TY - JOUR
T1 - Phase i trial of the parp inhibitor olaparib and akt inhibitor capivasertib in patients with brca1/2-and non–brca1/2-mutant cancers
AU - Yap, Timothy A.
AU - Kristeleit, Rebecca
AU - Michalarea, Vasiliki
AU - Pettitt, Stephen J.
AU - Lim, Joline S.J.
AU - Carreira, Suzanne
AU - Roda, Desamparados
AU - Miller, Rowan
AU - Riisnaes, Ruth
AU - Miranda, Susana
AU - Figueiredo, Ines
AU - Rodrigues, Daniel Nava
AU - Ward, Sarah
AU - Matthews, Ruth
AU - Parmar, Mona
AU - Turner, Alison
AU - Tunariu, Nina
AU - Chopra, Neha
AU - Gevensleben, Heidrun
AU - Turner, Nicholas C.
AU - Ruddle, Ruth
AU - Raynaud, Florence I.
AU - Decordova, Shaun
AU - Swales, Karen E.
AU - Finneran, Laura
AU - Hall, Emma
AU - Rugman, Paul
AU - Lindemann, Justin P.O.
AU - Foxley, Andrew
AU - Lord, Christopher J.
AU - Banerji, Udai
AU - Plummer, Ruth
AU - Basu, Bristi
AU - Lopez, Juanita S.
AU - Drew, Yvette
AU - de Bono, Johann S.
N1 - Funding Information:
The authors would like to thank and acknowledge all patients for taking part in this study, their caregivers, and the trial research nurses, data managers, and clinical coordinators. Funding for this academic study was provided by AstraZeneca through the Cancer Research UK Experimental Cancer Medicine Centre (ECMC) Combinations Alliance. The authors acknowledge the ECMC (London ? The Institute of Cancer Research, London-University College London, Cambridge, and Newcastle Centres), National Health Service (NHS) funding to the National Institute for Health Research (NIHR) Biomedical Research Centres at the Royal Marsden NHS Foundation Trust and The Institute of Cancer Research and University College London, NIHR Cambridge Clinical Research Facility, and Cancer Research Technology Limited. Capivasertib (AZD5363) was discovered by AstraZeneca after a collaboration with Astex Therapeutics (and its collaboration with The Institute of Cancer Research and Cancer Research Technology Limited). U. Banerji is a recipient of an NIHR award (RP-2016-07-028). The authors thank Dr. Filip Janku, MD, PhD (The University of Texas MD Anderson Cancer Center, Houston, TX) for helpful discussions on cfDNA studies.
Funding Information:
This investigator-initiated study (ClinicalTrials.gov: NCT02338622) was designed by T.A. Yap and J.S. de Bono, with support from Astra-Zeneca, and conducted in accordance with the provision of the Declaration of Helsinki and Good Clinical Practice guidelines. Dose escalation was conducted at the Royal Marsden NHS Foundation Trust (RM; London, United Kingdom), and the dose-expansion phase also involved University College London Hospital (London, United Kingdom), Northern Centre for Cancer Care (Newcastle, United Kingdom), and Cambridge University Hospitals NHS Foundation Trust (Cambridge, United Kingdom). The Central London Research Ethics Committee (REC) approved the protocol (REC reference 14/ LO/0103). The trial was cosponsored by the Institute of Cancer Research (ICR; London, United Kingdom) and RM, and centrally managed by the Drug Development Unit (DDU; Investigator Initiated Trials Team) at the ICR/RM. Funding was provided by the Experimental Cancer Medicine Centers (ECMC) network, National Institute of Health Research, Cancer Research UK (CRUK), and AstraZeneca.
Funding Information:
The authors would like to thank and acknowledge all patients for taking part in this study, their caregivers, and the trial research nurses, data managers, and clinical coordinators. Funding for this academic study was provided by AstraZeneca through the Cancer Research UK Experimental Cancer Medicine Centre (ECMC) Combinations Alliance. The authors acknowledge the ECMC (London – The Institute of Cancer Research, London - University College London, Cambridge, and Newcastle Centres), National Health Service (NHS) funding to the National Institute for Health Research (NIHR) Biomedical Research Centres at the Royal Marsden NHS Foundation Trust and The Institute of Cancer Research and University College London, NIHR Cambridge Clinical Research Facility, and Cancer Research Technology Limited. Capivasertib (AZD5363) was discovered by AstraZeneca after a collaboration with Astex Therapeutics (and its collaboration with The Institute of Cancer Research and Cancer Research Technology Limited). U. Banerji is a recipient of an NIHR award (RP-2016-07-028). The authors thank Dr. Filip Janku, MD, PhD (The University of Texas MD Anderson Cancer Center, Houston, TX) for helpful discussions on cfDNA studies.
Publisher Copyright:
©2020 American Association for Cancer Research.
PY - 2020
Y1 - 2020
N2 - Preclinical studies have demonstrated synergy between PARP and PI3K/AKT pathway inhibitors in BRCA1 and BRCA2 (BRCA1/2)–deficient and BRCA1/2-proficient tumors. We conducted an investigator-initiated phase I trial utilizing a prospective intrapatient doseescalation design to assess two schedules of capivasertib (AKT inhibitor) with olaparib (PARP inhibitor) in 64 patients with advanced solid tumors. Dose expansions enrolled germline BRCA1/2-mutant tumors, or BRCA1/2 wild-type cancers harboring somatic DNA damage response (DDR) or PI3K–AKT pathway alterations. The combination was well tolerated. Recommended phase II doses for the two schedules were: olaparib 300 mg twice a day with either capivasertib 400 mg twice a day 4 days on, 3 days off, or capivasertib 640 mg twice a day 2 days on, 5 days off. Pharmacokinetics were dose proportional. Pharmacodynamic studies confirmed phosphorylated (p) GSK3β suppression, increased pERK, and decreased BRCA1 expression. Twenty-five (44.6%) of 56 evaluable patients achieved clinical benefit (RECIST complete response/partial response or stable disease ≥ 4 months), including patients with tumors harboring germline BRCA1/2 mutations and BRCA1/2 wild-type cancers with or without DDR and PI3K–AKT pathway alterations. SIGNIfICANCE: In the first trial to combine PARP and AKT inhibitors, a prospective intrapatient doseescalation design demonstrated safety, tolerability, and pharmacokinetic–pharmacodynamic activity and assessed predictive biomarkers of response/resistance. Antitumor activity was observed in patients harboring tumors with germline BRCA1/2 mutations and BRCA1/2 wild-type cancers with or without somatic DDR and/or PI3K–AKT pathway alterations.
AB - Preclinical studies have demonstrated synergy between PARP and PI3K/AKT pathway inhibitors in BRCA1 and BRCA2 (BRCA1/2)–deficient and BRCA1/2-proficient tumors. We conducted an investigator-initiated phase I trial utilizing a prospective intrapatient doseescalation design to assess two schedules of capivasertib (AKT inhibitor) with olaparib (PARP inhibitor) in 64 patients with advanced solid tumors. Dose expansions enrolled germline BRCA1/2-mutant tumors, or BRCA1/2 wild-type cancers harboring somatic DNA damage response (DDR) or PI3K–AKT pathway alterations. The combination was well tolerated. Recommended phase II doses for the two schedules were: olaparib 300 mg twice a day with either capivasertib 400 mg twice a day 4 days on, 3 days off, or capivasertib 640 mg twice a day 2 days on, 5 days off. Pharmacokinetics were dose proportional. Pharmacodynamic studies confirmed phosphorylated (p) GSK3β suppression, increased pERK, and decreased BRCA1 expression. Twenty-five (44.6%) of 56 evaluable patients achieved clinical benefit (RECIST complete response/partial response or stable disease ≥ 4 months), including patients with tumors harboring germline BRCA1/2 mutations and BRCA1/2 wild-type cancers with or without DDR and PI3K–AKT pathway alterations. SIGNIfICANCE: In the first trial to combine PARP and AKT inhibitors, a prospective intrapatient doseescalation design demonstrated safety, tolerability, and pharmacokinetic–pharmacodynamic activity and assessed predictive biomarkers of response/resistance. Antitumor activity was observed in patients harboring tumors with germline BRCA1/2 mutations and BRCA1/2 wild-type cancers with or without somatic DDR and/or PI3K–AKT pathway alterations.
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U2 - 10.1158/2159-8290.CD-20-0163
DO - 10.1158/2159-8290.CD-20-0163
M3 - Article
C2 - 32532747
AN - SCOPUS:85088806404
SN - 2159-8274
VL - 10
SP - 1528
EP - 1543
JO - Cancer discovery
JF - Cancer discovery
IS - 10
ER -