A Phase 1 interventional study of Palbociclib and Rivaroxaban in Cancer, Solid Tumor and Thromboembolism, sponsored by Lebanese University. Recruiting at 2 sites in Lebanon. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2023-10-06.
Sponsored by Lebanese University · Phase 1, Interventional, and Prevention
This study aims to assess biomarkers and their related polymorphisms in the context of cancer-associated thromboembolism, with a particular focus on their interaction with the immune system. The roles of immune checkpoints, inflammatory and angiogenesis factors, as well as circulating immune cells will be elucidated. Additionally, our investigation extends to the exploration of long non-coding RNAs (LncRNAs) and genes associated with the coagulation vascular system. Initially, these aspects will be evaluated in the context of colorectal cancer, with the intention to expand our research to other solid tumors.
The identification of these biomarkers and genetic factors holds the potential to revolutionize therapeutic approaches for patients with cancer-associated thromboembolism, shedding light on their chemotherapy resistance. The effectiveness of combining immunotherapy with targeted inhibitors like Palbociclib and anticoagulants such as Rivaroxaban, among other potential interventions, will be assessed.
This study aims to make significant contributions to the understanding of these critical aspects, ultimately leading to the development of more effective treatment strategies for cancer patients.
Cancer, especially solid tumors, remains a significant global health challenge despite ongoing advancements in risk factor identification and targeted therapies. Among the various complexities of cancer treatment, the relationship between cancer and thromboembolism, characterized by arterial and venous thrombosis, has attracted attention due to its significant impact on patient outcomes.
Cancer cells activate the coagulation system, leading to prothrombotic disorders in the vascular wall and promoting tumor progression. Patients with cancer, particularly those undergoing systemic chemotherapy, face an increased risk of thromboembolism due to abnormal blood clotting mechanisms.
Recent research has emphasized the importance of identifying novel biomarkers for risk assessment, prognosis determination, and treatment selection in cancer. Among these biomarkers, long non-coding RNAs (LncRNAs) and those of the vascular coagulation system have emerged as pivotal players in cancer development and progression. However, their role as prognostic and predictive biomarkers for cancer risk and treatment response remains relatively unexplored.
Understanding the complex interplay between cancer, immune responses, and thromboembolism is crucial. Immunological subsets, including central immune effector T cells (CD8+, CD25+), NK cells, and macrophages, have been linked to cancer prognosis. Furthermore, therapies that modulate the immune system, such as immunotherapy and cell-based therapies, hold promise for improving cancer treatment outcomes.
Most notably, these therapies exhibit immunomodulatory effects, triggering immunogenic cell death and preventing immunosuppression. However, their efficacy may be compromised in cases of cancer associated with clotting abnormalities within the circulatory system. Progenitor cells, including stem cells and endothelial progenitor cells (EPCs), are emerging as potential players in cancer therapy, offering new avenues for research.
Among the innovative approaches is the assessment of circulating immune and endothelial progenitor cells (termed "CIEs"), which may play significant roles in the mechanisms underlying cancer-associated thromboembolism. Understanding the relationship between these cells, inflammatory and angiogenic factors, immune checkpoint, and cancer progression could pave the way for improved cancer risk assessment and treatment strategies.
This study seeks to contribute to our understanding of the intricate connections between LncRNA, coagulation-related biomarkers, thromboembolism, immune responses, and cancer, using solid tumors as a representative example. By shedding light on these complex interactions, this study aims to identify potential biomarkers that can guide risk assessment and treatment decisions, ultimately improving the management of cancer patients.
Exclusion Criteria:
Cancer patients without any incidence of thromboembolism will be included if they are non-carriers of the targeted gene-related polymorphism (GRP).
Genetic: SNP
Cancer patients without any incidence of thromboembolism will be included if they are carriers of the targeted gene-related polymorphism.
Genetic: SNP
Cancer patients with incidence of thromboembolism will be included if they are carriers of the targeted gene-related polymorphism.
Genetic: SNP
Cancer patients with incidence of thromboembolism will be included if they are carriers of the targeted gene-related polymorphism and will be subjected to Palbociclib treatment.
Drug: Palbociclib · Genetic: SNP
Cancer patients with incidence of thromboembolism will be included if they are carriers of the targeted gene-related polymorphism and will be subjected to anti-coagulant treatment.
Drug: Rivaroxaban · Genetic: SNP
Palbociclib will be administered at a dose of 125 mg oral on a 21/7 cycle.
Also known as: Ibrance
Rivaroxaban will be administered at a dosage of 15 mg intravenously twice a day for 21 days, followed by 20 mg once daily for the subsequent 21 days.
Also known as: Xarelto
diagnostics of patients' carriers or not of the risk allele(s)
Also known as: Risk Allele(s)
Venous Thromboembolism (VTE) Events including: Deep Vein Thrombosis (DVT), Pulmonary Embolism (PE), and other Thromboembolic Events (Vein Thrombosis, Portal Vein Thrombosis, Superior Mesenteric Vein Thrombosis, and Renal Vein Thrombosis)
The outcome measure of VTE including DVT, PE, and other thromboembolic events will be assessed by : (1) Clinical Assessment: Clinical symptoms such as swelling and pain in the lower limbs, tenderness behind the lower leg and/or medial thigh, and supplementary evaluation with color ultrasound of the veins in both lower limbs (lower extremity venography); (2) Imaging: CT pulmonary arteriography (CTPA) will be employed in conjunction with related clinical manifestations such as dyspnea and shortness of breath for diagnosing PE; (3) Laboratory Criteria: Diagnostic criteria will also consider laboratory parameters, including elevated D-dimer levels (\> 1000 ng/mL), increased fibrinogen levels (\> 700 mg/dL), and shortened activated partial thromboplastin time (aPTT) (\< 20 sec).
Time frame: up to 60 months
Assessment of Cancer Progression
The assessment of cancer progression will be conducted using the standardized TNM staging system and applying the Response Evaluation Criteria (RECIST) guideline (ver. 1.1). Clinical parameters, laboratory tests indicative of cancer progression (including tumor markers and histopathological analysis), and relevant imaging modalities (e.g., CT, MRI, or PET scans) will be employed to evaluate the extent of primary tumor growth, lymph node involvement, and the presence of distant metastases. Progression-Free Survival (PFS), a key primary clinical endpoint for assessing cancer progression, will be calculated as the duration (in months) from the date of enrollment in the study until the tumor progresses, new lesions appear, or until the participant's death from any cause. Cancer progression will be determined based on RECIST guidelines, considering an increase in tumor size or the appearance of new lesions according to imaging assessments and clinical evaluations.
Time frame: up to 60 months
Identification of Potential Biomarkers
The objective of this outcome is to identify and characterize novel biomarkers associated with thromboembolism and cancer progression. Specifically, the assessment will focus on Long Non-Coding RNAs (LncRNAs) such as CDKN2B and CDKN2B-AS1, and markers related to the vascular coagulation system including ACE, PAI-1, FXIII, and Prothrombin. This identification process will involve collecting biological samples (e.g., blood, tissue) from enrolled patients at the time of study enrollment. The assessment will analyze and evaluate the expression and polymorphisms of the studied genes (CDKN2B, CDKN2B-AS1, ACE, PAI-1, FXIII, and Prothrombin) using quantitative PCR (qPCR), with Ct (Cycle threshold) as the common unit of measure for all genes. This comprehensive assessment aims to enhance our understanding of the molecular signatures linked to thromboembolism and cancer progression, illuminating potential diagnostic and therapeutic avenues for improved patient outcomes.
Time frame: Once at the moment of the patient's enrollment in the study
Evaluation of Treatment Response to Palbociclib
This primary outcome assesses treatment response in patients undergoing Palbociclib therapy for controlling cancer progression and thromboembolism. The evaluation will employ RECIST criteria to measure the percentage change in tumor size, indicative of treatment effectiveness.
Time frame: up to 60 months
Survival Rates
Analysis of overall survival and progression-free survival rates among groups
Time frame: up to 60 months
Examination of Genetic Variants, specifically rs1333049 G>C Polymorphism within the CDKN2B-AS1 Gene
The objective of this secondary outcome is to examine genetic variants, with a specific focus on the rs1333049 G\>C polymorphism within the CDKN2B-AS1 gene. The screening for polymorphism(s) will be determined by genotyping analysis using TaqMan PCR-based genotyping for SNP identification.
Time frame: Once at the moment of the patient's enrollment in the study
Adverse Events
Monitoring and reporting of adverse events related to the Palbociclib and Rivaroxaban treatment regimen.
Time frame: up to 60 months
Immunophenotyping of Immune Cell Populations
This outcome aims to comprehensively assess immune cell populations involved in the immune response, including T cells, B cells, natural killer (NK) cells, dendritic cells (DCs), and macrophages. The objective is to characterize changes in immune cell subsets over time, providing insights into the immune response dynamics. The assessment will involve immunophenotyping using flow cytometry to quantify and analyze the different immune cell populations. The unit of measure for this assessment will be the percentage of change of T cells, B cells, NK cells, DCs, and macrophages in the total population. The percentage of change will be determined up to a period of 60 months relatively to their levels at the diagnostic time.
Time frame: up to 60 months
Inflammatory Cytokine Profiling
This outcome focuses on assessing the levels of cytokines secreted by immune cells, including interferons (IFNs), interleukins (ILs), and tumor necrosis factor (TNF). The objective is to understand cytokine dynamics and their role in the immune response. The assessment will involve cytokine profiling by flow cytometry or ELISA. The levels of IFNs, ILs, and TNF will be measured as a percentage of change over a period of 60 months, relative to their levels at the diagnostic time. This standardized approach of using a common unit of measure will enable a comprehensive and unified evaluation of cytokine variations, providing critical insights into the immune response dynamics throughout the study duration.
Time frame: up to 60 months
Evaluation of Tumor-Infiltrating Lymphocytes (TILs)
This outcome aims to evaluate the presence and distribution of TILs within the tumor microenvironment. The objective is to understand the role of TILs in the immune response against the tumor. The assessment will involve analyzing tissue samples for TIL presence and distribution by immunohistochemistry (IHC) or flow cytometry.
Time frame: up to 60 months
Assessment of Immune Checkpoint Expression (e.g., PD-1 and CTLA-4)
This outcome focuses on investigating the expression of immune checkpoint molecules, specifically programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). The objective is to understand the role of immune checkpoints in regulating the immune response. The assessment will involve evaluating immune checkpoint expression using techniques such as flow cytometry or PCR. The levels of PD-1 and CTLA-4 expression will be measured in the percentage of change over a period of 60 months, relative to their levels at the diagnostic time. Utilizing a standardized common unit of measure ensures a uniform assessment, allowing for a comprehensive understanding of the immune checkpoint dynamics and their impact on the immune response throughout the study's duration.
Time frame: up to 60 months
Measurement of Angiogenic Factors (e.g., VEGF)
This outcome aims to assess alterations in angiogenic factors, with a specific focus on Vascular Endothelial Growth Factor (VEGF), in relation to treatment and study outcomes. VEGF is a key regulator of angiogenesis and is associated with tumor vascularization. The serum concentrations of VEGF-A/C will be measured by ELISA, providing valuable insights into the angiogenic processes linked to the immune response and their potential impact on treatment outcomes.
Time frame: up to 60 months
Plan to share: No
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Lebanese University