Genomic and Methylation Markers in SCLC and LCNEC for Chemo-Immunotherapy Resistance Prediction (STRATUS)

NCT06717243 | Recruiting FDA Drug

• 1 other identifier: 2082/19-01-2024
• Study Type: observational
• Target: 111
• Locations: 2 countries
• Sites: 2

Brief Summary

The goal of this observational study is to understand how genomic and epigenetic factors contribute to resistance against chemo-immunotherapy in adults diagnosed with extensive-stage small cell lung cancer (ES-SCLC) or metastatic large cell neuroendocrine carcinoma (LCNEC). Both ES-SCLC and LCNEC are aggressive forms of lung cancer with limited treatment options and poor prognosis. While initial responses to chemo-immunotherapy are often promising, most patients develop resistance within a few months, resulting in disease progression and limited survival. This study seeks to explore the molecular and cellular changes that drive resistance, providing insights that could guide more personalized and effective treatment strategies in the future. The study focuses on identifying genomic and methylation signatures, as well as analyzing circulating tumor cells (CTCs) and tumor DNA (ctDNA), to better understand the mechanisms of resistance. By collecting and analyzing these biomarkers over time, researchers aim to identify patterns that distinguish patients who benefit long-term from therapy from those who experience early resistance. These findings may pave the way for new diagnostic tools and therapies to predict and overcome resistance to chemo-immunotherapy. The main questions this study seeks to answer are: Are there specific genomic or methylation patterns that predict resistance to chemo-immunotherapy in ES-SCLC and LCNEC? How are circulating tumor cells (CTCs) and tumor DNA (ctDNA) associated with disease progression, treatment response, and survival? What molecular differences exist between patients who respond long-term and those who develop resistance early in their treatment? Participants will: Provide blood and tumor tissue samples before treatment to establish baseline molecular profiles. Undergo follow-up visits every 9 weeks during treatment, where additional blood samples and imaging tests will be collected to monitor disease progression and treatment response. Optionally provide tissue samples through re-biopsy if the disease progresses, enabling researchers to compare changes in tumor biology over time. All blood and tissue samples will be de-identified and securely stored for genomic and epigenetic analyses. Blood samples will be examined for circulating tumor cells and tumor DNA, while tumor tissue samples will undergo in-depth genomic and methylation profiling. Researchers will use advanced molecular and bioinformatics techniques to uncover specific patterns associated with resistance, aiming to improve current treatment strategies and develop more precise therapies. The study will analyze data from patients over three years, encompassing various stages of treatment and disease progression. By examining longitudinal samples, the study aims to capture the dynamic changes that occur in the tumor microenvironment and how these relate to treatment outcomes. This research is particularly important because current treatment options for ES-SCLC and LCNEC are limited, and there are no established methods to predict which patients will respond to chemo-immunotherapy. Identifying biomarkers of resistance could transform clinical care, allowing oncologists to tailor treatments to individual patients' molecular profiles and improve survival outcomes. Ultimately, the findings from this study could lead to the development of new biomarkers for resistance, improve early detection of treatment failure, and provide the foundation for novel therapies targeting resistant cancer cells. By addressing a critical gap in the understanding of resistance mechanisms, the STRATUS trial has the potential to significantly advance the field of personalized oncology.

Conditions

Small Cell Lung Cancer; Large Cell Neuroendocrine (NE) Tumors; Treatment Failure; Biomarkers / Blood; Biomarkers; Immunotherapy

Keywords

Small Cell Lung Cancer (SCLC); Large Cell Neuroendocrine Carcinoma (LCNEC); Chemo-Immunotherapy; Treatment Resistance; Circulating Tumor Cells (CTCs); Circulating Tumor DNA (ctDNA); Liquid Biopsy; Genomic Profiling; Epigenetics; Biomarker Discovery; Lung Cancer; Molecular Signatures; Clonal Evolution; Personalized Oncology; Cancer Immunotherapy

Outcome Measures

Primary Outcomes (1)

• Number of Participants with Genomic and Epigenetic Alterations Associated with Resistance to Chemo-Immunotherapy

  Identification of genomic, methylation, and other epigenetic alterations that are associated with resistance to standard-of-care chemo-immunotherapy (platinum-based chemotherapy combined with immune checkpoint inhibitors) in patients with extensive-stage small cell lung cancer (ES-SCLC) and metastatic large cell neuroendocrine carcinoma (LCNEC).

  Baseline to disease progression (up to 36 months).

Secondary Outcomes (1)

• Association Between Circulating Biomarkers and Clinical Outcomes (PFS, OS) in Chemo-Immunotherapy Recipients

  Baseline to 36 months.

Other Outcomes (1)

• Molecular Changes in Tumor Microenvironment and Immune Response

  Baseline to disease progression (up to 36 months).

Study Arms (2)

Extensive-Stage Small Cell Lung Cancer (ES-SCLC) patients

This cohort includes adults with extensive-stage small cell lung cancer (ES-SCLC) receiving standard-of-care chemo-immunotherapy, such as platinum-based chemotherapy (cisplatin or carboplatin) combined with immune checkpoint inhibitors (atezolizumab or durvalumab). The study collects biospecimens, including blood (for circulating tumor DNA and circulating tumor cells) and tumor tissue, at baseline, during treatment, and at progression. These samples are analyzed to identify genomic, epigenetic, and transcriptomic signatures associated with treatment resistance. Insights gained will improve understanding of resistance mechanisms and guide personalized treatment strategies for ES-SCLC.

Drug: Carboplatin/Cisplatin -Etoposide - Atezolizumab

Large Cell Neuroendocrine Carcinoma (LCNEC) patients

This cohort includes adults diagnosed with metastatic large cell neuroendocrine carcinoma (LCNEC). Participants will receive standard-of-care systemic therapies, such as platinum-based chemotherapy (cisplatin or carboplatin), with or without immune checkpoint inhibitors, based on physician discretion. Biospecimens, including blood (for circulating tumor DNA and circulating tumor cells) and tumor tissue, will be collected at baseline, during treatment, and upon disease progression. These samples will undergo molecular analysis to identify genomic, epigenetic, and transcriptomic changes associated with treatment resistance and progression.

Drug: Carboplatin/Cisplatin -Etoposide - Atezolizumab

Interventions

Carboplatin/Cisplatin -Etoposide - Atezolizumab DRUG

This intervention represents the standard-of-care first-line treatment regimen for extensive-stage small cell lung cancer (ES-SCLC). The regimen includes: Carboplatin or Cisplatin: Platinum-based chemotherapeutic agents that cause DNA cross-linking, leading to tumor cell death. Etoposide: A topoisomerase II inhibitor that prevents DNA replication and tumor growth. Atezolizumab: A PD-L1 immune checkpoint inhibitor that enhances the immune system's ability to detect and destroy cancer cells. This combination therapy is administered as part of routine clinical practice. The study does not investigate the efficacy or safety of these drugs but rather focuses on analyzing molecular changes in tumors, such as genomic and epigenetic alterations, to understand mechanisms of treatment resistance. Biospecimens are collected from patients during treatment and progression for detailed analysis.

Extensive-Stage Small Cell Lung Cancer (ES-SCLC) patients; Large Cell Neuroendocrine Carcinoma (LCNEC) patients

Eligibility Criteria

• Age: 18 Years - 85 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

The study population includes adults aged 18 to 85 years diagnosed with extensive-stage small cell lung cancer (ES-SCLC) or metastatic large cell neuroendocrine carcinoma (LCNEC). Participants must have histologically confirmed disease and at least one measurable lesion as per RECIST 1.1 criteria. Eligible patients are those initiating standard-of-care chemo-immunotherapy, including platinum-based chemotherapy (cisplatin or carboplatin) combined with immune checkpoint inhibitors (atezolizumab or durvalumab). Patients with ECOG performance status of 0-2 and adequate organ function are included. Exclusion criteria involve prior systemic therapy for ES-SCLC or LCNEC, concurrent malignancies, or severe comorbidities. The study population will provide blood and tumor tissue samples for molecular analyses, aiming to uncover resistance mechanisms and develop predictive biomarkers for treatment outcomes.

You may qualify if:

• Age: Adults aged 18-85 years.
• Histologically confirmed locally advanced extensive-stage small cell lung cancer (ES-SCLC).
• Histologically confirmed locally advanced or metastatic large cell neuroendocrine carcinoma (LCNEC).
• Treatment Plan: Eligible patients must be initiating standard-of-care chemo-immunotherapy, including platinum-based chemotherapy (cisplatin or carboplatin) combined with immune checkpoint inhibitors (atezolizumab or durvalumab).
• Measurable Disease: At least one measurable or evaluable lesion as defined by RECIST 1.1 criteria.
• Baseline Biospecimen Availability: Patients must agree to provide baseline blood and tumor biopsy samples for molecular and genomic analyses.
• Treatment Naïve for Study Indication: Patients should not have received prior systemic therapy for ES-SCLC or LCNEC.
• Life Expectancy: Estimated life expectancy of at least 3 months, as determined by the treating physician.
• Follow-Up Commitment: Willingness to attend scheduled follow-up visits and provide additional biospecimens (blood and/or tissue) during treatment and at progression.
• Performance Status: ECOG performance status of 0-2.
• Organ Function: Adequate hematologic, renal, and hepatic function as per the treating physician's discretion.
• Consent: Ability and willingness to provide written informed consent for participation in the study and collection of biospecimens (e.g., blood and tumor tissue).
• Compliance with Study Protocol: Demonstrated ability and willingness to comply with all study-related procedures, including biospecimen collection and follow-up visits.
• Non-Pregnant and Non-Lactating: Women of childbearing potential must have a negative pregnancy test at baseline and agree to use effective contraception during the study period.
• Immunotherapy Eligibility: Patients must not have contraindications to immune checkpoint inhibitors (e.g., autoimmune diseases requiring systemic immunosuppressive therapy).

You may not qualify if:

• Uncontrolled Brain Metastases: Patients with untreated or progressive brain metastases causing significant neurological symptoms.
• Concurrent Malignancies: Presence of any active malignancy other than ES-SCLC or LCNEC within the past 3 years, except for treated non-melanoma skin cancer or in situ cervical carcinoma.
• Previous Systemic Therapy: Prior systemic chemotherapy or immunotherapy for ES-SCLC or LCNEC.
• Severe Comorbidities: Significant comorbidities, such as uncontrolled cardiovascular, respiratory, or autoimmune diseases, that could interfere with study participation or treatment.
• Active Infection: Patients with active infections requiring systemic therapy, including tuberculosis, hepatitis B or C, or HIV.
• Pregnancy or Lactation: Pregnant or lactating women, or women of childbearing potential who are not using effective contraception.
• Immunosuppressive Therapy: Patients requiring systemic immunosuppressive therapy, including high-dose corticosteroids (equivalent to \>10 mg/day prednisone), within 2 weeks prior to enrollment.
• Severe Allergic Reactions: History of severe hypersensitivity reactions to any component of the planned treatment regimen, including platinum-based chemotherapy or immune checkpoint inhibitors.
• Life-Threatening Conditions: Life expectancy less than 3 months, as assessed by the treating physician.
• Inability to Comply: Patients unable or unwilling to adhere to study protocols, including biospecimen collection and follow-up visits.

Sponsors & Collaborators

• Oncology Center of Biochemical Education And Research: lead
• National and Kapodistrian University of Athens: collaborator
• Icahn School of Medicine at Mount Sinai: collaborator
• Sotiria General Hospital: collaborator

Study Sites (2)

Icahn School of Medicine at Mount Sinai

New York, New York, 10029, United States

NOT YET RECRUITING

3rd Department of Medicine, National and Kapodistrian University of Athens, Sotiria Hospital

Athens, 11527, Greece

RECRUITING

Biospecimen

Retention: SAMPLES WITH DNA

The study will retain the following types of biospecimens: Blood samples: Plasma, serum, and buffy coat for analysis of circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), and other molecular markers. Tumor tissue samples: Fresh-frozen and formalin-fixed paraffin-embedded (FFPE) tumor biopsies for genomic, epigenetic, and transcriptomic analyses. Optional re-biopsy samples: Collected from newly emerged lesions during disease progression to study clonal evolution and resistance mechanisms. All samples will be securely stored in a biorepository, de-identified, and used for DNA extraction and molecular profiling, including next-generation sequencing and DNA methylation analysis.

MeSH Terms

Conditions

Small Cell Lung Carcinoma; Neoplasms; Neoplastic Cells, Circulating; Lung Neoplasms

Interventions

Carboplatin

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Lung Diseases; Respiratory Tract Diseases; Neoplasm Metastasis; Neoplastic Processes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Coordination Complexes; Organic Chemicals

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Medicine and Medical Oncology

Study Record Dates

• First Submitted: December 1, 2024
• First Posted: December 4, 2024
• Study Start: February 20, 2025
• Primary Completion (Estimated): March 20, 2028
• Study Completion (Estimated): December 1, 2028
• Last Updated: March 19, 2025

Record last verified: 2025-03

Locations

US (1); GR (1)