- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT05244434
Effects of Ribociclib and Palbociclib on Tumor and Blood Characteristics in Patients With Metastatic Breast Cancer
Comparative Effects of Ribociclib and Palbociclib on Circulating and Tumor Infiltrating Myeloid Cells in Metastatic Breast Cancer Patients
Study Overview
Status
Conditions
- Anatomic Stage III Breast Cancer AJCC v8
- Anatomic Stage IIIA Breast Cancer AJCC v8
- Anatomic Stage IIIB Breast Cancer AJCC v8
- Anatomic Stage IIIC Breast Cancer AJCC v8
- Prognostic Stage III Breast Cancer AJCC v8
- Prognostic Stage IIIA Breast Cancer AJCC v8
- Prognostic Stage IIIB Breast Cancer AJCC v8
- Prognostic Stage IIIC Breast Cancer AJCC v8
- Anatomic Stage IV Breast Cancer AJCC v8
- Prognostic Stage IV Breast Cancer AJCC v8
- Hormone Receptor-Positive Breast Carcinoma
- Metastatic HER2-Negative Breast Carcinoma
- Metastatic Breast Adenocarcinoma
- Advanced Breast Adenocarcinoma
- Advanced HER2-Negative Breast Carcinoma
Intervention / Treatment
Detailed Description
PRIMARY OBJECTIVE:
I. To identify predictive immune biomarkers and mechanisms of response to ribociclib or palbociclib in advanced, hormone receptor positive breast cancer patients.
SECONDARY OBJECTIVES:
I. Identify changes in antigen presentation machinery and costimulatory molecules on circulating myeloid cells as a result of ribociclib or palbociclib treatment.
II. Characterize the dynamic remodeling of circulating myeloid cell composition that occur as a result of ribociclib or palbociclib treatment.
III. Characterize acquired immune tumor microenvironment features of resistance in patients that progress while undergoing ribociclib or palbociclib treatment.
EXPLORATORY OBJECTIVE:
I. To study the association between immune biomarkers and clinical response.
OUTLINE: Patients are assigned to 1 of 2 cohorts.
PROSPECTIVE COHORT: Patients receive standard of care (SOC) treatment consisting of ribociclib or palbociclib plus aromatase inhibitor (AI). Patients undergo biopsy of tumor tissue at baseline and post-treatment. Patients also undergo collection of blood samples at baseline, on day 1 of SOC treatment cycles 2, 4, and 6, every 6 cycles thereafter, and at post-treatment.
RETROSPECTIVE COHORT: Patients' tumor tissue collected during previous SOC treatment (ribociclib or palbociclib plus AI) is used for analysis.
Study Type
Phase
- Not Applicable
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- Patients with histological confirmed breast adenocarcinoma who meet the following criteria:
- Age: >= 18 years and are post-menopausal
- Estrogen receptor positive (ER+) and human epidermal growth factor receptor 2 (HER2) negative breast cancer patients who prospectively may undergo evaluation for Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i), ribociclib or palbociclib, as part of first-line therapy. Retrospective cohorts will be built to include either ribociclib or palbociclib treated patients with known clinical outcome
- During routine standard of care procedure, tumor that is accessible for ultrasound guided biopsy (from breast, lymph node, subcutaneous tumor, or selected liver metastasis per treating physician's discretion) or skin punch biopsy (for dermal metastasis) will be collected
- Available tumor tissue or planning on biopsy prior to initiation of CDK4/6i treatment
- Available tumor tissue or planning on biopsy at time of progression, prior to initiating subsequent therapy
- Willing to provide consent for extra tissue and blood samples
Exclusion Criteria:
- Patient received prior treatment with any CDK4/6 inhibitor
- Prior treatment with any chemotherapy for metastatic disease
- Patient is cognitively impaired
- Lung or bone metastasis only (not accessible by ultrasound guided biopsy)
Patients with central nervous system (CNS) involvement unless they meet ALL the following criteria:
- Untreated brain metastases (e.g., lesions < 1cm) not needing immediate local therapy
- Previously treated brain metastases not needing immediate local therapy
At least 4 weeks from prior therapy completion (including radiation and/or surgery) to starting the study treatment
- Clinically stable CNS tumor at the time of screening and not receiving steroids and/or enzyme-inducing anti-epileptic medications for brain metastases
- Clinically significant, uncontrolled heart disease and/or cardiac repolarization abnormalities, including any of the following:
Patient is currently receiving any of the following medications and cannot be discontinued 7 days prior to starting study drug:
- Known strong inducers or inhibitors of CYP3A4/5, including grapefruit, grapefruit hybrids, pummelos, star-fruit, and Seville oranges
- That have a narrow therapeutic window and are predominantly metabolized through CYP3A4/5
- Herbal preparations/medications, dietary supplements
- Warfarin or other coumadin-derived anticoagulant for treatment, prophylaxis or otherwise. Therapy with heparin, low molecular weight heparin (LMWH), newer anticoagulation agents such as direct factor Xa inhibitors, or fondaparinux is allowed
Patient is currently receiving or has received systemic corticosteroids =< 2 weeks prior to starting study drug, or who have not fully recovered from side effects of such treatment
- The following uses of corticosteroids are permitted: single doses, topical applications (e.g., for rash), inhaled sprays (e.g., for obstructive airways diseases), eye drops or local injections (e.g., intra-articular)
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Basic Science
- Allocation: Non-Randomized
- Interventional Model: Parallel Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Prospective cohort (SOC treatment, biopsy, blood collection)
Patients receive SOC treatment consisting of ribociclib or palbociclib plus AI.
Patients undergo biopsy of tumor tissue at baseline and post-treatment.
Patients also undergo collection of blood samples at baseline, on day 1 of SOC treatment cycles 2, 4, and 6, every 6 cycles thereafter, and at post-treatment.
|
Undergo blood sample collection
Other Names:
Given standard of care ribociclib + AI or palbociclib + AI
Other Names:
Undergo biopsy of tumor tissue
Other Names:
Undergo analysis of previously collected tumor tissue
|
Experimental: Retrospective cohort
Patients' tumor tissue collected during previous SOC treatment (ribociclib or palbociclib plus AI) is used for analysis.
|
Undergo analysis of previously collected tumor tissue
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Immune cell frequency (relative abundance, cells per parental cell)
Time Frame: From date of initiation of CDK4/6 inhibitor (either ribociclib or palbociclib) to disease progression (clinical or imaging), or, up to a maximum of 5 years
|
Will be assessed by high dimensional flow cytometry.
One-way analysis of variance (ANOVAs) and non-parametric Kruskal-Wallis tests will be used to compare relative abundances across patient groups and over the course of therapy.
Wilcoxon rank-sum test will be used to examine the association between each biomarker of each sample collection and pathological response as appropriate.
Odds ratios and 95% conference intervals will be calculated to measure strength of associations.
P-values < 0.05 will be considered statistically significant.
No adjustment for multiple comparisons will be used in view of the exploratory nature of this analysis.
|
From date of initiation of CDK4/6 inhibitor (either ribociclib or palbociclib) to disease progression (clinical or imaging), or, up to a maximum of 5 years
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Single-cell gene expression
Time Frame: From date of initiation of CDK4/6 inhibitor (either ribociclib or palbociclib) to disease progression (clinical or imaging), or, up to a maximum of 5 years
|
Expected to identify > 30 myeloid and lymphocyte immune subsets.
Gene expression relating to maturation and function will be focused on in myeloid subsets especially.
Will be assessed by single-cell ribonucleic acid (RNA) sequencing.
Immune cell type identification and gene expression patterns will be identified by unsupervised clustering and non-linear dimensionality reduction approaches.
Cluster biomarkers will be identified by Seurat for annotating cell types (or functions) for each cell.
Within each cluster, will compare the cellular differences in RNA expression across response and non-response cohorts of tumor and peripheral blood mononuclear cell (PBMC) samples by built-in MAST package and Wilcoxon rank-sum test, respectively.
Single-cell trajectory analysis for single-cell RNA expression profile will be implemented by Monocle 3 to discover the transitions of cell states in the blood over the course of treatment.
|
From date of initiation of CDK4/6 inhibitor (either ribociclib or palbociclib) to disease progression (clinical or imaging), or, up to a maximum of 5 years
|
Psuedotime gene trajectory
Time Frame: From date of initiation of CDK4/6 inhibitor (either ribociclib or palbociclib) to disease progression (clinical or imaging), or, up to a maximum of 5 years
|
Will be assessed by multiplex immunofluorescence.
Cell classifications based on panel design will be created for all cell objects detected in whole slide images of tissues.
Tissue segmentation for tumor and stroma areas will be created.
Densities of cell classifications within whole tissue, tumor areas, and stroma areas will be calculated.
Neighborhood analysis, based off 25micron radius, will be examined using Cytomap to identify patterns of cell-cell interactions within tissues.
All quantitative image analysis data between pre-treatment and post-treatment samples will be compared in the context of clinical response to CDK4/6i by Wilcoxon rank-sum tests.
|
From date of initiation of CDK4/6 inhibitor (either ribociclib or palbociclib) to disease progression (clinical or imaging), or, up to a maximum of 5 years
|
Cells per mm^2 tissue
Time Frame: From date of initiation of CDK4/6 inhibitor (either ribociclib or palbociclib) to disease progression (clinical or imaging), or, up to a maximum of 5 years
|
Will be assessed by multiplex immunofluorescence.
Cell classifications based on panel design will be created for all cell objects detected in whole slide images of tissues.
Tissue segmentation for tumor and stroma areas will be created.
Densities of cell classifications within whole tissue, tumor areas, and stroma areas will be calculated.
Neighborhood analysis, based off 25micron radius, will be examined using Cytomap to identify patterns of cell-cell interactions within tissues.
All quantitative image analysis data between pre-treatment and post-treatment samples will be compared in the context of clinical response to CDK4/6i by Wilcoxon rank-sum tests.
|
From date of initiation of CDK4/6 inhibitor (either ribociclib or palbociclib) to disease progression (clinical or imaging), or, up to a maximum of 5 years
|
Cells per mm^2 cancer island
Time Frame: From date of initiation of CDK4/6 inhibitor (either ribociclib or palbociclib) to disease progression (clinical or imaging), or, up to a maximum of 5 years
|
Will be assessed by multiplex immunofluorescence.
Cell classifications based on panel design will be created for all cell objects detected in whole slide images of tissues.
Tissue segmentation for tumor and stroma areas will be created.
Densities of cell classifications within whole tissue, tumor areas, and stroma areas will be calculated.
Neighborhood analysis, based off 25micron radius, will be examined using Cytomap to identify patterns of cell-cell interactions within tissues.
All quantitative image analysis data between pre-treatment and post-treatment samples will be compared in the context of clinical response to CDK4/6i by Wilcoxon rank-sum tests.
|
From date of initiation of CDK4/6 inhibitor (either ribociclib or palbociclib) to disease progression (clinical or imaging), or, up to a maximum of 5 years
|
Average cell-cell distances (within neighborhood)
Time Frame: From date of initiation of CDK4/6 inhibitor (either ribociclib or palbociclib) to disease progression (clinical or imaging), or, up to a maximum of 5 years
|
Will be assessed by multiplex immunofluorescence.
Cell classifications based on panel design will be created for all cell objects detected in whole slide images of tissues.
Tissue segmentation for tumor and stroma areas will be created.
Densities of cell classifications within whole tissue, tumor areas, and stroma areas will be calculated.
Neighborhood analysis, based off 25micron radius, will be examined using Cytomap to identify patterns of cell-cell interactions within tissues.
All quantitative image analysis data between pre-treatment and post-treatment samples will be compared in the context of clinical response to CDK4/6i by Wilcoxon rank-sum tests.
|
From date of initiation of CDK4/6 inhibitor (either ribociclib or palbociclib) to disease progression (clinical or imaging), or, up to a maximum of 5 years
|
Cells per mm^2 stroma
Time Frame: From date of initiation of CDK4/6 inhibitor (either ribociclib or palbociclib) to disease progression (clinical or imaging), or, up to a maximum of 5 years
|
Will be assessed by multiplex immunofluorescence.
Cell classifications based on panel design will be created for all cell objects detected in whole slide images of tissues.
Tissue segmentation for tumor and stroma areas will be created.
Densities of cell classifications within whole tissue, tumor areas, and stroma areas will be calculated.
Neighborhood analysis, based off 25micron radius, will be examined using Cytomap to identify patterns of cell-cell interactions within tissues.
All quantitative image analysis data between pre-treatment and post-treatment samples will be compared in the context of clinical response to CDK4/6i by Wilcoxon rank-sum tests.
|
From date of initiation of CDK4/6 inhibitor (either ribociclib or palbociclib) to disease progression (clinical or imaging), or, up to a maximum of 5 years
|
Number of core cells with cell(s) in neighborhood
Time Frame: From date of initiation of CDK4/6 inhibitor (either ribociclib or palbociclib) to disease progression (clinical or imaging), or, up to a maximum of 5 years
|
Will be assessed by multiplex immunofluorescence.
Cell classifications based on panel design will be created for all cell objects detected in whole slide images of tissues.
Tissue segmentation for tumor and stroma areas will be created.
Densities of cell classifications within whole tissue, tumor areas, and stroma areas will be calculated.
Neighborhood analysis, based off 25micron radius, will be examined using Cytomap to identify patterns of cell-cell interactions within tissues.
All quantitative image analysis data between pre-treatment and post-treatment samples will be compared in the context of clinical response to CDK4/6i by Wilcoxon rank-sum tests.
|
From date of initiation of CDK4/6 inhibitor (either ribociclib or palbociclib) to disease progression (clinical or imaging), or, up to a maximum of 5 years
|
Number of spatial clusters
Time Frame: From date of initiation of CDK4/6 inhibitor (either ribociclib or palbociclib) to disease progression (clinical or imaging), or, up to a maximum of 5 years
|
Will be assessed by multiplex immunofluorescence.
Cell classifications based on panel design will be created for all cell objects detected in whole slide images of tissues.
Tissue segmentation for tumor and stroma areas will be created.
Densities of cell classifications within whole tissue, tumor areas, and stroma areas will be calculated.
Neighborhood analysis, based off 25micron radius, will be examined using Cytomap to identify patterns of cell-cell interactions within tissues.
All quantitative image analysis data between pre-treatment and post-treatment samples will be compared in the context of clinical response to CDK4/6i by Wilcoxon rank-sum tests.
|
From date of initiation of CDK4/6 inhibitor (either ribociclib or palbociclib) to disease progression (clinical or imaging), or, up to a maximum of 5 years
|
Collaborators and Investigators
Sponsor
Collaborators
Investigators
- Principal Investigator: Yuan Yuan, City of Hope Medical Center
Study record dates
Study Major Dates
Study Start (Anticipated)
Primary Completion (Anticipated)
Study Completion (Anticipated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- 21623 (City of Hope Medical Center)
- P30CA033572 (U.S. NIH Grant/Contract)
- NCI-2022-00238 (Registry Identifier: CTRP (Clinical Trial Reporting Program))
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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