PMID- 28750271 OWN - NLM STAT- MEDLINE DCOM- 20170911 LR - 20221207 IS - 1879-0852 (Electronic) IS - 0959-8049 (Linking) VI - 83 DP - 2017 Sep TI - Safety, tolerability and antitumour activity of LY2780301 (p70S6K/AKT inhibitor) in combination with gemcitabine in molecularly selected patients with advanced or metastatic cancer: a phase IB dose escalation study. PG - 194-202 LID - S0959-8049(17)31102-4 [pii] LID - 10.1016/j.ejca.2017.06.036 [doi] AB - 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/m(2)) 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/m(2). 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. CI - Copyright (c) 2017 Elsevier Ltd. All rights reserved. FAU - Angevin, Eric AU - Angevin E AD - Gustave Roussy, Universite Paris-Saclay, Drug Development Department (DITEP), Villejuif, F-94805, France. Electronic address: Eric.ANGEVIN@gustaveroussy.fr. FAU - Cassier, Philippe A AU - Cassier PA AD - Centre Leon Berard, Lyon, France. Electronic address: philippe.cassier@lyon.unicancer.fr. FAU - Italiano, Antoine AU - Italiano A AD - Institut Bergonie, Bordeaux, France. Electronic address: a.italiano@bordeaux.unicancer.fr. FAU - Goncalves, Anthony AU - Goncalves A AD - Aix-Marseille University, CNRS U7258, INSERM U1068, Institut Paoli-Calmettes, CRCM, Marseille, France. Electronic address: GONCALVESA@ipc.unicancer.fr. FAU - Gazzah, Anas AU - Gazzah A AD - Gustave Roussy, Universite Paris-Saclay, Drug Development Department (DITEP), Villejuif, F-94805, France. Electronic address: Anas.GAZZAH@gustaveroussy.fr. FAU - Terret, Catherine AU - Terret C AD - Centre Leon Berard, Lyon, France. Electronic address: catherine.terret@lyon.unicancer.fr. FAU - Toulmonde, Maud AU - Toulmonde M AD - Institut Bergonie, Bordeaux, France. Electronic address: m.toulmonde@bordeaux.unicancer.fr. FAU - Gravis, Gwenaelle AU - Gravis G AD - Aix-Marseille University, CNRS U7258, INSERM U1068, Institut Paoli-Calmettes, CRCM, Marseille, France. Electronic address: GRAVISG@ipc.unicancer.fr. FAU - Varga, Andrea AU - Varga A AD - Gustave Roussy, Universite Paris-Saclay, Drug Development Department (DITEP), Villejuif, F-94805, France. Electronic address: Andrea.VARGA@gustaveroussy.fr. FAU - Parlavecchio, Cedric AU - Parlavecchio C AD - Gustave Roussy, Universite Paris-Saclay, Drug Development Department (DITEP), Villejuif, F-94805, France. Electronic address: Cedric.PARLAVECCHIO@gustaveroussy.fr. FAU - Paci, Angelo AU - Paci A AD - Gustave Roussy, Universite Paris-Saclay, Drug Development Department (DITEP), Villejuif, F-94805, France. Electronic address: Angelo.PACI@gustaveroussy.fr. FAU - Poinsignon, Vianney AU - Poinsignon V AD - Gustave Roussy, Universite Paris-Saclay, Drug Development Department (DITEP), Villejuif, F-94805, France. Electronic address: Vianney.POINSIGNON@gustaveroussy.fr. FAU - Soria, Jean-Charles AU - Soria JC AD - Gustave Roussy, Universite Paris-Saclay, Drug Development Department (DITEP), Villejuif, F-94805, France. Electronic address: Jean-Charles.Soria@gustaveroussy.fr. FAU - Drubay, Damien AU - Drubay D AD - Gustave Roussy, Universite Paris-Saclay, Drug Development Department (DITEP), Villejuif, F-94805, France; CESP, Fac. de medecine - Univ. Paris-Sud, Fac. de medecine - UVSQ, INSERM, Universite Paris-Saclay, Villejuif, France. Electronic address: DAMIEN.DRUBAY@gustaveroussy.fr. FAU - Hollebecque, Antoine AU - Hollebecque A AD - Gustave Roussy, Universite Paris-Saclay, Drug Development Department (DITEP), Villejuif, F-94805, France. Electronic address: Antoine.HOLLEBECQUE@gustaveroussy.fr. LA - eng SI - ClinicalTrials.gov/NCT02018874 SI - ClinicalTrials.gov/NCT02018874 PT - Clinical Trial, Phase I PT - Journal Article PT - Multicenter Study PT - Research Support, Non-U.S. Gov't DEP - 20170724 PL - England TA - Eur J Cancer JT - European journal of cancer (Oxford, England : 1990) JID - 9005373 RN - 0 (Antimetabolites, Antineoplastic) RN - 0 (Antineoplastic Agents) RN - 0 (Protein Kinase Inhibitors) RN - 0W860991D6 (Deoxycytidine) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 70-kDa) RN - 0 (Gemcitabine) SB - IM MH - Adult MH - Aged MH - Antimetabolites, Antineoplastic/therapeutic use MH - Antineoplastic Agents/*therapeutic use MH - Antineoplastic Combined Chemotherapy Protocols/therapeutic use MH - Deoxycytidine/*analogs & derivatives/therapeutic use MH - Dose-Response Relationship, Drug MH - Humans MH - Male MH - Middle Aged MH - Neoplasms/*drug therapy MH - Protein Kinase Inhibitors/administration & dosage/*therapeutic use MH - Proto-Oncogene Proteins c-akt/antagonists & inhibitors MH - Ribosomal Protein S6 Kinases, 70-kDa/antagonists & inhibitors MH - Gemcitabine OTO - NOTNLM OT - Drug development OT - Dual p70S6K/AKT inhibition OT - Gemcitabine OT - LY2780301 OT - Molecular alterations OT - Molecular screening OT - PI3K/AKT/mTOR pathway OT - PTEN OT - Phase I EDAT- 2017/07/28 06:00 MHDA- 2017/09/12 06:00 CRDT- 2017/07/28 06:00 PHST- 2017/04/20 00:00 [received] PHST- 2017/06/27 00:00 [accepted] PHST- 2017/07/28 06:00 [pubmed] PHST- 2017/09/12 06:00 [medline] PHST- 2017/07/28 06:00 [entrez] AID - S0959-8049(17)31102-4 [pii] AID - 10.1016/j.ejca.2017.06.036 [doi] PST - ppublish SO - Eur J Cancer. 2017 Sep;83:194-202. doi: 10.1016/j.ejca.2017.06.036. Epub 2017 Jul 24.