Journal article

A Phase Ib Dose-Escalation and Expansion Study of the BCL2 Inhibitor Venetoclax Combined with Tamoxifen in ER and BCL2-Positive Metastatic Breast Cancer

Sheau W Lok, James R Whittle, Francois Vaillant, Charis E Teh, Louisa L Lo, Antonia N Policheni, Alice RT Bergin, Jayesh Desai, Sarah Ftouni, Luke C Gandolfo, Danny Liew, He K Liu, G Bruce Mann, Kate Moodie, Anand Murugasu, Bhupinder Pal, Andrew W Roberts, Mark A Rosenthal, Kylie Shackleton, Maria Joao Silva Show all



Venetoclax, a potent and selective BCL2 inhibitor, synergizes with endocrine therapy in preclinical models of ER-positive breast cancer. Using a phase Ib 3 + 3 dose-escalation and expansion study design, 33 patients with ER and BCL2-positive metastatic disease (mean prior regimens, 2; range, 0-8) were treated with daily tamoxifen (20 mg) and venetoclax (200-800 mg). Apart from uncomplicated "on-target" lymphopenia, no dose-limiting toxicities or high-grade adverse events were observed in the escalation phase (15 patients), and 800 mg was selected as the recommended phase II dose (RP2D). In the expansion phase (18 patients), few high-grade treatment-related adverse events were observed. For 2..

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Awarded by National Health and Medical Research Council, Australia (NHMRC)

Awarded by Victorian State Government through Victorian Cancer Agency

Awarded by National Breast Cancer Foundation (NBCF)

Awarded by NHMRC Peter Doherty Early Career Fellowship

Awarded by NHMRC Career Development Fellowship

Awarded by Victorian Cancer Agency Early Career Seed Grant

Awarded by NHMRC Project Grant

Awarded by NHMRC Research Fellowships

Funding Acknowledgements

The authors would like to thank the patients who participated in this study, as well as their referring doctors. We are grateful to P. Sherman and J. Hicks for expert assistance in helping to conduct the study; M. Bisignano in the Department of Anatomical Pathology, Royal Melbourne Hospital, for assistance; staff at the Royal Melbourne Hospital Tissue Bank for support; V. Bryant, J. Tempany, L. Beaton, and I. Wicks for assistance with the immune phenotyping; L. Whitehead for assistance with imaging and computation, and L. Garrett for providing independent data monitoring oversight for the study. We thank J. Leverson, M. Mabry, L. Unicombe, V. Komlosi, M. Mobasher, S. Rafii, D. Sampath, M.A. Anderson, and O. Kondrashova for helpful discussions. Coded breast tumor samples were provided by the Victorian Cancer Biobank (which is supported by the Victorian Government). This work was supported by AbbVie and Roche/Genentech, the National Health and Medical Research Council, Australia (NHMRC; 1016701, 1040978, 1054618, 1078763, and 1113133); NHMRC IRIISS; the Victorian State Government through Victorian Cancer Agency funding (TRP13041) and Operational Infrastructure Support; the Australian Cancer Research Foundation; The National Breast Cancer Foundation (NBCF; NT-13-06); The Qualtrough Cancer Research Fund; and The Joan Marshall Breast Cancer Research Fund. J.R. Whittle was supported by an NHMRC/NBCF Research Fellowship and the Royal Australasian College of Physicians; C.E. Teh by an NHMRC Peter Doherty Early Career Fellowship (1089072); A.N. Policheni by a Cancer Council Victoria Postdoctoral Research Fellowship; S.-J. Dawson by a CSL Centenary Fellowship; D.H.D. Gray by an NHMRC Career Development Fellowship (1090236); B. Pal by a Victorian Cancer Agency Early Career Seed Grant (13-035) and NHMRC Project Grant (1100807). NHMRC Research Fellowships have been awarded to G.K. Smyth (1058892), J.E. Visvader (1037230), and G.J. Lindeman (1078730).