2. Academic Validation
  3. 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)

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)

  • Eur J Cancer. 2018 Jun;96:6-16. doi: 10.1016/j.ejca.2018.03.012.
Andreas Wicki 1,  Nicholas Brown 2,  Alexandros Xyrafas 3,  Vincent Bize 3,  Hanne Hawle 3,  Simona Berardi 3,  Nataša Cmiljanović 4,  Vladimir Cmiljanović 4,  Michael Stumm 4,  Saša Dimitrijević 4,  Richard Herrmann 4,  Vincent Prêtre 5,  Reto Ritschard 5,  Alexandar Tzankov 6,  Viviane Hess 7,  Alexa Childs 2,  Cinta Hierro 8,  Jordi Rodon 8,  Dagmar Hess 9,  Markus Joerger 9,  Roger von Moos 10,  Cristiana Sessa 11,  Rebecca Kristeleit 2
Affiliations

Affiliations

  • 1 University Hospital Basel, Division of Oncology, Dept. of Biomedicine, Petersgraben 4, 4031 Basel, Switzerland. Electronic address: andreas.wicki@usb.ch.
  • 2 University College London Hospitals NHS Trust, Gynecological Oncology Team, 235 Euston Road, London NW1 2BU, United Kingdom.
  • 3 SAKK Coordinating Center, Effingerstrasse 33, 3008 Bern, Switzerland.
  • 4 Piqur Therapeutics AG, Hochbergstrasse 60C, 4057 Basel, Switzerland.
  • 5 University Hospital Basel, Dept. of Biomedicine, Petersgraben 4, 4031 Basel, Switzerland.
  • 6 University Hospital Basel, Dept. of Pathology, Schönbeinstrasse 40, 4056 Basel, Switzerland.
  • 7 University Hospital Basel, Division of Oncology, Dept. of Biomedicine, Petersgraben 4, 4031 Basel, Switzerland.
  • 8 Vall d'Hebron Institut d'Oncologia, Universitat Autonoma of Barcelona, Passeig Vall d'Hebron 119-129, 08035 Barcelona, Spain.
  • 9 Cantonal Hospital St. Gallen, Dept. of Oncology and Hematology, Rorschacherstrasse 95, 9007 St. Gallen, Switzerland.
  • 10 Cantonal Hospital Graubünden, Dept. of Oncology and Hematology, Loestrasse 170, 7000 Chur, Switzerland.
  • 11 Istituto Oncologico della Svizzera Italiana, Ospedale San Giovanni, 6500 Bellinzona, Switzerland.
PMID: 29660598 DOI: 10.1016/j.ejca.2018.03.012
Abstract

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 (Tmax 1-2 h) and dose proportionality for Cmax 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.

Keywords

PI3K; PQR309; Phase 1; Solid tumours; mTOR.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z