Maintenance Chemotherapy With or Without Local Consolidative Therapy in Treating Patients With Stage IV Non-small Cell Lung Cancer

Study Overview
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Brief Summary
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This randomized 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 docetaxel, pemetrexed disodium, erlotinib hydrochloride, 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. 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.

Detailed Description
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PRIMARY OBJECTIVES: Phase II To evaluate the impact of adding local consolidative therapy (LCT) 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 III 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. 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 DNA (ctDNA). OUTLINE: Patients are randomized into 1 of 2 arms. ARM 1 (CHEMOTHERAPY ALONE): ): Patients may receive docetaxel intravenously (IV) over 60 minutes on Day 1, erlotinib hydrochloride orally (PO) once daily (QD), or gemcitabine IV over 30 minutes on Days 1 and 8. Patients with non-squamous non-small cell lung cancer may receive pemetrexed disodium IV over 10 minutes on Day 1 alone or in combination with pembrolizumab IV over 30 minutes. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. ARM 2 (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.

Official Title
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Maintenance Systemic Therapy Versus Local Consolidative Therapy (LCT) Plus Maintenance Systemic Therapy for Limited Metastatic Non-Small Cell Lung Cancer (NSCLC): A Randomized Phase II/III Trial

Conditions
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Recurrent Non-Small Cell Lung Carcinoma, Stage IV Non-Small Cell Lung Cancer

Intervention / Treatment
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* Radiation: 3-Dimensional Conformal Radiation Therapy (3D-CRT)
* Drug: Docetaxel
* Drug: Gemcitabine
* Radiation: Intensity-Modulated Radiation Therapy (IMRT)
* Drug: Pemetrexed Disodium
* Radiation: Stereotactic Body Radiation Therapy (SBRT)
* Drug: Erlotinib Hydrochloride
* Drug: Pembrolizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have the psychological ability and general health that permits completion of the study requirements and required follow up Women of childbearing potential and men who are sexually active should be willing and able to use medically acceptable forms of contraception during the trial and for up to 180 days after completion of all treatment to prevent pregnancy or fathering a child. 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 metastases Appropriate stage for study entry based on the following diagnostic workup: History/physical examination within 30 days prior to registration Imaging proof of limited metastatic disease and response to therapy/stable disease, by at least CT chest through the adrenals or PET/CT within 30 days prior to registration Zubrod performance status 0, 1, or 2 within 30 days prior to registration Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 2.5 × upper limit of normal (ULN) or ≤ 5 × ULN with metastatic liver disease Total bilirubin ≤ 1.5 × ULN Absolute neutrophil count (ANC) ≥ 500 cells/mm^3 Creatinine clearance ≥ 45 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal Platelets ≥ 50,000 cells/mm^3 Negative serum pregnancy test within one week prior to registration for females of childbearing potential Patients must have received first-line/induction chemotherapy (4 cycles) and achieved stable disease or a partial response Prior systemic chemotherapy as part of concurrent treatment approach for previously diagnosed stage III NSCLC, as adjuvant therapy for previously resected NSCLC, or for other previous cancers is permitted Prior radiotherapy for patients with brain metastases prior to enrollment is acceptable Patients must have measurable disease at baseline and 3 or fewer discrete, extracranial metastatic disease sites that are technically amenable to SBRT 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; 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 If primary disease in the thoracic cavity was previously treated with local therapy in the form of surgery, any local/regional disease recurrence should be technically treatable with SBRT or hypofractionated radiation after induction systemic therapy Patients must be registered within 35 days of administration of the last dose of first-line/induction systemic therapy The patient or a legally authorized representative must provide study-specific informed consent prior to study entry Patients with brain metastases are eligible if these lesions have been previously treated and the patients have no clinical or radiographic evidence of progression prior to enrollment Exclusion Criteria: Clinical or radiologic evidence of untreated and/or progressive brain metastases Cutaneous metastasis of NSCLC Metastatic disease invading the esophagus, stomach, intestines, or mesenteric lymph nodes if not a candidate for surgery for these lesions Prior invasive malignancy (except non-melanomatous skin cancer, low or intermediate risk prostate cancer, or in situ carcinoma of breast, oral cavity, skin, or cervix) unless disease free for a minimum of one year Metastases located within 3 cm of previously irradiated (< 3Gy per fraction) structures if if not a candidate for surgery for these lesions and if: Spinal cord previously irradiated to > 40 Gy Brachial plexus previously irradiated to > 50 Gy Small intestine, large intestine, or stomach previously irradiated to > 45 Gy Brainstem previously irradiated to > 50 Gy Lung previously irradiated with prior V20 Gy > 35% Patients receiving targeted therapy (non-cytotoxic systemic therapy) for NSCLC in the first-line setting If a patient has progressed in previous areas of primary disease that received definitive doses of radiation, these patients would require re-irradiation in previous high dose anatomic areas and are not eligible for this study Patients with malignant pleural effusions that do not resolve after first-line systemic therapy; patients with pleural effusions that have become too small for thoracentesis at the time of registration would be permitted on study, indicating a significant response to first-line chemotherapy Patients with more than 3 discrete locations of extra-cranial metastatic disease after first-line systemic therapy requiring more than 3 SBRT plans to cover these distinct metastatic disease entities Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration Patients who are pregnant or nursing Participation in any investigational drug study (excluding non-oncology and/or symptom management studies) within 4 weeks prior to registration Known human immunodeficiency virus (HIV) positive with cluster of differentiation 4 (CD4) count < 200 cells/microliter; note that patients who are HIV positive are eligible, provided they are under treatment with highly active antiretroviral therapy (HAART) and have a CD4 count ≥ 200 cells/microliter within 30 days prior to registration; note also that HIV testing is not required for eligibility for this protocol For patients who received immunotherapy during induction, patients on chronic steroids or who have active autoimmune disease for which they received systemic treatment in the previous 2 years with corticosteroids, disease modifying agents, or immunosuppressive drugs are not eligible. Replacement therapy (thyroxine, insulin or physiological corticosteroid replacement for adrenal or pituitary insufficiency) is allowed. Patients with active interstitial lung disease or who have a history of pneumonitis for which they had received glucocorticoids are not eligible Prior bevacizumab therapy or other antiangiogenic therapy in first-line or planned maintenance therapy (due to potential for increased complications from local therapy)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm 1 (maintenance chemotherapy)<br>Patients may receive docetaxel IV over 60 minutes on day 1, erlotinib hydrochloride PO QD, or gemcitabine IV over 30 minutes on days 1 and 8. Patients with non-squamous non-small cell lung cancer may receive pemetrexed disodium IV over 10 minutes on day 1 alone or in combination with pembrolizumab IV over 30 minutes. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. | Drug: Docetaxel<br>* Given IV<br>* Other names: Taxotere Injection Concentrate;Drug: Gemcitabine<br>* Given IV<br>* Other names: Difluorodeoxycytidine;Drug: Pemetrexed Disodium<br>* Given IV<br>* Other names: N-[4-[2-(2-Amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic Acid Disodium Salt;Drug: Erlotinib Hydrochloride<br>* Given PO<br>* Other names: Tarceva;Drug: Pembrolizumab<br>* Given IV<br>* Other names: Keytruda;|
| Experimental: Arm 2 (SBRT + maintenance chemotherapy)<br>Patients undergo LCT over 2-4 weeks. If LCT cannot be used to treat primary disease sites, patients also undergo IMRT or 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. | Radiation: 3-Dimensional Conformal Radiation Therapy (3D-CRT)<br>* Undergo 3DCRT<br>* Other names: Radiation Conformal Therapy;Drug: Docetaxel<br>* Given IV<br>* Other names: Taxotere Injection Concentrate;Drug: Gemcitabine<br>* Given IV<br>* Other names: Difluorodeoxycytidine;Radiation: Intensity-Modulated Radiation Therapy (IMRT)<br>* Undergo IMRT<br>* Other names: Intensity-Modulated Radiotherapy;Drug: Pemetrexed Disodium<br>* Given IV<br>* Other names: N-[4-[2-(2-Amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic Acid Disodium Salt;Radiation: Stereotactic Body Radiation Therapy (SBRT)<br>* Undergo SBRT<br>* Other names: stereotactic body radiation therapy;Drug: Erlotinib Hydrochloride<br>* Given PO<br>* Other names: Tarceva;Drug: Pembrolizumab<br>* Given IV<br>* Other names: Keytruda;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase II - Progression-Free Survival (PFS) | Progression-Free Survival | From the time of randomization to date any documented progression or death due to any cause, whichever occurs first. Assessed for up to 3 years. | 
| Phase III - Overall Survival (OS) | Overall Survival | From the time of randomization to date of death due to any cause. Assessed up to 3 years. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to In-Field Failure | The time it takes for disease progression to occur within the radiation treatment field of disease will be measured. | Time from randomization to progression within the irradiated field at any time, assessed for up to 3 years | 
| Incidence of adverse events graded per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5 | Will be reported with the frequency and severity (e.g., type, grade, and attribution) by arm. | Up to 3 years | 
| Duration of Maintenance Chemotherapy Usage | Will be performed on an intent to treat basis. | Up to 3 years | 
| Time to Development of New Lesions | Will be performed on an intent to treat basis. | Time from randomization to the first occurrence of any new lesions that have not been treated with local consolidative therapy, assessed for up to 3 years |