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Breast Cancer Research and Treatment

, Volume 178, Issue 1, pp 121–133 | Cite as

A phase Ib, open-label, dose-escalation study of the safety and pharmacology of taselisib (GDC-0032) in combination with either docetaxel or paclitaxel in patients with HER2-negative, locally advanced, or metastatic breast cancer

  • Vandana G. AbramsonEmail author
  • Mafalda Oliveira
  • Andrés Cervantes
  • Hans Wildiers
  • Manish R. Patel
  • Todd M. Bauer
  • Philippe L. Bedard
  • Carlos Becerra
  • Stephen Richey
  • Michael C. Wei
  • Eric Reyner
  • John Bond
  • Na Cui
  • Timothy R. Wilson
  • Heather M. Moore
  • Cristina Saura
  • Ian E. Krop
Clinical trial

Abstract

Purpose

This open-label, phase Ib, dose-escalation, and dose-expansion study (NCT01862081) evaluated taselisib with a taxane in locally advanced or metastatic breast cancer (BC) and/or non-small cell lung cancer (NSCLC).

Methods

Patients received taselisib (2–6 mg tablet or 3–6 mg capsule) plus docetaxel or paclitaxel. Primary endpoints were safety, dose-limiting toxicities, maximum tolerated dose, and identification of a recommended phase II dose. Secondary endpoints included pharmacokinetics and antitumor activity assessment.

Results

Eighty patients (BC: 72; NSCLC: 7; BC/NSCLC: 1) were enrolled (docetaxel-receiving arms: 21; paclitaxel-receiving arms: 59). Grade ≥ 3 adverse events (AEs), serious AEs, and AEs leading to death were reported in 90.5%, 42.9%, and 14.3% of patients, respectively (docetaxel-receiving arms), and 78.9%, 40.4%, and 3.5% of patients, respectively (paclitaxel-receiving arms). Eight patients experienced dose-limiting toxicities. The maximum tolerated dose was exceeded with 3 mg taselisib (capsule) for 21 consecutive days plus 75 mg/m2 docetaxel and not exceeded with 6 mg taselisib (tablet) for 5 days on/2 days off plus 80 mg/m2 paclitaxel. Objective response rates and clinical benefit rates were 35.0% and 45.0%, respectively (docetaxel-receiving arms), and 20.4% and 27.8%, respectively (paclitaxel-receiving arms). Exposure for paclitaxel or docetaxel plus taselisib was consistent with the single agents.

Conclusions

Taselisib in combination with a taxane has a challenging safety profile. Despite evidence of antitumor activity, the benefit–risk profile was deemed not advantageous. Further development is not planned.

Keywords

Taselisib GDC-0032 PI3K PI3K inhibitor Metastatic breast cancer PIK3CA 

Abbreviations

AE

Adverse event

AEGT

Adverse event group term

AESI

Adverse event of special interest

AUC0–last

Area under the curve from time 0 to the last measurable concentration

AUC0–24

Area under the curve during 24 h

BC

Breast cancer

CBR

Clinical benefit rate

CI

Confidence interval

Cmax

Maximum observed plasma concentration

Cmin

Minimum observed plasma concentration

CR

Complete response

ctDNA

Circulating tumor DNA

DLT

Dose-limiting toxicity

DoR

Duration of response

ECOG PS

Eastern Cooperative Oncology Group performance status

ER

Estrogen receptor

G-CSF

Granulocyte-colony stimulating factor

HER2

Human epidermal growth factor receptor 2

HR

Hormone receptor

MBC

Metastatic breast cancer

MedDRA

Medical Dictionary for Regulatory Activities

MND

Mutation not detected

MTD

Maximum tolerated dose

NE

Not evaluable

NCI-CTCAE

National Cancer Institute-Common Terminology Criteria for Adverse Events

NSCLC

Non-small cell lung cancer

PCR

Polymerase chain reaction

PD

Progressive disease

PFS

Progression-free survival

PgR

Progesterone receptor

PIK3CA

Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha

PI3K

Phosphatidylinositol 3-kinase

PK

Pharmacokinetics

PR

Partial response

PTEN

Phosphatase and tensin homolog

qd

Once-daily

qw

Once-weekly

q3w

Every 3 weeks

RECIST

Response Evaluation Criteria in Solid Tumors

SAE

Serious adverse event

SD

Stable disease

SLD

Sum of the longest diameter

tmax

Time to maximum observed plasma concentration

Notes

Acknowledgements

We would like to thank the patients, their families, the nurses, and the investigators who participated in this study. The authors would like to thank Thomas J. Stout, PhD, Jerry Y. Hsu, MD, PhD, Jing He, MD, Alison Cardenas, RN, Deanna Wilson, MS, and Jiaheng Qiu, PhD (Genentech, Inc., South San Francisco, CA, USA), for input during the study. This study was funded by Genentech, Inc./F. Hoffmann-La Roche Ltd. F. Hoffmann-La Roche Ltd funded the study, provided study drugs, and was involved in the study design, protocol development, regulatory and ethics approvals, safety monitoring and reporting, data management, and data analysis and interpretation. Support for third-party writing assistance, furnished by Islay Steele, PhD, of Health Interactions, was provided by F. Hoffmann-La Roche Ltd.

Author contributions

VGA and IEK were involved in the conception and design of the study. VGA, MCW, and ER were involved in development of the methodology used. VGA, MO, AC, HW, MRP, TMB, PLB, CB, SR, HMM, CS, and IEK were involved in the acquisition of data (acquired and managed patients, provided facilities, etc.). HW, MCW, ER, JB, NC, TRW, and HMM were involved in analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis). MCW, ER, JB, NC, TRW, and HMM were involved in administrative, technical, or material support (i.e., reporting or organizing data, constructing databases). MCW was involved in study supervision. All authors were involved in the writing, review, and/or revision of this manuscript and approved the final manuscript.

Funding

This study was funded by Genentech, Inc./F. Hoffmann-La Roche Ltd. F. Hoffmann-La Roche Ltd funded the study, provided study drugs, and was involved in the study design, protocol development, regulatory and ethics approvals, safety monitoring and reporting, data management, and data analysis and interpretation.

Compliance with ethical standards

Conflict of interest

VGA has received research funding from Genentech, Astellas, and Lilly, and has consulted for Eisai and Novartis. MO has received remuneration from Roche, consulting or advisory fees from Roche, GSK, PUMA Biotechnology, and funding from AstraZeneca, Philips Healthcare, Genentech, Roche, Novartis, Immunomedics, Seattle Genetics, GSK, Boehringer-Ingelheim, PUMA Biotechnology (all to the Institution). AC has received consulting or advisory fees from Merck Serono, Roche, Beigene, Bayer, Servier, Lilly, Novartis, Takeda and Astelas, and funding from Genentech, Merck Serono, Roche, Beigene, Bayer, Servier, Lilly, Novartis, Takeda, Astelas, Fibrogen, Amcure, Sierra Oncology, Astra Zeneca, Medimmune, BMS, and MSD. HW has received travel support from Roche, TRM Oncology, Puma Biotechnology, and Pfizer (outside of the submitted work), and his institution has received consulting fees and honoraria from Roche, AstraZeneca, Amgen, Lilly, Novartis, AbbVie, Vifor Pharma, Pfizer, Celldex Therapeutics, Janssen-Cilag, TRM Oncology, Puma Biotechnology, Orion Corporation, and an unrestricted research grant from Roche (outside of the submitted work). MRP has received consulting or advisory fees from Exelixis, Pfizer, EMD Serono, Pharmacyclics, Genentech, and Celgene. TMB has received remuneration for employment Tennessee Oncology, remuneration for speakers’ bureau from Bayer (personal), remuneration for travel from Astellas Pharma, AstraZeneca, Celgene, Clovis Oncology, EMD Serono, Genentech, Lilly, Merck, Novartis, Ignyta, Pharmacyclics, Loxo, Bayer, Guardant Health, Moderna Therapeutics and Sysmex, consulting or advisory fees from Guardant Health (personal), Loxo (personal), Pfizer (personal), Leap Therapeutics (institutional), Ignyta (Institutional), Moderna Therapeutics (Institutional), Bayer (personal), Guardant Health and Pfizer (personal and Institutional), and Institutional funding from: Daiichi Sankyo, Medpacto, Inc., Incyte, Mirati Therapeutics, MedImmune, Abbvie, AstraZeneca, Leap Therapeutics, MabVax, Stemline Therapeutics, Merck, Lilly, GlaxoSmithKline, Novartis, Pfizer, Genentech/Roche, Deciphera, Merrimack, Immunogen, Millennium, Ignyta, Calithera Biosciences, Kolltan Pharmaceuticals, Principa Biopharma, Peleton, Immunocore, Aileron Therapeutics, Bristol-Myers Squibb, Amgen, Moderna Therapeutics, Sanofi, Boehringer Ingelheim, Astellas Pharma, Five Prime Therapeutics, Jacobio, Top Alliance BioScience, Loxo, Janssen, Clovis Oncology, Takeda, Karyopharm Therapeutics, Onyx, Phosplatin Therapeutics, Foundation Medicine and ARMO BioSciences and Bayer. PLB reports institutional grants from Bristol-Myers Squibb, Sanofi, AstraZeneca, Genentech/Roche, Servier, Merck, Nektar, Mersana, Novartis, GlaxoSmithKline, SignalChem, PTC Therapeutics (all during the conduct of the study), and is the current Chair of the Investigational New Drug Committee, Canadian Clinical Trials Group, an Executive Board Member for the Breast International Group, a Steering Committee Member for the American Association for Cancer Research Project GENIE, and a member of the NCI-BIO Breast Cancer Immunotherapy Task Force. CB has received honoraria from Taiho Pharmaceutical, consulting or advisory fees from SOBI, Ipsen, Takeda, Bayer, HERON, and Agenus, and fees from speakers’ bureau from Taiho Pharmaceutical, Bristol-Myers Squibb, and Celgene. SR has received remuneration from AstraZeneca, Genentech Inc., Genzyme Corporation, consulting or advisory fees from AstraZeneca, and funding from Acerta Pharma LLC, Eisai Inc., Eli Lilly and Company, EMD Serono, Inc., E.R. Squibb & Sons, L.L.C., Genentech, Inc., Ipsen Biopharmaceuticals, Inc., Janssen Research & Development, LLC., Janssen Research & Development, LLC., Novartis Pharmaceuticals Corporation, Tesaro, Inc. MCW, ER, JB, NC, TRW, and HMM are employees of Genentech and hold stock in Roche. CS has received travel grants from Puma Biotechnology, Pfizer, Roche, Astra Zeneca, Celgene, Daiichi Sankyo, Eisai, Genomyc Health, Novartis, Pierre Fabre, and Synthon Biopharmaceuticals, consulting or advisory fees from Puma Biotechnology, Pfizer, Roche, Astra Zeneca, Celgene, Daiichi Sankyo, Eisai, Genomyc Health, Novartis, Pierre Fabre, and Synthon Biopharmaceuticals, and funding from Roche-Genentech, Macrogenics, Pfizer, Piqur Therapeutics, Puma Biotechnology, Synthon Biopharmaceuticals, and Novartis. IEK has received grants and personal fees from Genentech/Roche (during the conduct of the study), grants from Pfizer, and personal fees from Macrogenics, Amgen, Taiho, Context Therapeutics, Seattle Genetics, and Daiichi Sankyo (outside of the submitted work). All authors received support for third-party writing assistance for this manuscript from Genentech, Inc./F. Hoffmann-La Roche Ltd.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee (Supplementary methods) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Supplementary material

10549_2019_5360_MOESM1_ESM.docx (183 kb)
Supplementary material 1 (DOCX 184 kb)

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Vandana G. Abramson
    • 1
    Email author
  • Mafalda Oliveira
    • 2
  • Andrés Cervantes
    • 3
  • Hans Wildiers
    • 4
  • Manish R. Patel
    • 5
    • 6
  • Todd M. Bauer
    • 6
  • Philippe L. Bedard
    • 7
  • Carlos Becerra
    • 8
  • Stephen Richey
    • 9
  • Michael C. Wei
    • 10
  • Eric Reyner
    • 11
  • John Bond
    • 12
  • Na Cui
    • 13
  • Timothy R. Wilson
    • 14
  • Heather M. Moore
    • 14
  • Cristina Saura
    • 2
  • Ian E. Krop
    • 15
  1. 1.Vanderbilt University Medical CenterNashvilleUSA
  2. 2.Department of Medical Oncology, Vall d’Hebron University HospitalVall d’Hebron Institute of Oncology (VHIO)BarcelonaSpain
  3. 3.CIBERONC, Medical Oncology Department, Institute of Health Research INCLIVAUniversity of ValenciaValenciaSpain
  4. 4.Department of General Medical Oncology, University Hospitals LeuvenLeuven Cancer InstituteLouvainBelgium
  5. 5.Florida Cancer Specialists/Sarah Cannon Research InstituteSarasotaUSA
  6. 6.Sarah Cannon Research Institute/Tennessee Oncology, PLLCNashvilleUSA
  7. 7.Division of Medical Oncology & Hematology, Department of Medicine, Princess Margaret Cancer Centre, University Health NetworkUniversity of TorontoTorontoCanada
  8. 8.US Oncology NetworkTexas OncologyDallasUSA
  9. 9.US Oncology NetworkTexas OncologyFort WorthUSA
  10. 10.Product Development OncologyGenentech, Inc.South San FranciscoUSA
  11. 11.Department of Clinical PharmacologyGenentech, Inc.South San FranciscoUSA
  12. 12.PDSS-Global Safety Risk Management Oncology GroupGenentech, Inc.South San FranciscoUSA
  13. 13.CStone PharmaceuticalsSuzhouChina
  14. 14.Oncology Biomarker DevelopmentGenentech, IncSouth San FranciscoUSA
  15. 15.Dana-Farber Cancer InstituteBostonUSA

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