A Phase I Trial of BKM120 (Buparlisib) in Combination with Fulvestrant in Postmenopausal Women with Estrogen Receptor-Positive Metastatic Breast Cancer

Cynthia X Ma; Jingqin Luo; Michael Naughton; Foluso Ademuyiwa; Rama Suresh; Malachi Griffith; Obi L Griffith; Zachary L Skidmore; Nicholas C Spies; Avinash Ramu; Lee Trani; Timothy Pluard; Gayathri Nagaraj; Shana Thomas; Zhanfang Guo; Jeremy Hoog; Jing Han; Elaine Mardis; Craig Lockhart; Matthew J Ellis

doi:10.1158/1078-0432.CCR-15-1745

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A Phase I Trial of BKM120 (Buparlisib) in Combination with Fulvestrant in Postmenopausal Women with Estrogen Receptor-Positive Metastatic Breast Cancer

Journal article

Open access

Peer reviewed

A Phase I Trial of BKM120 (Buparlisib) in Combination with Fulvestrant in Postmenopausal Women with Estrogen Receptor-Positive Metastatic Breast Cancer

Cynthia X Ma, Jingqin Luo, Michael Naughton, Foluso Ademuyiwa, Rama Suresh, Malachi Griffith, Obi L Griffith, Zachary L Skidmore, Nicholas C Spies, Avinash Ramu, …

Clinical cancer research, Vol.22(7), pp.1583-1591

2016-04-01

DOI: https://doi.org/10.1158/1078-0432.CCR-15-1745

PMID: 26563128

Abstract

Estradiol - analogs & derivatives

Receptors, Estrogen - metabolism

Humans

Middle Aged

Aminopyridines - pharmacokinetics

Antineoplastic Combined Chemotherapy Protocols - adverse effects

Phosphatidylinositol 3-Kinases - antagonists & inhibitors

Biomarkers, Tumor

Breast Neoplasms - metabolism

Neoplasm Metastasis

PTEN Phosphohydrolase

Postmenopause

Adult

Female

Aminopyridines - administration & dosage

Morpholines - administration & dosage

Estradiol - administration & dosage

Treatment Outcome

Breast Neoplasms - drug therapy

Estradiol - pharmacokinetics

Antineoplastic Combined Chemotherapy Protocols - therapeutic use

Breast Neoplasms - pathology

Receptors, Progesterone

Aged

Morpholines - pharmacokinetics

This trial was conducted to determine the maximum tolerated dose (MTD) and preliminary efficacy of buparlisib, an oral pan-class I PI3K inhibitor, plus fulvestrant in postmenopausal women with metastatic estrogen receptor positive (ER(+)) breast cancer. Phase IA employed a 3+3 design to determine the MTD of buparlisib daily plus fulvestrant. Subsequent cohorts (phase IB and cohort C) evaluated intermittent (5/7-day) and continuous dosing of buparlisib (100 mg daily). No more than 3 prior systemic treatments in the metastatic setting were allowed in these subsequent cohorts. Thirty-one patients were enrolled. MTD was defined as buparlisib 100 mg daily plus fulvestrant. Common adverse events (AE) included fatigue (38.7%), transaminases elevation (35.5%), rash (29%), and diarrhea (19.4%). C-peptide was significantly increased during treatment, consistent with on-target effect of buparlisib. Compared with intermittent dosing, daily buparlisib was associated with more frequent early onset AEs and higher buparlisib plasma concentrations. Among the 29 evaluable patients, the clinical benefit rate was 58.6% (95% CI, 40.7%-74.5%). Response was not associated with PIK3CA mutation or treatment cohort; however, loss of PTEN, progesterone receptor (PgR) expression, or mutation in TP53 was most common in resistant cases, and mutations inAKT1 and ESR1 did not exclude treatment response. Buparlisib plus fulvestrant is clinically active with manageable AEs in patients with metastatic ER(+)breast cancer. Weekend breaks in buparlisib dosing reduced toxicity. Patients with PgR negative and TP53 mutation did poorly, suggesting buparlisib plus fulvestrant may not be adequately effective against tumors with these poor prognostic molecular features.

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Collaboration types: Domestic collaboration
Citation topics: 1 Clinical & Life Sciences; 1.25 Molecular & Cell Biology - Cancer, Autophagy & Apoptosis; 1.25.803 mTOR
Web Of Science research areas: Oncology
ESI research areas: Clinical Medicine

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Title: A Phase I Trial of BKM120 (Buparlisib) in Combination with Fulvestrant in Postmenopausal Women with Estrogen Receptor-Positive Metastatic Breast Cancer
Creators: Cynthia X Ma - Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri. Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri. cma@dom.wustl.edu mjellis@bcm.edu
Jingqin Luo - Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, St. Louis, Missouri
Michael Naughton - Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri. Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri
Foluso Ademuyiwa - Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri. Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri
Rama Suresh - Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri. Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri
Malachi Griffith - Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri. The McDonnell Genome Institute, Washington University School of Medicine, St. Louis, Missouri. Department of Genetics, Washington University School of Medicine, St. Louis, Missouri
Obi L Griffith - Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri. Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri. The McDonnell Genome Institute, Washington University School of Medicine, St. Louis, Missouri. Department of Genetics, Washington University School of Medicine, St. Louis, Missouri
Zachary L Skidmore - The McDonnell Genome Institute, Washington University School of Medicine, St. Louis, Missouri
Nicholas C Spies - The McDonnell Genome Institute, Washington University School of Medicine, St. Louis, Missouri
Avinash Ramu - The McDonnell Genome Institute, Washington University School of Medicine, St. Louis, Missouri
Lee Trani - The McDonnell Genome Institute, Washington University School of Medicine, St. Louis, Missouri
Timothy Pluard - Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri. Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri
Gayathri Nagaraj - Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri
Shana Thomas - Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri
Zhanfang Guo - Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri
Jeremy Hoog - Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri
Jing Han - Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri
Elaine Mardis - Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri. The McDonnell Genome Institute, Washington University School of Medicine, St. Louis, Missouri. Department of Genetics, Washington University School of Medicine, St. Louis, Missouri. Division of Genomics and Bioinformatics, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri
Craig Lockhart - Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri. Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri
Matthew J Ellis - Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas. cma@dom.wustl.edu mjellis@bcm.edu
Publication Details: Clinical cancer research, Vol.22(7), pp.1583-1591
Publisher: United States
Grant note: P30 CA091842 / NCI NIH HHS K22 CA188163 / NCI NIH HHS
Academic Unit: Miller School of Medicine; UMMG Department of Medicine
Language: English
Resource Type: Journal article
PMID: 26563128
Record Identifier: 991031559554402976