Alternative Drug Names:
Paclitaxel (Taxol brand in the US and abroad), Trastuzumab (Herceptin is the brand in the US and abroad), Pertuzumab (Perjeta brand in the US and abroad)
Purpose of Trial:
The purpose of this phase 2 study is to evaluate the effectiveness of the 3 drug combination (Paclitaxel, Trastuzumab and Pertuzumab) in newly diagnosed stage III IBC patients as a component of tri-modal treatment. In addition, research biopsies will be obtained pre-treatment and after the first week of Pertuzumab and Trastuzumab alone to look for biomarkers that may predict the patients who will respond best to this treatment.
Why this study is relevant for IBC patients:
IBC patients currently receive chemotherapy and HER2 targeted therapy (if relevant) prior to surgery to decrease the volume of cancer in the breast and hopefully eradicate any circulating tumor cells. For the 40% of IBC patients who have tumors that overexpress HER2, we know that targeting HER2 in combination with chemotherapy results in synergistic tumor cell kill. Recently we have learned from early breast cancer studies that dual HER2 inhibition results in higher pathological complete response rates than Herceptin alone and we have reason to believe this is true in IBC as well. For this reason in the US, dual HER2 inhibition (using Herceptin and Pertuzumab) has become the standard of care for neoadjuvant chemotherapy that is used in locally advanced and inflammatory breast cancers. This specific trial opened prior to the FDA approval of Pertuzumab in the neoadjuvant setting, so the design is similar to today’s standard of care, with the exception of the possible anthracycline-component being given after surgery, and continuing Pertuzumab along with Herceptin for a total of 1 year, versus stopping Pertuzumab at surgery, which is the ‘approved’ schedule. All in all, a trial design that is similar to the current approved approach.
Paclitaxel is an anti-mitotic chemotherapy that has been approved for breast cancer treatment for many years. There is a known survival benefit to the addition of a taxane such as paclitaxel to anthracycline-containing chemotherapy. Trastuzumab is an antibody that targets HER2, both inhibiting HER2 signaling as well as inducing an immune response to HER2 positive tumor cells. Pertuzumab is another HER2 antibody, but it targets a different site on the HER2 protein than Trastuzumab. It was developed as a dimerization inhibitor, since HER2 must partner with other HER-family proteins (EGFR, HER3 or HER4) to actively signal to downstream growth/survival pathways.
This trial is for newly diagnosed stage 3 HER2-overexpressing IBC patients, regardless of hormone receptor status. No prior treatment is allowed.
This is complicated study in terms of the details (described below), but is not significantly more visits than would be standard of care in IBC. There are 3 phases –
(1) a 1 week run-in period of only HER2 antibodies,
(2) The main pre-operative systemic treatment when you will receive both HER2 drugs plus chemotherapy for 16 weeks, then
(3) Post-surgery (adjuvant) treatments (including radiation) – which will include an optional anthracycline chemo continuation, or radiation and HER2 antibodies to complete the 12 months of Trastuzumab and Pertuzumab.
Prior to the run-in period, there is a mandatory tumor biopsy required for participation in the trial. Then a second breast biopsy is done on day 8 before the next administration of drugs. This second biopsy will be used to understand the immediate responses to HER2 antibody treatment and correlate these with eventual patient outcomes.
All 3 drugs are given by IV administration. The schedule overall is weekly infusions prior to surgery, although not all drugs will be given each time. In the beginning to establish whether you can tolerate these drugs well, the study nurses will be observing you carefully during the first treatments. In week 1 (day 1), you will receive Trastuzumab over 1.5 hours and then 1 hour of observation. After this observation period you will next receive Pertuzumab over 1 hour and observed for an hour after this. If the treatment was well tolerated, the infusions may be shortened in subsequent weeks so that you are not stuck in clinic for 5 or more hours. The next 16 weeks will include infusions of Herceptin and Paclitaxel every week, and Pertuzumab every 3rd week, which will take 2-3 hours in total. Before you receive Paclitaxel, you will receive some pre-medications to reduce the chance of having a reaction to this drug (the solvent is what causes problems in some people).
Study treatment visits will occur at regular intervals during the period of study treatment, beginning on Week 1. During these study treatment visits the following will be done: physical exam, performance status, blood samples, and heart function tests.
After the 16 weeks of chemotherapy and HER2 drugs is complete, you will have repeat imaging and be scheduled for surgery if your breast has now become operable. Surgery will be 4-5 weeks after the last chemo. If more than 3 weeks has passed, then you will receive another infusion of Trastuzumab and Pertuzumab.
After surgery, based on your response, and other risk factors, your doctor will decide whether to give you more standard chemotherapy (adriamycin and cyclophosphamide – known as “AC”) or allow you to move directly onto radiation 4-5 weeks after surgery. If you have to receive AC, you will receive 4 cycles of both drugs every 2 or 3 weeks. Adriamycin is given by IV in 5-10 minutes and cyclophosphamide is given by IV in 30 minutes. AC is not combined with Trastuzumab and Pertuzumab concurrently due to the risk for heart damage, but you will continue the antibodies after the completion of AC, complete a total of 12 months of Trastuzumab and Pertuzumab
After completion of the active treatment, the investigators plan to follow yous for up to 13 years after the start of teh study. During these visits the following will be done: physical exam and questions about your health/medications you have taken (every 3 months for the first year, every 6 months for the next 4 years, yearly until the end of study follow up); blood draws (every 6 months for the first 4 years, yearly after that); mammograms will be performed annually, other scans may be performed as needed. The purpose of these follow ups is to make sure you are doing well (i.e. have no signs of recurrence), and document any long term side effects as a result of the treatments.
Location of Trial:
2 locations – Dana Farber Cancer Institute and Brigham and Women’s Hospital, both in Boston, MA.
For more information:
Is this study NCI Compliant?:
NCT trial number & link:
NCT# 01796197 – click for more info.
Poster from scientific meeting: