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Phase 1 study of TTC-352 in patients with metastatic breast cancer progressing on endocrine and CDK4/6 inhibitor therapy

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Abstract

Purpose

TTC-352 is a selective human estrogen receptor (ER) partial agonist developed for treatment of hormone-refractory ER + breast cancer.

Methods

This was an accelerated dose escalation study with the primary endpoint of maximum tolerated dose that evaluated five dose levels of TTC-352 in breast cancer progressing after at least two lines of hormonal therapy including one in combination with a CDK4/6 inhibitor. The secondary objectives were to determine treatment tolerability, pharmacokinetics of TTC-352, best response, progression-free survival (PFS), and PKCα expression in tumors.

Results

The study enrolled 15 patients. No dose-limiting toxicity was observed. Patients experienced the following grade 3 toxicities: asymptomatic pulmonary embolism, diarrhea, aspartate transaminase elevation, and myalgia, and one grade 4 toxicity of gamma glutamyltransferase elevation. Pharmacokinetic half-life was 7.6–14.3 h. The intra- and inter-individual variability for AUC0-∞ hampered assessment of the relationship between dose and AUC0-∞. Median PFS was 58 days (95% CI = 28,112). Higher PKCα expression in tumor stroma was associated with a trend toward longer PFS.

Conclusions

TTC-352 demonstrates safety and early clinical evidence of antitumor activity against heavily pretreated hormone-refractory breast cancer. Based upon TTC-352 plasma concentrations and tolerability, the 180 mg twice a day is recommended for further testing.

(ClinicalTrials.gov Identifier: NCT03201913)

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Data availability

For the data supporting the presented results please contact the corresponding author. Supplementary information is available at the British Journal of Cancer’s website.

Abbreviations

AI:

Aromatase inhibitors

CEE:

Conjugated equine estrogens

Cmax :

Maximum plasma concentration

CTCAE:

Cancer Institute Common Terminology Criteria for Adverse Events

DES:

Diethylstilbestrol

DLT:

Dose-limiting toxicity

E2:

17β-Estradiol

ECOG:

Eastern Cooperative Oncology Group

ER:

Estrogen receptor

ER + :

Estrogen receptor positive

HER2-:

Human epidermal growth factor receptor 2 negative

HDE:

High-dose estrogens

IHC:

Immunohistochemistry

MTD:

Maximum tolerated dose

PFS:

Progression-free survival

PI3K:

Phosphoinositide-3-kinase

PKCα:

Protein kinase C alpha SEMs

SEMs:

Selective estrogen mimics

ShERPA:

Selective human ER partial agonist

SRERD:

Selective estrogen receptor downregulator

t1/2-λz :

Terminal half-life

TTF:

Time-to-treatment failure

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Acknowledgements

We are thankful to James P. Zacny, PhD for his editorial support with the clinical protocol and manuscript.

Funding

We acknowledge funding from TTC Oncology, LLC, and the Engdahl Family Foundation.

Author information

Authors and Affiliations

  1. Regions Cancer Care Center, HealthPartners Institute, St. Paul, MN, USA

    Arkadiusz Z. Dudek & Randolph W. Hurley

  2. TTC Oncology, Edina, MN, USA

    Arkadiusz Z. Dudek, Debra A. Tonetti, Gregory R. J. Thatcher & Robert P. Venuti

  3. Division of Epidemiology and Biostatistics, School of Public Health, University of Illinois At Chicago, Chicago, IL, USA

    Li C. Liu

  4. Department of Pharmacy Practice, College of Pharmacy, University of Illinois At Chicago, Chicago, IL, USA

    James H. Fischer

  5. Department of Pathology, University of Illinois At Chicago, Chicago, IL, USA

    Elizabeth L. Wiley

  6. HonorHealth Research Institute, The Translational Genomics Research Institute, Scottsdale, AZ, USA

    Jasgit C. Sachdev

  7. Sanford Health, USD School of Medicine, SanfordSioux Falls, SD, USA

    Jonathan Bleeker

  8. Pharmaceutical Sciences, College of Pharmacy, University of Illinois At Chicago, Chicago, IL, USA

    Debra A. Tonetti & Gregory R. J. Thatcher

  9. Department of Medicine and Carbone Cancer Center, University of Wisconsin, CSC, 600 Highland Ave, Madison, WI, K4/54253792, USA

    Ruth M. O’Regan MD

Authors
  1. Arkadiusz Z. Dudek
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  2. Li C. Liu
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  3. James H. Fischer
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  4. Elizabeth L. Wiley
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  6. Jonathan Bleeker
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  7. Randolph W. Hurley
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  8. Debra A. Tonetti
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  9. Gregory R. J. Thatcher
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  10. Robert P. Venuti
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  11. Ruth M. O’Regan MD
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Corresponding author

Correspondence to Ruth M. O’Regan MD.

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Conflicts of interest

AZD serves as Chief Medical Officer and obtained honoraria from TTC Oncology and Vanquish Oncology. AZD has received honoraria for consulting work from EMD Serono. AZD has equity in TTC Oncology, IGF Oncology, Squarex, and Martell Diagnostic Laboratories. AZD reports research funding to institutions from Merck, and Eli Lilly. DAT and GRJT have equity in TTC Oncology. RPV has received honoraria from TTC Oncology. RMO serves as an advisor for Lilly, PUMA, Novartis, Genomic Health and Biotheranostics and receives grant support from PUMA, Novartis, Seattle Genetics, and Eisai. All other authors declare no competing interests.

Ethical approval

This clinical trial was approved by the Institutional Review Board at the participating institutions. It was conducted in accordance with the Declaration of Helsinki.

Informed consent

All participants provided written informed consent.

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Dudek, A.Z., Liu, L.C., Fischer, J.H. et al. Phase 1 study of TTC-352 in patients with metastatic breast cancer progressing on endocrine and CDK4/6 inhibitor therapy. Breast Cancer Res Treat 183, 617–627 (2020). https://doi.org/10.1007/s10549-020-05787-z

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  • DOI: https://doi.org/10.1007/s10549-020-05787-z

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