A First-in-Human Phase 1 Study of LY3023414, an Oral PI3K/mTOR Dual Inhibitor, in Patients with Advanced Cancer

The PI3K/mTOR pathway is frequently aberrated in cancer. LY3023414 is a potent and selective ATP-competitive inhibitor of class I PI3K isoforms, mTOR, and DNA-PK. Here we report the dose-escalation results of the first-in-human phase I study of LY3023414. A 3+3 dose escalation for once-daily and twi...

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Vydáno v:Clinical cancer research Ročník 24; číslo 14; s. 3253
Hlavní autoři: Bendell, Johanna C, Varghese, Anna M, Hyman, David M, Bauer, Todd M, Pant, Shubham, Callies, Sophie, Lin, Ji, Martinez, Ricardo, Wickremsinhe, Enaksha, Fink, Aaron, Wacheck, Volker, Moore, Kathleen N
Médium: Journal Article
Jazyk:angličtina
Vydáno: United States 15.07.2018
Témata:
Aged
Aged, 80 and over
Antineoplastic Agents - administration & dosage
Antineoplastic Agents - adverse effects
Antineoplastic Agents - pharmacokinetics
Antineoplastic Agents - therapeutic use
Biomarkers
Combined Modality Therapy
Female
Humans
Male
Middle Aged
Neoplasm Metastasis
Neoplasm Staging
Neoplasms - diagnosis
Neoplasms - drug therapy
Neoplasms - metabolism
Phosphoinositide-3 Kinase Inhibitors
Protein Kinase Inhibitors - administration & dosage
Protein Kinase Inhibitors - adverse effects
Protein Kinase Inhibitors - pharmacokinetics
Protein Kinase Inhibitors - therapeutic use
Pyridines - administration & dosage
Pyridines - adverse effects
Pyridines - pharmacokinetics
Pyridines - therapeutic use
Quinolones - administration & dosage
Quinolones - adverse effects
Quinolones - pharmacokinetics
Quinolones - therapeutic use
Retreatment
TOR Serine-Threonine Kinases - antagonists & inhibitors
Treatment Outcome
ISSN:1078-0432, 1557-3265, 1557-3265
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Shrnutí:The PI3K/mTOR pathway is frequently aberrated in cancer. LY3023414 is a potent and selective ATP-competitive inhibitor of class I PI3K isoforms, mTOR, and DNA-PK. Here we report the dose-escalation results of the first-in-human phase I study of LY3023414. A 3+3 dose escalation for once-daily and twice-daily oral dosing of LY3023414 was followed by an expansion cohort for CYP3A4 drug-drug interaction (DDI) assessment. The primary objective was to determine the recommended phase 2 dose (RP2D). Additional objectives included safety, pharmacokinetics/pharmacodynamics, and antitumor activity. Forty-seven patients with solid tumors received LY3023414 at once-daily (20-450 mg) or twice-daily dosing (150-250 mg). Dose-limiting toxicities were observed at 450 mg once-daily (thrombocytopenia, hypotension, hyperkalemia) in three of three patients, 250-mg twice-daily dosing (hypophosphatemia, fatigue, mucositis) in three of four patients, and in one of 15 patients at 200 mg twice-daily (nausea). Common related AEs included nausea (38%), fatigue (34%), and vomiting (32%) and were mostly mild or moderate. LY3023414 pharmacokinetics demonstrated dose-dependent increase in exposure with ≥ 90% target inhibition at doses ≥150 mg. DDI analysis demonstrated LY3023414 to be a weak inhibitor of CYP3A4. Durable partial response was observed in a patient with endometrial cancer harboring PIK3R1 and PTEN truncating mutations, and 13 additional patients (28%) had a decrease in their target lesions by up to 30%. LY3023414 has a tolerable safety profile and single-agent activity in patients with advanced cancers. The RP2D of LY3023414 monotherapy is 200 mg twice daily based on safety, tolerability, and pharmacokinetic/pharmacodynamic data. .
Bibliografie:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:1078-0432
1557-3265
1557-3265
DOI:10.1158/1078-0432.CCR-17-3421