Reference Detail

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	Vol	Issue	Date	Pages	Journal Short Title
Annals of oncology : official journal of the European Society for Medical Oncology	31	5	2020 05	626-633	Ann Oncol

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
Ipatasertib	Ipatasertib	22	10

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
Ipatasertib		GDC-0068\|RG-7440	Akt Inhibitor (Pan) 21	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 act mut	Advanced Solid Tumor	predicted - sensitive	Fluorouracil + Ipatasertib + Leucovorin + Oxaliplatin	Phase I	Actionable	In a Phase Ib trial, the combination of Ipatasertib (GDC-0068) and mFOLFOX6 resulted in an objective response rate (ORR) of 6.1% (2/33, partial responses) in patients with advanced solid tumors (n=33), and ORR was proportionally higher in patients harboring activating PIK3CA mutations (1/4) compared to in patients without PIK3CA activating mutations (1/29) (PMID: 32205017; NCT01362374).	32205017
PIK3CA act mut	Advanced Solid Tumor	sensitive	Ipatasertib + Paclitaxel	Phase I	Actionable	In a Phase Ib trial, the combination of Ipatasertib (GDC-0068) and Taxol (paclitaxel) resulted in an objective response rate (ORR) of 8.0% (2/25, partial responses) in patients with advanced solid tumors (n=25), and ORR was proportionally higher in patients harboring activating PIK3CA mutations (2/6) compared to patients without PIK3CA activating mutations (0/19) (PMID: 32205017; NCT01362374).	32205017
PTEN dec exp	triple-receptor negative breast cancer	sensitive	Docetaxel + Ipatasertib	Preclinical - Pdx	Actionable	In a preclinical study, the combination of Ipatasertib (GDC-0068) and Taxotere (docetaxel) inhibited tumor growth in a patient-derived xenograft (PDX) model of triple-negative breast cancer with low PTEN expression, and demonstrated increased activity over either agent alone (PMID: 32205017).	32205017
PIK3CA E545K	breast cancer	sensitive	Ipatasertib	Preclinical - Cell line xenograft	Actionable	In a preclinical study, Ipatasertib (GDC-0068) reduced tumor growth in a cell line xenograft model of hormone-receptor positive breast cancer harboring PIK3CA E545K (PMID: 32205017).	32205017
PIK3CA act mut	Advanced Solid Tumor	predicted - sensitive	Docetaxel + Ipatasertib	Phase I	Actionable	In a Phase Ib trial, the combination of Ipatasertib (GDC-0068) and Taxotere (docetaxel) resulted in an objective response rate (ORR) of 7.7% (2/26, partial responses) in patients with advanced solid tumors (n=26), and ORR was proportionally higher in patients harboring activating PIK3CA mutations (1/4) compared to patients without PIK3CA activating mutations (1/22) (PMID: 32205017; NCT01362374).	32205017
PTEN dec exp	triple-receptor negative breast cancer	sensitive	Ipatasertib	Preclinical - Pdx	Actionable	In a preclinical study, Ipatasertib (GDC-0068) reduced tumor growth in a patient-derived xenograft (PDX) model of triple-negative breast cancer with low PTEN expression (PMID: 32205017).	32205017
PTEN loss	stomach cancer	sensitive	Ipatasertib	Preclinical - Pdx	Actionable	In a preclinical study, Ipatasertib (GDC-0068) demonstrated activity against tumor growth in patient-derived xenograft (PDX) models of ERBB2 (HER2)-negative stomach cancer harboring PTEN loss (PMID: 32205017).	32205017
PTEN loss	stomach cancer	sensitive	Fluorouracil + Ipatasertib + Leucovorin + Oxaliplatin	Preclinical - Pdx	Actionable	In a preclinical study, the combination of Ipatasertib (GDC-0068) and FOLFOX inhibited tumor growth in a patient-derived xenograft (PDX) model of ERBB2 (HER2)-negative gastric cancer harboring PTEN loss, and demonstrated increased activity over either agent alone (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) inhibited tumor growth in a cell line xenograft model of hormone-receptor positive breast cancer harboring PIK3CA E545K, and demonstrated increased activity over either agent alone (PMID: 32205017).	32205017