Eric Angevin1, Philippe A Cassier2, Antoine Italiano3, Anthony Gonçalves4, Anas Gazzah5, Catherine Terret6, Maud Toulmonde7, Gwenaëlle Gravis8, Andrea Varga9, Cédric Parlavecchio10, Angelo Paci11, Vianney Poinsignon12, Jean-Charles Soria13, Damien Drubay14, Antoine Hollebecque15. 1. Gustave Roussy, Université Paris-Saclay, Drug Development Department (DITEP), Villejuif, F-94805, France. Electronic address: Eric.ANGEVIN@gustaveroussy.fr. 2. Centre Léon Bérard, Lyon, France. Electronic address: philippe.cassier@lyon.unicancer.fr. 3. Institut Bergonié, Bordeaux, France. Electronic address: a.italiano@bordeaux.unicancer.fr. 4. Aix-Marseille University, CNRS U7258, INSERM U1068, Institut Paoli-Calmettes, CRCM, Marseille, France. Electronic address: GONCALVESA@ipc.unicancer.fr. 5. Gustave Roussy, Université Paris-Saclay, Drug Development Department (DITEP), Villejuif, F-94805, France. Electronic address: Anas.GAZZAH@gustaveroussy.fr. 6. Centre Léon Bérard, Lyon, France. Electronic address: catherine.terret@lyon.unicancer.fr. 7. Institut Bergonié, Bordeaux, France. Electronic address: m.toulmonde@bordeaux.unicancer.fr. 8. Aix-Marseille University, CNRS U7258, INSERM U1068, Institut Paoli-Calmettes, CRCM, Marseille, France. Electronic address: GRAVISG@ipc.unicancer.fr. 9. Gustave Roussy, Université Paris-Saclay, Drug Development Department (DITEP), Villejuif, F-94805, France. Electronic address: Andrea.VARGA@gustaveroussy.fr. 10. Gustave Roussy, Université Paris-Saclay, Drug Development Department (DITEP), Villejuif, F-94805, France. Electronic address: Cedric.PARLAVECCHIO@gustaveroussy.fr. 11. Gustave Roussy, Université Paris-Saclay, Drug Development Department (DITEP), Villejuif, F-94805, France. Electronic address: Angelo.PACI@gustaveroussy.fr. 12. Gustave Roussy, Université Paris-Saclay, Drug Development Department (DITEP), Villejuif, F-94805, France. Electronic address: Vianney.POINSIGNON@gustaveroussy.fr. 13. Gustave Roussy, Université Paris-Saclay, Drug Development Department (DITEP), Villejuif, F-94805, France. Electronic address: Jean-Charles.Soria@gustaveroussy.fr. 14. Gustave Roussy, Université Paris-Saclay, Drug Development Department (DITEP), Villejuif, F-94805, France; CESP, Fac. de médecine - Univ. Paris-Sud, Fac. de médecine - UVSQ, INSERM, Université Paris-Saclay, Villejuif, France. Electronic address: DAMIEN.DRUBAY@gustaveroussy.fr. 15. Gustave Roussy, Université Paris-Saclay, Drug Development Department (DITEP), Villejuif, F-94805, France. Electronic address: Antoine.HOLLEBECQUE@gustaveroussy.fr.
Abstract
BACKGROUND: LY2780301, a dual inhibitor of protein kinase B (AKT) and the downstream effector p70 ribosomal protein S6 kinase (p70S6K), may inhibit progression in tumours relying on phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signalling pathway activation. This phase IB trial investigated the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), safety, pharmacokinetics (PK) and antitumour activity of LY2780301 plus gemcitabine in patients with advanced/metastatic solid tumours. METHODS: This was a non-randomised, open-label, dose escalation and dose expansion trial. Patients harbouring molecular alterations of the PI3K/AKT/mTOR pathway received once daily (QD) oral LY2780301 (400 or 500 mg) in combination with intravenous gemcitabine (750 or 1000 mg/m2) on days 1, 8 and 15 of a 28-d cycle. Dose escalation followed a 3 + 3 design. Assessments included adverse events (AEs), PK and preliminary antitumour activity. RESULTS: Fifty patients (median age, 53 years; 74% female) predominantly with mutations/amplifications of PI3K (60%) and phosphatase and tensin homologue (PTEN) gene/protein inactivation (42%) were treated for up to 14 cycles. The MTD was LY2780301 500 mg QD with gemcitabine 750 mg/m2. DLTs during cycle 1 were grade IV thrombocytopenia, grade III skin rash and grade III increase in alkaline phosphatase, gamma glutamyltransferase and alanine aminotransferase, occurring in one patient each. Most common AEs were anaemia (84%), fatigue (84%), transaminase increase (74%), thrombocytopenia (74%), nausea/vomiting (70%), neutropenia (68%) and lymphopenia (56%). Among the efficacy-evaluable population, two patients (5%) had a partial response; the disease control rate was 74% at cycle 2. CONCLUSIONS: Addition of LY2780301 to gemcitabine showed manageable toxicity and encouraging antitumour activity in patients with molecular alterations of the PI3K/AKT/mTOR pathway. CLINICAL TRIAL REGISTRATION NUMBER: NCT02018874.
BACKGROUND:LY2780301, a dual inhibitor of protein kinase B (AKT) and the downstream effector p70 ribosomal protein S6 kinase (p70S6K), may inhibit progression in tumours relying on phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signalling pathway activation. This phase IB trial investigated the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), safety, pharmacokinetics (PK) and antitumour activity of LY2780301 plus gemcitabine in patients with advanced/metastatic solid tumours. METHODS: This was a non-randomised, open-label, dose escalation and dose expansion trial. Patients harbouring molecular alterations of the PI3K/AKT/mTOR pathway received once daily (QD) oral LY2780301 (400 or 500 mg) in combination with intravenous gemcitabine (750 or 1000 mg/m2) on days 1, 8 and 15 of a 28-d cycle. Dose escalation followed a 3 + 3 design. Assessments included adverse events (AEs), PK and preliminary antitumour activity. RESULTS: Fifty patients (median age, 53 years; 74% female) predominantly with mutations/amplifications of PI3K (60%) and phosphatase and tensin homologue (PTEN) gene/protein inactivation (42%) were treated for up to 14 cycles. The MTD was LY2780301 500 mg QD with gemcitabine 750 mg/m2. DLTs during cycle 1 were grade IV thrombocytopenia, grade III skin rash and grade III increase in alkaline phosphatase, gamma glutamyltransferase and alanine aminotransferase, occurring in one patient each. Most common AEs were anaemia (84%), fatigue (84%), transaminase increase (74%), thrombocytopenia (74%), nausea/vomiting (70%), neutropenia (68%) and lymphopenia (56%). Among the efficacy-evaluable population, two patients (5%) had a partial response; the disease control rate was 74% at cycle 2. CONCLUSIONS: Addition of LY2780301 to gemcitabine showed manageable toxicity and encouraging antitumour activity in patients with molecular alterations of the PI3K/AKT/mTOR pathway. CLINICAL TRIAL REGISTRATION NUMBER: NCT02018874.
Authors: Luke Russell; Jessica Swanner; Alena Cristina Jaime-Ramirez; Yufeng Wang; Alex Sprague; Yeshavanth Banasavadi-Siddegowda; Ji Young Yoo; Gina M Sizemore; Raleigh Kladney; Jianying Zhang; Norman L Lehman; Michael C Ostrowski; Bangxing Hong; Michael Caligiuri; Jianhua Yu; Balveen Kaur Journal: Nat Commun Date: 2018-11-27 Impact factor: 14.919