PMID- 37278879
OWN - NLM
STAT- MEDLINE
DCOM- 20230717
LR  - 20231116
IS  - 1776-260X (Electronic)
IS  - 1776-2596 (Print)
IS  - 1776-2596 (Linking)
VI  - 18
IP  - 4
DP  - 2023 Jul
TI  - A Phase Ib Study Assessing the Safety, Tolerability, and Efficacy of the 
      First-in-Class Wee1 Inhibitor Adavosertib (AZD1775) as Monotherapy in Patients 
      with Advanced Solid Tumors.
PG  - 517-530
LID - 10.1007/s11523-023-00965-7 [doi]
AB  - BACKGROUND: Adavosertib (AZD1775) is a first-in-class, selective, small-molecule 
      inhibitor of Wee1. OBJECTIVE: The safety, tolerability, pharmacokinetics, and 
      efficacy of adavosertib monotherapy were evaluated in patients with various 
      solid-tumor types and molecular profiles. PATIENTS AND METHODS: Eligible patients 
      had the following: confirmed diagnosis of ovarian cancer (OC), triple-negative 
      breast cancer (TNBC), or small-cell lung cancer (SCLC); previous treatment for 
      metastatic/recurrent disease; and measurable disease. Patients were grouped into 
      six matched cohorts based on tumor type and presence/absence of biomarkers and 
      received oral adavosertib 175 mg twice a day on days 1-3 and 8-10 of a 21-day 
      treatment cycle. RESULTS: Eighty patients received treatment in the expansion 
      phase; median total treatment duration was 2.4 months. The most common 
      treatment-related adverse events (AEs) were diarrhea (56.3%), nausea (42.5%), 
      fatigue (36.3%), vomiting (18.8%), and decreased appetite (12.5%). 
      Treatment-related grade >/= 3 AEs and serious AEs were reported in 32.5% and 10.0% 
      of patients, respectively. AEs led to dose interruptions in 22.5%, reductions in 
      11.3%, and discontinuations in 16.3% of patients. One patient died following 
      serious AEs of deep vein thrombosis (treatment related) and respiratory failure 
      (not treatment related). Objective response rate, disease control rate, and 
      progression-free survival were as follows: 6.3%, 68.8%, 4.5 months (OC BRCA wild 
      type); 3.3%, 76.7%, 3.9 months (OC BRCA mutation); 0%, 69.2%, 3.1 months (TNBC 
      biomarker [CCNE1/MYC/MYCL1/MYCN] non-amplified [NA]); 0%, 50%, 2 months (TNBC 
      biomarker amplified); 8.3%, 33.3%, 1.3 months (SCLC biomarker NA); and 0%, 33.3%, 
      1.2 months (SCLC biomarker amplified). CONCLUSION: Adavosertib monotherapy was 
      tolerated and demonstrated some antitumor activity in patients with advanced 
      solid tumors. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02482311; 
      registered June 2015.
CI  - (c) 2023. The Author(s).
FAU - Bauer, Todd M
AU  - Bauer TM
AUID- ORCID: 0000-0002-3078-5043
AD  - Sarah Cannon Research Institute, Nashville, TN, USA.
AD  - Tennessee Oncology, PLLC, Nashville, TN, USA.
FAU - Moore, Kathleen N
AU  - Moore KN
AUID- ORCID: 0000-0002-5803-0718
AD  - Sarah Cannon Research Institute, Nashville, TN, USA.
AD  - Stephenson Cancer Center at the University of Oklahoma, Oklahoma City, OK, USA.
FAU - Rader, Janet S
AU  - Rader JS
AUID- ORCID: 0000-0001-7031-3385
AD  - Medical College of Wisconsin, Milwaukee, WI, USA.
FAU - Simpkins, Fiona
AU  - Simpkins F
AUID- ORCID: 0000-0002-0840-2368
AD  - Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.
FAU - Mita, Alain C
AU  - Mita AC
AD  - Samuel Oschin Comprehensive Cancer Institute at Cedars-Sinai Medical Center, Los 
      Angeles, CA, USA.
FAU - Beck, J Thaddeus
AU  - Beck JT
AUID- ORCID: 0000-0002-3341-9903
AD  - Highlands Oncology Group, Springdale, AR, USA.
FAU - Hart, Lowell
AU  - Hart L
AD  - Sarah Cannon Research Institute, Fort Myers, FL, USA.
FAU - Chu, Quincy
AU  - Chu Q
AD  - University of Alberta Cross Cancer Institute, Edmonton, Canada.
FAU - Oza, Amit
AU  - Oza A
AD  - Princess Margaret Cancer Centre, Toronto, Canada.
FAU - Tinker, Anna V
AU  - Tinker AV
AUID- ORCID: 0000-0002-1190-7746
AD  - BC Cancer, Vancouver, Canada.
FAU - Imedio, Esteban Rodrigo
AU  - Imedio ER
AUID- ORCID: 0000-0001-5666-666X
AD  - Oncology R&D, AstraZeneca, Cambridge, UK.
FAU - Kumar, Sanjeev
AU  - Kumar S
AD  - Oncology R&D, AstraZeneca, Cambridge, UK.
FAU - Mugundu, Ganesh
AU  - Mugundu G
AUID- ORCID: 0000-0002-3736-1884
AD  - Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and 
      Safety Sciences, AstraZeneca, Boston, MA, USA.
FAU - Jenkins, Suzanne
AU  - Jenkins S
AUID- ORCID: 0000-0003-2435-1836
AD  - Precision Medicine and Biosamples, R&D, AstraZeneca, Cambridge, UK.
FAU - Chmielecki, Juliann
AU  - Chmielecki J
AD  - Translational Medicine, Oncology Research and Early Development, AstraZeneca, 
      Boston, MA, USA.
FAU - Jones, Suzanne
AU  - Jones S
AUID- ORCID: 0000-0001-6881-8050
AD  - Sarah Cannon Research Institute, Nashville, TN, USA.
FAU - Spigel, David
AU  - Spigel D
AUID- ORCID: 0000-0003-3215-9465
AD  - Sarah Cannon Research Institute, Nashville, TN, USA.
AD  - Tennessee Oncology, PLLC, Nashville, TN, USA.
FAU - Fu, Siqing
AU  - Fu S
AUID- ORCID: 0000-0002-1933-0419
AD  - The University of Texas MD Anderson Cancer Center, Houston, TX, USA. 
      siqingfu@mdanderson.org.
LA  - eng
SI  - ClinicalTrials.gov/NCT02482311
PT  - Clinical Trial, Phase I
PT  - Journal Article
DEP - 20230606
PL  - France
TA  - Target Oncol
JT  - Targeted oncology
JID - 101270595
RN  - K2T6HJX3I3 (adavosertib)
RN  - 0 (Pyrimidinones)
RN  - 0 (Pyrazoles)
SB  - IM
MH  - Female
MH  - Humans
MH  - *Triple Negative Breast Neoplasms
MH  - Pyrimidinones/therapeutic use
MH  - Pyrazoles/therapeutic use
MH  - *Ovarian Neoplasms/pathology
MH  - *Small Cell Lung Carcinoma
MH  - *Lung Neoplasms/drug therapy
PMC - PMC10345044
COIS- T.M. Bauer has received fees for consulting or advisory roles for Guardant 
      Health, Ignyta (Inst), Loxo, Moderna Therapeutics (Inst), and Pfizer. K. Moore 
      has received fees for advisory boards from AstraZeneca, Aravive, Clovis, 
      Immunogen, Genentech/Roche, GSK/Tesaro, Mersana, Vavotar, Samumed, Mereo, Merck, 
      Pfizer, Janssen, Oncomed, and VBL Therapeutics and is a principal investigator 
      for investigator-initiated clinical trials funded by AstraZeneca and Immunogen. 
      F. Simpkins has participated in advisory boards for AstraZeneca and is a 
      principal investigator for an investigator-initiated clinical trial funded by 
      AstraZeneca. J.T. Beck has received grant funding from AstraZeneca, Bristol-Myers 
      Squibb, Lilly, Novartis, Genentech, AbbVie, Seattle Genetics, Pfizer, and Johnson 
      & Johnson. Q. Chu has received honoraria (unrelated to adavosertib) from and 
      participated in advisory boards for AstraZeneca. A. Oza has participated in 
      advisory boards for AstraZeneca, GlaxoSmithKline, Tesaro, and Clovis and is a 
      principal investigator and has participated in steering committees for clinical 
      trials funded by AstraZeneca. A.V. Tinker has received research funding and 
      honoraria from AstraZeneca and has participated in advisory boards and received 
      honoraria from GlaxoSmithKline. S. Kumar and S. Jenkins are employees and 
      shareholders of AstraZeneca UK Limited. At the time of the study, E. Rodrigo 
      Imedio, G. Mugundu, and J. Chmielecki were employees and shareholders of 
      AstraZeneca UK Limited. E. Rodrigo Imedio and G. Mugundu are employees and 
      shareholders of Takeda. D. Spigel reports grants and/or other from 
      Genentech/Roche, Novartis, Celgene, Bristol-Myers Squibb, AstraZeneca, Pfizer, 
      Boehringer Ingelheim, AbbVie, Foundation Medicine, GlaxoSmithKline, Lilly, Merck, 
      Moderna Therapeutics, Nektar, Takeda, Amgen, TRM Oncology, Precision Oncology, 
      Evelo Therapeutics, Illumina, PharmaMar, University of Texas Southwestern Medical 
      Center Simmons Cancer Center, G1 Therapeutics, Neon Therapeutics, Celldex, Clovis 
      Oncology, Daiichi Sankyo, EMD Serono, Acerta Pharma, Oncogenex, Astellas Pharma, 
      GRAIL, Transgene, Aeglea Biotherapeutics, Tesaro, Ipsen, ARMO BioSciences, 
      Millennium, Genzyme, Intuitive Surgical, Purdue Pharma, Spectrum Pharmaceuticals, 
      and Sysmex. S. Fu, J.S. Rader, A.C. Mita, L. Hart, and S. Jones declare that they 
      have no conflicts of interest.
EDAT- 2023/06/06 13:09
MHDA- 2023/07/17 06:42
PMCR- 2023/06/06
CRDT- 2023/06/06 11:08
PHST- 2023/03/27 00:00 [accepted]
PHST- 2023/07/17 06:42 [medline]
PHST- 2023/06/06 13:09 [pubmed]
PHST- 2023/06/06 11:08 [entrez]
PHST- 2023/06/06 00:00 [pmc-release]
AID - 10.1007/s11523-023-00965-7 [pii]
AID - 965 [pii]
AID - 10.1007/s11523-023-00965-7 [doi]
PST - ppublish
SO  - Target Oncol. 2023 Jul;18(4):517-530. doi: 10.1007/s11523-023-00965-7. Epub 2023 
      Jun 6.