Phase II Study of Eribulin Mesylate, Trastuzumab, and Pertuzumab in Women With Metastatic, Unresectable Locally Advanced, or Locally Recurrent HER2-Positive Breast Cancer
Phase: Phase 2
Diagnosis: Breast: Metastatic
NCT ID: NCT01912963
(View complete trial on ClinicalTrials.gov)
DFCI Protocol ID: 13-163
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.
Dana-Farber Cancer Institute, Dana Farber Cancer Institute at Faulkner Hospital, Brigham and Women's Hospital, Massachusetts General Hospital
Erica Mayer, MD,
Dana-Farber Cancer Institute
Rachel Freedman, MD,
Dana Farber Cancer Institute
Nadine Tung, MD,
Beth Israel Deaconess Medical Center
Steven Isakoff, MD, PhD,
Massachusetts General Hospital
Dana-Farber Cancer Institute:
Breast Cancer Nursing Team, 617-632-3478
Beth-Israel Deaconess Medical Center:
Cancer Trials Call Center, 617-667-3060
Massachusetts General Hospital:
Cancer Trials Call Center, 877-789-6100
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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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.