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Comparing Standard Treatment Alone to Radiation Therapy with or without Surgery with Standard Treatment for Patients with Limited Metastatic Non-Small Cell Lung Cancer

Status
Temporarily Closed
Cancer Type
Lung Cancer
Trial Phase
Phase II
Phase III
Eligibility
18 Years and older, Male and Female
Study Type
Treatment
NCT ID
NCT03137771
Protocol IDs
NRG-LU002 (primary)
NRG-LU002
NCI-2016-00849
Study Sponsor
NRG Oncology

Summary

This phase II/III trial studies how well giving maintenance chemotherapy with or without local consolidation therapy works in treating patients with stage IV non-small cell lung cancer. Drugs used in maintenance chemotherapy, such as pemetrexed and gemcitabine 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 with monoclonal antibodies, such as pembrolizumab, nivolumab, atezolizumab and ipilimumab may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Local consolidation therapy such as radiation/stereotactic body radiation or surgery may kill cancer cells left after initial treatment. Giving maintenance chemotherapy and local consolidation therapy together may work better than maintenance chemotherapy alone in treating patients with stage IV non-small cell lung cancer.

Objectives

PRIMARY OBJECTIVES:
I. To evaluate the impact of adding LCT (local consolidative therapy) to maintenance systemic therapy versus maintenance systemic therapy alone on progression-free survival for patients with metastatic non-small cell lung cancer (NSCLC) with no evidence of progression and limited metastatic sites after first-line systemic therapy. (Phase II)
II. To evaluate the impact of adding LCT to maintenance systemic therapy versus maintenance systemic therapy alone on overall survival for patients with metastatic NSCLC with no evidence of progression and limited metastatic sites after first-line systemic therapy. (Phase III)

SECONDARY OBJECTIVES:
I. To evaluate the impact of adding LCT to maintenance systemic therapy versus maintenance systemic therapy alone on in-field local failure.
II. To evaluate the impact of adding LCT to maintenance systemic therapy versus maintenance systemic therapy alone on the time to development of new lesions.
III. To evaluate the impact of adding LCT to maintenance systemic therapy versus maintenance systemic therapy alone on toxicity.
IV. To evaluate the impact of adding LCT to maintenance systemic therapy versus maintenance systemic therapy alone on duration of maintenance systemic therapy usage.
V. To evaluate the effect of adding LCT to systemic therapy in limited stage IV NSCLC on quality of life (QOL).
VI. To collect biospecimens and evaluate the correlation between clinical outcomes and circulating tumor deoxyribonucleic acid (DNA) (ctDNA).

OUTLINE: Patients are randomized into 1 of 2 arms.

ARM I (CHEMOTHERAPY ALONE): Patients may receive on of the following regimens: pemetrexed intravenously (IV) over 10 minutes on day 1 alone or in combination with pembrolizumab IV over 30 minutes on day 1 or; gemcitabine IV over 30 minutes on days 1 and 8 or; pembrolizumab IV over 30 minutes on day 1 or; atezolizumab IV over 30-60 minutes on day 1 or; nivolumab IV over 30 minutes and ipilimumab IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients may opt to receive nivolumab IV over 30 minutes on days 1, 15, 29 and ipilimumab IV over 30 minutes on day 1 every 42 days for up to 2 years in the absence of disease progression or unacceptable toxicity.

ARM II (SBRT AND CHEMOTHERAPY): Patients undergo LCT over 2-4 weeks. If LCT cannot be used to treat primary disease sites, patients also undergo intensity-modulated radiation therapy (IMRT) or 3-dimensional conformal radiation therapy (3DCRT) over 3-5 weeks. Within 2 weeks after completion of radiation therapy, patients receive chemotherapy as in Arm 1. Patients may possibly undergo surgery.

After completion of study treatment, patients are followed up every 3 months for 2 years, every 6 months for 3 years, then annually thereafter.

Eligibility

  1. Patients must have the psychological ability and general health that permits completion of the study requirements and required follow up.
  2. Women of childbearing potential and men who are sexually active should be willing and able to use medically acceptable forms of contraception during treatment on this study and for up to 180 days after completion of all treatment to prevent pregnancy or fathering a child
  3. Pathologically proven diagnosis of NSCLC, with metastases (stage IV disease) present prior to registration; this includes patients newly diagnosed with metastatic disease or those initially diagnosed and treated for stage I-III NSCLC who ultimately develop limited metastases; limited metastases is defined as 3 or fewer sites of metastatic disease.
  4. Appropriate stage for study entry based on the following diagnostic workup: * History/physical examination by a radiation oncologist (and a surgeon if surgery is planned) within 30 days prior to registration * Imaging proof of limited metastatic disease and response to therapy/stable disease, by at least diagnostic quality computed tomography (CT) chest through the adrenals or positron emission tomography (PET)/CT, within 30 days prior to registration.
  5. Age >= 18 years.
  6. Zubrod performance status 0, 1, or 2 within 30 days prior to registration.
  7. Aspartate transaminase (AST) and alanine transaminase (ALT) =< 2.5 x upper limit of normal (ULN) or =< 5 x ULN with metastatic liver disease within 14 days prior to registration.
  8. Total bilirubin =< 1.5 x ULN within 14 days prior to registration.
  9. Absolute neutrophil count (ANC) >= 500 cells/mm^3 within 14 days prior to registration.
  10. Platelets >= 50,000 cells/mm^3 within 14 days prior to registration.
  11. Creatinine =< 1.5 x ULN; or creatinine clearance > 45 mL/min if creatinine > 1.5 x ULN (calculated creatinine clearance [CrCl] based on Cockcroft-Gault equation)
  12. Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
  13. For patients who will undergo resection of disease (if randomized to Arm 2 and dispositioned to receive surgery), adequate pre-surgical work-up for anticipated surgery, as defined by institutional guidelines
  14. Negative serum pregnancy test within one week prior to registration for females of childbearing potential.
  15. Patients must have received first-line/induction systemic therapy comprising of immunotherapy and/or platinum-based chemotherapy (at least 4 cycles or courses but less than 6, i.e. 4-5 cycles/courses), and achieved stable disease or a partial response; though the intention is for every course/cycle to be identical in an induction regimen, some but not all of the 4-5 cycles may omit an immunotherapy or platinum compound if the treating physician determines it is in the patient’s best interest secondary to toxicity or other institutional parameter. * For patients treated with nivolumab, ipilimumab and 2 cycles of chemotherapy, the 4-5 cycles requirement will be met by 4-5 total doses of nivolumab * For patients treated with nivolumab and ipilimumab, this requirement will be met by 2 doses of ipilimumab and 4-5 doses of nivolumab.
  16. After induction systemic therapy, patients must have a minimum of one site of disease, primary or metastasis, present for potential consolidation with local therapy; all sites of disease present after induction systemic therapy, primary and metastases (up to 3) are able to be consolidated with local therapy
  17. Prior systemic therapy as part of concurrent treatment approach for previously diagnosed stage I-III NSCLC, adjuvant or neo-adjuvant therapy for stage I-III NSCLC, as adjuvant therapy for previously resected or irradiated NSCLC, or for other previous cancers is permitted.
  18. For de novo stage IV NSCLC patients (patients with metastatic disease at first presentation), primary disease must be treatable with local therapy in the form of SBRT or hypofractionated radiation; if the primary disease is found in the peripheral or central lung parenchyma without nodal disease, for instance, SBRT may be employed at the discretion of the treating institution; if primary disease is more advanced with involvement of the mediastinum (T4 tumor, N1-N3 disease, etc.), these volumes should be technically treatable with hypofractionated radiation; surgery should only be used for metastatic tumors that can be completely resected by lobectomy, segmentectomy, or wide wedge resection.
  19. If primary disease in the thoracic cavity was previously treated with local therapy in the form of surgery or radiation, any new local/regional disease recurrence should be technically treatable with SBRT or hypofractionated radiation after induction systemic therapy.
  20. The patient or a legally authorized representative must provide study-specific informed consent prior to study registration.
  21. Radiotherapy for patients with brain metastases prior to registration is acceptable.
  22. Patients with brain metastases are eligible if these lesions have been previously treated or resolved and the patients have no clinical or radiographic evidence of progression prior to registration.
  23. Subjects may receive palliative radiotherapy for symptomatic metastases or primary disease prior to registration provided that there is at least one other non-irradiated lesion amenable to LCT at the time of registration.

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