Zunsemetinib + Capecitabine for Breast Cancer

Recruiting at 2 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

Trial Summary

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. ^{1 2 3 4 5}

Is 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. ^{3 6 7 8 9}

What 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. ^{1 3 10 11 12}

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).

Research Team

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

Principal Investigator

Washington University School of Medicine

Eligibility 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.

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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]

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]

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 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]

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]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

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

2. United States pubmed.ncbi.nlm.nih.gov

Capecitabine and docetaxel in advanced breast cancer: analyses of a phase III comparative trial. [2018]

3. United States pubmed.ncbi.nlm.nih.gov

Future options with capecitabine (Xeloda) in (neo)adjuvant treatment of breast cancer. [2019]

4. Switzerland pubmed.ncbi.nlm.nih.gov

Efficacy of the oral fluorouracil pro-drug capecitabine in cancer treatment: a review. [2023]

5. Switzerland 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. [2021]

6. United States pubmed.ncbi.nlm.nih.gov

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

7. Scotland pubmed.ncbi.nlm.nih.gov

Development of and clinical experience with capecitabine (Xeloda) in the treatment of solid tumours. [2015]

8. England pubmed.ncbi.nlm.nih.gov

A phase II trial of capecitabine in previously untreated patients with advanced and/or metastatic gastric cancer. [2022]

9. United States pubmed.ncbi.nlm.nih.gov

Safety and efficacy of two different doses of capecitabine in the treatment of advanced breast cancer in older women. [2022]

10. England pubmed.ncbi.nlm.nih.gov

A retrospective observational study on the use of capecitabine in patients with severe renal impairment (GFR [2022]

11. United States pubmed.ncbi.nlm.nih.gov

Pharmacology and clinical status of capecitabine. [2015]

12. Greece pubmed.ncbi.nlm.nih.gov

Capecitabine (Xeloda) as monotherapy in advanced breast and colorectal cancer: effectiveness and side-effects. [2022]