Zunsemetinib + Capecitabine for Breast Cancer

Recruiting at 3 trial locations

Overseen By Cynthia X Ma, M.D., Ph.D.

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

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 All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 42

152 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to test the safety and effectiveness of a new treatment combination for individuals with hormone receptor-positive and HER2-negative metastatic breast cancer. It explores how well zunsemetinib, a new drug, works alongside capecitabine, a commonly used cancer medication. The trial includes different groups to compare this combination against other standard treatments. Suitable candidates have this specific type of breast cancer, have undergone prior endocrine therapy with a CDK4/6 inhibitor, and are eligible for capecitabine according to their doctor. Those meeting these criteria and interested in new treatment options might consider this trial. As a Phase 1, Phase 2 trial, this research focuses on understanding how the treatment works in people and measuring its effectiveness in an initial, smaller group, offering participants a chance to be among the first to benefit from this new approach.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that the combination of two drugs, zunsemetinib and capecitabine, is being tested for safety in patients with a specific type of breast cancer. Zunsemetinib is an investigational drug, meaning it is still under study and not yet fully approved. In contrast, capecitabine is already approved for use in certain cancers, indicating that its safety is well-understood.

Previous patients treated with this combination have generally tolerated it well. In earlier studies, researchers carefully adjusted the doses to find levels that caused the fewest side effects. For example, they selected doses that did not cause severe side effects in more than one out of six patients for further testing.

While the combination of these drugs is still under evaluation, the approval of capecitabine for other uses provides some reassurance about its safety in humans. However, since zunsemetinib remains under study, its long-term effects are not fully known. Trial participants are closely monitored to ensure any side effects are managed quickly. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of zunsemetinib and capecitabine for breast cancer because this treatment offers a potentially new way to tackle the disease. Zunsemetinib is a novel compound that might work differently from standard chemotherapy by targeting specific pathways involved in cancer cell growth. This approach could mean more effective results with possibly fewer side effects compared to traditional treatments like hormone therapy or conventional chemotherapy. By combining it with capecitabine, an established chemotherapy drug, there’s hope for enhanced efficacy, potentially offering patients a more powerful and precise treatment option.

What evidence suggests that this trial's treatments could be effective for metastatic breast cancer?

Research has shown that capecitabine effectively treats advanced breast cancer, particularly in patients unresponsive to other treatments. Studies have found that combining capecitabine with other drugs can extend the time patients live without their cancer worsening. This trial tests zunsemetinib with capecitabine in different treatment arms to evaluate their combined effectiveness. Zunsemetinib targets specific aspects of cancer growth and may enhance capecitabine's effects. Although further research is necessary to confirm the efficacy of this combination, early results appear promising. ^{1 2 6 7 8}

Who Is on the Research Team?

Cynthia X Ma, M.D., Ph.D.

Principal Investigator

Washington University School of Medicine

Are You a Good Fit for This Trial?

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.

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.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• Capecitabine
• Zunsemetinib

Trial Overview 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.

How Is the Trial Designed?

Group I: Phase Ib: Zunsemetinib + Capecitabine Experimental Treatment 2 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) + Capecitabine Experimental Treatment 2 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) + Capecitabine Experimental Treatment 2 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 + Capecitabine Active Control 3 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

Who Is Running the Clinical Trial?

Washington University School of Medicine

Lead Sponsor

Trials

2,027

Recruited

2,353,000+

Aclaris Therapeutics, Inc.

Industry Sponsor

Trials

35

Recruited

4,900+

United States Department of Defense

Collaborator

Trials

940

Recruited

339,000+

Published Research Related to This Trial

Capecitabine (Xeloda) is an oral chemotherapy that delivers 5-FU directly to tumors, offering superior response rates and equivalent survival outcomes compared to intravenous 5-FU in first-line metastatic colorectal cancer (MCRC).

Capecitabine has a favorable safety profile, with manageable side effects like hand-foot syndrome and diarrhea, allowing for prompt dose adjustments without compromising treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Development of and clinical experience with capecitabine (Xeloda) in the treatment of solid tumours. Sternberg, CN., Reichardt, P., Holland, M.[2015]

Xeloda (capecitabine) is an effective oral treatment for metastatic breast cancer patients who have not responded to anthracycline and paclitaxel chemotherapy, showing a 20% overall response rate in a phase II trial with 163 patients and a median survival of 12.8 months.

Xeloda is well tolerated, with common side effects including hand-foot syndrome and nausea, and it has demonstrated higher response rates compared to paclitaxel and cyclophosphamide/methotrexate/5-FU in additional studies, making it a valuable option for patients with limited treatment choices.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Xeloda in the treatment of metastatic breast cancer. Blum, JL.[2017]

Capecitabine is an oral pro-drug of fluorouracil that has been approved by the FDA as a first-line treatment for metastatic colorectal cancer and for use in metastatic breast cancer patients who are resistant to other treatments.

The drug has shown improved tolerability and comparable efficacy to intravenous fluorouracil, making it a convenient and effective option for treating various carcinomas, including prostate, pancreatic, renal cell, and ovarian cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of the oral fluorouracil pro-drug capecitabine in cancer treatment: a review. Koukourakis, GV., Kouloulias, V., Koukourakis, MJ., et al.[2023]

Capecitabine is an orally administered chemotherapy that selectively activates in tumor cells, leading to high levels of fluorouracil (5-FU) while minimizing damage to normal tissues, thanks to its reliance on the enzyme thymidine phosphorylase, which is more abundant in tumors.

It has shown significant effectiveness against various cancers, including metastatic breast cancer and advanced colorectal carcinoma, and is currently being studied for use in other types of tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacology and clinical status of capecitabine. Schilsky, RL.[2015]

The combination of capecitabine and docetaxel significantly improved tumor response rates, time to disease progression, and overall survival in patients with advanced breast cancer compared to single-agent docetaxel, indicating its efficacy in this treatment setting.

Lower doses of the combination treatment reduced toxicity without compromising effectiveness, suggesting that dose adjustments could enhance patient safety while maintaining therapeutic benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Capecitabine and docetaxel in advanced breast cancer: analyses of a phase III comparative trial. O'Shaughnessy, J.[2018]

A retrospective study of 12 patients with severe renal impairment (GFR <30 mL/min) showed that capecitabine can be safely administered with close monitoring and dose adjustments, despite previous contraindications from the manufacturer based on a small Phase II trial.

Most patients experienced only mild to moderate adverse effects, and some showed a positive response to treatment, indicating that capecitabine may still be effective in this population when managed carefully.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A retrospective observational study on the use of capecitabine in patients with severe renal impairment (GFR Jhaveri, KD., Flombaum, C., Shah, M., et al.[2022]

Capecitabine is a well-tolerated treatment for metastatic breast cancer, showing minimal side effects like myelosuppression and hair loss, which makes it a promising option for combination therapies with other anticancer drugs.

Ongoing phase II/III trials are investigating the use of capecitabine in early breast cancer treatment, and preliminary results indicate that it may provide significant benefits when used as part of adjuvant and neoadjuvant therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Future options with capecitabine (Xeloda) in (neo)adjuvant treatment of breast cancer. Fumoleau, P., Cameron, D.[2019]

In a study of 44 previously untreated patients with advanced gastric cancer, capecitabine demonstrated an objective response rate of 34% and a median overall survival of 9.5 months, indicating its efficacy as a first-line treatment.

Capecitabine was generally well tolerated, with the most common side effects being hand-foot syndrome and nausea, and severe myelosuppression was not observed, suggesting a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase II trial of capecitabine in previously untreated patients with advanced and/or metastatic gastric cancer. Hong, YS., Song, SY., Lee, SI., et al.[2022]

Capecitabine is shown to be safe and effective for older women with advanced breast cancer, with a favorable safety profile and low incidence of severe toxicities, particularly at a reduced dose of 1,000 mg/m².

In a study of 73 patients aged 65 to 89, both the standard dose (1,250 mg/m²) and the reduced dose (1,000 mg/m²) demonstrated similar response rates of approximately 36.7% and 34.9%, respectively, indicating that the lower dose may be a suitable standard for this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of two different doses of capecitabine in the treatment of advanced breast cancer in older women. Bajetta, E., Procopio, G., Celio, L., et al.[2022]

In a study of 42 patients with advanced breast and colorectal cancer, capecitabine showed a partial response rate of 29.16% for breast cancer and 11.76% for colorectal cancer, indicating its potential efficacy in these pretreated patients.

Capecitabine was well tolerated with low toxicity levels, as most adverse reactions were mild, although 7.14% of patients experienced grade 3 hand-foot syndrome, and hypertriglyceridemia was noted in some patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Capecitabine (Xeloda) as monotherapy in advanced breast and colorectal cancer: effectiveness and side-effects. Stathopoulos, GP., Koutantos, J., Lazaki, H., et al.[2022]

Lapatinib, a dual tyrosine kinase inhibitor, has been shown to be effective in treating metastatic breast cancer, particularly in patients with tumors that express the human epidermal growth factor receptor.

In a specific case, a patient achieved a complete clinical response to a combination treatment of lapatinib and gemcitabine, which was sustained for one year, highlighting the potential of this combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

One year of complete clinical response in a metastatic breast cancer patient treated with a combination of lapatinib and gemcitabine. Gasent Blesa, JM., Laforga Canales, J., Candel, VA.[2021]

Capecitabine is the first oral chemotherapy approved in Canada for treating metastatic breast and colorectal cancer, allowing for home-based administration which requires careful side-effect management by oncology nurses.

While capecitabine is generally well tolerated, it can cause hand-foot syndrome, the most common dose-limiting side effect, necessitating proactive management strategies and patient education to optimize treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Current Canadian experience with capecitabine: partnering with patients to optimize therapy. Gerbrecht, BM.[2019]

Citations

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Study Details | NCT06374459 | Zunsemetinib in ... 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- ...

2. withpower.com withpower.com/trial/phase-2-breast-neoplasms-6-2024-f1951

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.

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Zunsemetinib in Combination with Capecitabine for the ... This phase Ib/II trial tests the safety, side effects and best dose of zunsemetinib in combination with capecitabine and how well it works in treating patients

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Addition of Capecitabine in Breast Cancer First-line ... Capecitabine-based combination first-line chemotherapy compared with non-combination had significant impacts on disease-free survival (HR = 0.84, 95% CI: 0.76- ...

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Zunsemetinib in Combination With Capecitabine ... This is a phase Ib/II study evaluating the safety and efficacy of zunsemetinib (ATI-450) with capecitabine in patients with hormone receptor- ...

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A Phase II Study Evaluating the Safety and Efficacy ... Similarly, there have been two phase III trials evaluating sunitinib in combination with capecitabine in advanced breast cancer both of which showed no ...

7. smartpatients.com smartpatients.com/trials/NCT06374459

Zunsemetinib in Combination With Capecitabine ... This is a phase Ib/II study evaluating the safety and efficacy of zunsemetinib (ATI-450) with capecitabine in patients with ... breast cancer (MBC).

8. sciencedirect.com sciencedirect.com/science/article/pii/S2589537025004687

Efficacy and safety of systemic therapies following ... Zunsemetinib in combination with capecitabine in patients with hormone receptor-positive and HER2-negative metastatic breast cancer with bone metastasis.