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
Overview
- Phase
- Phase 2
- Status
- Terminated
- Sponsor
- Dana-Farber Cancer Institute
- Enrollment
- 32
- Locations
- 2
- Primary Endpoint
- Dose Limiting Toxicity (DLT) [Phase I]
Overview
Brief Summary
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.
Study Design
- Study Type
- Interventional
- Allocation
- Non Randomized
- Intervention Model
- Single Group
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
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
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
Arms & Interventions
Phase I: Dose Level 1 (D1)
Pertuzumab: 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.
Intervention: Pertuzumab (Drug)
Phase I: Dose Level 1 (D1)
Pertuzumab: 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.
Intervention: Trastuzumab (Drug)
Phase I: Dose Level 1 (D1)
Pertuzumab: 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.
Intervention: eribulin (Drug)
Phase II Cohort A: Without Prior Pertuzumab Exposure
Pertuzumab: 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.
Intervention: Pertuzumab (Drug)
Phase II Cohort A: Without Prior Pertuzumab Exposure
Pertuzumab: 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.
Intervention: Trastuzumab (Drug)
Phase II Cohort A: Without Prior Pertuzumab Exposure
Pertuzumab: 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.
Intervention: eribulin (Drug)
Phase II Cohort B: With Prior Pertuzumab Exposure
Pertuzumab: 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.
Intervention: Pertuzumab (Drug)
Phase II Cohort B: With Prior Pertuzumab Exposure
Pertuzumab: 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.
Intervention: Trastuzumab (Drug)
Phase II Cohort B: With Prior Pertuzumab Exposure
Pertuzumab: 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.
Intervention: eribulin (Drug)
Outcomes
Primary Outcomes
Dose Limiting Toxicity (DLT) [Phase I]
Time Frame: The observation period for DLTs was the 1st cycle of treatment.
A DLT was defined as an adverse event that (a) is deemed by the investigator to be probably or likely related with protocol therapy and (b) occurs during and/or begins during the first cycle of the study treatment, and (c) meets any of the following criteria: grade 4 hematologic toxicity with \> 1 week of duration, grade 3 or 4 febrile neutropenia of any duration; or grade 3 or 4 non hematologic toxicity (excluding nausea, vomiting, and alopecia).
Objective Response Rate (ORR) [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.
The objective response rate (ORR) was defined as the proportion of participants achieving complete response (CR) or partial response (PR) 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. PR or better overall response assumes at a minimum incomplete response/stable disease (SD) for the evaluation of non-target lesions and absence of new lesions.
Eribulin the Recommended Phase II Dose (RP2D) [Phase I]
Time Frame: The observation period for the RP2D was the 1st cycle of treatment.
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 Outcomes
- Grade 4 Treatment-Related Toxicity Rate(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.)
- Clinical Benefit Rate (CBR) [Phase II](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.)
- Progression-free Survival (PFS) [Phase II](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).)
- Overall Survival (OS) [Phase II](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).)
Investigators
Rachel Freedman, MD, MPH
Principal Investigator
Dana-Farber Cancer Institute