Characterization of LY3023414, a Novel PI3K/mTOR Dual Inhibitor Eliciting Transient Target Modulation to Impede Tumor Growth

Smith, Michèle C.; Mader, Mary M.; Cook, James A.; Iversen, Philip W.; Ajamie, Rose T.; Perkins, E.J.; Bloem, Laura J.; Yip, Yvonne Y.; Barda, David A.; Waid, Philip P.; Zeckner, Douglas J.; Young, Debra A.; Sánchez-Félix, Manuel; Donoho, Gregory P.; Wacheck, Volker

doi:10.1158/1535-7163.mct-15-0996

Cited by 64 publications

(48 citation statements)

References 44 publications

(50 reference statements)

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“…In parallel with the short half-life of LY3023414 of about 2 hours, dephosphorylation by !50% of 4EBP1 lasted for about 4 hours and returned to baseline after 6 hours postdose. While this pharmacodynamic data in PBMCs can be only considered as surrogate for the pharmacodynamic effects in patients tumor tissue, the target inhibition kinetics are consistent with data in tumor xenograft models showing intermittent target inhibition in tumors to be associated with singleagent activity of LY3023414 (7). Therefore, assessment of PBMCs was considered a scientifically acceptable and clinically feasible surrogate approach to reflect pharmacodynamic effects of LY3023414 in patient's tumors in this phase I study.…”

Section: Discussionsupporting

confidence: 65%

“…LY3023414 is a novel and selective inhibitor of class I PI3K isoforms, mTORC1/2 and DNA-PK, as demonstrated in biochemical testing against approximately 266 kinases, with high solubility across a wide pH range (7). LY3023414 shows dose-dependent inhibition of phosphorylation of PI3K/Akt/mTOR pathway downstream substrates for 4 to 6 hours in vivo, reflecting the drug's half-life of 2 hours, and leads to potent antitumor activity in tumor xenograft models (7).…”

Section: Introductionmentioning

confidence: 99%

“…LY3023414 shows dose-dependent inhibition of phosphorylation of PI3K/Akt/mTOR pathway downstream substrates for 4 to 6 hours in vivo, reflecting the drug's half-life of 2 hours, and leads to potent antitumor activity in tumor xenograft models (7). An intermittent, "quick-on/quickoff" target engagement mechanism has been suggested to enhance clinical tolerability of PI3K/mTOR inhibitors as well as potentially reduce the emergence of compensatory resistance mechanisms (7,8). The pharmacokinetic parameters of LY3023414 in rats and dogs suggest that the drug is extensively absorbed at relevant doses and subsequently cleared in part via oxidative metabolism by CYP enzymes (7).…”

Section: Introductionmentioning

confidence: 99%

“…An intermittent, "quick-on/quickoff" target engagement mechanism has been suggested to enhance clinical tolerability of PI3K/mTOR inhibitors as well as potentially reduce the emergence of compensatory resistance mechanisms (7,8). The pharmacokinetic parameters of LY3023414 in rats and dogs suggest that the drug is extensively absorbed at relevant doses and subsequently cleared in part via oxidative metabolism by CYP enzymes (7). CYP3A4 and CYP1A2 are responsible for 82% and 18% of the CYP-mediated LY3023414 clearance, respectively.…”

Section: Introductionmentioning

confidence: 99%

“…In addition, in vitro data suggest that LY3023414 may be a timedependent inhibitor of CYP3A4 metabolism, which could lead to increased plasma concentration of CYP3A4 substrates (Eli Lilly and Company, data on file). The nonclinical toxicology profile of LY3023414 provided a favorable benefit-risk profile enabling clinical studies of LY3023414 (7).…”

Section: Introductionmentioning

confidence: 99%

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

Bendell

Varghese

Hyman

et al. 2018

Clinical Cancer Research

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Purpose: 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.Experimental Design: A 3þ3 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.Results: 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%.Conclusions: 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. Clin Cancer Res; 1-10. Ó2018 AACR.

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Section: Discussionsupporting

confidence: 65%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

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

Bendell

Varghese

Hyman

et al. 2018

Clinical Cancer Research

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New prospectives on treatment opportunities in RASopathies

Gelb

Yohe

Wolf

et al. 2022

American J of Med Genetics Pt C

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The RASopathies are a group of clinically defined developmental syndromes caused by germline variants of the RAS/mitogen-activated protein (MAPK) cascade. The prototypic RASopathy is Noonan syndrome, which has phenotypic overlap with related disorders such as cardiofaciocutaneous syndrome, Costello syndrome, Noonan syndrome with multiple lentigines, and others. In this state-of-the-art review, we summarize current knowledge on unmet therapeutic needs in these diseases and novel treatment approaches informed by insights from RAS/MAPK-associated cancer therapies, in particular through inhibition of MEK1/2 and mTOR in patients with severe disease manifestations. We explore the possibilities of integrating a larger arsenal of molecules currently under development into future care plans. Lastly, we describe both medical and ethical challenges and opportunities for future clinical trials in the field.

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Phase 2 study of LY3023414 in patients with advanced endometrial cancer harboring activating mutations in the PI3K pathway

Rubinstein

Hyman

Caird

et al. 2019

Cancer

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Background PI3K pathway activation is common in endometrial cancer. We evaluated the safety and efficacy of the dual PI3K/mTOR inhibitor, LY3023414, in patients with advanced endometrial cancer harboring activating mutations in the PI3K pathway. Methods We conducted a single‐arm phase 2 study of monotherapy LY3023414. Eligible patients had advanced endometrial cancer of any grade, prior management with 1‐4 cytotoxic lines, and PI3K pathway activation prospectively defined as a loss‐of‐function PTEN alteration or activating alteration in PIK3CA, AKT1, PIK3R1, PIK3R2, or MTOR. The primary objective was best overall response rate (ORR) per RECIST 1.1. Results Twenty‐eight patients were treated; histologies included endometroid (39%), carcinosarcoma (25%), serous (21%), and mixed (14%). Patients were heavily pretreated, with a median of 2 prior cytotoxic lines (range, 1‐3). The most common alterations involved PIK3CA (68%), PTEN (43%), and PIK3R1 (32%). In the 25 efficacy‐evaluable patients, the ORR was 16% (90% CI, 7%‐100%), and the clinical benefit rate was 28% (90% CI, 16%‐100%). Four patients had a confirmed partial response, and 2 responses lasted for >9 months. The median progression‐free survival and overall survival were 2.5 months (95% CI, 1.2‐3.0) and 9.2 months (95% CI, 5.0‐15.9), respectively. The most common all‐grade treatment‐related adverse events were anemia (71%), hyperglycemia (71%), hypoalbuminemia (68%), and hypophosphatemia (61%). No correlation between molecular alterations and response was observed. Conclusion In patients with heavily pretreated advanced endometrial cancer prospectively selected for tumors with activating PI3K pathway mutations, LY3023414 demonstrated modest single‐agent activity and a manageable safety profile.

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Characterization of LY3023414, a Novel PI3K/mTOR Dual Inhibitor Eliciting Transient Target Modulation to Impede Tumor Growth

Abstract: The PI3K/AKT/mTOR pathway is among the most frequently altered pathways in cancer cell growth and survival.

Cited by 64 publications

References 44 publications

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

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

New prospectives on treatment opportunities in RASopathies

Phase 2 study of LY3023414 in patients with advanced endometrial cancer harboring activating mutations in the PI3K pathway

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