Clinical trial NCT01796197: Paclitaxel + Trastuzumab + Pertuzumab as Pre-Op for Inflammatory BrCa
Official title: Phase II Trial of Paclitaxel Combined With Trastuzumab and Pertuzumab as Pre-Operative Therapy for Inflammatory Breast Cancer
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Breast Cancer
Lead sponsor: Dana-Farber Cancer Institute
Sponsor class: OTHER
First posted: 2013-02-21
Enrollment: 23
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This research study is a Phase II clinical trial, which tests the safety and effectiveness of an investigational drug to learn whether the drug works in treating a specific cancer. In this study, paclitaxel and trastuzumab are being combined with pertuzumab which is "investigational" for the preoperative treatment of inflammatory breast cancer. Trastuzumab is given for a total of 12 months for the treatment of HER2 positive breast cancer. This study also adds pertuzumab to trastuzumab so that both drugs are given for a total of 12 months; this combination is also "investigational".

"Investigational" means that pertuzumab is being studied. It also means that although the FDA has approved pertuzumab for preoperative use to treat breast cancer, it has not been thoroughly studied in combination with paclitaxel and trastuzumab for preoperative treatment of inflammatory breast cancer. It has been FDA approved for specific use in advanced breast cancer that is HER2 positive.

Pertuzumab is an antibody, which is a protein that attacks a foreign substance is the body. Pertuzumab blocks the function of the HER2 protein like trastuzumab does. However, pertuzumab binds to a different part of the HER2 receptor and stops cancer cells from growing. This drug has been used in the treatment of advanced breast cancer that is HER2 positive, and has been combined with trastuzumab and chemotherapy in those studies. Information from those other research studies suggests that pertuzumab may help to kill the cancer cells in the breast and enable you to undergo a mastectomy. The addition of pertuzumab may also help reduce the chance of cancer recurrence.

In this research study, we are combining pertuzumab with paclitaxel and trastuzumab as preoperative therapy and will determine the response of the cancer remaining in the breast at the time of mastectomy. In addition, we are combining trastuzumab with pertuzumab for a total of 12 months and we are looking to see whether the combination reduces the chance that the cancer will return.

Another goal of this research study is to determine whether we can develop a way to identify tumors that will respond well to this study treatment. We will do research tests on your tumor tissue before, during and after study treatment. These tests may help doctors understand how the study treatment may work to treat your type of breast cancer. In the future, these tests may help us find ways to help match patients with the drugs most likely to work against their specific tumors before treatment begins.

Detailed description: If you agree to take part in this study we will ask you to undergo some screening tests and procedures to confirm that you are eligible. Many of these tests and procedures are likely to be part of regular cancer care and may be done even if it turns out that you do not take part in the research study. If you have had some of these tests or procedures recently, they may or may not have to be repeated. The screening process will include the following: a medical history, performance status, physical examination, scans and x-rays, blood samples, blood pregnancy test, electrocardiogram, echocardiogram. If these tests show that you are eligible to participate in the research study, you will begin the study treatment. If you do not meet the eligibility criteria you will not be able to participate in this research study.

Before beginning study treatment you will undergo a tumor biopsy and have photographs of your tumor taken to assess the response of your tumor to the study treatment.

On the first day of study treatment (Week 1, Day 1) with trastuzumab and pertuzumab, you will receive an intravenous infusion of trastuzumab over about 90 minutes, followed by a 60 minutes observation period. If the trastuzumab infusion is tolerated, you will receive the rest of your study treatment, the pertuzumab. This will also be given as an intravenous infusion over about 60 minutes with you being observed for a further 60 minutes. Thus, the total duration of infusion and observation periods for the first dose of study treatment (Week 1, Day 1) is about 5 hours. If the drugs are well tolerated at Week 1, the duration of the infusion with trastuzumab and pertuzumab may be shortened for subsequent doses.

Prior to starting Week 2, you will undergo a second research biopsy of your breast. The biopsy will be performed either prior to Week 2, Day 8 or on the same day. You will then receive an infusion of trastuzumab and begin chemotherapy. If the infusion of trastuzumab was tolerated on Week 1, Day 1, then the infusion time is reduced to about 30 minutes. You will then be pre-medicated with drugs to reduce the chance of having a sensitivity reaction to paclitaxel. This takes approximately 30 minutes. The paclitaxel is give by intravenous infusion over about 60 minutes. If you tolerate the paclitaxel infusions, then the pre-medication can be changed by your doctor.

The pertuzumab is given every 3 weeks beginning on Week 1 and continues until paclitaxel administration is complete. Trastuzumab is given weekly beginning on Week 1 and continues until paclitaxel administration is complete. Paclitaxel is given weekly for a total of 16 doses beginning on Week 2. After completing 16 doses of paclitaxel, trastuzumab and pertuzumab may be continued every 3 weeks until surgery.

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, heart function tests.

After completing 16 doses of paclitaxel in combination with pertuzumab and trastuzumab, you will undergo surgery for removal of your breast cancer. This will occur approximately 4-5 weeks after your last paclitaxel infusion. Prior to surgery, you will have the following assessments: a repeat breast MRI, PET scan (if necessary), physical exam, vital signs, performance status, blood tests, tumor tissue tests.

Approximately 4-5 weeks after surgery, when you are well-healed, you will have two options for treatment (at your physician's discretion):

Option 1: Doxorubicin and cyclophosphamide (AC), every 2-3 weeks x 4 cycles. This is standard chemotherapy for IBC. Followed by trastuzumab and pertuzumab every 3 weeks to complete 12 months of HER2-directed therapy.

Option 2: Continue trastuzumab and pertuzumab every 3 weeks to complete 12 months of HER2-directed therapy.

Doxorubicin is given by vein over about 5-10 minutes. This is followed by cyclophosphamide by vein given about 30 minutes. Anti-nausea medicine is given first under the direction of your doctor.

Approximately 4-5 weeks after finishing the AC treatment if you pursue Option 1 (or 4-5 weeks after surgery if you pursue Option 2), you will receive radiation therapy to the mastectomy site and the surrounding lymph nodes. This will be given daily, Monday through Friday for approximately 6-7 weeks. This will be administered as standard of care for IBC.

Approximately 3-4 weeks following the completion of AC if you pursue Option 1 (or 3-4 weeks after surgery if you pursue Option 2), you will begin maintenance therapy with trastuzumab and pertuzumab. As with Week 1, Day 1, you will receive an intravenous infusion of trastuzumab over about 90 minutes followed by a 60 minute observation period. If the trastuzumab infusion is tolerated, you will receive the rest of your study treatment, the pertuzumab. This will also be given as an intravenous infusion over about 60 minutes with your being observed for a further 60 minutes. Thus, the total duration of infusion and observation periods for the first day of maintenance study treatment is about 5 hours. If the study drugs are well tolerated, the duration of the infusion with trastuzumab and pertuzumab may be shortened for subsequent doses. Both trastuzumab and pertuzumab will be given every 3 weeks to complete a 12 month duration of HER2-directed therapy. Every 9 weeks (every third dose of trastuzumab and pertuzumab) you will undergo the same procedure as taht described above in Study Treatment visits.

About one month after your last dose of study treatment, you will be asked to return to the clinic. At this visit tests will be done to check your physical condition and to check that you have recovered from any side effects of study treatment. During this visit the following will be done: physical exam, vital signs, performance status and blood tests.

You will be asked to attend regular follow up visits to check if you are experiencing any long term side effects and to check taht the cancer has not come back. We plan to follow participants 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.

Eligibility criteria: Inclusion Criteria:

* Histologically confirmed invasive breast cancer
* HER2 positive breast cancer
* Clinical diagnosis of inflammatory breast cancer
* Without evidence of visceral or bone involvement with metastatic cancer on physical exam or any diagnostic study. Extensive nodal involvement is allowed
* Willingness to undergo a research biopsy of the affected breast

Exclusion Criteria:

* Prior therapy for the treatment of breast cancer
* Receiving any other investigational or commercial agents or therapies
* Known brain metastases
* Symptomatic intrinsic lung disease or extensive tumor involvement of the lungs resulting in dyspnea at rest
* History of allergic reactions attributed to compounds of similar chemical or biologic composition to paclitaxel, trastuzumab, pertuzumab
* Uncontrolled intercurrent illness
* Pregnant or breastfeeding
* History of a different malignancy except for the following circumstances: disease-free for at least 5 years and at low risk of recurrence, or cervical cancer in situ or basal or squamous cell carcinoma of the skin
* HIV positive on combination anti-retroviral therapy

Primary outcomes:
measure: Percentages of Participants With Pathologic Complete Response
timeFrame: 18 weeks
measure: Residual Cancer Burden Rate
timeFrame: 18 Weeks
Secondary outcomes:
measure: Number of Participants With Congestive Heart Failure
timeFrame: 1 year and 8 months
measure: Median Disease Free Survival
timeFrame: 63 months
measure: Median Time to Treatment Failure
timeFrame: 63 months
measure: Median Overall Survival
timeFrame: 63 months
measure: Pathological Complete Response Rate by Intrinsic Subtype
timeFrame: 18 Weeks
measure: Residual Disease Rate by Intrinsic Subtype
timeFrame: 18 Weeks
measure: Predictive Accuracy Rate of Pre-Treatment Versus On-Treatment Tumor Biopsy RNA Sequencing Profiles
timeFrame: 18 Weeks
measure: Residual Cancer Burden Rate by ctDNA Profile Change
timeFrame: 18 weeks
Other outcomes:
Locations:
city: Boston
country: United States
facility: Brigham and Women's Hospital
state: Massachusetts
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
Study officials:
affiliation: Dana-Farber Cancer Institute
name: Filipa Lynce, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Pernas S, Guerriero JL, Naumenko S, Goel S, Regan MM, Hu J, Harrison BT, Lynce F, Lin NU, Partridge A, Morikawa A, Hutchinson J, Mittendorf EA, Sokolov A, Overmoyer B. Early on-treatment transcriptional profiling as a tool for improving pathological response prediction in HER2-positive inflammatory breast cancer. Ther Adv Med Oncol. 2022 Jul 30;14:17588359221113269. doi: 10.1177/17588359221113269. eCollection 2022.