Hormone Receptor Positive HER-2 Negative Metastatic Breast CancerPhase 1/2NCT06374459
Zunsemetinib in Combination With Capecitabine in Patients With Hormone Receptor-Positive and HER2-Negative Metastatic Breast Cancer With Bone Metastasis
A Phase 1/2 study testing Zumsemetinib, Capecitabine and Zoledronic acid in people with Hormone Receptor Positive HER-2 Negative Metastatic Breast Cancer, run by Washington University School of Medicine at 3 sites in United States.
Trial summary
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). Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Hormone Receptor Positive HER-2 Negative Metastatic Breast Cancer
- What is being tested?
- Zumsemetinib, Capecitabine and Zoledronic acid
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 152 participants
- Where
- 3 sitesUnited States
- Study dates
- 30 Jan 2025to 31 May 2032
- Phase
- Phase 1/2
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Hormone receptor-positive, HER2-negative metastatic breast cancer.
- Measurable or non-measurable but evaluable disease by RECIST v1.1.
- Candidate for capecitabine treatment per physician decision. See below phase-specific eligibility criteria for further guidance.
- No more than one prior chemotherapy for metastatic disease.
- Patient must have received prior endocrine therapy with CDK4/6 inhibitor.
- If patient is on denosumab or zoledronic acid prior to enrollment, patient must have been on the regimen for at least 6 months prior to study. However, a washout of 3 weeks is required prior to C1D1.
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- At least 18 years of age.
- ECOG performance status 0, 1, or 2
- Life expectancy of at least 12 weeks.
- Adequate bone marrow and organ function as defined below:
- Leukocytes ≥ 3 K/cumm
- Absolute neutrophil count (ANC) ≥ 1.5 K/cumm
- Platelets ≥ 100 K/cumm
- Total bilirubin ≤ 1.5 x IULN (or total bilirubin ≤ 3 mg/dL if patient has known Gilbert Syndrome)
- AST(SGOT)/ALT(SGPT) ≤ 3.0 x IULN
- Creatinine clearance > 60 mL/min by Cockcroft-Gault
- Calcium within normal limits
- Women of childbearing potential and men who are heterosexually active must agree to use adequate contraception as specified in the protocol. Contraception should continue for 6 months (for women) or 3 months (for men) after the end of treatment. Should a woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately.
- Ability to understand and willingness to sign an IRB approved written informed consent document.
- Patients must have archival tissue sample available from prior metastatic biopsy. If no tissue is available, patient may still be able to enroll with PI approval.
- Presence of bone metastasis is not required.
- Candidate for, or currently on stable doses of capecitabine, defined as capecitabine: 1000 mg/m^2 BID, 14 days on and 7 days off. A stable dose of capecitabine is defined as no more than grade 1 AEs related to capecitabine on the 1000 mg/m^2 BID, 14 days on and 7 days off dose for at least 1 cycle. Capecitabine is not counted as a prior chemotherapy regimen in these patients.
- Progressive bone metastasis per the most recent tumor imaging studies by RECIST 1.1 or clinical progression (such as worsening bone pain, elevation of tumor marker) per treating physician.
Who cannot join
- Patients may not have received the following investigational or SOC therapies within the below specified time frames prior to C1D1:
- Radiation therapy within 1 week
- Systemic chemotherapy, including antibody drug conjugates with chemotherapy payload, within 3 weeks.
- Immunotherapy within 3 weeks
- Oral chemotherapy or molecularly targeted therapy within 5 half-lives of the agent.
- Endocrine therapies do not have a required washout and may be continued until C1D1.
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- Strong and moderate CYP3A4 and CYP2C8 inhibitors (including grapefruit), strong and moderate CYP3A and CYP2C8 inducers, and drugs with QT prolonging potential within 5 half-lives of the agent.
- Untreated brain metastases. Patients with treated brain metastases are eligible if they show no evidence of progression and are off steroids.
- A history of allergic reactions attributed to compounds of similar chemical or biologic composition to zunsemetinib or other agents used in the study.
- History of acute, untreated skeletal related events (SRE) or active untreated SRE or a change or an anticipated change in the SOC anti-resorptive agents after entering the study.
- Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, or cardiac arrhythmia.
- Pregnant and/or breastfeeding. Women of childbearing potential must have a negative pregnancy test within 14 days of C1D1.
- Patients with HIV are eligible unless their CD4+ T-cell counts are < 350 cells/mcL or they have a history of AIDS-defining opportunistic infection within the 12 months prior to Cycle 1 Day 1. Concurrent treatment with effective ART according to DHHS treatment guidelines is recommended.
- Screening resting QTcF above 470 msec.
- Capecitabine within 2 weeks prior to C1D1. Patients may be currently taking capecitabine, but must not have dosed within 2 weeks prior to C1D1 for study correlative purposes.
- Prior capecitabine in the metastatic setting.
- History of other malignancy, unless all treatment was completed and patient had no evidence of disease within 2 years of C1D1.
Trial locations and contacts
3 sites in 1 country. Contact the study team or a site near you to ask about taking part.
United States3 sites, 3 recruiting
- Recruiting
Mayo Clinic
Rochester, Minnesota, 55905
Ciara O'Sullivan, M.D., B.Ch., 507-284-2511
Ciara O'Sullivan, M.D., B.Ch.
- Recruiting
Washington University School of Medicine
St Louis, Missouri, 63110
Cynthia X Ma, M.D., Ph.D., 314-362-8903, cynthiaxma@wustl.edu
Cynthia X Ma, M.D., Ph.D.
- Recruiting
The University of Kansas Cancer Center
Westwood, Kansas, 66205
Qamar Khan, M.D., 913-588-1227
Qamar Khan, M.D.
About this study
Official title: A Phase Ib/II Trial of Zunsemetinib in Combination With Capecitabine in Patients With Hormone Receptor-Positive and HER2-Negative Metastatic Breast Cancer With Bone Metastasis
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).
- Being tested
- Zumsemetinib, Capecitabine, Zoledronic acid, Denosumab
- Keywords
- Zunsemetinib, ATI-450, MK-2, Bone metastasis, Breast Cancer, HR-positive/HER2-negative, Capecitabine
- Medical subject headings
- Breast Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
ZumsemetinibDrug
Also called ATI-450
Patients should take zunsemetinib at approximately the same times every day, with or without food with 8 oz of water.
CapecitabineDrug
Patients should take capecitabine at approximately the same times every day, within 30 minutes after a meal.
Zoledronic acidDrug
Standard of care. Will receive zoledronic acid or denosumab.
DenosumabDrug
Standard of care. Will receive zoledronic acid or denosumab.
| Study group | Role | What they receive |
|---|---|---|
| Phase Ib: Zunsemetinib + Capecitabine | Experimental | 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. Receives: Drug: Zumsemetinib; Drug: Capecitabine |
| Phase II Arm 1: Standard of care anti-resorptive + Capecitabine | Active comparator | 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. Receives: Drug: Capecitabine; Drug: Zoledronic acid; Drug: Denosumab |
| Phase II Arm 2: Zunsemetinib (RP2D-L1) + Capecitabine | Experimental | 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. Receives: Drug: Zumsemetinib; Drug: Capecitabine |
| Phase II Arm 3: Zunsemetinib (RP2D-L2) + Capecitabine | Experimental | 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. Receives: Drug: Zumsemetinib; Drug: Capecitabine |
What is being measured
The primary outcome is the main question the study is designed to answer.
Number of participants with adverse events (Phase Ib only)
Measured: From start of treatment through 30 days after end of treatment (estimated to be 11 months)
Recommended phase II dose of zunsemetinib (Phase Ib only)
Measured: Through end of 1st cycle (each cycle is 21 days)
Number of participants with dose-limiting toxicities (Phase Ib only)
Measured: Through end of 1st cycle (each cycle is 21 days)
Percent change in serum CTX (Phase II only)
Measured: Baseline and Day 1 of week 7
Progression-free survival (PFS) (Phase II only)
Measured: From start of treatment through completion of follow-up (estimated to be 3 years and 10 months)
Secondary outcomes (9)
Treatment-induced changes in DEXA BMD (g/cm^2) at hip and spine (Phase Ib only)
Measured: Baseline, end of cycle 8 (each cycle is 21 days), and end of treatment (estimated to be 10 months)
Treatment-induced changes in sCTX by clinical assay (Phase II only)
Measured: Baseline, cycle 1 day 1 pre-dose, cycle 1 day 8 pre-dose, cycle 1 day 15 pre-dose, day 1 of subsequent cycles (each cycle is 21 days), and end of treatment (estimated to be 10 months)
Objective response rate (ORR) (Phase II only)
Measured: Through completion of treatment (estimated to be 10 months)
Clinical benefit rate (Phase II only)
Measured: Through completion of treatment (estimated to be 10 months)
Overall survival (OS) (Phase II only)
Measured: From start of treatment through completion of follow-up (estimated to be 3 years and 10 months)
Treatment-induced changes in DEXA BMD (g/cm^2) at hip and spine (Phase II only)
Measured: Baseline, end of cycle 8, and end of treatment (estimated to be 10 months)
Treatment-induced changes in quality of life as measured by EORTC QLQ-C30 (Phase II only)
Measured: Prior to start of 1st treatment, cycle 5 day 1, every 4 cycles thereafter (each cycle is 21 days), and at the time of progression (estimated to be 3 years and 10 months)
Treatment-induced changes in pain as measured by Brief Pain Inventory (BPI) (Phase II only)
Measured: Prior to start of 1st treatment, cycle 5 day 1, every 4 cycles thereafter (each cycle is 21 days), and at the time of progression (estimated to be 3 years and 10 months)
Number of participants with adverse events (Phase II only)
Measured: From start of treatment through 30 days after end of treatment (estimated to be 11 months)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted18 Apr 2024
- Study start30 Jan 2025
- Primary completion31 May 2032 (estimated)
- Study completion31 May 2032 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Hormone Receptor Positive HER-2 Negative Metastatic Breast CancerStudies of the same condition, open and under way.
- More trials run by Washington University School of MedicineThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Sequential
- Model description
- The Phase I portion of the study is sequential and patients will not be randomized and the Phase II portion is parallel and patients will be randomized.
- Masking
- None (open label)
- Enrolment
- 152 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Washington University School of Medicine
- Sponsor type
- University, hospital or other
- Collaborators
- United States Department of Defense, Aclaris Therapeutics, Inc.
- Responsible party
- Sponsor
- Investigators
- Cynthia X Ma, M.D., Ph.D., Principal investigator, Washington University School of Medicine
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06374459
- Sponsor's protocol ID
- 202406065
- Other IDs
- BC200714
- Status last verified
- Oct 2026
- First submitted
- 10 Apr 2024
- Last updated
- 13 Oct 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: The investigator will share deidentified individual patient level data upon request after publication of the trial results.