Zunsemetinib + Capecitabine for Breast Cancer
Recruiting in Palo Alto (17 mi)
+2 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1 & 2
Recruiting
Sponsor: Washington University School of Medicine
Must be taking: Capecitabine
Must not be taking: CYP3A4 inhibitors, CYP2C8 inducers
Disqualifiers: Untreated brain metastases, Uncontrolled illness, others
No Placebo Group
Trial Summary
What is the purpose of this trial?This is a phase Ib/II study evaluating the safety and efficacy of zunsemetinib (ATI-450) with capecitabine in patients with hormone receptor-positive and HER2-negative (HR+/HER2-) metastatic breast cancer (MBC).
Do I have to stop taking my current medications for the trial?
The trial requires a 3-week washout period (time without taking certain medications) for denosumab or zoledronic acid before starting the study. Endocrine therapies can be continued until the first day of the trial. Other medications, like certain chemotherapy and immunotherapy drugs, have specific washout periods, so you may need to stop them before joining the trial.
What data supports the effectiveness of the drug combination Zunsemetinib + Capecitabine for breast cancer?
Research shows that Capecitabine (Xeloda) is effective in treating metastatic breast cancer, especially in patients who have not responded to other treatments. It has been shown to improve survival and response rates when used alone or in combination with other drugs like docetaxel.
12345Is the combination of Zunsemetinib and Capecitabine safe for humans?
Capecitabine (also known as Xeloda) is generally well-tolerated in humans, with common side effects including hand-foot syndrome (redness, swelling, and pain on the palms of the hands or soles of the feet), stomatitis (inflammation of the mouth), and diarrhea. It is important for patients to work closely with healthcare providers to manage these side effects effectively.
36789What makes the drug Zunsemetinib + Capecitabine unique for breast cancer treatment?
The combination of Zunsemetinib and Capecitabine is unique because Capecitabine is an oral drug that becomes active specifically at the tumor site, potentially reducing side effects on normal tissues, and it is known for its effectiveness in patients who have not responded to other treatments. This combination may offer a new option for breast cancer patients, especially those with limited treatment choices.
13101112Eligibility Criteria
This trial is for individuals with HR+/HER2- metastatic breast cancer that has spread to the bones. Participants should not have received certain prior treatments and must meet specific health conditions.Inclusion Criteria
I have been treated with hormone therapy and CDK4/6 inhibitors.
My breast cancer is hormone receptor-positive and HER2-negative.
I am fully active or can carry out light work.
+10 more
Exclusion Criteria
I have a history of cancer.
Patient is living outside the US
I haven't had cancer in the last 5 years, except for skin cancer.
+7 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Phase Ib Treatment
Patients receive zunsemetinib and capecitabine with dose escalation of zunsemetinib using a 3+3 design
6 weeks
Visits every 21 days
Phase II Treatment
Patients receive zunsemetinib and capecitabine or capecitabine with standard of care anti-resorptive agents
Ongoing 21-day cycles
Visits every 21 days
Follow-up
Participants are monitored for safety and effectiveness after treatment
4-8 weeks
Participant Groups
The study tests zunsemetinib combined with capecitabine's effectiveness in treating breast cancer. It's a phase Ib/II trial, which means it's looking at safety and how well the drugs work together.
4Treatment groups
Experimental Treatment
Active Control
Group I: Phase Ib: Zunsemetinib + CapecitabineExperimental Treatment2 Interventions
Patients will receive zunsemetinib by mouth (PO) twice per day (BID) at an assigned dose along with capecitabine (1000 mg/m\^2 PO BID on Days 1-14 an every 21-day cycle). For patients enrolled in phase Ib, capecitabine is dosed on days 2-15 during cycles 1-2. Dose escalation of zunsemetinib will utilize a 3+3 design. A maximum of 3 dose levels of zunsemetinib will be tested, and the two highest dose levels which did not lead to more than 1 of 6 patients with DLT in cycle 1 will be chosen as the RP2D-L1 and RP2D-L2 for Phase II. If only one dose level of zunsemetinib was found tolerable, then only one RP2D will be chosen for Phase II.
Group II: Phase II Arm 3: Zunsemetinib (RP2D-L2) + CapecitabineExperimental Treatment2 Interventions
Patients will receive zunsemetinib by mouth (PO) twice per day (BID) at an assigned dose. In general, capecitabine will be taken twice daily at a dose of 1000 mg/m\^2 on Days 1 through 14 of every 21-day cycle. The first 4 patients enrolling to phase II will take capecitabine on a different schedule for PK purposes in Cycles 1 and 2 ONLY. Patients will take capecitabine at a dose of 1000mg/m\^2 on Days 2 through 15 of Cycles 1 and 2, and then on Days 1 through 14 starting with Cycle 3. If only one dose level of zunsemetinib plus capecitabine was found tolerable in phase Ib testing, the phase II trial will proceed with 2:1 two-arm randomization with Arm 2 of capecitabine plus zunsemetinib and Arm 1 of capecitabine plus standard of care anti-resorptive agent.
Group III: Phase II Arm 2: Zunsemetinib (RP2D-L1) + CapecitabineExperimental Treatment2 Interventions
Patients will receive zunsemetinib by mouth (PO) twice per day (BID) at an assigned dose. In general, capecitabine will be taken twice daily at a dose of 1000 mg/m\^2 on Days 1 through 14 of every 21-day cycle. The first 4 patients enrolling to phase II will take capecitabine on a different schedule for PK purposes in Cycles 1 and 2 ONLY. Patients will take capecitabine at a dose of 1000mg/m\^2 on Days 2 through 15 of Cycles 1 and 2, and then on Days 1 through 14 starting with Cycle 3.
Group IV: Phase II Arm 1: Standard of care anti-resorptive + CapecitabineActive Control3 Interventions
Standard of care anti-resorptives will consist of bisphosphonate (zoledronic acid) is to be administered every 4-12 weeks, or denosumab is to be administered every 4-6 weeks, as per physician choice and institutional practice. In general, capecitabine will be taken twice daily at a dose of 1000 mg/m\^2 on Days 1 through 14 of every 21-day cycle. The first 4 patients enrolling to phase II will take capecitabine on a different schedule for PK purposes in Cycles 1 and 2 ONLY. Patients will take capecitabine at a dose of 1000mg/m\^2 on Days 2 through 15 of Cycles 1 and 2, and then on Days 1 through 14 starting with Cycle 3.
Capecitabine is already approved in European Union, United States, Canada, Japan for the following indications:
🇪🇺 Approved in European Union as Xeloda for:
- Colorectal cancer
- Breast cancer
🇺🇸 Approved in United States as Xeloda for:
- Colorectal cancer
- Breast cancer
🇨🇦 Approved in Canada as Xeloda for:
- Colorectal cancer
- Breast cancer
🇯🇵 Approved in Japan as Xeloda for:
- Colorectal cancer
- Breast cancer
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
The University of Kansas Cancer CenterWestwood, KS
Mayo ClinicRochester, MN
Washington University School of MedicineSaint Louis, MO
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Who Is Running the Clinical Trial?
Washington University School of MedicineLead Sponsor
Aclaris Therapeutics, Inc.Industry Sponsor
United States Department of DefenseCollaborator
References
Xeloda in the treatment of metastatic breast cancer. [2017]There are few treatment options available for patients with metastatic breast cancer who have failed anthracycline- and paclitaxel-based chemotherapy. Xeloda (capecitabine) is a novel selectively tumoractivated fluoropyrimidine carbamate producing clinically active levels of 5-fluorouracil (5-FU) at the tumor site. Xeloda is active in breast cancer and is administered orally. It is the only registered treatment for patients in whom anthracycline and taxoid treatment has failed. In a phase II trial of 163 paclitaxel-refractory patients with metastatic breast cancer, the overall response rate with Xeloda was 20%, with three complete responses, and the median survival was 12.8 months. A total of 20% of patients experienced a Clinical Benefit Response (a composite assessment of clinical benefit). Furthermore, Xeloda was well tolerated; the most common treatment-related adverse events were hand-foot syndrome, diarrhea, nausea, vomiting, and fatigue. Two additional studies of Xeloda in patients with metastatic breast cancer have also been completed. In the first study, patients with anthracycline-resistant metastatic breast cancer received either Xeloda or paclitaxel; the response rates were 36 and 26%, respectively. In the second study, women aged >/=55 years received first-line treatment with either Xeloda or cyclophosphamide/methotrexate/5-FU. The response rates were 25 and 16%, respectively. These studies show that Xeloda is an active agent in the treatment of metastatic breast cancer with the additional advantage of oral administration.
Capecitabine and docetaxel in advanced breast cancer: analyses of a phase III comparative trial. [2018]A recent phase III trial demonstrated that the combination of capecitabine (Xeloda) and docetaxel (Taxotere) significantly improved objective tumor response rate, time to disease progression, and overall survival compared with single-agent docetaxel in anthracycline-pretreated patients with advanced breast cancer. Early separation of survival curves suggests that combined treatment prevented early mortality seen with single-agent docetaxel and, thus, that the capecitabine/docetaxel combination may be more beneficial than sequential treatment in some patients in this setting. Dose reduction of the combination (eg, to capecitabine at 950 mg/m2) did not reduce effectiveness of treatment and was associated with reduced toxicity; study of the combination in the adjuvant setting has been initiated with a lower capecitabine starting dose. Poststudy treatment with capecitabine in patients in the docetaxel-alone group was associated with significantly improved survival compared with poststudy treatment with all other cytotoxic agents, suggesting that some patients may benefit from sequential therapy with docetaxel and capecitabine. No difference in reduction of riskfor death was seen according to whether combined treatment was given as first-, second-, or third-line therapy. The capecitabine/docetaxel combination appears to influence the natural history of metastatic breast cancer in a significant manner; it remains to be determined whether the benefits of the combination reflect additive or synergistic effects and whether greater benefit may be derived from sequential or combined treatment in overall populations or patient subgroups.
Future options with capecitabine (Xeloda) in (neo)adjuvant treatment of breast cancer. [2019]As an active and well-tolerated agent in the treatment of metastatic breast cancer, capecitabine (Xeloda, F. Hoffmann-La Roche, Basel, Switzerland) has the potential to confer significant clinical benefits in the primary treatment of breast cancer. The minimal myelosuppression and alopecia associated with capecitabine, together with its potential for synergistic activity with a range of other anticancer therapies, lend support to its use in combination regimens with other commonly used cytotoxic agents. Trials to date show that capecitabine combinations incorporating taxanes, vinorelbine, anthracyclines, and cisplatin are active and well tolerated in the metastatic setting. To more fully explore the clinical utility of capecitabine in early breast cancer, an extensive, worldwide phase II/III program is evaluating capecitabine as a component of adjuvant and neoadjuvant therapy. Results presented to date of the large adjuvant and neoadjuvant trials incorporating capecitabine are encouraging and suggest that women with breast cancer might benefit from the activity of capecitabine early in the disease course.
Efficacy of the oral fluorouracil pro-drug capecitabine in cancer treatment: a review. [2023]Capecitabine (Xeloda) was developed as a pro-drug of fluorouracil (FU), with the aim of improving tolerability and intratumor drug concentrations through its tumorspecific conversion to the active drug. The purpose of this paper is to review the available information on capecitabine, focusing on its clinical effectiveness against various carcinomas. Identification of all eligible English trails was made by searching the PubMed and Cochrane databases from 1980 to 2007. Search terms included capecitabine, Xeloda and cancer treatment. Nowadays, FDA has approved the use of capecitabine as a first line therapy in patients with metastatic colorectal cancer when single-agent fluoropyrimidine is preferred. The drug is also approved for use as a single agent in metastatic breast cancer patients who are resistant to both anthracycline and paclitaxel-based regimens or when further anthracycline treatment is contraindicated. It is also approved in combination with docetaxel after failure of prior anthracycline-based chemotherapy. In patients with prostate, pancreatic, renal cell and ovarian carcinomas, capecitabine as a single-agent or in combination with other drugs has also shown benefits. Improved tolerability and comparable efficacy, compared with the intravenous FU/LV combination, in addition to its oral administration, make capecitabine an attractive option for the treatment of several types of carcinomas.
One year of complete clinical response in a metastatic breast cancer patient treated with a combination of lapatinib and gemcitabine. [2021]The treatment of metastatic breast cancer is challenging. We recently assisted in the development of targeted therapies (in combination with chemotherapy or as monotherapy) that have improved results for selected groups of patients. Lapatinib is a dual tyrosine kinase inhibitor that has shown efficacy in breast cancer. Consequently, its use has been approved, in combination with capecitabine, for the treatment of disease positive for the human epidermal growth factor receptor. Here, we present a case of complete clinical response to a combination of lapatinib and gemcitabine that was maintained for 1 year.
Current Canadian experience with capecitabine: partnering with patients to optimize therapy. [2019]Capecitabine (Xeloda) is the first oral chemotherapeutic agent to be used in Canada for the treatment of metastatic breast cancer and metastatic colorectal cancer. The home-based administration of this drug, coupled with the importance of prompt side-effect management, presents unique challenges to oncology nurses and gives them an expanded role in optimizing therapeutic outcomes. Fulfillment of this role involves partnering with patients to help them become educated active participants in their own treatment, and to ensure that side effects are prevented, recognized, and managed adeptly. Although well tolerated, capecitabine, as with all chemotherapy, can require interventions and dose modification. Hand-foot syndrome, the most common dose-limiting toxicity, requires particular attention. Drawing from published articles and interviews with Canadian oncology care providers, this article reviews the development and safety profile of capecitabine. Best practices in side-effect management are discussed, with a particular focus on managing hand-foot syndrome and building patient partnerships.
Development of and clinical experience with capecitabine (Xeloda) in the treatment of solid tumours. [2015]The oral fluoropyrimidine capecitabine (Xeloda) delivers 5-FU to the tumour site, thereby limiting the side effects and other complications associated with intravenous (i.v.) 5-FU. As an oral drug, capecitabine is preferred to 5-FU by many patients as it can be conveniently taken at home. In first-line metastatic colorectal cancer (MCRC), capecitabine results in superior response rates and equivalent progression-free and overall survival compared with i.v. 5-FU/LV. There is also increasing evidence for replacing i.v. 5-FU with capecitabine in combination with other anticancer agents (e.g. oxaliplatin and irinotecan) in MCRC and in the adjuvant treatment of early stage colon cancer. In anthracycline-pretreated metastatic breast cancer (MBC), adding capecitabine to docetaxel improves survival, time to progression (TTP) and response rates beyond docetaxel. Single-agent capecitabine is also effective in pretreated MBC and is a promising first-line therapy. Capecitabine has a favourable safety profile, the most frequent adverse events being hand-foot syndrome, stomatitis and diarrhoea. Because capecitabine is orally administered, it is possible to intervene promptly with dose interruption/reduction to resolve adverse events without impacting on efficacy. The increasing availability of capecitabine in the home-based setting requires careful consideration of the role of the oncology nurse, who is the key link between the patient and clinician for effective and efficient management.
A phase II trial of capecitabine in previously untreated patients with advanced and/or metastatic gastric cancer. [2022]Capecitabine (Xeloda) is a novel, oral, selectively tumor-activated fluoropyrimidine with proven activity in the treatment of advanced colorectal cancer. This trial was conducted to evaluate the efficacy, safety and feasibility of capecitabine in previously untreated patients with advanced and/or metastatic gastric cancer, with a view to replacing 5-fluorouracil (5-FU) in such patients.
Safety and efficacy of two different doses of capecitabine in the treatment of advanced breast cancer in older women. [2022]To evaluate the safety and efficacy of capecitabine in older women with advanced breast cancer.
A retrospective observational study on the use of capecitabine in patients with severe renal impairment (GFR [2022]Capecitabine (Xeloda) is an orally administered precursor of 5'deoxy-5-fluorouridine, which is a preferentially activated to 5-fluorouracil in tumors. It is used in the treatment of colorectal, gastric, and breast cancers. Based on a single Phase II trial, which included a total of 4 patients with severe renal impairment (GFR
Pharmacology and clinical status of capecitabine. [2015]Capecitabine (Xeloda) is a new, orally administered, enzyme-activated fluoropyrimidine carbamate designed to generate high levels of fluorouracil (5-FU) in tumor cells. Selective tumor activation of 5'-deoxy-5-fluorouridine, the last enzymatic step of a three-enzyme process, is catalyzed by thymidine phosphorylase, a tumor-associated angiogenic growth factor. Since levels of thymidine phosphorylase are often higher in tumors than in surrounding normal tissues, this stepwise process provides tumor selectivity and potentially decreases toxicity to normal tissues. Preclinical studies show that capecitabine has significant activity against a variety of tumor types when used as monotherapy and in combination with other chemotherapeutic agents. Capecitabine is currently approved for the treatment of patients with metastatic breast cancer resistant to paclitaxel (Taxol) and in whom further anthracycline therapy is contraindicated. It has demonstrated efficacy in patients with advanced colorectal carcinoma, and studies are ongoing in other tumor types.
Capecitabine (Xeloda) as monotherapy in advanced breast and colorectal cancer: effectiveness and side-effects. [2022]Capecitabine (Xeloda) is a fluoropyrimidine which is transformed to 5-fluorouracil (5-FU) at the tumor site. The aim of the present study was to estimate the efficacy of this agent in pretreated patients with advanced breast and colorectal cancer, and to determine the response rate and adverse reactions.