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NCT Number: NCT07835789

Testing Repeat Radiation Therapy for Recurrent Non-small Cell Lung Cancer

This phase II trial compares repeat radiation therapy (RT) to standard drug treatment alone in treating patients with stage II-III non-small cell lung cancer (NSCLC) that has come back after initial radiation at or adjacent to the site of the original tumor (locally recurrent). Radiation therapy uses high energy x-rays, particles, or radioactive seeds to kill cancer cells and shrink tumors. Chemotherapy drugs used in standard drug treatment work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Immunotherapy drugs used in standard drug treatment may induce changes in body's immune system and may interfere with the ability of tumor cells to grow and spread. Targeted therapy drugs used in standard treatment identify and attack specific tumor cells. This trial may help doctors determine whether repeat RT delays the cancer from growing or spreading by 6 months or more after initial radiation compared to standard drug treatment alone in patients with stage II-III locally recurrent NSCLC.

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Key information

Conditions

Locally Recurrent Lung Non-Small Cell Carcinoma Lung Diseases Lung Neoplasms Neoplasms Neoplasms by Site Respiratory Tract Diseases Respiratory Tract Neoplasms Stage II Lung Cancer AJCC v8 Stage III Lung Cancer AJCC v8 Thoracic Neoplasms

Age range

18 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 2

About this study

PRIMARY OBJECTIVE:

I. In patients with NSCLC who develop locoregional disease recurrence after thoracic radiotherapy, to compare progression-free survival outcomes following curative-intent reirradiation versus systemic therapy alone.

SECONDARY OBJECTIVES:

I. To compare overall survival outcomes across study arms. II. To compare clinician-scored adverse events, scored using Common Terminology Criteria for Adverse Events (CTCAE), across study arms.

III. To compare patient-reported adverse events, scored using Patient-Reported Outcomes (PRO)-CTCAE, across study arms.

IV. To compare patterns of disease progression across study arms.

EXPLORATORY OBJECTIVES:

I. To evaluate clinical and dosimetric predictors of high-grade treatment-related toxicity within the experimental study arm.

II. To compare the toxicity and efficacy of proton beam radiotherapy versus photon radiotherapy within the experimental study arm.

III. To calculate regional lung ventilation using four-dimensional (4D) computed tomography (CT) planning scans and evaluate associated predictors of pulmonary toxicity.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM 1: Patients receive standard of care (SOC) systemic therapy, which may include chemotherapy, immunotherapy, and/or targeted therapy on study. Patients also undergo positron emission tomography/computed tomography (PET/CT) and magnetic resonance imaging (MRI) during screening, as well as chest CT and optional blood sample collection throughout the study.

ARM 2: Patients undergo radiation therapy (RT) for 20 treatment fractions over approximately 5 weeks or RT for 30 treatment fractions over approximately 6 weeks in the absence of disease progression or unacceptable toxicity. Patients receiving 6-week RT may also receive chemotherapy during RT per decision of patient and doctor decision. Patients also undergo PET/CT and MRI during screening, as well as chest CT and optional blood sample collection throughout the study.

After completion of study treatment, patients are followed up periodically until 5 years.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • History of stage II-III NSCLC treated with fractionated (≤ 4 Gy per fraction) curative-intent (total dose ≥ 45 Gy) thoracic radiotherapy, completed ≥ 12 months before study entry
  • Participants must have recurrent/progressive disease in the lung and/or regional lymph nodes that is not suitable for treatment with stereotactic body radiation therapy (SBRT) and for which palliative thoracic radiotherapy is not required at the time of study entry
  • Biopsy to confirm recurrent/progressive disease at some point after the previous course of thoracic radiotherapy and before entering this study is required
  • A portion of the disease that would be treated with radiotherapy on Arm 2 of this protocol must fall within the 50% isodose cloud of the radiotherapy plan
  • New systemic lung cancer therapy initiated within 12 weeks prior to study entry that is still ongoing is not permitted
  • Participants must not have definitive clinical or radiographic evidence of distant metastatic NSCLC at present or in the past
  • Age ≥ 18
  • Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2
  • Not Pregnant and Not Nursing
  • Negative urine or serum pregnancy test (in persons of childbearing potential) within 14 days prior to registration. Childbearing potential is defined as any person who has experienced menarche and who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) or who is not postmenopausal
  • Prior thoracic radiotherapy for NSCLC must have been delivered as definitive treatment, as opposed to in the preoperative or postoperative setting. One prior radiotherapy course must meet the specifications, and the radiotherapy plan from that course must be available in Digital Imaging and Communications in Medicine (DICOM) format
  • Patients who have received additional prior radiotherapy (i.e., more than one prior radiotherapy course) may be enrolled, provided that only one prior radiotherapy course is deemed to affect the risks associated with treatment with radiotherapy on this study. As examples, prior radiotherapy for an extrathoracic malignancy would likely not affect the risks associated with reirradiation on this study. Prior radiotherapy for breast cancer may be permissible, depending on the extent of lung irradiation. Similarly, prior SBRT for a peripheral lung tumor may be permissible
  • No prior SBRT for a central lung tumor, hilar lymph node, or mediastinal lymph node
  • Prior lobar and sublobar lung resections are allowed, but prior pneumonectomy is not allowed
  • Prior chemotherapy, targeted therapy, and/or immunotherapy for lung cancer is allowed
  • No history of CTCAE version (v.) 5.0 grade 2-4 RT pneumonitis or ongoing CTCAE v. 5.0 grade 2-4 pneumonitis from any cause
  • No clinically significant interstitial lung disease

Treatment and study plan

Biospecimen Collection

Procedure

Undergo blood sample collection

Other names: Biological Sample Collection, Biospecimen Collected, Sample Collection, Specimen Collection

Computed Tomography

Procedure

Undergo PET/CT and/or chest CT

Other names: CAT, CAT Scan, Computed Axial Tomography, Computerized Axial Tomography, Computerized axial tomography (procedure), Computerized Tomography, Computerized Tomography (CT) scan, CT, CT Scan, Diagnostic CAT Scan, Diagnostic CAT Scan Service Type, tomography

Immunotherapy

Other

Given SOC immunotherapy

Other names: Immunological, Immunological Therapy, Immunologically Directed Therapy

Magnetic Resonance Imaging

Procedure

Undergo MRI

Other names: Magnetic Resonance, Magnetic Resonance Imaging (MRI), Magnetic resonance imaging (procedure), Magnetic Resonance Imaging Scan, Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance, MR, MR Imaging, MRI, MRI Scan, MRIs, NMR Imaging, NMRI, Nuclear Magnetic Resonance Imaging, sMRI, Structural MRI

Positron Emission Tomography

Procedure

Undergo PET/CT

Other names: Medical Imaging, Positron Emission Tomography, PET, PET Scan, Positron emission tomography (procedure), Positron Emission Tomography Scan, Positron-Emission Tomography, PT

radiation therapy

Radiation

Undergo repeat RT

Other names: Cancer Radiotherapy, Energy Type, ENERGY_TYPE, Irradiate, Irradiated, Irradiation, Radiation, Radiation Therapy, NOS, Radiotherapeutics, Radiotherapy, RT, Therapy, Radiation

systemic chemotherapy

Drug

Given SOC chemotherapy

Targeted Therapy

Other

Given SOC targeted therapy

Other names: Target/Mechanism, Targeted, Targeting Therapy

Primary outcomes

  1. Progression-free survival (PFS)

    Time frame: From randomization to the first occurrence of disease progression or death from any cause, whichever occurs first, assessed up to 5 years

    The primary analysis of PFS will be conducted in the intent-to-treat population, defined as all randomized patients. The distributions of PFS will be estimated by the Kaplan-Meier method. The primary comparison between arms will use a one-sided stratified log-rank test with the randomization stratification factors. A stratified Cox proportional hazards model will be used to estimate the hazard ratio and corresponding confidence interval. An unstratified log-rank test and unstratified Cox proportional hazards model will also be provided as sensitivity analyses. No post hoc modification or collapsing of stratification categories based on observed event counts will be performed. If the stratified Cox model is not estimable because of sparse data, the unstratified Cox model will be used to summarize the treatment hazard ratio and confidence interval, with the reason documented.

Secondary outcomes

  1. Overall survival

    Time frame: From randomization to death from any cause, assessed up to 5 years

    Will be summarized using Kaplan-Meier methods. Comparisons between arms will be summarized descriptively using hazard ratio estimates and corresponding confidence intervals.

  2. Incidence of clinician-scored treatment-related adverse events

    Time frame: Up to 5 years

    Clinician-scored adverse events will be summarized by study arm using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE). For each patient, the maximum severity reported for each adverse event will be used in the summaries. Adverse events will be summarized regardless of relationship to protocol treatment as assessed by the investigator. All adverse events, adverse events leading to withdrawal, interruption or modification of protocol treatment, Grade ≥ 3 adverse events, and serious adverse events will be summarized. Deaths and cause of death will be summarized. Event summaries will be presented by type, grade, and attribution and will be performed at the time of the primary endpoint analysis.

  3. Incidence of patient-reported adverse events

    Time frame: Up to 5 years

    A composite grading algorithm (Basch 2021) will be utilized to derive a single numerical grade for each adverse event scored at each timepoint using Patient-Reported Outcomes (PRO)-CTCAE. Patient-reported adverse events measured using PRO-CTCAE will also be summarized descriptively by arm and time point, together with compliance and missing-data patterns.

  4. Site of first disease progression

    Time frame: Up to 5 years

    Patterns of first failure will be summarized descriptively by arm using the categories specified in the protocol, including locoregional/intrathoracic progression, distant progression, or both. Formal hypothesis testing for these secondary endpoints is not planned unless otherwise specified in a future statistical analysis plan.

Other outcomes

  1. Clinical and dosimetric predictors of high-grade treatment-related toxicity

    Time frame: Up to 5 years

    These analyses will be restricted to patients who initiate protocol reirradiation and will be descriptive and hypothesis-generating. Candidate predictors may include baseline clinical characteristics, prior treatment characteristics, and dosimetric parameters from the reirradiation and composite treatment plans. Associations with high-grade treatment-related toxicity will be summarized using appropriate descriptive and regression-based methods, as feasible given the number of observed events.

  2. Radiotherapy modality toxicity and efficacy outcomes

    Time frame: Up to 5 years

    Will include descriptive comparisons of toxicity and efficacy outcomes, including time-to-event outcomes and treatment-related adverse events, among patients treated with proton versus photon radiotherapy within Arm 2. Because radiotherapy modality is selected by the treating team and not randomized within Arm 2, these analyses will be considered descriptive and hypothesis-generating only.

  3. Regional lung ventilation metrics

    Time frame: Up to 5 years

    Among Arm 2 patients with available four-dimensional computed tomography planning scans, additional exploratory analyses may derive regional lung ventilation metrics and evaluate their association with pulmonary toxicity. These analyses are intended to identify potential imaging-based predictors of pulmonary toxicity and to generate hypotheses for future study.

Interested in participating?

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Sponsors and collaborators

Lead sponsor

NRG Oncology

Other

Registry information

Official study title

A Phase II Randomized Study of Reirradiation for Locally Recurrent Non-Small Cell Lung Cancer

Important dates

Study start
2026
Primary completion
2029
Study completion
2034
First posted
Sep 23, 2026
Registry last updated
Sep 23, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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