TBCRC 008: A Multi-Institutional Double-Blind Phase II Study Evaluating Response and Measurable Outcome to Carboplatin and nab-Paclitaxel (CP) With or Without Vorinostat as Preoperative Chemotherapy in HER2-negative Primary Operable Breast Cancer

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Purpose of the Study: 

Cancer may develop due to changes in an individuals' genetic make-up (DNA). Recent research indicates that certain chemical changes that occur at the sites where genes are switched on or off may also lead to cancer development and growth. New drugs, which specifically target these “epigenetic” alterations, include the histone deacetylase (HDAC) inhibitors (e.g. vorinostat). We conducted this multicenter randomized phase II trial of carboplatin and nanoparticle albumin-bound paclitaxel with vorinostat or placebo in women with stage II/III HER2-negative breast cancer to evaluate whether adding vorinostat to chemotherapy could help the chemotherapy to be more effective.

Sponsor: 

Specialized Program of Research Excellence in Breast Cancer (P50 CA88843), NCI Quantitative Imaging Network (QIN) contract (5U01CA140204), Imaging Response Assessment Core Lab (3 P30 CA006973), Abraxis Bioscience, Merck & Co, Inc., the Translational Breast Cancer Research Consortium (TBCRC) and the Cindy Rosencrans Fund for Triple Negative Breast Cancer Research. Vorinostat and placebo were supplied by Merck & Co, Inc. Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) was supplied by Abraxis Bioscience (Celgene Corporation). Support was also provided by QVC and Fashion Footwear Association of New York (FFANY).

Participating Sites: 
  • Johns Hopkins University
  • Mayo Clinic Cancer Center
  • Indiana University
  • University of Alabama at Birmingham
  • Anne Arundel Medical Center
Start Date & Stop Date: 

Date First Site Activated: May, 2008

Date Trial Closed to Accrual: November, 2011

Key Eligibility Requirements: 
  • Women >18
  • Histologically confirmed invasive breast cancer
  • Clinically measurable disease
  • Stage II or III
  • Grade 2 or 3 (infiltrating lobular not allowed)
  • Eastern Cooperative Oncology Group (ECOG) scale of performance status 0-2
  • Adequate hematological, renal, hepatic function
Study Design: 
  • Clinical trial of carboplatin and nab-paclitaxel chemotherapy with or without vorinostat, administered before surgery to women with stage II and III breast cancer
  • Double-blind phase II study with a 1:1 randomization (selected in a random order)
  • Stratification by hormone receptor status
  • Sample size: 31 patients per arm
Results: 
  • Sixty-two women enrolled at 5 centers nationally with the support of the Translational Breast Cancer Research Consortium (TBCRC).
  • The number of patients experiencing complete disappearance of their tumor at the time of surgery (pathologic complete response) was similar in both arms of the study (vorinostat 25.8%, placebo 29.0%).
  • An association was found between metabolic changes (sugar uptake) on the PET scan, and pathologic complete response. This metabolic change may predict which patients are more or less likely to benefit from chemotherapy pre surgery.
  • Future studies will assess whether these changes observed on the PET scan can help with early treatment decisions for breast cancer patients.
  • No significant differences in changes of the rate of tumor growth were observed between the two groups in changes.
Next Steps: 

The initial study results have been published in the Journal of Nuclear Medicine. Publication of these results will provide valuable information for other breast cancer researchers as they develop new studies with chemotherapy and new treatment approaches for patients with breast cancer.

We are completing additional correlative studies that can help set the stage for new studies to examine new biomarkers that may predict optimal response to the therapy.

Scientific Publications Available for this Clinical Trial: 

Connolly, R.M., Jeter, S., Zorzi, J.,  Zhang, Z.,  Armstrong, D.K.,  Fetting, J.H., Wolff, A.C., Goetz, M.P.,  Storniolo, A.M., Stearns, V. A multi-institutional double-blind phase II study evaluating response and surrogate biomarkers to carboplatin and nab-paclitaxel (CP) with or without vorinostat as preoperative systemic therapy (PST) in HER2-negative primary operable breast cancer (TBCRC008). 2010 ASCO, Trials in Progress Poster, Abstract #TPS111.

Connolly, R.M., Leal, J.P., Goetz, M.P., Zhang, Z., Zhou, X.C., Mhlanga, J., Jeter, S.C., Walsh, B., Powers, P., Zorzi, J., Carpenter, J., Storniolo, A.M., Watkins, S., Fetting, J., Miller, R., Sideras, K., Khouri, N., Gabrielson, E., Wahl, R.L., Stearns, V. Early change in 18-fluorodeoxyglucose (FDG) uptake on positron emission tomography (PET) predicts response to preoperative systemic therapy (PST) in HER2-negative primary operable breast cancer: Translational Breast Cancer Research Consortium (TBCRC008). 2012 ASCO, Poster Discussion, Abstract #10509.

Connolly, R.M., Leal, J.P., Goetz, M.P., Zhang, Z., Zhou, X.C., Jacobs, L.A., Mhlanga, J., Carpenter, J., Storniolo, A.M., Watkins, S., Fetting, J., Miller, R., Sideras, K., Jeter, S.C., Walsh, B., Powers, P., Zorzi, J., Davidson, N.E., Carey, L.A., Wolff, A.C., Khouri, N., Gabrielson, E., Wahl, R.L., Stearns, V. TBCRC 008: Randomized Phase II Study Evaluating Response and Treatment-Selection Biomarkers to Preoperative Carboplatin and Nanoparticle Albumin-bound Paclitaxel with or without Vorinostat in HER2-negative Primary Operable Breast Cancer. J Nucl Med 56(1): 2015.

Connolly, R.M., Elkin, E.P., Timms, K., Goetz, M.P., Zhang, Z., Walsh, B., Carpenter, J., Storniolo, A.M., Watkins, S., Gabrielson, E., Hartman, A.R., Stearns, V. Homologous recombination deficiency (HRD) as a predictive biomarker of response to preoperative systemic therapy (PST) in TBCRC 008 comprising a platinum in HER2-negative primary operable breast cancer. 2015 SABCS, Poster.

Link to the NCI Summary: 

NCT00616967

 *This summary was reviewed by: Roisin Connolly, M.B., B.Ch. It was also reviewed and approved by the members of the TBCRC Patient Advocate Working Group.