PMID- 29660598
OWN - NLM
STAT- MEDLINE
DCOM- 20190128
LR  - 20191210
IS  - 1879-0852 (Electronic)
IS  - 0959-8049 (Linking)
VI  - 96
DP  - 2018 Jun
TI  - First-in human, phase 1, dose-escalation pharmacokinetic and pharmacodynamic 
      study of the oral dual PI3K and mTORC1/2 inhibitor PQR309 in patients with 
      advanced solid tumors (SAKK 67/13).
PG  - 6-16
LID - S0959-8049(18)30730-5 [pii]
LID - 10.1016/j.ejca.2018.03.012 [doi]
AB  - BACKGROUND: PQR309 is an orally bioavailable, balanced 
      pan-phosphatidylinositol-3-kinase (PI3K), mammalian target of rapamycin (mTOR) C1 
      and mTORC2 inhibitor. PATIENTS AND METHODS: This is an accelerated titration, 
      3 + 3 dose-escalation, open-label phase I trial of continuous once-daily (OD) 
      PQR309 administration to evaluate the safety, pharmacokinetics (PK) and 
      pharmacodynamics in patients with advanced solid tumours. Primary objectives were 
      to determine the maximum tolerated dose (MTD) and recommended phase 2 dose 
      (RP2D). RESULTS: Twenty-eight patients were included in six dosing cohorts and 
      treated at a daily PQR309 dose ranging from 10 to 150 mg. Common adverse events 
      (AEs; >/=30% patients) included fatigue, hyperglycaemia, nausea, diarrhoea, 
      constipation, rash, anorexia and vomiting. Grade (G) 3 or 4 drug-related AEs were 
      seen in 13 (46%) and three (11%) patients, respectively. Dose-limiting toxicity 
      (DLT) was observed in two patients at 100 mg OD (>14-d interruption in PQR309 due 
      to G3 rash, G2 hyperbilirubinaemia, G4 suicide attempt; dose reduction due to G3 
      fatigue, G2 diarrhoea, G4 transaminitis) and one patient at 80 mg (G3 
      hyperglycaemia >7 d). PK shows fast absorption (T(max) 1-2 h) and dose 
      proportionality for C(max) and area under the curve. A partial response in a 
      patient with metastatic thymus cancer, 24% disease volume reduction in a patient 
      with sinonasal cancer and stable disease for more than 16 weeks in a patient with 
      clear cell Bartholin's gland cancer were observed. CONCLUSION: The MTD and RP2D 
      of PQR309 is 80 mg of orally OD. PK is dose-proportional. PD shows PI3K pathway 
      phosphoprotein downregulation in paired tumour biopsies. Clinical activity was 
      observed in patients with and without PI3K pathway dysregulation. CLINICAL TRIAL 
      REGISTRATION: ClinicalTrials.gov # NCT01940133.
CI  - Copyright (c) 2018 Elsevier Ltd. All rights reserved.
FAU - Wicki, Andreas
AU  - Wicki A
AD  - University Hospital Basel, Division of Oncology, Dept. of Biomedicine, 
      Petersgraben 4, 4031 Basel, Switzerland. Electronic address: 
      andreas.wicki@usb.ch.
FAU - Brown, Nicholas
AU  - Brown N
AD  - University College London Hospitals NHS Trust, Gynecological Oncology Team, 235 
      Euston Road, London NW1 2BU, United Kingdom.
FAU - Xyrafas, Alexandros
AU  - Xyrafas A
AD  - SAKK Coordinating Center, Effingerstrasse 33, 3008 Bern, Switzerland.
FAU - Bize, Vincent
AU  - Bize V
AD  - SAKK Coordinating Center, Effingerstrasse 33, 3008 Bern, Switzerland.
FAU - Hawle, Hanne
AU  - Hawle H
AD  - SAKK Coordinating Center, Effingerstrasse 33, 3008 Bern, Switzerland.
FAU - Berardi, Simona
AU  - Berardi S
AD  - SAKK Coordinating Center, Effingerstrasse 33, 3008 Bern, Switzerland.
FAU - Cmiljanovic, Natasa
AU  - Cmiljanovic N
AD  - Piqur Therapeutics AG, Hochbergstrasse 60C, 4057 Basel, Switzerland.
FAU - Cmiljanovic, Vladimir
AU  - Cmiljanovic V
AD  - Piqur Therapeutics AG, Hochbergstrasse 60C, 4057 Basel, Switzerland.
FAU - Stumm, Michael
AU  - Stumm M
AD  - Piqur Therapeutics AG, Hochbergstrasse 60C, 4057 Basel, Switzerland.
FAU - Dimitrijevic, Sasa
AU  - Dimitrijevic S
AD  - Piqur Therapeutics AG, Hochbergstrasse 60C, 4057 Basel, Switzerland.
FAU - Herrmann, Richard
AU  - Herrmann R
AD  - Piqur Therapeutics AG, Hochbergstrasse 60C, 4057 Basel, Switzerland.
FAU - Pretre, Vincent
AU  - Pretre V
AD  - University Hospital Basel, Dept. of Biomedicine, Petersgraben 4, 4031 Basel, 
      Switzerland.
FAU - Ritschard, Reto
AU  - Ritschard R
AD  - University Hospital Basel, Dept. of Biomedicine, Petersgraben 4, 4031 Basel, 
      Switzerland.
FAU - Tzankov, Alexandar
AU  - Tzankov A
AD  - University Hospital Basel, Dept. of Pathology, Schonbeinstrasse 40, 4056 Basel, 
      Switzerland.
FAU - Hess, Viviane
AU  - Hess V
AD  - University Hospital Basel, Division of Oncology, Dept. of Biomedicine, 
      Petersgraben 4, 4031 Basel, Switzerland.
FAU - Childs, Alexa
AU  - Childs A
AD  - University College London Hospitals NHS Trust, Gynecological Oncology Team, 235 
      Euston Road, London NW1 2BU, United Kingdom.
FAU - Hierro, Cinta
AU  - Hierro C
AD  - Vall d'Hebron Institut d'Oncologia, Universitat Autonoma of Barcelona, Passeig 
      Vall d'Hebron 119-129, 08035 Barcelona, Spain.
FAU - Rodon, Jordi
AU  - Rodon J
AD  - Vall d'Hebron Institut d'Oncologia, Universitat Autonoma of Barcelona, Passeig 
      Vall d'Hebron 119-129, 08035 Barcelona, Spain.
FAU - Hess, Dagmar
AU  - Hess D
AD  - Cantonal Hospital St. Gallen, Dept. of Oncology and Hematology, 
      Rorschacherstrasse 95, 9007 St. Gallen, Switzerland.
FAU - Joerger, Markus
AU  - Joerger M
AD  - Cantonal Hospital St. Gallen, Dept. of Oncology and Hematology, 
      Rorschacherstrasse 95, 9007 St. Gallen, Switzerland.
FAU - von Moos, Roger
AU  - von Moos R
AD  - Cantonal Hospital Graubunden, Dept. of Oncology and Hematology, Loestrasse 170, 
      7000 Chur, Switzerland.
FAU - Sessa, Cristiana
AU  - Sessa C
AD  - Istituto Oncologico della Svizzera Italiana, Ospedale San Giovanni, 6500 
      Bellinzona, Switzerland.
FAU - Kristeleit, Rebecca
AU  - Kristeleit R
AD  - University College London Hospitals NHS Trust, Gynecological Oncology Team, 235 
      Euston Road, London NW1 2BU, United Kingdom.
LA  - eng
SI  - ClinicalTrials.gov/NCT01940133
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Multicenter Study
PT  - Research Support, Non-U.S. Gov't
DEP - 20180413
PL  - England
TA  - Eur J Cancer
JT  - European journal of cancer (Oxford, England : 1990)
JID - 9005373
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 0 (Protein Kinase Inhibitors)
RN  - EC 2.7.1.137 (Phosphatidylinositol 3-Kinase)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 2)
SB  - IM
MH  - Administration, Oral
MH  - Adult
MH  - Aged
MH  - Antineoplastic Agents/*administration & dosage/adverse effects/*pharmacokinetics
MH  - Dose-Response Relationship, Drug
MH  - Europe
MH  - Female
MH  - Humans
MH  - Male
MH  - Maximum Tolerated Dose
MH  - Mechanistic Target of Rapamycin Complex 1/*antagonists & inhibitors/metabolism
MH  - Mechanistic Target of Rapamycin Complex 2/*antagonists & inhibitors/metabolism
MH  - Middle Aged
MH  - Molecular Targeted Therapy
MH  - Neoplasms/*drug therapy/enzymology/pathology
MH  - Phosphatidylinositol 3-Kinase/metabolism
MH  - *Phosphoinositide-3 Kinase Inhibitors
MH  - Protein Kinase Inhibitors/*administration & dosage/adverse 
      effects/*pharmacokinetics
MH  - Signal Transduction/drug effects
MH  - Treatment Outcome
MH  - Young Adult
OTO - NOTNLM
OT  - PI3K
OT  - PQR309
OT  - Phase 1
OT  - Solid tumours
OT  - mTOR
EDAT- 2018/04/17 06:00
MHDA- 2019/01/29 06:00
CRDT- 2018/04/17 06:00
PHST- 2017/12/08 00:00 [received]
PHST- 2018/03/09 00:00 [revised]
PHST- 2018/03/13 00:00 [accepted]
PHST- 2018/04/17 06:00 [pubmed]
PHST- 2019/01/29 06:00 [medline]
PHST- 2018/04/17 06:00 [entrez]
AID - S0959-8049(18)30730-5 [pii]
AID - 10.1016/j.ejca.2018.03.012 [doi]
PST - ppublish
SO  - Eur J Cancer. 2018 Jun;96:6-16. doi: 10.1016/j.ejca.2018.03.012. Epub 2018 Apr 
      13.