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Ref Type Journal Article
PMID (32205017)
Authors Isakoff SJ, Tabernero J, Molife LR, Soria JC, Cervantes A, Vogelzang NJ, Patel MR, Hussain M, Baron A, Argilés G, Conkling PR, Sampath D, Maslyar D, Patel P, Chan W, Gendreau S, Musib L, Xu N, Ma H, Lin K, Bendell J
Title Antitumor activity of ipatasertib combined with chemotherapy: results from a phase Ib study in solid tumors.
Journal Annals of oncology : official journal of the European Society for Medical Oncology
Vol 31
Issue 5
Date 2020 05
URL
Abstract Text 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.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.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.Ipatasertib in combination with chemotherapy or hormonal therapy was well tolerated with a safety profile consistent with that of ATP-competitive AKT inhibitors.NCT01362374.

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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
Ipatasertib GDC-0068|RG-7440 Akt Inhibitor (Pan) 19 Ipatasertib (GDC-0068) binds to and inhibits the activity of AKT in an ATP-competitive manner, which may result in the inhibition of the PI3K-AKT signaling pathway and tumor cell proliferation (PMID: 22934575, PMID: 32205017).
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
PIK3CA E545K breast cancer sensitive Ipatasertib Preclinical - Cell line xenograft Actionable In a preclinical study, Ipatasertib (GDC-0068) demonstrated activity against tumor growth in cell line xenograft models of breast cancer cells harboring PIK3CA E545K (PMID: 32205017). 32205017
PIK3CA E545K breast cancer sensitive Ipatasertib + Paclitaxel Preclinical - Cell line xenograft Actionable In a preclinical study, the combination of Ipatasertib (GDC-0068) and Taxol (paclitaxel) synergistically inhibited tumor growth in cell line xenograft models of breast cancer cells harboring PIK3CA E545K (PMID: 32205017). 32205017
Unknown unknown Advanced Solid Tumor not applicable Docetaxel + Ipatasertib Phase I Actionable In a Phase Ib trial, the combination of Ipatasertib (GDC-0068) and Taxotere (docetaxel) demonstrated safety in patients with advanced solid tumors, and resulted in an overall response rate of 7.7% (2/26), including partial responses in two patients, stable disease in 53.8% (14/26) of patients, a six-month progression-free survival rate of 11.5% (3/26), and maximum progression-free survival duration of 10 months in a lung cancer patient (PMID: 32205017; NCT01362374). 32205017
Unknown unknown prostate cancer not applicable Enzalutamide + Ipatasertib Phase I Actionable In a Phase Ib trial, the combination of Ipatasertib (GDC-0068) and Xtandi (enzalutamide) demonstrated safety in prostate cancer patients, and resulted in an overall response rate of 11.8% (2/17), including partial responses in two patients, stable disease in 23.5% (4/17) of patients, a six-month progression-free survival rate of 23.5% (4/17), and maximum progression-free survival duration of 19.5 months (PMID: 32205017; NCT01362374). 32205017
Unknown unknown Advanced Solid Tumor not applicable Fluorouracil + Ipatasertib + Leucovorin + Oxaliplatin Phase I Actionable In a Phase Ib trial, the combination of Ipatasertib (GDC-0068) and mFOLFOX6 demonstrated safety in patients with advanced solid tumors, and resulted in an overall response rate of 6.1% (2/33), including partial responses in two patients, stable disease in 51.5% (17/33) of patients, a six-month progression-free survival rate of 18.2% (6/33), and maximum progression-free survival duration of 50 months in a patient with appendix cancer (PMID: 32205017; NCT01362374). 32205017
Unknown unknown Advanced Solid Tumor not applicable Ipatasertib + Paclitaxel Phase I Actionable In a Phase Ib trial, the combination of Ipatasertib (GDC-0068) and Taxol (paclitaxel) demonstrated safety in patients with advanced solid tumors, and resulted in an overall response rate of 8.0% (2/25), including partial responses in two patients, stable disease in 56.0% (14/25) of patients, a six-month progression-free survival rate of 12.0% (3/25), and maximum progression-free survival duration of 14 months in a breast cancer patient (PMID: 32205017; NCT01362374). 32205017