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Breast Cancer Research and Treatment
Published in: Breast Cancer Research and Treatment 3/2020

01-10-2020 | Breast Cancer | Clinical trial

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

Authors: Arkadiusz Z. Dudek, Li C. Liu, James H. Fischer, Elizabeth L. Wiley, Jasgit C. Sachdev, Jonathan Bleeker, Randolph W. Hurley, Debra A. Tonetti, Gregory R. J. Thatcher, Robert P. Venuti, Ruth M. O’Regan, MD

Published in: Breast Cancer Research and Treatment | Issue 3/2020

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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)
Appendix
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Literature
1.
Messina C, Cattrini C, Buzzatti G, Cerbone L, Zanardi E, Messina M, Boccardo F (2018) CDK4/6 inhibitors in advanced hormone receptor-positive/HER2-negative breast cancer: a systematic review and meta-analysis of randomized trials. Breast Cancer Res Treat 172(1):9–21PubMedCrossRef
2.
Li J, Wang Z, Shao Z (2019) Fulvestrant in the treatment of hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer: A review. Cancer Med 8(5):1943–1957PubMedPubMedCentralCrossRef
3.
Iorfida M, Mazza M, Munzone E (2020) Fulvestrant in Combination with CDK4/6 Inhibitors for HER2- Metastatic Breast Cancers: Current Perspectives. Breast Cancer (Dove Med Press) 12:45–56
4.
Molloy ME, White BE, Gherezghiher T, Michalsen BT, Xiong R, Patel H, Zhao H, Maximov PY, Jordan VC, Thatcher GR et al (2014) Novel selective estrogen mimics for the treatment of tamoxifen-resistant breast cancer. Mol Cancer Ther 13(11):2515–2526PubMedPubMedCentralCrossRef
5.
Xiong R, Patel HK, Gutgesell LM, Zhao J, Delgado-Rivera L, Pham TND, Zhao H, Carlson K, Martin T, Katzenellenbogen JA et al (2016) Selective Human Estrogen Receptor Partial Agonists (ShERPAs) for Tamoxifen-Resistant Breast Cancer. J Med Chem 59(1):219–237PubMedCrossRef
6.
Mackay HJ, Twelves CJ (2003) Protein kinase C: a target for anticancer drugs? Endocr Relat Cancer 10(3):389–396PubMedCrossRef
7.
Assender JW, Gee JM, Lewis I, Ellis IO, Robertson JF, Nicholson RI (2007) Protein kinase C isoform expression as a predictor of disease outcome on endocrine therapy in breast cancer. J Clin Pathol 60(11):1216–1221PubMedPubMedCentralCrossRef
8.
Lonne GK, Cornmark L, Zahirovic IO, Landberg G, Jirstrom K, Larsson C (2010) PKCalpha expression is a marker for breast cancer aggressiveness. Mol Cancer 9:76PubMedPubMedCentralCrossRef
9.
Yao K, Lee ES, Bentrem DJ, England G, Schafer JI, O'Regan RM, Jordan VC (2000) Antitumor action of physiological estradiol on tamoxifen-stimulated breast tumors grown in athymic mice. Clin Cancer Res 6(5):2028–2036PubMed
10.
Chisamore MJ, Ahmed Y, Bentrem DJ, Jordan VC, Tonetti DA (2001) Novel antitumor effect of estradiol in athymic mice injected with a T47D breast cancer cell line overexpressing protein kinase Calpha. Clin Cancer Res 7(10):3156–3165PubMed
11.
12.
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M et al (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45(2):228–247PubMedCrossRef
13.
Tonetti DA, Morrow M, Kidwai N, Gupta A, Badve S (2003) Elevated protein kinase C alpha expression may be predictive of tamoxifen treatment failure. Br J Cancer 88(9):1400–1402PubMedPubMedCentralCrossRef
14.
Tonetti DA, Gao W, Escarzaga D, Walters K, Szafran A, Coon JS (2012) PKCalpha and ERbeta Are Associated with Triple-Negative Breast Cancers in African American and Caucasian Patients. Int J Breast Cancer 2012:740353PubMedPubMedCentralCrossRef
15.
Allred DC, Clark GM, Elledge R, Fuqua SA, Brown RW, Chamness GC, Osborne CK, McGuire WL (1993) Association of p53 protein expression with tumor cell proliferation rate and clinical outcome in node-negative breast cancer. J Natl Cancer Inst 85(3):200–206PubMedCrossRef
16.
Spring LM, Wander SA, Andre F, Moy B, Turner NC, Bardia A (2020) Cyclin-dependent kinase 4 and 6 inhibitors for hormone receptor-positive breast cancer: past, present, and future. Lancet 395(10226):817–827PubMedCrossRef
17.
Costa C, Wang Y, Ly A, Hosono Y, Murchie E, Walmsley CS, Huynh T, Healy C, Peterson R, Yanase S et al (2020) PTEN Loss Mediates Clinical Cross-Resistance to CDK4/6 and PI3Kalpha Inhibitors in Breast Cancer. Cancer Discov 10(1):72–85PubMedCrossRef
18.
Ellis MJ, Gao F, Dehdashti F, Jeffe DB, Marcom PK, Carey LA, Dickler MN, Silverman P, Fleming GF, Kommareddy A et al (2009) Lower-dose vs high-dose oral estradiol therapy of hormone receptor-positive, aromatase inhibitor-resistant advanced breast cancer: a phase 2 randomized study. JAMA 302(7):774–780PubMedPubMedCentralCrossRef
19.
20.
Peethambaram PP, Ingle JN, Suman VJ, Hartmann LC, Loprinzi CL (1999) Randomized trial of diethylstilbestrol vs. tamoxifen in postmenopausal women with metastatic breast cancer. An updated analysis. Breast Cancer Res Treat 54(2):117–122PubMedCrossRef
21.
Matelski H, Greene R, Huberman M, Lokich J, Zipoli T (1985) Randomized trial of estrogen vs tamoxifen therapy for advanced breast cancer. Am J Clin Oncol 8(2):128–133PubMedCrossRef
22.
Jordan VC (2015) The new biology of estrogen-induced apoptosis applied to treat and prevent breast cancer. Endocr Relat Cancer 22(1):R1–31PubMedCrossRef
23.
Chlebowski RT, Aragaki AK, Anderson GL (2015) Menopausal Hormone Therapy Influence on Breast Cancer Outcomes in the Women's Health Initiative. J Natl Compr Canc Netw 13(7):917–924PubMedCrossRef
24.
Zucchini G, Armstrong AC, Wardley AM, Wilson G, Misra V, Seif M, Ryder WD, Cope J, Blowers E, Howell A et al (2015) A phase II trial of low-dose estradiol in postmenopausal women with advanced breast cancer and acquired resistance to aromatase inhibition. Eur J Cancer 51(18):2725–2731PubMedCrossRef
25.
Coelingh Bennink HJ, Verhoeven C, Dutman AE, Thijssen J (2017) The use of high-dose estrogens for the treatment of breast cancer. Maturitas 95:11–23PubMedCrossRef
26.
Roberts MS, Magnusson BM, Burczynski FJ, Weiss M (2002) Enterohepatic circulation: physiological, pharmacokinetic and clinical implications. Clin Pharmacokinet 41(10):751–790PubMedCrossRef
27.
Davies NM, Takemoto JK, Brocks DR, Yanez JA (2010) Multiple peaking phenomena in pharmacokinetic disposition. Clin Pharmacokinet 49(6):351–377PubMedCrossRef
28.
Ogungbenro K, Pertinez H, Aarons L (2015) Empirical and semi-mechanistic modelling of double-peaked pharmacokinetic profile phenomenon due to gastric emptying. AAPS J 17(1):227–236PubMedCrossRef
29.
Rossi L, Biagioni C, McCartney A, Migliaccio I, Curigliano G, Sanna G, Moretti E, Minisini AM, Cinieri S, Tondini C et al (2019) Clinical outcomes after palbociclib with or without endocrine therapy in postmenopausal women with hormone receptor positive and HER2-negative metastatic breast cancer enrolled in the TREnd trial. Breast Cancer Res 21(1):71PubMedPubMedCentralCrossRef
30.
Lin X, Yu Y, Zhao H, Zhang Y, Manela J, Tonetti DA (2006) Overexpression of PKCalpha is required to impart estradiol inhibition and tamoxifen-resistance in a T47D human breast cancer tumor model. Carcinogenesis 27(8):1538–1546PubMedCrossRef
31.
Wallace JA, Pitarresi JR, Sharma N, Palettas M, Cuitino MC, Sizemore ST, Yu L, Sanderlin A, Rosol TJ, Mehta KD et al (2014) Protein kinase C Beta in the tumor microenvironment promotes mammary tumorigenesis. Front Oncol 4:87PubMedPubMedCentralCrossRef
32.
Ponten F, Jirstrom K, Uhlen M (2008) The Human Protein Atlas–a tool for pathology. J Pathol 216(4):387–393PubMedCrossRef
Metadata
Title
Phase 1 study of TTC-352 in patients with metastatic breast cancer progressing on endocrine and CDK4/6 inhibitor therapy
Authors
Arkadiusz Z. Dudek
Li C. Liu
James H. Fischer
Elizabeth L. Wiley
Jasgit C. Sachdev
Jonathan Bleeker
Randolph W. Hurley
Debra A. Tonetti
Gregory R. J. Thatcher
Robert P. Venuti
Ruth M. O’Regan, MD
Publication date
01-10-2020
Publisher
Springer US
Published in
Breast Cancer Research and Treatment / Issue 3/2020
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI
https://doi.org/10.1007/s10549-020-05787-z

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