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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| Published in: | Clinical cancer research Vol. 24; no. 14; p. 3253 |
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| Main Authors: | , , , , , , , , , , , |
| Format: | Journal Article |
| Language: | English |
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15.07.2018
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| ISSN: | 1078-0432, 1557-3265, 1557-3265 |
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| Abstract | 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.
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| AbstractList | 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.
. 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.Patients and Methods: 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.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; 24(14); 3253-62. ©2018 AACR.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.Patients and Methods: 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.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; 24(14); 3253-62. ©2018 AACR. |
| Author | Martinez, Ricardo Wacheck, Volker Fink, Aaron Bauer, Todd M Wickremsinhe, Enaksha Moore, Kathleen N Bendell, Johanna C Pant, Shubham Varghese, Anna M Hyman, David M Callies, Sophie Lin, Ji |
| Author_xml | – sequence: 1 givenname: Johanna C surname: Bendell fullname: Bendell, Johanna C email: jbendell@tnonc.com organization: Sarah Cannon Research Institute/Tennessee Oncology, Nashville, Tennessee. jbendell@tnonc.com – sequence: 2 givenname: Anna M surname: Varghese fullname: Varghese, Anna M organization: Memorial Sloan Kettering Cancer Center, New York, New York – sequence: 3 givenname: David M surname: Hyman fullname: Hyman, David M organization: Memorial Sloan Kettering Cancer Center, New York, New York – sequence: 4 givenname: Todd M surname: Bauer fullname: Bauer, Todd M organization: Sarah Cannon Research Institute/Tennessee Oncology, Nashville, Tennessee – sequence: 5 givenname: Shubham surname: Pant fullname: Pant, Shubham organization: Stephenson Oklahoma Cancer Center/Sarah Cannon Research Institute, Oklahoma City, Oklahoma – sequence: 6 givenname: Sophie surname: Callies fullname: Callies, Sophie organization: Eli Lilly and Company, Indianapolis, Indiana – sequence: 7 givenname: Ji orcidid: 0000-0001-7206-6111 surname: Lin fullname: Lin, Ji organization: Eli Lilly and Company, Indianapolis, Indiana – sequence: 8 givenname: Ricardo surname: Martinez fullname: Martinez, Ricardo organization: Eli Lilly and Company, Indianapolis, Indiana – sequence: 9 givenname: Enaksha surname: Wickremsinhe fullname: Wickremsinhe, Enaksha organization: Eli Lilly and Company, Indianapolis, Indiana – sequence: 10 givenname: Aaron surname: Fink fullname: Fink, Aaron organization: Eli Lilly and Company, Indianapolis, Indiana – sequence: 11 givenname: Volker surname: Wacheck fullname: Wacheck, Volker organization: Eli Lilly and Company, Indianapolis, Indiana – sequence: 12 givenname: Kathleen N surname: Moore fullname: Moore, Kathleen N organization: Stephenson Oklahoma Cancer Center/Sarah Cannon Research Institute, Oklahoma City, Oklahoma |
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| Snippet | 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... 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,... |
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| SubjectTerms | 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 |
| Title | A First-in-Human Phase 1 Study of LY3023414, an Oral PI3K/mTOR Dual Inhibitor, in Patients with Advanced Cancer |
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