TY - JOUR
T1 - Pharmacokinetic Effects and Safety of Olaparib Administered with Endocrine Therapy
T2 - A Phase I Study in Patients with Advanced Solid Tumours
AU - Plummer, Ruth
AU - Verheul, Henk M
AU - De Vos, Filip Y F L
AU - Leunen, Karin
AU - Molife, L Rhoda
AU - Rolfo, Christian
AU - Grundtvig-Sørensen, Peter
AU - De Grève, Jacques
AU - Rottey, Sylvie
AU - Jerusalem, Guy
AU - Italiano, Antoine
AU - Spicer, James
AU - Dirix, Luc
AU - Goessl, Carsten
AU - Birkett, Joseph
AU - Spencer, Stuart
AU - Learoyd, Maria
AU - Bailey, Christopher
AU - Dean, Emma
N1 - Funding Information:
Funding. This study was sponsored by AstraZeneca and is part of an alliance between AstraZeneca and Merck & Co., Inc. Article processing charges and the Open Access fee were also funded by AstraZeneca and Merck & Co., Inc. All authors had full access to all of the data in this study and take complete responsibility for the integrity of the data and accuracy of the data analysis.
Funding Information:
Medical Writing and other Editorial Assistance. Medical writing assistance was provided by Lizzie Wilkins PhD, of Mudskipper Business Ltd, funded by AstraZeneca and Merck and Co, Inc. The UK centres involved were Experimental Cancer Medicine Centres supported by Cancer Research UK and the Department of Health.
Funding Information:
The authors would like to thank the patients who took part in the study and Dr. Marlies Langenberg, UMC Utrecht, for her contribution as a trial investigator. This study was sponsored by AstraZeneca and is part of an alliance between AstraZeneca and Merck & Co., Inc. Article processing charges and the Open Access fee were also funded by AstraZeneca and Merck & Co., Inc. All authors had full access to all of the data in this study and take complete responsibility for the integrity of the data and accuracy of the data analysis. Medical writing assistance was provided by Lizzie Wilkins PhD, of Mudskipper Business Ltd, funded by AstraZeneca and Merck and Co, Inc. The UK centres involved were Experimental Cancer Medicine Centres supported by Cancer Research UK and the Department of Health. All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval of the version to be published. Christian Rolfo has received research grants from OncoDNA, honoraria from Mylan and speakers? fees from MSD, Novartis and Guardant Health. Their current affiliation is University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD, USA.
Publisher Copyright:
© 2018, Springer Healthcare Ltd., part of Springer Nature.
PY - 2018/11
Y1 - 2018/11
N2 - INTRODUCTION: The PARP inhibitor olaparib is efficacious as monotherapy and has potential application in combination with endocrine therapy for the treatment of breast cancer. This phase I study assessed the safety and pharmacokinetic (PK) profiles of olaparib combined with tamoxifen, anastrozole or letrozole in patients with advanced solid tumours.METHODS: During part A, PK profiles were assessed in three consecutive treatment periods: (1) olaparib (tablet) 300 mg bid, days 1-5 followed by a 4-day washout; (2) cohort 1, tamoxifen 60 mg loading dose qd days 10-13, 20 mg qd days 14-26; cohort 2, anastrozole 1 mg qd days 10-19; cohort 3, letrozole 2.5 mg qd days 10-38; (3) as for period 2, with concomitant olaparib 300 mg bid for 5 days. Patients could then enter part B and receive olaparib monotherapy (300 mg bid continuously). Safety was assessed in parts A and B until 12 months after the last patient entered part B.RESULTS: Seventy-nine patients (20.3% with breast cancer) received treatment in part A; 72 completed part A and 69 entered part B. Anastrozole and letrozole had no effect on the PK profile of olaparib and vice versa. Co-administration with tamoxifen produced a modest decrease in exposure to olaparib [geometric least-squares mean (GLSmean) Cmax,ss and AUC0-τ decreased by 20% (90% CI 0.71-0.90) and 27% (0.63-0.84), respectively]. Exposure to tamoxifen was slightly increased when combined with olaparib [GLSmean Cmax,ss and AUC0-τ increased by 13% (1.06-1.22) and 16% (1.11-1.21), respectively]; however, the 90% CI fell within the 0.7-1.43 boundary and there were no changes in exposure to tamoxifen metabolites. The safety profile for olaparib alone and in combination with the antihormonal therapies was acceptable.CONCLUSIONS: The combination of olaparib and either anastrozole, letrozole or tamoxifen was generally well tolerated, with no clinically relevant PK interactions identified.FUNDING: AstraZeneca.CLINICAL TRIAL REGISTRATION: NCT02093351.
AB - INTRODUCTION: The PARP inhibitor olaparib is efficacious as monotherapy and has potential application in combination with endocrine therapy for the treatment of breast cancer. This phase I study assessed the safety and pharmacokinetic (PK) profiles of olaparib combined with tamoxifen, anastrozole or letrozole in patients with advanced solid tumours.METHODS: During part A, PK profiles were assessed in three consecutive treatment periods: (1) olaparib (tablet) 300 mg bid, days 1-5 followed by a 4-day washout; (2) cohort 1, tamoxifen 60 mg loading dose qd days 10-13, 20 mg qd days 14-26; cohort 2, anastrozole 1 mg qd days 10-19; cohort 3, letrozole 2.5 mg qd days 10-38; (3) as for period 2, with concomitant olaparib 300 mg bid for 5 days. Patients could then enter part B and receive olaparib monotherapy (300 mg bid continuously). Safety was assessed in parts A and B until 12 months after the last patient entered part B.RESULTS: Seventy-nine patients (20.3% with breast cancer) received treatment in part A; 72 completed part A and 69 entered part B. Anastrozole and letrozole had no effect on the PK profile of olaparib and vice versa. Co-administration with tamoxifen produced a modest decrease in exposure to olaparib [geometric least-squares mean (GLSmean) Cmax,ss and AUC0-τ decreased by 20% (90% CI 0.71-0.90) and 27% (0.63-0.84), respectively]. Exposure to tamoxifen was slightly increased when combined with olaparib [GLSmean Cmax,ss and AUC0-τ increased by 13% (1.06-1.22) and 16% (1.11-1.21), respectively]; however, the 90% CI fell within the 0.7-1.43 boundary and there were no changes in exposure to tamoxifen metabolites. The safety profile for olaparib alone and in combination with the antihormonal therapies was acceptable.CONCLUSIONS: The combination of olaparib and either anastrozole, letrozole or tamoxifen was generally well tolerated, with no clinically relevant PK interactions identified.FUNDING: AstraZeneca.CLINICAL TRIAL REGISTRATION: NCT02093351.
KW - Journal Article
KW - Anastrozole
KW - PARP inhibitor
KW - Endocrine therapy
KW - Olaparib
KW - Safety
KW - Pharmacokinetics
KW - Tamoxifen
KW - Antihormonal therapy
KW - Letrozole
KW - Lynparza
KW - Antineoplastic Agents, Hormonal/administration & dosage
KW - Letrozole/administration & dosage
KW - Humans
KW - Middle Aged
KW - Male
KW - Dose-Response Relationship, Drug
KW - Drug Interactions
KW - Adult
KW - Female
KW - Breast Neoplasms/drug therapy
KW - Piperazines/administration & dosage
KW - Phthalazines/administration & dosage
KW - Drug Therapy, Combination/adverse effects
KW - Treatment Outcome
KW - Tamoxifen/administration & dosage
KW - Anastrozole/administration & dosage
KW - Poly(ADP-ribose) Polymerase Inhibitors/administration & dosage
KW - Drug Monitoring/methods
KW - Neoplasms/classification
KW - Aged
KW - Neoplasm Staging
UR - http://www.scopus.com/inward/record.url?scp=85055511393&partnerID=8YFLogxK
U2 - 10.1007/s12325-018-0804-z
DO - 10.1007/s12325-018-0804-z
M3 - Article
C2 - 30324586
SN - 0741-238X
VL - 35
SP - 1945
EP - 1964
JO - Advances in Therapy
JF - Advances in Therapy
IS - 11
ER -