Clinical Trials /

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

NCT01912963

Description:

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).

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Terminated

Phase:

Phase 2

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: 13-163
  • NCT ID: NCT01912963

Conditions

  • HER-2 Positive Breast Cancer

Interventions

DrugSynonymsArms
Pertuzumab, Trastuzumab and EribulinPertuzumab, Trastuzumab and Eribulin

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.

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.
    

Trial Arms

NameTypeDescriptionInterventions
Pertuzumab, Trastuzumab and EribulinExperimentalTo 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.
  • Pertuzumab, Trastuzumab and Eribulin

Eligibility 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. Prior pertuzumab is allowed in the
             phase II portion of the trial.

          -  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 are not eligible for enrollment
             on the phase II 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Safety and tolerability of the combination regimen
Time Frame:2 Years
Safety Issue:
Description:Determine if the combination of eribulin mesylate, perutuzmab, and trastuzumab can be administered with 1.4 or 1.1 mg/m2 of eribulin mesylate

Secondary Outcome Measures

Measure:Clinical benefit rate (CBR)
Time Frame:2 years
Safety Issue:
Description:To describe clinical benefit rate (CBR), defined as CR, PR and stable disease (SD) ≥ 6 months by RECIST 1.1 criteria.
Measure:Progression-free survival (PFS)
Time Frame:2 Years
Safety Issue:
Description: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).
Measure:overall survival (OS)
Time Frame:2 Years
Safety Issue:
Description:defined as the time from the date of the first dose of study treatment until the date of death from any cause.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Active, not recruiting
Lead Sponsor:Dana-Farber Cancer Institute

Trial Keywords

  • HER-2 Positive Breast Cancer

Last Updated

September 19, 2017