Triple Drug Combo for Advanced Breast Cancer
Recruiting in Palo Alto (17 mi)
+5 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: Criterium, Inc.
Must not be taking: Warfarin, Coumarin, others
Disqualifiers: Eribulin, Anthracyclines, Cardiopulmonary disease, others
No Placebo Group
Prior Safety Data
Breakthrough Therapy
Trial Summary
What is the purpose of this trial?The purpose of this study is to evaluate the safety and efficacy of the three-drug combination of tucatinib, trastuzumab, and eribulin in patients with de novo and recurrent unresectable metastatic HER-2/neu positive breast cancer as assessed by ORR, PFS and OS after prior treatment with a taxane, trastuzumab, and T-DM1.
Do I need to stop my current medications to join the trial?
The trial protocol does not specify if you need to stop taking your current medications. However, you cannot participate if you are currently on warfarin or other coumarin derivatives, or if you have used strong CYP3A4 or CYP2C8 inhibitors or inducers recently. It's best to discuss your specific medications with the trial team.
What data supports the effectiveness of the triple drug combo for advanced breast cancer?
The combination of HER2-targeted drugs like trastuzumab (Herceptin) and tucatinib (Tukysa) has shown to significantly improve outcomes for patients with HER2-positive advanced breast cancer. Additionally, eribulin has been proven to extend overall survival in patients with advanced breast cancer who have undergone multiple prior treatments.
12345Is the triple drug combo for advanced breast cancer safe?
The combination of eribulin and trastuzumab has been shown to be generally safe and well-tolerated in patients with advanced HER2-positive breast cancer. Common side effects include neutropenia (low white blood cell count), which is manageable, and no severe heart issues were observed. However, regular monitoring of heart function is recommended.
678910What makes the triple drug combo of Eribulin, Trastuzumab, and Tucatinib unique for advanced breast cancer?
This triple drug combo is unique because it combines Eribulin, which is promising in combination with Trastuzumab for HER2-positive breast cancer, with Tucatinib, a newer drug that specifically targets HER2, potentially offering a more comprehensive treatment approach for advanced cases.
1112131415Eligibility Criteria
This trial is for adults with HER2+ breast cancer that's advanced and can't be surgically removed. Participants must have had prior treatments including trastuzumab and a taxane, but not necessarily tucatinib. They should be in relatively good health otherwise, able to follow the study plan, and women of childbearing age must test negative for pregnancy.Inclusion Criteria
My liver is functioning well.
I agree to use effective birth control during the study.
Have a life expectancy of at least 6 months, in the opinion of the site investigator
+14 more
Exclusion Criteria
I have chronic Hepatitis B, C, or another long-term liver disease.
All side effects from my previous cancer treatments are mild.
You have been diagnosed with HIV.
+14 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment
Participants receive tucatinib, trastuzumab, and eribulin in 21-day cycles
2 years
Every 21 days (in-person)
Follow-up
Participants are monitored for safety and effectiveness after treatment
4 weeks
Participant Groups
The trial tests how safe and effective the combination of tucatinib, trastuzumab, and eribulin is in treating patients who've already received certain other breast cancer treatments. The effectiveness will be measured by tumor response rate, progression-free survival (PFS), and overall survival (OS).
1Treatment groups
Experimental Treatment
Group I: Tucatinib/Eribulin/TrastuzumabExperimental Treatment3 Interventions
* The initial dose of trastuzumab will be given as a loading dose of 8 mg/kg intravenously (IV), unless trastuzumab was administered within the prior 4 weeks, then the initial dose of trastuzumab will be administered at a dose of 6 mg/kg. Each trastuzumab dose is given once every 21 days, except in specific circumstances where it may be given weekly to compensate for modifications in treatment schedule
* Tucatinib 300 mg orally twice daily (PO BID) every day (Days 1-21) of each 21-day cycle using a modified schedule of events. Subcutaneous trastuzumab is given only once every three weeks as there is no allowance for weekly dosing.
* Eribulin will be given at a dose of 1.4 mg/M2 intravenously over a 2-5 minute period on days 1 and 8 of each 21-day cycle.
Eribulin is already approved in European Union, United States, Japan, Canada for the following indications:
🇪🇺 Approved in European Union as Halaven for:
- Locally advanced or metastatic breast cancer
🇺🇸 Approved in United States as Halaven for:
- Metastatic breast cancer
- Liposarcoma
🇯🇵 Approved in Japan as Halaven for:
- Breast cancer
- Soft tissue sarcoma
🇨🇦 Approved in Canada as Halaven for:
- Metastatic breast cancer
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
George Washington Medical Faculty AssociatesWashington, United States
New Mexico Cancer Care AllianceAlbuquerque, NM
Swedish Cancer InstituteIssaquah, WA
Cancer Care NorthwestSpokane Valley, WA
More Trial Locations
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Who Is Running the Clinical Trial?
Criterium, Inc.Lead Sponsor
References
HER2-directed therapy for metastatic breast cancer. [2014]Human epidermal growth factor receptor 2 (HER2) overexpression drives the biology of 20% of breast cancers, and predicts a poor prognosis for patients. HER2-targeted therapies significantly improve outcomes for HER2-positive patients with both early and metastatic breast cancer. Currently three HER2-targeted agents, trastuzumab (Herceptin), lapatinib (Tykerb), and pertuzumab (Perjeta), are available for the treatment of HER2-positive metastatic breast cancer (MBC). Numerous studies have attempted to optimize their use by combining them with each other, or with endocrine and cytotoxic therapies. Most recently, the FDA approved the combination of trastuzumab, pertuzumab, and docetaxel as first-line treatment for MBC, and in late February 2013 approved a fourth HER2-targeted agent, trastuzumab emtansine (T-DM1, Kadcyla), for accelerated approval. These advances create a number of clinical dilemmas, including identification of the optimal sequence of HER2-targeted agents and the best drug combinations to use, as well as the recognition of primary and acquired drug resistance. In this article, we review clinical data informing the effective management of HER2-positive MBC.
Current and Future Management of HER2-Positive Metastatic Breast Cancer. [2022]Human epidermal growth factor receptor 2 (HER2) is overexpressed and/or amplified in approximately 20% of breast cancers, conferring an aggressive tumor behavior but also an opportunity for targeted therapies. In the advanced setting, the prognosis of patients suffering from this disease has greatly improved after the introduction of new anti-HER2 drugs beyond trastuzumab. For most patients, a taxane combined with trastuzumab and pertuzumab in the first-line setting, followed by trastuzumab-emtansine in second line, should be considered the standard of care today. However, chemo-free anti-HER2 strategies in hormone receptor-positive, HER2-positive breast cancer could also be considered in selected patients. In the third-line setting and beyond, several emerging anti-HER2 therapies are becoming available, including tucatinib, fam-trastuzumab deruxtecan-nxki (DS-8201a), neratinib, and margetuximab-cmkb. In addition, new compounds and combinations are showing promising results in the late-line setting. The treatment landscape of HER2-positive advanced disease is evolving constantly, active drugs such as pertuzumab and trastuzumab-emtansine are moving to early-stage, many biomarkers, including quantification of HER2 itself, are being explored to improve patient selection, and patient populations with specific needs are emerging, such as those with brain metastasis. Here, we provide an overview of the current and future management of HER2-positive advanced breast cancer.
Anti-HER2 Drugs for the Treatment of Advanced HER2 Positive Breast Cancer. [2023]Approximately 15-20% of breast cancers (BC) demonstrate HER2 overexpression/gene amplification. Historically, before the era of HER2-directed therapies, this subtype was associated with poor prognosis. Anti-HER2 agents dramatically changed the natural course of disease and significantly prolonged patients' survival. In recent years, a number of new anti-HER2 therapies have been developed, and their approvals offer new therapeutic options for patients with advanced HER2-positive breast cancer. At present, HER2 pathway blocking drugs used in the treatment of metastatic breast cancer worldwide include trastuzumab and pertuzumab in the first-line treatment; trastuzumab deruxtecan and trastuzumab emtansine in the second line; and tucatinib, neratinib, lapatinib, and margetuximab in further lines of treatment of advanced HER2 positive breast cancer. Additionally, there are many clinical trials underway evaluating drugs blocking the HER2 pathway in advanced disease setting. This article presents new treatment options, discussing the most important findings from clinical trials and real-world reports, clinical benefits and risks of treatment, as well as efficacy of re-treatment with trastuzumab in metastatic breast cancer. New data challenge the current standards, and a number of questions arise regarding the optimal sequence of anti-HER2 targeted therapies, the optimal combination, including endocrine agents in luminal HER2 positive tumors and treatment of special patient population such as patients with brain metastases (BM).
Phase 2 Study of Dose-Dense Doxorubicin and Cyclophosphamide Followed by Eribulin Mesylate With or Without Prophylactic Growth Factor for Adjuvant Treatment of Early-Stage Human Epidermal Growth Factor Receptor 2-Negative Breast Cancer. [2023]Eribulin has significantly improved overall survival for patients with metastatic breast cancer who received ≥ 2 prior chemotherapy regimens for advanced disease. This trial assessed eribulin as adjuvant therapy for patients with early-stage breast cancer.
Eribulin mesylate for the treatment of patients with refractory metastatic breast cancer: use of a "physician's choice" control arm in a randomized approval trial. [2016]This work describes the considerations that led to the approval by the U.S. Food and Drug Administration (FDA), on November 15, 2010, of eribulin mesylate (Halaven; Eisai, Inc.) for the treatment of patients with refractory metastatic breast cancer. The FDA review focused primarily on the results of a single randomized, open-label, multicenter trial of 762 patients with refractory locally advanced or metastatic breast cancer. The patients were randomized to receive eribulin or any single-agent treatment of the physician's choice, selected prior to randomization. The FDA's approval of eribulin mesylate was based on demonstration of a statistically significant prolongation of overall survival (OS) in patients who had been randomized to receive eribulin. The median OS was 13.1 months in the eribulin arm compared with 10.6 months in the control arm [HR 0.81 (95% CI, 0.66-0.99); P = 0.041]. Treatment with eribulin did not show a statistically significant treatment effect [HR 0.87 (95% CI, 0.71-1.05)] on progression-free survival as determined by independent review. This approval highlights the appropriate use of an innovative trial design and shows that improvement in OS is an achievable endpoint in the setting of advanced breast cancer. On the basis of the different conclusions arising from the OS and progression-free survival results, investigators should consider using OS as a primary endpoint in clinical trials for refractory breast cancer.
Long-term combination chemotherapy using eribulin and trastuzumab for three patients with human epidermal growth factor receptor 2-positive metastatic breast cancer. [2020]The combination chemotherapy regimen of eribulin (ERI) and trastuzumab (TRA)-the ERI-TRA regimen-has been shown to be highly tolerable for patients with recurrent or metastatic human epidermal growth factor receptor 2 (HER2)-positive breast cancer. However, no sufficient clinical evidence is available for the long-term safety profile of the regimen. We report on three patients in the Phase I combination study of the regimen, for whom the regimen could be conducted over the long term. Patient #1 was a 68-year-old woman and underwent the regimen until cycle 23. Patient #2 was a 61-year-old woman and underwent the regimen until cycle 27. Patient #3 was a 59-year-old woman and underwent the regimen until cycle 22. All these patients had undergone TRA-based combination therapy before the onset of the regimen. Any new categories of adverse events did not occur in association with the long-term combination chemotherapy. Neutropenia experienced by these patients was reversible and easily manageable by dose adjustment (interruption/delay and reduction). Neither increase in the risk of cardiomyopathy nor the worsening of peripheral neuropathy greater than grade 1 was found. The present regimen was suggested to be a novel chemotherapeutic option for patients with HER2-positive recurrent or metastatic breast cancer. The fact that the long-term ERI-TRA regimen was successfully conducted for these patients can be supplementary clinical information that is beneficial for clinical oncologists.
Pertuzumab, trastuzumab and eribulin mesylate therapy for previously treated advanced HER2-positive breast cancer: a feasibility study with analysis of biomarkers. [2019]The standard treatment for advanced human epidermal growth factor receptor 2 (HER2)-positive breast cancer is the triple combination of pertuzumab, trastuzumab and docetaxel, but some patients cannot tolerate taxane. To explore a non-taxane triple therapy, we conducted a feasibility study of pertuzumab, trastuzumab and eribulin mesylate (PTE) therapy for previously treated advanced HER2-positive breast cancer with analyses of quality of life and biomarkers. Ten patients were enrolled, two of whom had a history of docetaxel allergy. The median number of prior regimens was 3. The most common Grade 3 toxicities were leukopenia (70%) and neutropenia (70%). Grade 4 or 5 adverse events were not observed. An improving trend for the Functional Assessment of Cancer Therapy-Breast (FACT-B) score at 3 months was observed. Eight cases were included in the biomarker analysis. The peripheral CD8+ T cell/ CD4+Foxp3+ regulatory T cells (Tregs) ratio was significantly increased (p = 0.039). The frequency of peripheral Tregs was associated with the trastuzumab trough concentration (p = 0.019). In a non-clinical analysis, Eribulin mesylate significantly inhibited Ser473 Akt phosphorylation in PIK3CA wild-type cells and mutated cells. These results suggest that PTE therapy is a feasible and promising option for advanced HER2-positive breast cancer. Further investigation is warranted.
Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer. [2021]Eribulin mesylate (Halaven®) is a novel inhibitor of microtubule dynamics that has demonstrated a survival benefit in patients with locally recurrent or metastatic breast cancer who previously received at least two chemotherapeutic regimens including an anthracycline and a taxane. Although trastuzumab is indicated for patients with human epidermal growth factor receptor 2 positive (HER2+) breast cancer, a phase 1 study to evaluate tolerability/safety of eribulin mesylate with trastuzumab has not been conducted. Therefore, a study of eribulin mesylate in combination with trastuzumab was conducted to evaluate dose limiting toxicity (DLT), tolerability/safety, pharmacokinetics (PK), and efficacy and to estimate the recommended dose in Japanese patients with advanced or recurrent HER2+ breast cancer. Eribulin mesylate (1.4 mg/m(2)) was administered on days 1 and 8 of every 3 week cycle. Trastuzumab was administered with a 4 mg/kg loading dose followed by 2 mg/kg weekly doses or with an 8 mg/kg loading dose followed by 6 mg/kg tri-weekly doses. A total of 12 patients (six for each regimen) received eribulin mesylate and trastuzumab. No DLT was observed and the recommended dose of eribulin mesylate in combination with trastuzumab was estimated as 1.4 mg/m(2). Common adverse events were neutropenia, leukopenia, anaemia and alopecia. This combination therapy was well tolerated and the neutropenia observed was manageable. No PK drug-drug interaction between eribulin and trastuzumab was observed. Since a transient ejection fraction decreased was observed in two patients, cardiac function should be routinely assessed in patients receiving the combination therapy of eribulin mesylate with trastuzumab (ClinicalTrials.gov Identifier: NCT01432886).
A phase II study of efficacy, toxicity, and the potential impact of genomic alterations on response to eribulin mesylate in combination with trastuzumab and pertuzumab in women with human epidermal growth factor receptor 2 (HER2)+ metastatic breast cancer. [2021]There are limited data on trastuzumab-pertuzumab (HP)-based treatments beyond the first-line, HER2+ metastatic breast cancer (MBC) setting. We conducted a phase II study of eribulin mesylate, which extends survival in MBC, with HP in patients with previously treated HER2+ MBC to evaluate efficacy, toxicity, and genomic alterations driving therapeutic response.
Phase 2, multicenter, single-arm study of eribulin mesylate with trastuzumab as first-line therapy for locally recurrent or metastatic HER2-positive breast cancer. [2022]The aim of this study was to assess efficacy and safety of eribulin with trastuzumab as first-line therapy for locally recurrent or metastatic HER2+ breast cancer.
Long-term efficacy and safety of a third-line treatment with eribulin plus trastuzumab in a young breast cancer patient. [2016]Eribulin mesylate is approved for the treatment of metastatic breast cancer (MBC) patients after progression with anthracyclines and taxanes. Eribulin appears especially promising when combined with trastuzumab, according to the results of a recent Phase II trial in first-line setting. Here we report the case of a young, pretreated, HER2(-) MBC patient, who achieved a long-term clinical benefit with eribulin alone and in combination with trastuzumab after re-biopsy on liver metastases showed HER2 amplification. Although it is unique for its evolving clinical/biomolecular picture, this case adds anecdotal evidence to the efficacy and tolerability of this combination. However, Phase III trials are warranted to confirm its potential in first and subsequent lines of MBC treatment.
Taxane versus vinorelbine in combination with trastuzumab and pertuzumab for first-line treatment of metastatic HER2-positive breast cancer: a retrospective two-center study. [2021]The combination of a taxane with trastuzumab and pertuzumab is standard of care for first-line treatment of human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. The combination of vinorelbine with trastuzumab and pertuzumab showed anti-tumor activity in a phase 2 trial.
First report of eribulin in combination with pertuzumab and trastuzumab for advanced HER2-positive breast cancer. [2018]The efficacy and safety of continuing multiple anti-HER2 therapies in advanced breast cancer (ABC) patients remains unclear. This study investigated eribulin in combination with pertuzumab and trastuzumab for both taxane- and trastuzumab-pretreated HER2-positive ABC patients.
Maximizing clinical benefit with trastuzumab. [2019]To optimize patient management in breast cancer a number of factors are considered, including hormone receptor and HER2 status. A feasible approach for women with less aggressive, estrogen receptor/HER2-positive metastatic breast cancer is to consider trastuzumab (Herceptin; F. Hoffmann-La Roche, Basel, Switzerland) combined with endocrine therapy. Randomized clinical trials are ongoing to assess the combination of trastuzumab with aromatase inhibitors. In patients with aggressive HER2-positive metastatic breast cancer, trastuzumab/chemotherapy combination regimens are warranted. When administered first line in combination with a taxane, trastuzumab improves all clinical outcome parameters, including survival, in such patients. Trastuzumab adds little to the toxicity profile of taxanes, and trastuzumab combination therapy is associated with improvements in quality of life when compared with chemotherapy alone. There is encouraging evidence of improved efficacy when trastuzumab is combined with other cytotoxic agents with proven single-agent activity in breast cancer, including capecitabine (Xeloda; F. Hoffmann-La Roche), gemcitabine, and vinorelbine. Trastuzumab is also being investigated as part of triplet drug regimens. Trastuzumab has good single-agent activity in first-line therapy. This is of relevance to women with HER2-positive disease who are not suitable for, or do not wish to receive, cytotoxic chemotherapy. The benefits noted with trastuzumab-containing regimens were documented in clinical trials where trastuzumab was given until disease progression. A further rationale exists to continue trastuzumab beyond progression. Data from retrospective reviews indicate that this strategy is feasible.
A phase IIa dose-finding and safety study of first-line pertuzumab in combination with trastuzumab, capecitabine and cisplatin in patients with HER2-positive advanced gastric cancer. [2021]Pertuzumab plus trastuzumab provides a more comprehensive blockade of HER2 signalling than trastuzumab alone. Therefore, we conducted a phase IIa study of the pharmacokinetics and safety of pertuzumab plus trastuzumab and chemotherapy in advanced gastric cancer (aGC).