Tucatinib + Doxil for Breast Cancer
Recruiting in Palo Alto (17 mi)
+7 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: SCRI Development Innovations, LLC
Must not be taking: CYP2C8 inhibitors, CYP3A4 inducers
Disqualifiers: Uncontrolled hypertension, Diabetes, HIV, others
No Placebo Group
Prior Safety Data
Breakthrough Therapy
Trial Summary
What is the purpose of this trial?This clinical trial is evaluating tucatinib in combination with Doxil in participants with human epidermal growth factor 2 positive (HER2+) locally advanced or metastatic breast cancer. The main goals of this study are to:
* Learn how well the combination of tucatinib and Doxil works
* Learn more about the side effects of the combination of tucatinib and Doxil
Will I have to stop taking my current medications?
The trial does not specify if you must stop taking your current medications. However, you cannot use strong CYP2C8 inhibitors or strong CYP3A4 inducers within 5 days before starting the study treatment. It's best to discuss your current medications with the study team.
What data supports the effectiveness of the drug combination Tucatinib + Doxil for breast cancer?
Research shows that Doxil, a form of doxorubicin, is effective in treating metastatic breast cancer and has been used in combination with other drugs for advanced breast cancer. This suggests potential effectiveness when combined with Tucatinib for breast cancer treatment.
12345Is the combination of Tucatinib and Doxil generally safe for humans?
Doxil (also known as Caelyx or liposomal doxorubicin) has been studied in various cancers, showing moderate toxicity with some serious side effects like hepatorenal failure (liver and kidney failure) and febrile neutropenia (low white blood cell count with fever). However, it generally has a reduced risk of heart damage compared to traditional doxorubicin, even at higher doses.
13567What makes the drug combination of Tucatinib and Doxil unique for breast cancer treatment?
The combination of Tucatinib and Doxil is unique because Tucatinib is a highly selective HER2 tyrosine kinase inhibitor that can enhance the effectiveness of other HER2-targeted therapies, potentially offering a new option for patients whose cancer has progressed despite existing treatments. This combination may provide improved outcomes, especially for those with HER2-positive breast cancer, including cases with brain metastases.
89101112Eligibility Criteria
This trial is for adults with HER2+ advanced or metastatic breast cancer who've had at least one anti-HER2 therapy. They must be in good health, not planning to have children, and able to use two forms of contraception. Excluded are those with other active cancers, recent major surgery, certain infections like HIV or hepatitis B/C, uncontrolled diseases such as hypertension or diabetes, and specific heart conditions.Inclusion Criteria
My blood counts are within a healthy range.
Your heart is pumping blood effectively, as shown in a recent heart test.
My brain MRI meets the specific criteria for brain metastases.
+10 more
Exclusion Criteria
Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol and/or follow-up procedures outlined in the protocol
I don't have large brain tumors, uncontrolled seizures, or certain brain diseases.
I do not have stomach or bowel problems that affect how my body handles medicine.
+12 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
4 weeks
1 visit (in-person)
Safety Lead-in
First 6 patients are evaluated weekly for one treatment cycle to ensure the regimen is safe and tolerable
4 weeks
4 visits (in-person)
Treatment
Participants receive tucatinib 300mg by mouth twice daily continuously in combination with Doxil 40mg/m2 intravenously on day 1 of each 28-day cycle
Up to 40 months
Monthly visits (in-person)
Follow-up
Participants are monitored for safety and effectiveness after treatment
4 weeks
1 visit (in-person)
Participant Groups
The study tests the effectiveness and side effects of combining tucatinib with Doxil in treating HER2+ breast cancer that has spread. Participants will receive both medications and researchers will monitor how well this combination works compared to previous treatments they've received.
1Treatment groups
Experimental Treatment
Group I: Tucatinib Experimental Treatment ArmExperimental Treatment2 Interventions
Participants will receive tucatinib 300mg by mouth twice daily continuously in combination with Doxil 40mg/m2 given intravenously on day 1 of each cycle. Cycles will be 28 days. Up to 36 participants will be enrolled in this Phase 2 study.
Doxil is already approved in United States, European Union, Canada for the following indications:
🇺🇸 Approved in United States as Doxil for:
- Ovarian cancer
- AIDS-related Kaposi's sarcoma
- Multiple myeloma
🇪🇺 Approved in European Union as Caelyx for:
- Ovarian cancer
- AIDS-related Kaposi's sarcoma
- Multiple myeloma
- Breast cancer
🇨🇦 Approved in Canada as Doxorubicin liposomal for:
- Ovarian cancer
- AIDS-related Kaposi's sarcoma
- Multiple myeloma
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Tennessee OncologyNashville, TN
SCRI Oncology PartnersNashville, TN
Maryland Oncology HematologyColumbia, MD
Texas Oncology- DFWDallas, TX
More Trial Locations
Loading ...
Who Is Running the Clinical Trial?
SCRI Development Innovations, LLCLead Sponsor
PfizerIndustry Sponsor
Seagen Inc.Industry Sponsor
References
Caelyx/Doxil for the treatment of metastatic ovarian and breast cancer. [2022]Caelyx/Doxil is a novel pegylated liposomal formulation of the first-generation anthracycline, doxorubicin. The pharmacokinetics of this polyethylene-glycol-coated liposome are characterized by a reduced volume of distribution, a long intravascular circulating half-life and slow plasma clearance compared with free doxorubicin. This, coupled with a small vesicular size, uniquely promotes the localization of Caelyx/Doxil at tumor sites and explains its altered toxicity profile. The FDA and EMEA have approved its use for the treatment of AIDS-related Kaposi's sarcoma and, more recently, for recurrent epithelial ovarian cancer (EOC). Numerous investigations have focused on its use in the treatment of metastatic breast cancer, as well as recurrent squamous cell cervical carcinoma, soft tissue sarcoma, squamous head and neck cancers, prostate cancers and malignant gliomas. Ongoing clinical studies of combination regimens incorporating Caelyx/Doxil will further clarify its role in the treatment of advanced solid tumors.
Neoadjuvant chemotherapy with a combination of pegylated liposomal doxorubicin (Caelyx) and paclitaxel in locally advanced breast cancer: a phase II study by the Hellenic Cooperative Oncology Group. [2020]To determine the activity and safety of the combination of paclitaxel and pegylated liposomal doxorubicin (Caelyx) in patients with locally advanced breast cancer.
Treatment of advanced breast cancer with sterically stabilized liposomal doxorubicin: results of a multicenter phase II trial. [2017]A multicenter phase II study to determine the activity and toxicity of Caelyx (Doxil; Sequus Pharmaceuticals Inc, Menlo Park, CA) in patients with metastatic breast cancer.
Topotecan and doxorubicin combination to treat recurrent ovarian cancer: the influence of drug exposure time and delivery systems to achieve optimum therapeutic activity. [2018]To provide proof-of-concept data to support use of Doxil-liposomal topotecan (Topophore C) combinations to treat ovarian cancer.
Phase II study of liposomal doxorubicin in advanced gynecologic cancers. [2013]Pegylated liposomal doxorubicin (Doxil) may have enhanced therapeutic efficacy and reduced toxicity compared with the parent compound. This phase II study further evaluates the activity of Doxil in patients with ovarian cancer and explores activity in other gynecologic cancers.
First line therapy with paclitaxel (Taxol) and pegylated liposomal doxorubicin (Caelyx) in patients with metastatic breast cancer: a multicentre phase II study. [2015]The aim of this multicentric phase II study was to investigate the efficacy and toxicity of a combination of chemotherapy containing paclitaxel (Taxol) and a novel compound, a liposomal encapsulated doxorubicin (Caelyx), as first line therapy for patients with metastatic breast cancer. Thirty-four patients with advanced breast cancer were treated with a combination of paclitaxel 175 mg/m2 and liposomal doxorubicin 30 mg/m2, every 3 weeks. The combination chemotherapy was effective in 73% of the patients (ITT) (95% CI 55-86%) (7 complete and 18 partial responses). Grade 3/4 toxicities were documented in a small number of patients. Two toxic deaths (6%) were documented, one a hepatorenal failure and another a febrile neutropenia. One patient experienced pulmonary embolism but continued on treatment after appropriate therapy. The combination of paclitaxel and liposomal encapsulated doxorubicin induces a high and durable response rate with a moderate toxicity profile.
Pegylated liposomal doxorubicin (doxil): reduced clinical cardiotoxicity in patients reaching or exceeding cumulative doses of 500 mg/m2. [2022]The indications for pegylated liposomal doxorubicin (doxil) are expanding. We, therefore, wished to assess the safety of delivering doses exceeding 500 mg/m2 of doxil to patients with solid tumors.
Evaluation of Safety and Clinically Relevant Drug-Drug Interactions with Tucatinib in Healthy Volunteer s. [2022]Tucatinib is approved for treatment of human epidermal growth factor receptor 2-positive metastatic breast cancer. Understanding potential drug-drug interactions (DDIs) informs proper dosing when co-administering tucatinib with other therapies. The aim of this study was to evaluate DDIs between tucatinib and metabolizing enzymes and transporters in healthy volunteers.
Tucatinib, Trastuzumab, and Capecitabine for HER2-Positive Metastatic Breast Cancer. [2021]Patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer who have disease progression after therapy with multiple HER2-targeted agents have limited treatment options. Tucatinib is an investigational, oral, highly selective inhibitor of the HER2 tyrosine kinase.
Preclinical Activity of HER2-Selective Tyrosine Kinase Inhibitor Tucatinib as a Single Agent or in Combination with Trastuzumab or Docetaxel in Solid Tumor Models. [2021]HER2 is a transmembrane tyrosine kinase receptor that mediates cell growth, differentiation, and survival. HER2 is overexpressed in approximately 20% of breast cancers and in subsets of gastric, colorectal, and esophageal cancers. Both antibody and small-molecule drugs that target HER2 and block its tyrosine kinase activity are effective in treating HER2-driven cancers. In this article, we describe the preclinical properties of tucatinib, an orally available, reversible HER2-targeted small-molecule tyrosine kinase inhibitor. In both biochemical and cell signaling experiments, tucatinib inhibits HER2 kinase activity with single-digit nanomolar potency and provides exceptional selectivity for HER2 compared with the related receptor tyrosine kinase EGFR, with a >1,000-fold enhancement in potency for HER2 in cell signaling assays. Tucatinib potently inhibits signal transduction downstream of HER2 and HER3 through the MAPK and PI3K/AKT pathways and is selectively cytotoxic in HER2-amplified breast cancer cell lines in vitro. In vivo, tucatinib is active in multiple HER2+ tumor models as a single agent and shows enhanced antitumor activity in combination with trastuzumab or docetaxel, resulting in improved rates of partial and complete tumor regression. These preclinical data, taken together with the phase-I tucatinib clinical trial results demonstrating preliminary safety and activity, establish the unique pharmacologic properties of tucatinib and underscore the rationale for investigating its utility in HER2+ cancers. GRAPHICAL ABSTRACT: http://mct.aacrjournals.org/content/molcanther/19/4/976/F1.large.jpg.
Tucatinib with capecitabine and trastuzumab in advanced HER2-positive metastatic breast cancer with and without brain metastases: a non-randomised, open-label, phase 1b study. [2022]Tucatinib is a potent and selective oral HER2 tyrosine kinase inhibitor, with the potential to provide a well tolerated new treatment option for patients whose disease has progressed on currently available therapies. We aimed to determine the recommended phase 2 dose, safety, pharmacokinetics, and preliminary activity of tucatinib in combination with capecitabine or trastuzumab in patients with HER2-positive breast cancer with or without brain metastases.
HER2-Selective and Reversible Tyrosine Kinase Inhibitor Tucatinib Potentiates the Activity of T-DM1 in Preclinical Models of HER2-positive Breast Cancer. [2023]The oncogenic receptor HER2 is overexpressed in many cancers, including up to 20% of breast cancers. Despite the availability of HER2-targeted treatments, patients’ disease often progresses during therapy, underscoring the need for novel treatment strategies. The addition of tucatinib, a reversible, highly selective HER2 tyrosine kinase inhibitor (TKI), to treatment with trastuzumab and capecitabine significantly improved survival outcomes of patients with HER2-positive metastatic breast cancer, including those with active brain metastases. We rationalized that combining tucatinib with other HER2-targeting agents with complementary mechanisms of action would further increase efficacy against tumors. We characterized the activity of tucatinib with the antibody–drug conjugate T-DM1 in preclinical models of breast cancer, including HER2-positive breast cancer cells and patient-derived xenograft (PDX) models. Mechanistic details on tucatinib activity were obtained in internalization and catabolism studies. In combination, tucatinib and T-DM1 showed an enhanced, often synergistic, cytotoxic response and demonstrated improved antitumor activity in vivo, including in PDX models refractory to T-DM1 single-agent activity. Mechanistically, tucatinib mediated an increase in inactive HER2 molecules at the cell surface through inhibition of HER2 ubiquitination, resulting in increased internalization and catabolism of T-DM1. The combination was correlated with enhanced HER2 pathway inhibition, decreased proliferation, and increased apoptosis. In a xenograft model of brain metastasis, tucatinib penetrated intracranial tumor tissues, inhibiting tumor growth and improving survival. These results suggest that tucatinib may be the optimal TKI partner for HER2-targeted therapies and support clinical studies of its combination with T-DM1, including in patients with brain metastases.