Skip to main content
  • AACR Publications
    • Blood Cancer Discovery
    • Cancer Discovery
    • Cancer Epidemiology, Biomarkers & Prevention
    • Cancer Immunology Research
    • Cancer Prevention Research
    • Cancer Research
    • Clinical Cancer Research
    • Molecular Cancer Research
    • Molecular Cancer Therapeutics

AACR logo

  • Register
  • Log in
  • My Cart
Advertisement

Main menu

  • Home
  • About
    • The Journal
    • AACR Journals
    • Journal Sections
    • Subscriptions
    • Permissions and Reprints
  • Articles
    • OnlineFirst
    • Current Issue
    • Past Issues
    • Collections
      • COVID-19 & Cancer Resource Center
      • Clinical Trials
      • Immuno-oncology
      • Editors' Picks
      • "Best of" Collection
  • For Authors
    • Information for Authors
    • Author Services
    • Best of: Author Profiles
    • Submit
  • Alerts
    • Table of Contents
    • Editors' Picks
    • OnlineFirst
    • Citation
    • Author/Keyword
    • RSS Feeds
    • My Alert Summary & Preferences
  • News
    • Cancer Discovery News
    • Journal Press Releases
  • COVID-19
  • Webinars
  • 10th Anniversary
  • Search More

    Advanced Search

  • AACR Publications
    • Blood Cancer Discovery
    • Cancer Discovery
    • Cancer Epidemiology, Biomarkers & Prevention
    • Cancer Immunology Research
    • Cancer Prevention Research
    • Cancer Research
    • Clinical Cancer Research
    • Molecular Cancer Research
    • Molecular Cancer Therapeutics

User menu

  • Register
  • Log in
  • My Cart

Search

  • Advanced search
Cancer Discovery
Cancer Discovery
  • Home
  • About
    • The Journal
    • AACR Journals
    • Journal Sections
    • Subscriptions
    • Permissions and Reprints
  • Articles
    • OnlineFirst
    • Current Issue
    • Past Issues
    • Collections
      • COVID-19 & Cancer Resource Center
      • Clinical Trials
      • Immuno-oncology
      • Editors' Picks
      • "Best of" Collection
  • For Authors
    • Information for Authors
    • Author Services
    • Best of: Author Profiles
    • Submit
  • Alerts
    • Table of Contents
    • Editors' Picks
    • OnlineFirst
    • Citation
    • Author/Keyword
    • RSS Feeds
    • My Alert Summary & Preferences
  • News
    • Cancer Discovery News
    • Journal Press Releases
  • COVID-19
  • Webinars
  • 10th Anniversary
  • Search More

    Advanced Search

Research Articles

Phase I, Dose-Escalation, Two-Part Trial of the PARP Inhibitor Talazoparib in Patients with Advanced Germline BRCA1/2 Mutations and Selected Sporadic Cancers

Johann de Bono, Ramesh K. Ramanathan, Lida Mina, Rashmi Chugh, John Glaspy, Saeed Rafii, Stan Kaye, Jasgit Sachdev, John Heymach, David C. Smith, Joshua W. Henshaw, Ashleigh Herriott, Miranda Patterson, Nicola J. Curtin, Lauren Averett Byers and Zev A. Wainberg
Johann de Bono
1Drug Development Unit, Royal Marsden Hospital, London, United Kingdom.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: johann.de-bono@icr.ac.uk
Ramesh K. Ramanathan
2Clinical Trials Program, Virginia G. Piper Cancer Center at Scottsdale Healthcare/TGen, Scottsdale, Arizona.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Lida Mina
3Simon Cancer Center, Indiana University, Indianapolis, Indiana.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Rashmi Chugh
4Division of Hematology/Oncology, University of Michigan, Ann Arbor, Michigan.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
John Glaspy
5Division of Hematology/Oncology, David Geffen School of Medicine at UCLA, Los Angeles, California.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Saeed Rafii
1Drug Development Unit, Royal Marsden Hospital, London, United Kingdom.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Stan Kaye
1Drug Development Unit, Royal Marsden Hospital, London, United Kingdom.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jasgit Sachdev
2Clinical Trials Program, Virginia G. Piper Cancer Center at Scottsdale Healthcare/TGen, Scottsdale, Arizona.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
John Heymach
6Department of Thoracic Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
David C. Smith
4Division of Hematology/Oncology, University of Michigan, Ann Arbor, Michigan.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Joshua W. Henshaw
7Pharmacokinetics/Pharmacodynamics, BioMarin Pharmaceutical, Inc., Novato, California.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Ashleigh Herriott
8Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Miranda Patterson
8Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Nicola J. Curtin
8Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Lauren Averett Byers
6Department of Thoracic Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Zev A. Wainberg
5Division of Hematology/Oncology, David Geffen School of Medicine at UCLA, Los Angeles, California.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
DOI: 10.1158/2159-8290.CD-16-1250 Published June 2017
  • Article
  • Figures & Data
  • Info & Metrics
  • PDF
Loading

Article Figures & Data

Figures

  • Tables
  • Additional Files
  • Figure 1.
    • Download figure
    • Open in new tab
    • Download powerpoint
    Figure 1.

    Patient enrollment and disposition. Abbreviation: ECOG PS, Eastern Cooperative Oncology Group Performance Status.

  • Figure 2.
    • Download figure
    • Open in new tab
    • Download powerpoint
    Figure 2.

    PK and PD features of talazoparib. A–D, Mean concentration–time profiles of talazoparib. Linear mean talazoparib plasma concentration–timeprofiles over the initial 24 hours after dose and log-linear mean talazoparib plasma concentration–time profiles over the complete sampling interval following (A and B) single doses of talazoparib and (C and D) multiple daily doses of talazoparib. E–H, Dose proportionality of talazoparib PK and dose–response and exposure–response relationships between talazoparib and PBMC PARP activity. E, Plasma Cmax following multiple daily doses ranging from 0.025 to 1.1 mg. F, AUC0–24 following multiple daily doses ranging from 0.025 to 1.1 mg. Filled circles represent the mean value at each dose level, and error bars represent the standard deviations. Solid line represents the power model fit through the data. G, Dose–response relationship between talazoparib and PBMC PARP activity. H, Exposure–response relationship between talazoparib and PBMC PARP activity. Percentage baseline PBMC PARP activity defined as the mean of the predose PARP activity assessments during the multiple dosing assessment phase (i.e., predose assessments on days 15, 22, and 35 of cycle 1). Abbreviations: AUC0–24, AUC from 0 to 24 h; IC50, half maximal inhibitory concentration; ID50, inhibitory dose 50%; PD, pharmacodynamic.

  • Figure 3.
    • Download figure
    • Open in new tab
    • Download powerpoint
    Figure 3.

    Percentage change in target lesion for patients undergoing treatment with talazoparib who have (A) gBRCA breast cancer and (B) gBRCA ovarian cancer. Positive values indicate tumor growth, negative values indicate tumor reduction, and the dashed line represents the definition of partial response from RECIST guidelines. Abbreviations: gBRCA, germline BRCA mutated; SLD, sum of longest diameter.

Tables

  • Figures
  • Additional Files
  • Table 1.

    Demographics and baseline clinical characteristics

    Demographic parameterDose escalation (Part 1; n = 39)Dose expansion (Part 2; n = 71)Overall (N = 110)
    Median age, years (range)58.0 (19–81)57.0 (18–88)57.0 (18–88)
    Male, n (%)6 (15.4)28 (39.4)34 (30.9)
    ECOG performance status, n (%)
     023 (59.0)37 (52.1)60 (54.5)
     116 (41.0)34 (47.9)50 (45.5)
    Tumor type, n (%)
     Breast8 (20.5)12 (16.9)20 (18.2)
     Ovarian/peritoneal23 (59.0)11 (15.5)34 (30.9)
     Prostate1 (2.6)3 (4.2)4 (3.6)
     Pancreatic3 (7.7)10 (14.1)13 (11.8)
     Ewing sarcoma2 (5.1)12 (16.9)14 (12.7)
     SCLC023 (32.4)23 (20.9)
     Colorectal2 (5.1)02 (1.8)
    Deleterious mutation, n (%)
     gBRCA116 (41.0)13 (18.3)29 (26.4)
     gBRCA27 (17.9)20 (28.2)27 (24.5)
     gBRCA1/21 (2.6)2 (2.8)3 (2.7)
    Median prior chemotherapy regimens, n (range)4.0 (1.0–13.0)2.0 (0.0–6.0)2.5 (0.0–13.0)
    Median prior platinum regimens, n (range)2.0 (0.0–4.0)1.0 (0.0–4.0)1.0 (0.0–4.0)
    • Abbreviations: ECOG, Eastern Cooperative Oncology Group; gBRCA, germline BRCA mutated.

  • Table 2.

    Part 1 dose escalation schema, DLTs, dose reductions, and common AEs (>15%) or grade 3 to 4 AEs (>4%) assessed by investigator as related at the recommended dose

    Dose levelPatients (n = 39)DLTs in first cycleDose reductions (any cycle)Number of treatment days
    NumberDescriptionNumberMedian (range)
    0.025 mg30—235 (35–98)
    0.05 mg30—299 (34–205)
    0.10 mg30—2119 (65–253)
    0.20 mg30—2281 (35–427)
    0.40 mg30—1226 (97–268)
    0.60 mg60—4185 (58–289)
    0.90 mg61Grade 3 TCP5261 (30–1114)
    1.00 mg60—5214 (84–960)
    1.10 mg6a2Grade 3–4 TCP460 (14–196)
    Adverse eventAll grade (n = 71)Grade 3–4 (n = 71)
    Any treatment-emergent AE, n (%)55 (77)32 (45)
    Blood and lymphatic system disorders, n (%)40 (56)30 (42)
     Anemia25 (35)16 (23)
     TCP15 (21)13 (18)
     Neutropenia11 (15)7 (10)
    Gastrointestinal disorders, n (%)27 (38)—
     Nausea23 (32)—
    General disorders and administration site conditions, n (%)27 (38)2 (3)
     Fatigue26 (37)2 (3)
    Skin and subcutaneous tissue disorders, n (%)19 (27)—
     Alopecia14 (20)—
    • Abbreviation: TCP, thrombocytopenia.

    • ↵aOne patient discontinued from the trial on study day 21 for progressive disease, having received only 8 days of continuous dosing.

  • Table 3.

    PK parameters and PARP inhibition following single and multiple daily dosing

    Single talazoparib dose, mg
    PK parameter0.025 (n = 3)0.05 (n = 3)0.1 (n = 3)0.2 (n = 3)0.4 (n = 3)0.6 (n = 6)0.9 (n = 6)1.0 (n = 5)1.1 (n = 7)
    Tmax, median (min, max), h7.92 (1.95, 9.95)1.00 (0.80, 1.02)1.02 (1.00, 3.98)1.03 (1.00, 2.32)2.03 (0.75, 2.95)0.835 (0.75, 1.95)2.00 (1.02, 9.98)1.03 (0.73, 2.07)1.00 (0.73, 2.05)
    Cmax, mean (SD), pg/mL60.0 (15.9)79.7 (7.50)214 (50.9)788 (369)1,830 (699)4,100 (1,400)6,100 (3,060)10,600 (4,220)13,200 (3,220)
    AUC0–24, mean (SD), pg·h/mL952 (386)1,160 (166)3,160 (1,270)9,130 (3,540)13,500 (5,200)37,900 (12,900)58,200 (24,300)85,100 (29,100)91,600 (31,800)
    AUC0–t, mean (SD), pg·h/mL3,600 (1,360)5,340 (1,960)16,600 (5,320)39,300 (11,700)43,700 (15,000)97,900 (30,000)160,000 (66,100)182,000 (62,400)201,000 (93,400)
    AUC0-∞, mean (SD), pg·h/mL5,330 (1,840)8,320 (1,960)37,600 (6,620)92,700 (48,500)60,100 (15,900)120,000 (26,000)188,000 (85,700)200,000 (64,000)235,000 (111,000)
    t1/2, mean (SD), h100 (11.9)129 (42.6)229 (158)212 (126)102 (27.2)58.6 (17.3)60.4 (10.9)52.9 (13.4)71.0 (20.6)
    CL/F, mean (SD), L/h5.17 (2.10)6.27 (1.66)2.72 (0.532)2.61 (1.35)6.95 (1.71)5.19 (0.99)5.49 (2.08)5.39 (1.59)5.32 (1.64)
    Vz/F, mean (SD), L756 (351)1,240 (742)839 (487)678 (217)1,050 (431)441 (143)468 (169)415 (170)549 (232)
    Multiple daily talazoparib dosing, mg/day
    0.025 (n = 3)0.05 (n = 2)0.1 (n = 2)0.2 (n = 3)0.4 (n = 3)0.6 (n = 6)0.9 (n = 5)1.0 (n = 6)1.1 (n = 4)
    Tmax, median (min, max), h1.02 (0.58, 3.98)5.43 (0.77, 10.1)0.76 (0.75, 0.82)1.97 (1.00, 3.02)0.98 (0.75, 2.00)1.04 (0.73, 5.98)1.02 (0.97, 2.07)1.02 (0.75, 2.00)1.48 (0.98, 2.00)
    Cmax, mean (SD), pg/mL300 (78.8)615 (74.2)1,880 (332)5,620 (3,530)6,560 (1,500)11,300 (3,230)15,400 (1,540)21,000 (7,990)23,400 (4,810)
    AUC0-24, mean (SD), pg·h/mL3,960 (759)9,770 (2,440)30,000 (4,490)83,100 (49,300)67,300 (22,600)119,000 (19,900)157,000 (24,500)202,000 (54,000)188,000 (29,200)
    t1/2, mean (SD), h107 (84.2)132 (12.3)98.2 (4.83)50.9 (19.1)90.7 (32.7)63.7 (12.7)71.0 (14.5)50.0 (16.6)52.8 (23.2)
    CLss/F, mean (SD), L/h6.43 (1.23)5.28 (1.32)3.37 (0.502)3.12 (1.91)6.40 (2.07)5.15 (0.897)5.86 (0.951)5.24 (1.39)5.96 (0.837)
    Vz/F, mean (SD), L1,070 (971)1,020 (345)475 (47.8)264 (249)818 (326)477 (136)604 (169)373 (144)472 (254)
    Cmin, mean (SD), pg/mL169 (58.0)299 (133)1,020 (107)2,880 (1,710)2,230 (957)3,470 (1,050)3,180 (802)3,720 (1,590)2,910(803)
    PARP activity, % baseline
    0.025 (n = 3)0.05 (n = 3)0.1 (n = 3)0.2 (n = 3)0.4 (n = 3)0.6 (n = 4)0.9 (n = 4)1.0 (n = 4)1.1 (n = 2)
    PARP activity, mean (SD)172 (206)141 (52.5)102 (98.0)14.7 (5.04)111 (96.5)24.7 (8.19)34.7 (27.4)21.1 (14.9)16.3 (5.63)
    • Abbreviations: AUC0–24, AUC from 0 to 24 h; AUC0–∞, AUC from time 0 extrapolated to infinity; AUC0–t, AUC from time 0 to last quantifiable concentration; CLss/F, CL/F at steady state; SD, standard deviation; Tmax, time to Cmax.

  • Table 4.

    Clinical response rate (RECIST) by cancer type in patients treated with talazoparib 1.0 mg/day (recommended phase II dose)

    ResponseBreasta (n = 14)Ovarian/peritoneala (n = 12)SCLC (n = 23)Pancreatic (n = 10)Ewing sarcoma (n = 13)
    ORR,%50.041.78.720.00
    CR, n11000
    PR, n64220
    SD, n53413
    CBR,%b85.766.726.130.023.1
    Median PFS, weeks34.636.4c11.1NDND
    • Abbreviations: ND, not determined; SD, stable disease.

    • ↵aPatients had BRCA1/2 mutation.

    • ↵bClinical benefit = CR + PR + SD ≥24 weeks for breast and ovarian cancers, and CR + PR + SD ≥16 weeks for SCLC, pancreatic cancer, and Ewing sarcoma.

    • ↵cAnalysis on 14 patients, as 2 patients who did not have measurable disease at baseline were included in the PFS analysis but not in the response analysis.

Additional Files

  • Figures
  • Tables
  • Supplementary Data

    • Supplementary Methods - Supplementary Methods includes additional details on these topics: tumors eligible for dose escalation phase; tumors eligible for dose expansion phase; patients enrolled using a local laboratory; study design and participants; additional inclusion criteria; full list of exclusion criteria; study treatment; study procedures; pharmacodynamic (PD) analysis; inhibition of PBMC PARP activity.
    • Supplementary Figure S1 - Supplementary Figure S1. Talazoparib inhibition of PBMC PARP activity.
    • Supplementary Table S1 - Supplementary Table S1. Dose-response and exposure-response parameters.
PreviousNext
Back to top
Cancer Discovery: 7 (6)
June 2017
Volume 7, Issue 6
  • Table of Contents
  • Table of Contents (PDF)
  • About the Cover
  • Editorial Board (PDF)

Sign up for alerts

View this article with LENS

Open full page PDF
Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for sharing this Cancer Discovery article.

NOTE: We request your email address only to inform the recipient that it was you who recommended this article, and that it is not junk mail. We do not retain these email addresses.

Enter multiple addresses on separate lines or separate them with commas.
Phase I, Dose-Escalation, Two-Part Trial of the PARP Inhibitor Talazoparib in Patients with Advanced Germline BRCA1/2 Mutations and Selected Sporadic Cancers
(Your Name) has forwarded a page to you from Cancer Discovery
(Your Name) thought you would be interested in this article in Cancer Discovery.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Phase I, Dose-Escalation, Two-Part Trial of the PARP Inhibitor Talazoparib in Patients with Advanced Germline BRCA1/2 Mutations and Selected Sporadic Cancers
Johann de Bono, Ramesh K. Ramanathan, Lida Mina, Rashmi Chugh, John Glaspy, Saeed Rafii, Stan Kaye, Jasgit Sachdev, John Heymach, David C. Smith, Joshua W. Henshaw, Ashleigh Herriott, Miranda Patterson, Nicola J. Curtin, Lauren Averett Byers and Zev A. Wainberg
Cancer Discov June 1 2017 (7) (6) 620-629; DOI: 10.1158/2159-8290.CD-16-1250

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Share
Phase I, Dose-Escalation, Two-Part Trial of the PARP Inhibitor Talazoparib in Patients with Advanced Germline BRCA1/2 Mutations and Selected Sporadic Cancers
Johann de Bono, Ramesh K. Ramanathan, Lida Mina, Rashmi Chugh, John Glaspy, Saeed Rafii, Stan Kaye, Jasgit Sachdev, John Heymach, David C. Smith, Joshua W. Henshaw, Ashleigh Herriott, Miranda Patterson, Nicola J. Curtin, Lauren Averett Byers and Zev A. Wainberg
Cancer Discov June 1 2017 (7) (6) 620-629; DOI: 10.1158/2159-8290.CD-16-1250
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Abstract
    • Introduction
    • Results
    • Discussion
    • Methods
    • Statistical Analysis
    • Disclosure of Potential Conflicts of Interest
    • Authors' Contributions
    • Grant Support
    • Acknowledgments
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • PDF
Advertisement

Related Articles

Cited By...

More in this TOC Section

  • Epigenetic and Transcriptional Control of Antitumor Immunity
  • Autonomous IFN Program in Aggressive Ductal-Derived PDAC
  • Machine-Learning Approach Predicts Hippo Pathway Dependency
Show more Research Articles
  • Home
  • Alerts
  • Feedback
  • Privacy Policy
Facebook   Twitter   LinkedIn   YouTube   RSS

Articles

  • OnlineFirst
  • Current Issue
  • Past Issues

Info For

  • Authors
  • Subscribers
  • Advertisers
  • Librarians

About Cancer Discovery

  • About the Journal
  • Editors
  • Journal Sections
  • Permissions
  • Submit a Manuscript
AACR logo

Copyright © 2021 by the American Association for Cancer Research.

Cancer Discovery
eISSN: 2159-8290
ISSN: 2159-8274

Advertisement