Zunsemetinib in Combination with Capecitabine for the Treatment of Patients with Hormone Receptor-Positive and HER2-Negative Metastatic Breast Cancer
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 with hormone receptor-positive and HER2-negative breast cancer that has spread from where it first started (primary site) to other places in the body (metastatic). Bone metastases are common in metastatic breast patients and increases the risk for skeletal-related events (SREs), including bone fractures and spinal cord compression. SREs are associated with reduced survival. Currently, bisphosphonates and denosumab are used to reduce the risk of SREs but they have little effect on pain relief and anti-tumor activity. Zunsemetinib works by targeting a molecule which may play a role in inflammation and bone loss. Zunsemetinib may also slow or stop the growth of tumor cells as well as potentially to improve symptoms. Capecitabine is in a class of medications called antimetabolites. It is taken up by tumor cells and breaks down into fluorouracil, a substance that kills tumor cells. Giving zunsemetinib in combination with capecitabine may be safe, tolerable, and/or effective in treating patients with hormone-receptor positive and HER2-negative metastatic breast cancer.
Inclusion Criteria
- Hormone receptor-positive, HER2-negative metastatic breast cancer
- Measurable or non-measurable but evaluable disease by Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1
- Candidate for capecitabine treatment per physician decision
- 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 cycle 1 day 1 (C1D1)
- At least 18 years of age
- Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2
- Life expectancy of at least 12 weeks
- Leukocytes ≥ 3 K/cumm
- Absolute neutrophil count (ANC) ≥ 1.5 K/cumm
- Platelets ≥ 100 K/cumm
- Total bilirubin ≤ 1.5 x institutional upper limit of normal (IULN) (or total bilirubin ≤ 3 mg/dL if patient has known Gilbert syndrome)
- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) /alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [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 Institutional Review Board (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 principal investigator (PI) approval
- PHASE IB ONLY: Presence of bone metastasis is not required
- PHASE IB ONLY: 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 adverse events (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
- PHASE II ONLY: 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
Exclusion Criteria
- 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 C1D1. Concurrent treatment with effective anti-retroviral therapy (ART) according to Department of Health and Human Services (DHHS) treatment guidelines is recommended
- Screening resting Fridericia’s formula–corrected QT interval (QTcF) above 470 msec
- PHASE IB ONLY: 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
- PHASE II ONLY: Prior capecitabine in the metastatic setting
- PHASE II ONLY: History of other malignancy, unless all treatment was completed and patient had no evidence of disease within 2 years of C1D1
Additional locations may be listed on ClinicalTrials.gov for NCT06374459.
Locations matching your search criteria
United States
Missouri
Saint Louis
PRIMARY OBJECTIVES:
I. To determine the safety, tolerability, and recommended phase 2 dose (RP2D) of zunsemetinib plus capecitabine. (Phase Ib)
II. To assess whether zunsemetinib plus capecitabine is more effective in reducing serum C-telopeptide crosslink (CTX) level than continuing standard of care anti-resorptive agents with capecitabine when measured after 6 weeks of therapy. (Phase II)
III. To assess whether zunsemetinib is more effective in increasing progression-free survival (PFS) compared to standard of care anti-resorptive agents when combined with capecitabine. (Phase II)
SECONDARY OBJECTIVES:
I. To assess treatment-induced changes in bone mineral density (BMD). (Phase Ib)
II. To assess treatment-induced changes in serum (s)CTX over time. (Phase II)
III. To compare the anti-tumor activity of zunsemetinib-containing arm(s) with the standard of care (SOC) anti-resorptive arm. (Phase II)
IV. To compare changes in BMD at 6 months (or end of treatment) between zunsemetinib-containing arm(s) and the SOC anti-resorptive arm. (Phase II)
V. To compare health-related quality of life and bone pain in patients on the zunsemetinib-containing arm(s) and the SOC anti-resorptive arm. (Phase II)
VI. To determine the adverse events, tolerability of zunsemetinib plus capecitabine. (Phase II)
TERTIARY/EXPLORATORY OBJECTIVES:
I. To explore tissue and blood for predictors of response or adverse events. (Phase Ib)
II. To assess treatment-induced changes in circulating tumor deoxyribonucleic acid (ctDNA). (Phase Ib)
III. To assess treatment-induced changes in circulating immune cell population. (Phase Ib)
IV. To assess impact of zunsemetinib in reducing serum CTX level, other bone turnover markers, inflammatory response and other pharmacodynamic effects in tumor and blood. (Phase Ib)
V. To assess zunsemetinib pharmacokinetics (PK). (Phase Ib)
VI. To assess the anti-tumor effect of zunsemetinib plus capecitabine. (Phase Ib)
VII. To compare treatment-induced changes in levels of other bone turnover markers, plasma inflammatory markers, and other pharmacodynamic effects, over time in zunsemetinib-containing arm(s) and the SOC anti-resorptive arm. (Phase II)
VIII. To explore tissue and blood for predictors of response or adverse events. (Phase II)
IX. To compare ctDNA changes in patients on the zunsemetinib-containing arm(s) and the SOC anti-resorptive arm. (Phase II)
X. To compare treatment-induced changes in circulating immune cell population in patients on the zunsemetinib-containing arm(s) and the SOC anti-resorptive arm. (Phase II)
XI. To compare the rate of SREs and time to first on-study SREs in patients on the zunsemetinib-containing arm(s) and the SOC anti-resorptive arm. (Phase II)
OUTLINE: This is a phase Ib, dose-escalation study of zunsemetinib in combination with capecitabine followed by a randomized phase II study.
Phase Ib: Patients receive zunsemetinib orally (PO) twice daily (BID) on days 1-21 of each cycle and capecitabine PO BID on days 2-15 of cycles 1 and 2 and then on days 1-14 of subsequent cycles. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo blood sample collection, dual X-ray absorptiometry (DEXA), and computed tomography (CT) or bone scan on study. Patients may also undergo optional tumor biopsy or may provide archival tumor sample on study.
Phase II: Patients are randomized to 1 of 3 arms.
ARM I: Patients receive bisphosphonate therapy every 4-12 weeks or denosumab every 4-6 weeks per SOC and capecitabine PO BID on days 1-14 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo blood sample collection, DEXA, and CT or bone scan on study. Patients may also undergo optional tumor biopsy or may provide archival tumor sample on study.
ARM II: Patients receive RP2D dose level 1 zunsemetinib PO BID on days 1-21 and capecitabine PO BID on days 1-14 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo blood sample collection, DEXA, and CT or bone scan on study. Patients may also undergo optional tumor biopsy or may provide archival tumor sample on study.
ARM III: Patients receive RP2D dose level 2 zunsemetinib PO BID on days 1-21 and capecitabine PO BID on days 1-14 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo blood sample collection, DEXA, and CT or bone scan on study. Patients may also undergo optional tumor biopsy or may provide archival tumor sample on study.
After completion of study treatment, patients are followed up at 30 days then yearly for 3 years.
Trial PhasePhase I/II
Trial Typetreatment
Lead OrganizationSiteman Cancer Center at Washington University
Principal InvestigatorCynthia Xiuguang Ma
- Primary ID202406065
- Secondary IDsNCI-2024-07328
- ClinicalTrials.gov IDNCT06374459