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

  • HER2-positive Breast Cancer
  • Metastatic Breast Cancer

Interventions

DrugSynonymsArms
PertuzumabPerjetaPhase I: Dose Level 1 (D1)
TrastuzumabHerceptinPhase I: Dose Level 1 (D1)
eribulineribulin mesylate, HalavenPhase I: Dose Level 1 (D1)

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).

Detailed Description

      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. Another scientific goal 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.

      After the Phase I run-in, two cohorts based on prior exposure to pertuzumab were evaluated.
      The target accrual for Cohort A, without prior pertuzumab, is 56 participants. Using a
      two-stage design (n=34 stage 1, n=22 stage 2), there is 90% power assuming 10% Type I error
      to determine whether objective response (OR) rate is consistent with the alternative rate of
      40% versus the null rate of 24%. There is 57% probability of stopping the trial at stage one
      if the true OR rate is 24%. Cohort B, with prior pertuzumab, is evaluated using a single
      stage design. There is 91% power to detect an improvement in OR from 10% to 30% with accrual
      of 25 participants.
    

Trial Arms

NameTypeDescriptionInterventions
Phase I: Dose Level 1 (D1)ExperimentalPertuzumab: 840 mg/cycle 1 then 420 mg/cycle IV on day 1 Trastuzumab: 8 mg/kg/cycle 1 then 6 mg/kg cycle IV on day 1 Eribulin: 1.4 mg/m2/cycle IV on days 1 and 8 (D1) Cycle duration=21 days The Phase I run-in potentially evaluates 2 dose levels of eribulin in combination with pertuzumab and trastuzumab. Participants first receive antibody administration then eribulin. In the treatment phase, participants receive up to 6 cycles of combination therapy unless disease progression (PD) or withdrawal for other reasons (w/d). Participants who complete 6 cycles have the option to continue with antibody therapy only until PD or w/d in the extension phase.
  • Pertuzumab
  • Trastuzumab
  • eribulin
Phase II Cohort A: Without Prior Pertuzumab ExposureExperimentalPertuzumab: 840 mg/cycle 1 then 420 mg/cycle IV on day 1 Trastuzumab: 8 mg/kg/cycle 1 then 6 mg/kg cycle IV on day 1 Eribulin: 1.4 mg/m2/cycle IV on days 1 and 8 (recommended phase II dose) Cycle duration=21 days In the Phase II study, participants enrolled into two possible cohorts based on prior pertuzumab exposure. Participants first receive antibody administration then eribulin. In the treatment phase, participants receive up to 6 cycles of combination therapy unless disease progression (PD) or withdrawal for other reasons (w/d). Participants who complete 6 cycles have the option to continue with antibody therapy only until PD or w/d in the extension phase.
  • Pertuzumab
  • Trastuzumab
  • eribulin
Phase II Cohort B: With Prior Pertuzumab ExposureExperimentalPertuzumab: 840 mg/cycle 1 then 420 mg/cycle IV on day 1 Trastuzumab: 8 mg/kg/cycle 1 then 6 mg/kg cycle IV on day 1 Eribulin: 1.4 mg/m2/cycle IV on days 1 and 8 (recommended phase II dose) Cycle duration=21 days In the Phase II study, participants enrolled into two possible cohorts based on prior pertuzumab exposure. Participants first receive antibody administration then eribulin. In the treatment phase, participants receive up to 6 cycles of combination therapy unless disease progression (PD) or withdrawal for other reasons (w/d). Participants who complete 6 cycles have the option to continue with antibody therapy only until PD or w/d in the extension phase.
  • Pertuzumab
  • Trastuzumab
  • 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 human
        epidermal growth factor receptor 2 (HER2)-positive status, defined as presence of one or
        more of the following criteria: Over-expression by immunohistochemistry (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%.

          -  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

          -  Aspartate Aminotransferase (AST, SGOT)/ALT(Alanine Aminotransferase, SGPT) ≤ 3 X
             institutional ULN without liver metastases, or ≤ 5 times institutional upper limit
             normal (ULN) with liver metastases (if liver metastases felt to be cause of Liver
             function tests (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.

          -  left ventricular ejection fraction (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 adverse events (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 Common Toxicity Criteria for Adverse Events
             (CTCAE) Version 4.0)

          -  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:Eribulin the Recommended Phase II Dose (RP2D) [Phase I]
Time Frame:The observation period for the RP2D was the 1st cycle of treatment.
Safety Issue:
Description:The RP2D of eribulin in combination with pertuzumab and trastuzumab is determined by the number of patients who experience a dose limiting toxicity (DLT). See subsequent primary outcome measure for the DLT definition. The RP2D is defined as the highest dose at which fewer than one-third of six patients experience a DLT. In this Phase I run-in, only 2 dose levels were under evaluation: a starting dose (D1) and a de-escalation dose (D-1) if 2 or more DLTs are observed in Dose Level 1 (DL1).

Secondary Outcome Measures

Measure:Clinical Benefit Rate (CBR) [Phase II]
Time Frame:Disease was evaluated radiologically at baseline and every 2 or 3 cycles in the treatment and extension phase, respectively. Median (range) treatment duration was 7(2-25) cycles for Cohort A and 4(3-18) cycles for Cohort B.
Safety Issue:
Description:The clinical benefit rate (CBR) was defined as the proportion of participants achieving complete response (CR), partial response (PR), or stable disease (SD) for 24 weeks or longer based on RECIST 1.1 criteria on treatment. Per RECIST 1.1 for target lesions: CR is complete disappearance of all target lesions and PR is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. PD is at least a 20% increase in sum LD of target lesions (smallest sum LD reference), new lesions, and/or unequivocal progression of existing non-target lesions. Stable disease (SD) is defined as any condition not meeting the above criteria.
Measure:Progression-free Survival (PFS) [Phase II]
Time Frame:Disease was evaluated radiologically at baseline, every 2 or 3 cycles in the treatment and extension phase, respectively, and every 9 weeks post-treatment until disease progression. Median follow-up in this study cohort was 15.6 months (up to 20).
Safety Issue:
Description:Progression-free survival based on the Kaplan-Meier method is defined as the duration of time from study entry to documented disease progression (PD) or death. Per RECIST 1.1 criteria: progressive disease (PD) is at least a 20% increase in the sum of longest diameter (LD) of target lesions taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. PD for the evaluation of non-target lesions is the appearance of one or more new lesions and/or equivocal progression of non-target lesions.(whichever occurs first).
Measure:Overall Survival (OS) [Phase II]
Time Frame:In long-term follow-up, participants were followed for survival every 6 months up to 1 year after treatment discontinuation. Median follow-up in this study cohort was 15.6 months (up to 20).
Safety Issue:
Description:Overall survival (OS) is defined as the time from the date of registration to the date of death, or censored at the date the participant was last known alive. OS is estimated based on the Kaplan-Meier method.
Measure:Grade 4 Treatment-Related Toxicity Rate
Time Frame:AEs were assessed every cycle on treatment. Median (range) treatment duration was 7(2-25) cycles for Cohort A and 4(3-18) cycles for Cohort B.
Safety Issue:
Description:Grade 4 treatment-related toxicity rate is the percentage of participants experiencing at least one treatment-related grade 4 adverse event (AE) of any type during the time of observation as reported on case report forms. 'Treatment-related' is a treatment attribution of possibly, probably or definite based on the NCI Common Toxicity Criteria for Adverse Events (CTCAE) version 4.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Terminated
Lead Sponsor:Dana-Farber Cancer Institute

Trial Keywords

  • HER-2 Positive Breast Cancer
  • Metastatic Breast Cancer

Last Updated

December 5, 2018