Phase II Study of Eribulin Mesylate, Trastuzumab, and Pertuzumab in Women With Metastatic, Unresectable Locally Advanced, or Locally Recurrent HER2-Positive Breast Cancer

This study is currently recruiting participants. (see Contacts and Locations)
Verified December 2013 by Dana-Farber Cancer Institute
Sponsor:
Collaborators:
Eisai Inc.
Genentech
Information provided by (Responsible Party):
Rachel Freedman, Dana-Farber Cancer Institute
ClinicalTrials.gov Identifier:
NCT01912963
First received: July 24, 2013
Last updated: July 6, 2014
Last verified: December 2013
  Purpose

In this study, the investigators are testing the effectiveness of the combination of eribulin, pertuzumab and trastuzumab to learn whether this combination of drugs works in treating advanced HER2-positive breast cancer that had received at least one prior treatment previously. At this point, the standard treatment for HER2-positive cancer that has progressed (grown) after a first treatment is chemotherapy combined with therapies that target the HER2 protein (e.g., trastuzumab or lapatinib).

All of the medications that are being tested in this study are approved by the Food and Drug administration (FDA) for the treatment of metastatic breast cancer. However, the combination of these three medications in participants has not yet been tested. Eribulin is a chemotherapy agent that is approved for the treatment of metastatic breast cancer for women who have previously received at least two prior chemotherapeutic regimens for the treatment of their metastatic disease. Pertuzumab and trastuzumab are also both approved for the treatment of advanced HER2-positive breast cancer. Both agents help treat breast cancer by binding HER2 receptor. However, pertuzumab and trastuzumab bind to different parts of the HER2 receptor.

The goal of this research study is to find out if adding pertuzumab, trastuzumab and eribulin is effective in treating women with metastatic, HER2-positive breast cancer. The Investigators, will also gather more information on the side effects of these treatments

The investigators also plan to gather genetic information from participants' tumors (collected at biopsies). Cancers occur when the molecules that control normal cell growth (genes and proteins) are altered. Changes in the tumor genes and in the genes of normal cells are called "alterations." Many of these alterations can be detected by directly examining cancer cells in a tumor or circulating in blood. Several alterations that occur repeatedly in certain types of cancers have already been identified. These discoveries have led to the development of new drugs that "target" those alterations. More remain to be discovered.

Some of the alterations are found in genes. Genes are composed of DNA "letters," which contain the instructions that tell the cells in our bodies how to grow and work. Genes make proteins which actually carry out the instructions in our cells.

The investigator would like to use your DNA to look for alterations in the genes in cancer cells and blood cells using a technology called "sequencing." Gene sequencing is a way of reading the DNA to identify errors in genes that may contribute to the behavior of cells. Some changes in genes occur only in cancer cells. Others occur in normal cells as well, in the genes that may have been passed from parent to child. This research study will examine both kinds of genes.

One of the scientific goals of this research study is to perform gene sequencing (gene tests) on your cancer cells (obtained from biopsies or surgery) and normal tissues (usually blood). The results of the gene tests will be used to try to develop better ways to treat and prevent cancers. As part of this work, we may also learn things about the genes in your normal cells. However, because interpretation of these tests will require further study,the investigator will not disclose these results to participants who participate on this component of the study.


Condition Intervention Phase
HER-2 Positive Breast Cancer
Drug: Pertuzumab, Trastuzumab and Eribulin
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase II Study of Eribulin Mesylate in Combination With Trastuzumab and Pertuzumab in Women With Metastatic, Unresectable Locally Advanced, or Locally Recurrent Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer

Resource links provided by NLM:


Further study details as provided by Dana-Farber Cancer Institute:

Primary Outcome Measures:
  • Safety and tolerability of the combination regimen [ Time Frame: 2 Years ] [ Designated as safety issue: Yes ]
    Determine if the combination of eribulin mesylate, perutuzmab, and trastuzumab can be administered with 1.4 or 1.1 mg/m2 of eribulin mesylate

  • Efficacy of treatment regimen [ Time Frame: 2 Years ] [ Designated as safety issue: No ]
    Evaluate the anti-tumor activity of the combination therapy by objective response rate (ORR). Objective response rate (ORR) is defined as complete response (CR) or partial response (PR) by RECIST 1.1 criteria


Secondary Outcome Measures:
  • Clinical benefit rate (CBR) [ Time Frame: 2 years ] [ Designated as safety issue: No ]
    To describe clinical benefit rate (CBR), defined as CR, PR and stable disease (SD) ≥ 6 months by RECIST 1.1 criteria.

  • Progression-free survival (PFS) [ Time Frame: 2 Years ] [ Designated as safety issue: No ]
    defined as the time from the date of the first dose of study treatment until the date of first documentation of progressive disease (PD) or death from any cause (whichever occurs first).

  • overall survival (OS) [ Time Frame: 2 Years ] [ Designated as safety issue: No ]
    defined as the time from the date of the first dose of study treatment until the date of death from any cause.


Other Outcome Measures:
  • Explore mechanisms of benefit and resistance of HER2-directed therapy: [ Time Frame: 2 Years ] [ Designated as safety issue: No ]
    • describe the frequency of acquiring MET (Hepatocyte growth factor receptor) amplification in circulating tumor cells (CTCs) at the time of disease progression
    • describe the association between whole exome sequencing and copy number findings and clinical outcomes (ORR, CBR, PFS and OS)

  • Compare whole exome sequencing and copy number findings between primary and metastatic tumors [ Time Frame: 2 Years ] [ Designated as safety issue: No ]
  • Compare whole exome sequencing and copy number findings between pre-treatment and resistant tumors. [ Time Frame: 2 Years ] [ Designated as safety issue: No ]

Estimated Enrollment: 68
Study Start Date: August 2013
Estimated Study Completion Date: January 2021
Estimated Primary Completion Date: May 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Pertuzumab, Trastuzumab and Eribulin
To evaluate the activity of trastuzumab and pertuzumab in combination with eribulin mesylate in women with metastatic or locally recurrent HER2-positive breast cancer that are refractory to trastuzumab-containing regimens.There will be a safety run-in prior to the start of the Phase II study. Each study treatment cycle lasts 21 days (3 weeks). The patient will receive eribulin on the first day (day 1) and on the 8th day (day 8) of the cycle. The patient will also receive trastuzumab and pertuzumab on day 1. All drugs will be given to the patient intravenously in clinic. The dose of pertuzumab and trastuzumab will be the same for everyone on study, and will be the standard approved dose for each of these medications.
Drug: Pertuzumab, Trastuzumab and Eribulin

Each study treatment cycle lasts 21 days. The patient will receive eribulin on the first day (day 1) and on the 8th day (day 8) of the cycle. The patient will also receive trastuzumab and pertuzumab on day 1. All drugs will be given to intravenously in clinic.

In the first portion of the study, we will examine which dose of eribulin is the safest when given in combination with pertuzumab and trastuzumab. For the first 6 participants enrolled onto the study, we will be look to see if the standard dose of eribulin can be administered safely with standard doses pertuzumab and trastuzumab. If this dose of eribulin is not tolerated well, we will test the three-medication combination with a lower dose of eribulin. The highest dose that will be found to be safe will be used in the next participants. The dose you receive will depend on the number of participants who have been enrolled in the study before you and how well they have tolerated their doses.


  Hide Detailed Description

Detailed Description:

Each study treatment cycle lasts 21 days (3 weeks). The patients will receive eribulin on the first day (day 1) and on the 8th day (day 8) of the cycle. The patients will also receive trastuzumab and pertuzumab on day 1. All drugs will be given intravenously.

The dose of pertuzumab and trastuzumab will be the same for all patients on study, and will be the standard approved dose for each of these medications.

In the first portion of the study, the investigators will examine which dose of eribulin is the safest when given in combination with pertuzumab and trastuzumab. For the first 6 participants enrolled onto the study,the investigators will be looking to see if the standard dose of eribulin can be administered safely with standard doses pertuzumab and trastuzumab. If this dose of eribulin is not tolerated well, the investigator will test the three-medication combination with a lower dose of eribulin. The highest dose that will be found to be safe will be used in the next participants. The dose the patients receive will depend on the number of participants who have been enrolled in the study before and how well they have tolerated their doses.

At the start of each cycle the patients will have:

  • A medical history, which includes questions about your health, current medications, and any allergies.
  • Performance status, which evaluates how the patients are able to carry on with their usual activities.
  • Physical examination
  • Blood tests will be drawn for tests to monitor body's function.
  • An assessment of the patient's tumor using the exams of your doctor's choice, either CT (Computerized Tomography) scan or MRI (Magnetic Resonance Imaging). In addition, the patients may also receive a bone scan or PET scan. Assessments of the patient's tumor will be performed after every 2 cycles for the first 6 cycles. From there, this testing will occur after every 3 cycles until tumor progression.
  • Electrocardiogram (EKG), which shows the electrical activity of the heart. It will performed on Day 1 of cycle 2.
  • Echocardiogram (ECHO) (ultrasound of the heart) or MUGA scan (test of heart function using a small amount of a radioactive substance). This will be performed every 3-4 months.

Additional research procedures to be performed:

  • Archival Tumor Tissue Sample: A sample of the patient's tumor tissue (from a past surgery and/or biopsy) will be collected and used to learn more about the development of metastatic breast cancer.
  • Blood tests for research (which will include 5-6 tablespoons) to get levels of substances that may help to indicate the response of breast cancer to study treatment. This only will be performed to the participants enrolled after determination the safest dose of eribulin. It is planned at baseline.
  • Tumor biopsy to research purposes. The purpose of this part of the study is to perform gene sequencing (gene tests) on each participant's cancer cells. The investigator will request your permission to obtain samples of one of these areas: breast, skin, chest, lymph node, soft tissue, bone, or liver for research purposes. The chosen area will be the one that the treating provider considers appropriate. Alternatively we will be asking the patient to use fluid from a thoracentesis or paracentesis. If the patients are having a biopsy/thoracentesis or paracentesis as clinical care, then some tissue will be removed from that sample for research. If a biopsy biopsy is not be needed for clinical care then it will be performed for research purposes. This only will be performed to the participants enrolled after determination the safest dose of eribulin. It is planned at baseline. The biopsy after tumor progression is optional.

One of the main reasons to study the genetic characteristics of cancers is to learn whether they can predict response to existing treatments. Therefore, in this study, the investigators would also link the results of the gene tests on the patient's cancer with medical information that has been generated during the course of the patient's study treatment. The medical information required for this part of the study will be gathered from the patient's medical record. Some of the patients specimens, as well as some of the material generated during the analysis of the patient's tissues or blood, may be useful for study in the future, with newer technologies and approaches. The investigators are asking the patient's permission to store these specimens and materials in a secure biological sample storage facility for possible later research.

Finally, rapid progress in understanding and treating cancer will occur when some of the genetic information derived from the patient's tissues and blood can be shared with other researchers. In particular, the National Institutes of Health (NIH) and other organizations have developed special data (information) repositories that analyze data and collect the results of certain types of genetic studies. These central banks will store the patient's genetic information, samples, and survey/interview information and provide them to qualified researchers to do more studies. Therefore, the Investigators are also asking the patient's permission to share their results with these special banks.

After the final dose of the study drug:

The patient will have a follow-up visit one month after coming off study treatment every 9 weeks. During that visit, the patient will have a physical examination, functional assessment, assessment of any side effect and current medications. If the patient continues to have ongoing side effects related to the study treatment, the investigator will continue to follow the patient until these side effects resolve. If the patient withdraws from the study for another reason other than tumor progression, the patient will continue to be followed until tumor progression.

In addition, the investigator will collect about 5-6 additional tablespoons of blood for research and to measure if a marker for particular breast cancer exists. The patient also will be asked to perform another tumor biopsy for research purposes.

The investigator would like to keep track of the patient's medical condition for the rest of their life. The investigator would like to do this by calling the patient on the telephone once a year to see how they are doing. Keeping in touch with the patient and checking the condition every year helps the investigator look at the long-term effects of the research study. This is an optional procedure.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

Participants must meet the following criteria on screening examination to be eligible to participate in the study:

- Participants must have invasive primary tumor or metastatic tissue confirmation of HER2-positive status, defined as presence of one or more of the following criteria: Over-expression by IHC with score of 3+ AND/OR HER2 gene amplification (> 6 HER2 gene copies per nucleus or a FISH ratio [HER2 gene copies to chromosome 17 signals] of ≥ 2.0) Note: Participants with a negative or equivocal overall result (FISH ratio of <2.0 or ≤ 6.0 HER2 gene copies per nucleus) and IHC staining scores of 0, 1+, 2+ are not eligible for enrollment.

  • Participants must have metastatic, unresectable locally advanced, or locally recurrent HER2-positive breast cancer. For the phase II portion of the study, it is required that participants have measurable disease, as defined by RECIST 1.1, which can be accurately evaluated on computerized tomography (CT) or magnetic resonance (MRI). Measurable disease is defined as: at least one lesion of >10 mm in the longest diameter for a non-lymph node or >15 mm in the short-axis diameter for a lymph node which is serially measurable according to RECIST 1.1.criteria.1
  • Participants must have received at least 1 line of chemotherapy for advanced or metastatic breast cancer and/or relapse/progressed while on or within 6 months of completion of neoadjuvant or adjuvant trastuzumab.
  • Participants must have had prior trastuzumab therapy (either in the adjuvant or metastatic setting).
  • Participants must be at least 2 weeks out from prior endocrine therapy, chemotherapy,radiotherapy, or other cancer-directed therapy (including novel agents), with adequate recovery of toxicity to baseline, or grade ≤1, with the exception of alopecia and hot flashes. Participants may have initiated bisphosphonate/denosumab therapy prior to start of protocol therapy. Biphosphonate/denosumab therapy may continue during protocol treatment. Such participants will have bone lesions considered evaluable for progression. Washout for trastuzumab is not necessary.
  • Women and men, age 18 years at the time of informed consent.
  • Participants must have an Eastern Cooperative Oncology Group (ECOG) performance status 0-1 or a Karnofsky Performance Scale (KP) 70% (see Appendix A).
  • Participants must have normal organ and marrow function as defined below:
  • Absolute neutrophil count > 1,500/mcL
  • Platelets > 75,000/mcL
  • Hemoglobin >9g/dl
  • Total bilirubin ≤2.0 X institutional upper limit of normal
  • AST(SGOT)/ALT(SGPT) ≤ 3 X institutional ULN without liver metastases, or ≤ 5X institutional ULN with liver metastases (if liver metastases felt to be cause of LFT abnormalities)
  • Alkaline phosphatase (ALP) ≤3 x institutional upper limit of normal If total ALP is >3x institutional upper limit normal (in the absence of liver metastasis) or >5x institutional upper limit of normal (in subjects with liver metastasis) AND the subject is known to have bone metastases, then liver ALP isoenzyme should be used to assess liver function rather than total ALP.
  • Creatinine 2.0 mg/dL or creatinine clearance ≥50 mL/min.
  • LVEF ≥50%, as determined by radionucleoventilugrams (RVG) (multi-gated acquisition-MUGA) or Echocardiogram (ECHO) within 60 days prior to initiation of protocol therapy.
  • Adequate IV access
  • The effects of eribulin mesylate, trastuzumab, and pertuzumab on the developing human fetus are unknown. Pre-clinical data was suggestive of a teratogenic effect of eribulin mesylate. Pertuzumab caused oligohydramnios, delayed renal development and embryo-fetal deaths in pregnant cynomolgus monkeys. In the post-marketing setting, cases of oligohydramnios, some associated with fatal pulmonary hypoplasia of the fetus have been reported in pregnant women receiving trastuzumab. For these reasons women of child bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.
  • Ability to understand and willingness to sign a written informed consent document (approved by Institutional review board or independent ethics committee) obtained prior to any study procedure, with the understanding that the subject may withdraw at any time without prejudice.
  • Laboratory tests required for eligibility must be completed within 14 days prior study entry. Baseline tumor measurements must be documented from tests within 28 days of study entry. Other non-laboratory tests must be performed within 28 days of study entry.
  • For the Phase 2 portion of the study; patients must have tissue that is amenable to biopsy and must be willing to undergo research biopsy.

Exclusion Criteria: - Participants who exhibit any of the following conditions at screening will not be eligible for admission into the study:

  • Participants receiving any other study agents.
  • Participants receiving any other cancer directed concurrent therapy; such as concurrent chemotherapy, radiotherapy, or hormonal therapy. Concurrent treatment with biphosphonates/denosumab is allowed but should be started before starting treatment on study.
  • Active brain metastases: Participants with previously diagnosed brain metastases are eligible if they have completed treatment at least one month prior to enrollment, are neurologically stable, and have recovery from effects of radiotherapy or surgery.
  • History of allergic reaction attributed to compounds of similar chemical or biologic composition to eribulin mesylate, trastuzumab or pertuzumab, which cannot be managed by premedication.
  • Participants who previously received eribulin mesylate or pertuzumab are not eligible for enrollment on the phase II portion. However, participants who have previously received pertuzumab will be eligible for the run-in portion.
  • Prior chemotherapy, targeted therapy, hormonal therapy, or radiation therapy (including any investigational agents) within 2 weeks prior entering the study or those who have not recovered adequately from AEs due to agents administered more than 4 weeks earlier (excluding alopecia and hot flashes). A washout period is not necessary for trastuzumab (or pertuzumab for run-in patients when applicable).
  • A baseline corrected QT interval of > 470 ms.
  • Pre-existing neuropathy ≥ grade 2 (NCI CTCAE Version 4.0- Appendix B)
  • Uncontrolled intercurrent illness including, not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements or other significant diseases or disorders that, in the investigator's opinion, would exclude the subject from participating in the study
  • Symptomatic intrinsic lung disease or extensive tumor involvement of the lungs, resulting in grade 2 or higher dyspnea at rest.
  • Currently pregnant or breast-feeding. All females must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of β-Human Chorionic Gonadotropin (β-Hcg) at the Baseline visit [within 7 days of the first dose of study treatment]). Females of childbearing potential must agree to use a medically acceptable method of contraception (e.g., abstinence, an intrauterine device, a double-barrier method such as condom + spermicidal or condom + diaphragm with spermicidal, a contraceptive implant, an oral contraceptive or have a vasectomized partner with confirmed azoospermia) throughout the entire study period and for 30 days after discontinuation of study treatment. The only subjects who will be exempt from this requirement are postmenopausal women (defined as women who have been amenorrheic for at least 12 consecutive months, in the appropriate age group, without other known or suspected primary cause) or subjects who have been sterilized surgically or who are otherwise proven sterile (i.e., bilateral tubal ligation with surgery at least 1 month before start of study treatment, hysterectomy, or bilateral oophorectomy with surgery at least 1 month before start of study treatment). Current, ongoing protocols containing pertuzumab have included continuous pregnancy monitoring during the trial and for six months after the last dose of study drug is administered. Because of the long half-life of pertuzumab, women should be warned not to become pregnant for at least six months after completion of treatment.
  • Individuals with a history of different malignancy are ineligible except for the following circumstances. Individuals with a history of other malignancies are eligible if they have been disease-free for at least 5 years and are deemed by the investigator to be at low risk for recurrence of that malignancy. Individuals with the following cancers are eligible if diagnosed and treated within the past 5 years: cervical cancer in situ, and non-melanoma cancer of the skin.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01912963

Contacts
Contact: Rachel Freedman, MD 617) 632-3000 rafreedman@partners.org

Locations
United States, Massachusetts
Beth Israel Deaconness Medical Center Recruiting
Boston, Massachusetts, United States, 02215
Contact: Nadine Tung, MD    617-667-7081    ntung@bidmc.harvard.edu   
Principal Investigator: Nadine Tung, MD         
Dana-Farber Cancer Institute Recruiting
Boston, Massachusetts, United States, 02115
Contact: Rachel Freedman, MD       rafreedman@partners.org   
Principal Investigator: Rachel Freedman, MD         
Massachusetts General Hospital Recruiting
Boston, Massachusetts, United States, 02114
Contact: Steven Isakoff, MD, PhD    617-726-4920    sisakoff@partners.org   
Principal Investigator: Steven Isakoff, MD, PhD         
Sponsors and Collaborators
Dana-Farber Cancer Institute
Eisai Inc.
Genentech
Investigators
Principal Investigator: Rachel Freedman, MD Dana-Farber Cancer Institute
  More Information

No publications provided

Responsible Party: Rachel Freedman, Principal Investigator, Dana-Farber Cancer Institute
ClinicalTrials.gov Identifier: NCT01912963     History of Changes
Other Study ID Numbers: 13-163
Study First Received: July 24, 2013
Last Updated: July 6, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Dana-Farber Cancer Institute:
HER-2 Positive Breast Cancer

Additional relevant MeSH terms:
Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Trastuzumab
Pertuzumab
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions

ClinicalTrials.gov processed this record on September 18, 2014