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Paclitaxel + Trastuzumab + Pertuzumab as Pre-Op for Inflammatory BrCa

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01796197
Recruitment Status : Active, not recruiting
First Posted : February 21, 2013
Results First Posted : September 5, 2021
Last Update Posted : May 19, 2022
Sponsor:
Information provided by (Responsible Party):
Filipa Lynce, MD, Dana-Farber Cancer Institute

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.


Condition or disease Intervention/treatment Phase
Breast Cancer Drug: Trastuzumab Drug: Pertuzumab Drug: Paclitaxel Drug: Doxorubicin Drug: Cyclophosphamide Procedure: Mastectomy Radiation: Radiation Therapy Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 23 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase II Trial of Paclitaxel Combined With Trastuzumab and Pertuzumab as Pre-Operative Therapy for Inflammatory Breast Cancer
Actual Study Start Date : August 2013
Actual Primary Completion Date : June 2018
Estimated Study Completion Date : March 2023


Arm Intervention/treatment
Experimental: Treatment Arm

Run in: Trastuzumab IV 4 mg/kg, Pertuzumab IV 840 mg (Day 1 Week 1)

Pre-Op:

Trastuzumab IV 2 mg/kg weekly, Paclitaxel 80 mg/m2 IV weekly (beginning on Day 8 Week 2) x 16 doses.

Starting Day 21 (week 4) continue trastuzumab and paclitaxel as above, add Pertuzumab 420 mg IV x 3 weeks. After completing 16 doses of Paclitaxel, Trastuzumab (6 mg/kg IV) and Pertuzumab 420 mg IV may be continued x 3 weeks until surgery Modified Radical Mastectomy

Post-Op:

Option 1: Adriamycin 60 mg/m2 IV and Cyclophosphamide 600 mg/m2 IV x 2-3 weeks x 4 cycles. Followed by Trastuzumab 8 mg/kg and Pertuzumab 840 IV load; followed by Trastuzumab 6 mg/kg every and Pertuzumab 420 mg IV every 3 weeks to complete 12 months of HER2-directed therapy Option 2: Continue Trastuzumab 6 mg/kg and Pertuzumab 420 mg x 3 weeks to complete 12 months of HER2-directed therapy Post-mastectomy radiation to the chest wall / regional lymph nodes and endocrine therapy by standard of care.

Drug: Trastuzumab
Drug: Pertuzumab
Drug: Paclitaxel
Drug: Doxorubicin
Drug: Cyclophosphamide
Procedure: Mastectomy
Radiation: Radiation Therapy



Primary Outcome Measures :
  1. Percentages of Participants With Pathologic Complete Response [ Time Frame: 18 weeks ]
    Pathologic complete response (pCR) is defined as absence of invasive carcinoma within the breast and axillary lymph nodes following preoperative treatment. Participants whose disease is not surgically resectable following preoperative treatment are considered as not having pCR.

  2. Residual Cancer Burden Rate [ Time Frame: 18 Weeks ]

    Residual cancer burden is calculated an then categorized based on the methods described in the following: Symmans WF, Peintinger F, Hatzis C, et al. Measurement of residual breast cancer burden to predict survival after neoadjuvant chemotherapy. J Clin Oncol 2007;25(28): 4414-22.

    This method uses tumor size, the proportion of that tumor that is invasive carcinoma, the number of axillary lymph nodes containing metastatic carcinoma and the diameter of the largest metastasis in an axillary lymph node. These parameters are combined in a formula that outputs a RCB index. This index is divided into 4 categories: RCB-0, RCB-I, RCB-II, and RCB-III. The previous categories are in order of increasing severity of RCB.



Secondary Outcome Measures :
  1. Number of Participants With Congestive Heart Failure [ Time Frame: 1 year and 8 months ]
    Number of participants with clinically significant congestive heart failure (CHF) as determined by established medical practices.

  2. Median Disease Free Survival [ Time Frame: 63 months ]
    Disease-free survival (DFS) is defined for the participants who undergo surgery, as the duration of time from surgery until ipsilateral local-regional, contralateral or distant invasive recurrence or death from any cause; in the absence of an event, DFS will be censored at the date last know alive and free from recurrence.

  3. Median Time to Treatment Failure [ Time Frame: 63 months ]
    Time to treatment failure (TTF) will be defined among all participants, as the duration of time from treatment initiation to a DFS event or progressive disease during preoperative therapy or treatment disease that is not surgically resectable; in the absence of an event, TTF will be censored at the date last know alive and free from recurrence or progression.

  4. Median Overall Survival [ Time Frame: 63 months ]
    Overall survival (OS) will be defined among all participants, as the duration of time from treatment initiation to death from any cause, or is censored at date last known alive. Post-surgery OS will be defined among the participants who undergo surgery, as the duration of time from treatment initiation to death from any cause, or is censored at date last known alive.

  5. Pathological Complete Response Rate by Intrinsic Subtype [ Time Frame: 18 Weeks ]

    Pathologic complete response (pCR) is defined as absence of invasive carcinoma within the breast and axillary lymph nodes following preoperative treatment. Participants whose disease is not surgically resectable following preoperative treatment are considered as not having pCR. PAM50 analysis was performed on the biopsy specimen taken on day 1.

    Participants' pCR was tabulated according to the intrinsic subtype and the association of intrinsic subtype (Estrogen receptor 2 - enriched vs. other) with pCR was assessed using Fisher's exact test.


  6. Residual Disease Rate by Intrinsic Subtype [ Time Frame: 18 Weeks ]
    Residual Disease Rate is the percentage of participants who do not achieve Pathologic complete response (pCR) by the end of preoperative treatment. pCR is defined as absence of invasive carcinoma within the breast and axillary lymph nodes following preoperative treatment. Residual disease within the breast at time of mastectomy was assessed by microarray analysis. Residual disease rate was reported by intrinsic subtype identified using day 1 RNAseq analysis.

  7. Predictive Accuracy Rate of Pre-Treatment Versus On-Treatment Tumor Biopsy RNA Sequencing Profiles [ Time Frame: 18 Weeks ]
    Tumor RNA expression from pre-treatment (Day 1) and on-treatment (Day 8) biopsies were evaluated to see if the expression profiles had predictive accuracy of pCR. pCR is defined as absence of invasive carcinoma within the breast and axillary lymph nodes following preoperative treatment. Participants whose disease is not surgically resectable following preoperative treatment are considered as not having pCR. The biopsies were analyzed by differential expression analysis using standard procedures in R package, limma. A predictive Random Forest model was trained using leave-pair-out-cross-validation with the 80 genes most associated with pCR and/or non-pCR. This model gives an accuracy rate, which indicates the percentage of time that the gene profile predicts pCR or non-pCR for both the pre-treatment and on-treatment profiles. An increase in accuracy for the on-treatment profile would indicate an adaptive response within the tumor associated with resistance to HER2 directed therapies.

  8. Residual Cancer Burden Rate by ctDNA Profile Change [ Time Frame: 18 weeks ]

    Residual cancer burden is calculated an then categorized based on the methods described in the following: Symmans WF, Peintinger F, Hatzis C, et al. Measurement of residual breast cancer burden to predict survival after neoadjuvant chemotherapy. J Clin Oncol 2007;25(28): 4414-22.

    This method uses tumor size, the proportion of that tumor that is invasive carcinoma, the number of axillary lymph nodes containing metastatic carcinoma and the diameter of the largest metastasis in an axillary lymph node. These parameters are combined in a formula that outputs a RCB index. This index is divided into 4 categories: RCB-0, RCB-I, RCB-II, and RCB-III. The previous categories are in order of increasing severity of RCB.

    Biopsy/blood will be collected on day 1 and day 8 of therapy for analysis of circulating biomarkers, including ctDNA.

    Associations between change in ctDNA during therapy and residual cancer burden at the time of definitive surgery will be evaluated.




Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01796197


Locations
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United States, Massachusetts
Brigham and Women's Hospital
Boston, Massachusetts, United States, 02215
Dana-Farber Cancer Institute
Boston, Massachusetts, United States, 02215
United States, Michigan
University of Michigan
Ann Arbor, Michigan, United States, 48109
Sponsors and Collaborators
Dana-Farber Cancer Institute
Investigators
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Principal Investigator: Beth Overmoyer, MD Dana-Farber Cancer Institute
  Study Documents (Full-Text)

Documents provided by Filipa Lynce, MD, Dana-Farber Cancer Institute:
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Responsible Party: Filipa Lynce, MD, Prinicipal Investigator, Dana-Farber Cancer Institute
ClinicalTrials.gov Identifier: NCT01796197    
Other Study ID Numbers: 12-497
First Posted: February 21, 2013    Key Record Dates
Results First Posted: September 5, 2021
Last Update Posted: May 19, 2022
Last Verified: May 2022
Additional relevant MeSH terms:
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Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Paclitaxel
Cyclophosphamide
Doxorubicin
Trastuzumab
Pertuzumab
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Myeloablative Agonists
Antibiotics, Antineoplastic
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Antineoplastic Agents, Immunological