A Study of Local Ablative Therapy (LAT) in People With Non-Small Cell Lung Cancer (NSCLC)

Overview

The purpose of this study is to see whether receiving local ablative therapy (LAT) when minimal residual disease/MRD levels are rising can reduce MRD levels and control metastatic non-small cell lung cancer/NSCLC longer compared to systemic therapy.

Full Title of Study: “A Phase II Adaptive Study of Local Ablative Therapy (LAT) for Patients With Metastatic Non-Small Cell Lung Cancer (NSCLC) Using Minimal Residual Disease (MRD) as an Integral Biomarker”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Non-Randomized
    • Intervention Model: Sequential Assignment
    • Primary Purpose: Treatment
    • Masking: None (Open Label)
  • Study Primary Completion Date: June 15, 2025

Interventions

  • Procedure: Local ablative therapy
    • In part I, 33 patients with metastatic NSCLC with: a) NR-VAF but b) without radiographic progression of disease, will be treated with LAT. In Part II of the study, patients will be randomized to standard of care (continuation of systemic therapy) vs. LAT to all sites of disease
  • Other: Blood collection to assess for ctDNA
    • Participants will undergo ctDNA collection in conjunction with their standard of care therapy.

Arms, Groups and Cohorts

  • Experimental: Part I
    • In part I, 33 patients with metastatic NSCLC with: a) NR-VAF but b) without radiographic progression of disease, will be treated with LAT to determine if ablation to all sites of disease leads to acceptable rates of mean VAF reduction, thus indicating a discernible molecular/clinical response in this subgroup of patients with metastatic disease.
  • Active Comparator: Part II – standard of care
    • If the appropriate criteria are met in part I,, in part II 60 patients with NR-VAF but without radiographic progression of disease will be randomized to one of two arms: continuation of systemic therapy (standard of care) vs. ablation to all sites of disease (experimental arm), with a primary endpoint of progression free survival.
  • Experimental: Part II – ablation to all sites of disease (experimental arm)
    • If the appropriate criteria are met in part I,, in part II 60 patients with NR-VAF but without radiographic progression of disease will be randomized to one of two arms: continuation of systemic therapy (standard of care) vs. ablation to all sites of disease (experimental arm), with a primary endpoint of progression free survival.

Clinical Trial Outcome Measures

Primary Measures

  • Measure the reduction in mean variant allele frequency/VAF by 6 months after Local Ablative Therapy/LAT
    • Time Frame: 6 months
    • To determine whether Local Ablative Therapy/LAT (ablation to all sites of disease) causes a reduction in mean variant allele frequency/VAF by 6 months after LAT in patients with metastatic NSCLC who have non-responding variant allele frequency/NR-VAF (<50% reduction in mean VAF) but no radiographic progression of disease
  • Progression Free Survival/PFS
    • Time Frame: 3 months +/- 2 weeks after enrollment
    • PFS will be evaluated through imaging obtained Q3 months +/-2 weeks after enrollment. Progression will be evaluated by RECIST 1.1 guidelines. To determine whether LAT improves PFS in patients with metastatic NSCLC who have NR-VAF but no radiographic progression of disease compared to patients who continue systemic therapy.

Participating in This Clinical Trial

Participant Inclusion Criteria (both Part I and Part II) Monitoring Phase

  • Stage IV NSCLC. Note that patients are eligible for the study if they have received definitive treatment for early stage disease, presuming that they remain candidates for local ablative therapy (LAT). – AJCC 8th Edition Stage IV disease – Up to four cycles of standard first-line systemic therapy, defined as: a) platinum-doublet chemotherapy, b) ICI, or c) platinum-doublet chemotherapy + ICI. – Ten or less metastatic lesions (Note that this criterion includes lesions, not sites: 3 brain metastases = 3 lesions). – All lesions amenable to LAT. – At least one site of measurable disease – Detectable ctDNA – ECOG Performance status 0 – 2. – Age ≥ 18 years. – The participant, or their legally authorized representative (LAR) are able to provide informed consent. – Female subjects must either be of non-reproductive potential (i.e. post-menopausal by history: >/= 60 years old and no menses for 1> year without an alternative medical cause; OR history of hysterectomy, OR history of bilateral tubal ligation, OR history of bilateral oophorectomy) or must have a negative pregnancy test (serum) within 2 weeks or a urine pregnancy test the day of treatment. – Adequate baseline organ function to allow SBRT to all relevant targets, as determined by the treating radiation oncologist based on lesion location, lesion size, and proximity to relevant organs at risk. Therapeutic Phase – Has received at least 2 cycles of treatment, remains on first-line therapy – No evidence of radiographic RECIST 1.1* progression (as defined above), as measured through the following imaging modalities: – 1) PET/CT scan or CT scan of the chest/abdomen/pelvis within 4 weeks of enrollment – 2) MRI or CT scan of the brain at baseline, AND within 4 weeks of enrollment – NR-VAF within 4 weeks of enrollment – All active lesions amenable to LAT – Note that patients who receive local therapy (radiation, surgery, or RFA) prior to enrollment for palliative purposes or to CNS lesions are eligible for enrollment if: a) all other eligibility criteria are met and b) at least one other lesion is amenable to LAT and is RECIST evaluable. All lesions treated for palliative purposes will also be counted towards the total number of lesions. Exclusion Criteria:

  • Complete response radiographically (no lesions to target) – Patients with CNS-only disease (due to limited capacity of peripheral blood ctDNA to detect CNS lesions) – Patient to be treated by targeted agents (e.g. tyrosine kinase inhibitors) or patient not a candidate for systemic therapy – Serious medical co-morbidities precluding radiotherapy or ablation, determined at the discretion of the treating investigator. – Pregnant or lactating women. – Physical limitation to undergo stereotactic radiotherapy. – Other active malignancy within the last year except for basal cell carcinoma of the skin and in situ malignancy even if without evidence of disease.

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Memorial Sloan Kettering Cancer Center
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Daniel Gomez, MD, Principal Investigator, Memorial Sloan Kettering Cancer Center
  • Overall Contact(s)
    • Daniel Gomez, MD, 212-639-2087, gomezd@mskcc.org

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