Zunsemetinib in Combination With Capecitabine in Patients With Hormone Receptor-Positive and HER2-Negative Metastatic Breast Cancer With Bone Metastasis

NCT06374459 | Recruiting Phase 1 DMC FDA Drug

• 2 other identifiers: 202406065BC200714
• Study Type: interventional
• Target: 152
• Locations: 1 country
• Sites: 3

Brief 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).

Conditions

Hormone Receptor Positive HER-2 Negative Metastatic Breast Cancer

Keywords

Zunsemetinib; ATI-450; MK-2; Bone metastasis; Breast Cancer; HR-positive/HER2-negative; Capecitabine

Outcome Measures

Primary Outcomes (5)

• Number of participants with adverse events (Phase Ib only)

  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)

  Through end of 1st cycle (each cycle is 21 days)

• Number of participants with dose-limiting toxicities (Phase Ib only)

  Through end of 1st cycle (each cycle is 21 days)

• Percent change in serum CTX (Phase II only)

  Baseline and Day 1 of week 7

• Progression-free survival (PFS) (Phase II only)

  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)

  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)

  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)

  Through completion of treatment (estimated to be 10 months)

• Clinical benefit rate (Phase II only)

  Through completion of treatment (estimated to be 10 months)

• Overall survival (OS) (Phase II only)

  From start of treatment through completion of follow-up (estimated to be 3 years and 10 months)

Study Arms (4)

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.

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.

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.

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.

Drug: Zumsemetinib; Drug: Capecitabine

Interventions

Zumsemetinib DRUG

Patients should take zunsemetinib at approximately the same times every day, with or without food with 8 oz of water.

Also known as: ATI-450

Phase II Arm 2: Zunsemetinib (RP2D-L1) + Capecitabine; Phase II Arm 3: Zunsemetinib (RP2D-L2) + Capecitabine; Phase Ib: Zunsemetinib + Capecitabine

Capecitabine DRUG

Patients should take capecitabine at approximately the same times every day, within 30 minutes after a meal.

Phase II Arm 1: Standard of care anti-resorptive + Capecitabine; Phase II Arm 2: Zunsemetinib (RP2D-L1) + Capecitabine; Phase II Arm 3: Zunsemetinib (RP2D-L2) + Capecitabine; Phase Ib: Zunsemetinib + Capecitabine

Zoledronic acid DRUG

Standard of care. Will receive zoledronic acid or denosumab.

Phase II Arm 1: Standard of care anti-resorptive + Capecitabine

Denosumab DRUG

Standard of care. Will receive zoledronic acid or denosumab.

Phase II Arm 1: Standard of care anti-resorptive + Capecitabine

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• 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

You may not qualify if:

• 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.
• 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.

Sponsors & Collaborators

• Washington University School of Medicine: lead
• United States Department of Defense: collaborator
• Aclaris Therapeutics, Inc.: collaborator

Study Sites (3)

The University of Kansas Cancer Center

Westwood, Kansas, 66205, United States

RECRUITING

Mayo Clinic

Rochester, Minnesota, 55905, United States

NOT YET RECRUITING

Washington University School of Medicine

St Louis, Missouri, 63110, United States

RECRUITING

Related Links

• Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine

MeSH Terms

Conditions

Breast Neoplasms

Interventions

Capecitabine; Zoledronic Acid; Denosumab

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Fluorouracil; Uracil; Pyrimidinones; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Diphosphonates; Organophosphonates; Organophosphorus Compounds; Organic Chemicals; Imidazoles; Azoles; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Cynthia X Ma, M.D., Ph.D.

  Washington University School of Medicine

  PRINCIPAL INVESTIGATOR

Central Study Contacts

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

CONTACT

314-362-8903; cynthiaxma@wustl.edu

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: April 10, 2024
• First Posted: April 18, 2024
• Study Start: January 30, 2025
• Primary Completion (Estimated): May 31, 2032
• Study Completion (Estimated): May 31, 2032
• Last Updated: April 20, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP
• Time Frame: After publication of trial results.
• Access Criteria: Data use agreement will be needed and contact can be made with the Principal Investigator for requests.

Locations

US (3)