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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

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Breast Cancer Research and Treatment Aims and scope Submit manuscript

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.

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Data availability

Qualified researchers may request access to individual patient-level data through the clinical study data request platform: www.clinicalstudydatarequest.com. Further details on Roche’s criteria for eligible studies are available here: https://clinicalstudydatarequest.com/Study-Sponsors/Study-Sponsors-Roche.aspx. For further details on Roche’s Global Policy on the Sharing of Clinical Information and how to request access to related clinical study documents, see here: https://www.roche.com/research_and_development/who_we_are_how_we_work/clinical_trials/our_commitment_to_data_sharing.htm.

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

C max :

Maximum observed plasma concentration

C min :

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

t max :

Time to maximum observed plasma concentration

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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.

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.

Author information

Authors and Affiliations

Authors

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.

Corresponding author

Correspondence to Vandana G. Abramson.

Ethics declarations

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.

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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.

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

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Abramson, V.G., Oliveira, M., Cervantes, A. et al. 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. Breast Cancer Res Treat 178, 121–133 (2019). https://doi.org/10.1007/s10549-019-05360-3

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