UHPLC–MS/MS method to determine FP-208 in human plasma and its application to a pharmacokinetic study

Bioanalysis ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 367-378
Author(s):  
Huanhuan Wang ◽  
Teng Wang ◽  
Zhanqing Wang ◽  
Zhenjian Du ◽  
Qian Zhao ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Mammalian Target Of Rapamycin ◽  
Human Study ◽  
Pharmacokinetic Profile ◽  
Target Of Rapamycin ◽  
Precipitation Method ◽  
Molecule Inhibitor ◽  
Ionization Mode ◽  
First Time ◽  
Reliable Analytical Method

Aim: FP-208 is a novel and effective small-molecule inhibitor blocking the mammalian target of rapamycin complex-1/mammalian target of rapamycin complex-2/PI3Ka. To investigate the pharmacokinetic profile of FP-208, a rapid and reliable analytical method was needed to be established to determine FP-208 in the plasma of patients with solid tumors. Materials & methods: FP208 was separated on a charged surface hybrid (CSH) C18 column (2.1 mm × 50 mm, 1.7 μm) after the plasma samples were purified using a protein precipitation method. Detection was performed on an AB Sciex 5500 mass spectrometer in the positive electrospray ionization mode. The established method was validated according to the bioanalytical guidelines. Conclusion: For the first time, the developed and validated method was successfully applied in the first-in-human study for FP-208 in patients with solid tumors after oral administration (Number: CTR20180683).

A phase Ib study of prexasertib, a checkpoint kinase (CHK1) inhibitor, and LY3023414, a dual inhibitor of class I phosphatidylinositol 3-kinase (PI3K) and the mammalian target of rapamycin (mTOR) in patients with advanced solid tumors.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 3091-3091
Author(s):  
David S. Hong ◽  
Kathleen N. Moore ◽  
Johanna C. Bendell ◽  
Daniel D. Karp ◽  
Judy Sing-Zan Wang ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Data Transfer ◽  
Mammalian Target Of Rapamycin ◽  
Pharmacokinetic Profile ◽  
Maximum Tolerated Dose ◽  
In Vitro Models ◽  
Unknown Primary ◽  
Dual Inhibitor ◽  
Pik3ca Mutations

3091 Background: Prexasertib inhibits CHK1, a kinase involved in DNA repair and replication. LY3023414 inhibits PI3K/mTOR signaling, implicated in the development of malignant disease. Prexasertib + LY3023414 has resulted in enhanced antitumor activity in triple negative breast cancer (TNBC) in vitro models. Methods: This Phase 1b study in patients (pts) with solid tumors assessed escalating doses of prexasertib (60-105 mg/m2 IV every 14 days [q14d]) and LY3023414 (100-200 mg orally twice daily [BID]). Dose escalation ceased once the maximum tolerated dose of each monotherapy was reached. An initial expansion cohort (Arm E) explored prexasertib 105 mg/m2 q14d + LY3023414 200 mg BID. Subsequent expansion cohorts evaluated prexasertib 105 mg/m2 q14d + LY3023414 150 mg BID in pts with solid tumors with PIK3CA mutations (Arm E2) or TNBC (Arm E3). Results: Fifty pts were enrolled (escalation: n = 13; Arm E: n = 9; Arm E2: n = 15; Arm E3: n = 13). No dose-limiting toxicities (DLTs) were observed during escalation however DLT-equivalent toxicities were observed in 2 pts in Arm E (anemia, neutropenia, thrombocytopenia, oral mucositis, abdominal pain, fatigue). Due to toxicity, a reduced dose of LY3023414 (150 mg BID) was assessed in Arm E2/E3. In the 28 patients treated in Arms E2/E3, common treatment-related adverse events (any grade; grade ≥3) were: leukopenia/neutropenia (82%; 79%), thrombocytopenia (46%; 36%), nausea (46%; 0%), stomatitis (39%, 4%), vomiting (36%; 0%), and anemia (29%; 18%). Febrile neutropenia was reported in 25% of pts. Dose reductions in Arm E2/E3 were common. In escalation, 2 pts achieved a partial response (PR) and 3 pts achieved stable disease (SD). In Arm E, 78% of pts achieved SD. Of the pts evaluable at the time of data transfer, PRs were achieved in 1 pt with an unknown primary (Arm E2) and 2 pts with TNBC (Arm E3). Each agent’s pharmacokinetic profile was consistent with prior monotherapy data. Conclusions: Prexasertib + LY3023414 showed preliminary efficacy in heavily pretreated pts with solid tumors but was associated with toxicity, suggesting supportive care may be required. Clinical trial information: NCT02124148.

First-time in-human study of VMD-928, an allosteric and irreversible TrkA selective inhibitor, in patients with solid tumors or lymphoma.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS3146-TPS3146 ◽  
Author(s):  
Vincent Chung ◽  
Ling Wang ◽  
Margaret S. Fletcher ◽  
Erminia Massarelli ◽  
Karen L. Reckamp ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Phase 1 ◽  
Human Study ◽  
Selective Inhibitor ◽  
Biologically Active ◽  
Egfr Inhibitors ◽  
Advanced Solid Tumors ◽  
Multiple Tumor ◽  
First Time

TPS3146 Background: Tropomysin receptor kinase A (TrkA) is a protein encoded by the NTRK1 gene. NTRK fusions involving the kinase domain are oncogenic for multiple tumor types and larotrectinib was recently approved for advanced solid tumors harboring NTRK gene fusions. Larotrectinib, an ATP-competitive, reversible pan-TrkA/B/C inhibitor, has shown impressive response rates in patients harboring these fusions; however, resistance can develop due to acquired ATP-site mutations. This has been previously identified in other oncogenic driver kinases such as ALK and EGFR treated with ATP-competitive kinase inhibitors. A newly approved allosteric ALK/EGFR inhibitor brigatinib was able to clinically overcome acquired resistance of many ATP-competitive ALK/EGFR inhibitors (1). Also, irreversible EGFR inhibitors such as afatinib (ATP-competitive) were active against tumors resistant to first-generation inhibitors (2), although their efficacy can be compromised by acquired ATP-site mutations (3). VMD-928 is the first oral small-molecule TrkA (NTRK1) selective inhibitor with dual allosteric and irreversible mechanisms of action. It inhibits TrkA non-competitively at an allosteric (non-ATP) site and has no resistance in vitro to acquired ATP-site mutations such as G667C. VMD-928 in vitro has little or no activity against 348 other kinases including TrkB (NTRK2) and TrkC (NTRK3). We are conducting the first time in human phase 1 trial of oral VMD-928, a novel allosteric and irreversible TrkA selective inhibitor. Methods: This is an open label, Phase 1 study investigating the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of oral VMD-928 in adults with advanced solid tumors or lymphoma (NCT03556228). In part 1 of the study, an accelerated titration scheme will be utilized to determine the recommended phase 2 dose and evaluate PK / PD of VMD-928. In part 2, expansion cohorts including patients with thymic, pancreatic, triple-negative breast carcinoma, or solid tumors with TrkA alterations will be accrued to further evaluate safety and efficacy. Part 3 of the study will characterize the biologically active dose. The study is open and accruing patients at City of Hope. Clinical trial information: NCT03556228.

scholarly journals A First-Time-in-Human Study of GSK2636771, a Phosphoinositide 3 Kinase Beta-Selective Inhibitor, in Patients with Advanced Solid Tumors

2017 ◽  
Vol 23 (19) ◽  
pp. 5981-5992 ◽  
Author(s):  
Joaquin Mateo ◽  
Gopinath Ganji ◽  
Charlotte Lemech ◽  
Howard A. Burris ◽  
Sae-Won Han ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Human Study ◽  
Selective Inhibitor ◽  
Advanced Solid Tumors ◽  
Phosphoinositide 3 Kinase ◽  
First Time

Dose- and Schedule-Dependent Inhibition of the Mammalian Target of Rapamycin Pathway With Everolimus: A Phase I Tumor Pharmacodynamic Study in Patients With Advanced Solid Tumors

2008 ◽  
Vol 26 (10) ◽  
pp. 1603-1610 ◽  
Author(s):  
Josep Tabernero ◽  
Federico Rojo ◽  
Emiliano Calvo ◽  
Howard Burris ◽  
Ian Judson ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Mammalian Target Of Rapamycin ◽  
Mtor Pathway ◽  
Initiation Factor ◽  
Target Of Rapamycin ◽  
Advanced Solid Tumors ◽  
Eukaryotic Initiation Factor ◽  
Dependent Inhibition ◽  
Grade 3

PurposeEverolimus is a selective mammalian target of rapamycin (mTOR) inhibitor with promising anticancer activity. In order to identify a rationally based dose and schedule for cancer treatment, we have conducted a tumor pharmacodynamic phase I study in patients with advanced solid tumors.Patients and MethodsFifty-five patients were treated with everolimus in cohorts of 20, 50, and 70 mg weekly or 5 and 10 mg daily. Dose escalation depended on dose limiting toxicity (DLT) rate during the first 4-week period. Pre- and on-treatment steady-state tumor and skin biopsies were evaluated for total and phosphorylated (p) protein S6 kinase 1, eukaryotic initiation factor 4E (elF-4E) binding protein 1 (4E-BP1), eukaryotic initiation factor 4G (eIF-4G), AKT, and Ki-67 expression. Plasma trough levels of everolimus were determined on a weekly basis before dosing during the first 4 weeks.ResultsWe observed a dose- and schedule-dependent inhibition of the mTOR pathway with a near complete inhibition of pS6 and peIF-4G at 10 mg/d and ≥ 50 mg/wk. In addition, pAKT was upregulated in 50% of the treated tumors. In the daily schedule, there was a correlation between everolimus plasma trough concentrations and inhibition of peIF4G and p4E-BP1. There was good concordance of mTOR pathway inhibition between skin and tumor. Clinical benefit was observed in four patients including one patient with advanced colorectal cancer achieving a partial response. DLTs occurred in five patients: one patient at 10 mg/d (grade 3 stomatitis) and four patients at 70 mg/wk (two with grade 3 stomatitis, one with grade 3 neutropenia, and one with grade 3 hyperglycemia).ConclusionEverolimus achieved mTOR signaling inhibition at doses below the DLT. A dosage of 10 mg/d or 50 mg/wk is recommended for further development.

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