J. MaslyarWai Y. ChanJosep TaberneroN. XuSteven J. IsakoffGuillem ArgilesL. R. MolifeHan MaDeepak SampathSteven Gendreausubject
Male0301 basic medicinemedicine.medical_specialtyMaximum Tolerated Dosemedicine.medical_treatmentCàncer - Quimioteràpia:Otros calificadores::Otros calificadores::/efectos adversos [Otros calificadores]GastroenterologyAKT inhibitorPiperazinesMedicaments antineoplàstics - Efectes secundaris:neoplasias [ENFERMEDADES]03 medical and health scienceschemistry.chemical_compound0302 clinical medicineNeoplasmsInternal medicineAntineoplastic Combined Chemotherapy Protocols:Other subheadings::Other subheadings::/adverse effects [Other subheadings]medicineadvanced cancerHumansEnzalutamide:terapéutica::protocolos clínicos::protocolos antineoplásicos::protocolos de quimioterapia antineoplásica combinada [TÉCNICAS Y EQUIPOS ANALÍTICOS DIAGNÓSTICOS Y TERAPÉUTICOS]Adverse effectChemotherapybusiness.industryHematologyphase I:Therapeutics::Clinical Protocols::Antineoplastic Protocols::Antineoplastic Combined Chemotherapy Protocols [ANALYTICAL DIAGNOSTIC AND THERAPEUTIC TECHNIQUES AND EQUIPMENT]Oxaliplatin:Neoplasms [DISEASES]Pyrimidines030104 developmental biologyOncologyDocetaxelTolerabilityPaclitaxelchemistryResponse Evaluation Criteria in Solid Tumors030220 oncology & carcinogenesisbusinessmedicine.drugdescription
Inhibidor d'AKT; Càncer avançat; Fase I Inhibidor de AKT; Cáncer avanzado; Fase I AKT inhibitor; Advanced cancer; Phase I Background This phase Ib study evaluated the safety, tolerability, pharmacokinetics, and preliminary efficacy of the oral AKT inhibitor ipatasertib and chemotherapy or hormonal therapy in patients with advanced or metastatic solid tumors to determine combined dose-limiting toxicities (DLTs), maximum tolerated dose, and recommended phase II doses and schedules. Patients and methods The clinical study comprised four combination treatment arms: arm A (with docetaxel), arm B [with mFOLFOX6 (modified leucovorin, 5-fluorouracil, and oxaliplatin)], arm C (with paclitaxel), and arm D (with enzalutamide). Primary endpoints were safety and tolerability; secondary endpoints were pharmacokinetics, clinical activity per Response Evaluation Criteria in Solid Tumors v1.1, and prostate-specific antigen levels. Results In total, 122 patients were enrolled. Common adverse events were diarrhea, nausea, vomiting, decreased appetite, and fatigue. The safety profiles of the combination regimens were consistent with those of the background regimens, except for diarrhea, hyperglycemia, and rash, which were previously observed with ipatasertib treatment. The only combination DLT across all treatment arms was one event of grade 3 dehydration (ipatasertib 600 mg and paclitaxel). Recommended phase II doses for ipatasertib were 600 mg (and mFOLFOX6) and 400 mg (and paclitaxel), respectively. The maximum assessed dose of ipatasertib 600 mg combined with docetaxel or enzalutamide was well tolerated. Coadministration with enzalutamide (a cytochrome P450 3A inducer) resulted in approximately 50% lower ipatasertib exposure. Conclusions Ipatasertib in combination with chemotherapy or hormonal therapy was well tolerated with a safety profile consistent with that of ATP-competitive AKT inhibitors. This work was supported by Genentech, Inc., a member of the Roche Group, and F. Hoffmann-La Roche Ltd. (no grant number).
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2020-05-01 | Annals of Oncology |