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Clinical Trial Details — Status: Recruiting

Administrative data

NCT number NCT04929041
Other study ID # NCI-2021-06042
Secondary ID NCI-2021-06042A0
Status Recruiting
Phase Phase 2/Phase 3
First received
Last updated
Start date October 7, 2022
Est. completion date December 31, 2027

Study information

Verified date March 2024
Source National Cancer Institute (NCI)
Contact n/a
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial Summary

This phase II/III trial compares the addition of radiation therapy to the usual treatment (immunotherapy with or without chemotherapy) versus (vs.) usual treatment alone in treating patients with non-small cell lung cancer that may have spread from where it first started to nearby tissue, lymph nodes, or distant parts of the body (advanced) or that has spread from where it first started (primary site) to other places in the body (metastatic) whose tumor is also negative for a molecular marker called PD-L1. Stereotactic body radiation therapy (SBRT) is a type of radiation therapy that uses high energy x-rays to kill tumor cells and shrink tumors. This method uses special equipment to position a patient and precisely deliver radiation to tumors with fewer doses over a shorter period and may cause less damage to normal tissue than conventional radiation therapy. Immunotherapy with monoclonal antibodies, such as nivolumab, ipilimumab may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. The addition of radiation therapy to usual treatment may stop the cancer from growing and increase the life of patients with advanced non-small cell lung cancer who are PD-L1 negative.


Description:

PRIMARY OBJECTIVE: I. To assess if stereotactic body radiation therapy (SBRT) improves the progression free survival (PFS, phase II portion) and overall survival (OS, phase III portion) of advanced stage non-small cell lung cancer (NSCLC) patients with PD-L1 tumor proportion score (TPS) < 1% who receive immunotherapy with or without chemotherapy. SECONDARY OBJECTIVES: I. To estimate and compare the rates of >= grade 3-4 and all grade adverse events by Common Terminology Criteria for Adverse Events (CTCAE) version (v)5.0 between the arms. II. To summarize and compare progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors (RECIST) between the arms. III. To determine and compare the objective response rate (ORR) per RECIST between the arms (including at both irradiated and un-irradiated sites). QUALITY OF LIFE (QOL) OBJECTIVE: I. To assess the health-related QOL in both treatment arms. CORRELATIVE SCIENCE OBJECTIVE: I. To evaluate changes in the peripheral immune microenvironment between the arms. OUTLINE: Patients are randomized to 1 of 2 arms. ARM A: Patients receive nivolumab intravenously (IV) over 30 minutes on days 1 and 22 and ipilimumab IV over 30 minutes on day 1 of each cycle. Cycles repeat every 6 weeks for 24 months in the absence of disease progression or unacceptable toxicity or patients may receive standard of care systemic immunotherapy. Patients also undergo magnetic resonance imaging (MRI), computed tomography (CT), or positron emission tomography (PET) throughout the trial. Patients may undergo blood sample collection and tissue biopsy on study as well as echocardiography (ECHO) during screening. Arm B: Patients receive nivolumab IV over 30 minutes on days 1 and 22 and ipilimumab IV over 30 minutes on day 1 of each cycle. Cycles repeat every 6 weeks for 24 months in the absence of disease progression or unacceptable toxicity or patients may receive standard of care systemic immunotherapy. Patients also undergo 3 fractions of SBRT every other day. Patients also undergo MRI, CT, or PET throughout the trial. Patients may undergo blood sample collection and tissue biopsy on study as well as ECHO during screening. After completion of study treatment, patients are followed up every 3 months for 3 years and then every 6 months for years 4-5 following randomization until disease progression. Following disease progression patients are followed for survival every 6 months for up to 5 years following randomization.


Recruitment information / eligibility

Status Recruiting
Enrollment 427
Est. completion date December 31, 2027
Est. primary completion date December 31, 2027
Accepts healthy volunteers No
Gender All
Age group 18 Years and older
Eligibility Inclusion Criteria: - Histologic or cytologic diagnosis of stage IV NSCLC using version American Joint Committee on Cancer (AJCC) 8th edition (includes M1a, M1b, and M1c stage disease). Patients with stage IIIB and IIIC disease are eligible if they are not a candidate for combined chemotherapy and radiation - PD-L1 expression tumor proportion score (TPS) < 1% in tumor cells. If PD-L1 expression TPS is unevaluable or the testing could not be completed patients are not eligible. The assay must have been performed locally by a Clinical Laboratory Improvement Act (CLIA) (or equivalent) certified laboratory. The type of assay will be recorded - For non-squamous patients only (adenocarcinoma or adenosquamous): EGFR, ALK and ROS1 testing must be done locally. No patients with known actionable EGFR mutations (except exon 20 insertion), ALK or ROS1 mutations that can be treated with oral tyrosine inhibitors - Measurable disease based on RECIST 1.1, including at least two cancerous deposits. At least one deposit must be RECIST measurable (and not to be irradiated) while at least one OTHER deposit (measurable or non-measurable) must meet criteria for SBRT - Age >= 18 years - Eastern Cooperative Oncology Group (ECOG) performance status 0-2 - No more than three weeks of treatment with systemic chemotherapy or immunotherapy for advanced NSCLC - No more than three weeks of treatment with checkpoint inhibitors for metastatic lung cancer - No treatment with chemotherapy or immunotherapy for non-metastatic disease (e.g., adjuvant therapy) within 6 months prior to registration - No systemic immunostimulatory or immunosuppressive drugs, including > 10 mg prednisone equivalent per day, within 2 weeks or 5 half-live of the drug, whichever is shorter. Steroid premedication per local standard is allowed - >= 1 week prior to registration since palliative (including central nervous system [CNS]) radiotherapy to any tumor site - No prior allogeneic tissue/solid organ transplant - No uncontrolled intercurrent illness including, but not limited to, serious ongoing or active infection, symptomatic congestive heart failure, uncontrolled cardiac arrhythmia, unstable angina pectoris, that would limit compliance with study requirements - No current pneumonitis or history of non-infectious pneumonitis that required steroids - Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months of registration - No active auto-immune disease that requires systemic therapy within 2 years prior to registration. Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid release therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed - No known history of hepatitis B (defined as hepatitis B surface antigen [HBsAg] reactive) or known hepatitis C virus (defined as HCV ribonucleic acid [RNA] [qualitative] is detected) infection - No patients with symptomatic central nervous system metastases and/or carcinomatous meningitis. Patients with small asymptomatic brain metastases are eligible as are patients with treated brain metastases that require no steroids - Not pregnant and not nursing, because this study involves radiation as well as potentially chemotherapy which have known genotoxic, mutagenic and teratogenic effects. Therefore, for women of childbearing potential only, a negative urine or serum pregnancy test done =< 7 days prior to registration is required - No patients with a "currently active" second malignancy that is progressing or has required active treatment within the last 2 years. Participants with non-melanoma skin cancers or carcinoma in-situ (e.g., breast carcinoma, urothelial carcinoma or cervical cancer in situ) or localized prostate cancer (T1-3, N0, M0) that have undergone potentially curative therapy are eligible - No hypersensitivity (>= grade 3) to immunotherapy and/or any of its excipients - No live vaccine within 30 days prior to registration. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guerin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g.,FluMist [registered trademark]) are live attenuated vaccines and are not allowed. COVID-19 vaccine is allowed - Absolute neutrophil count (ANC) >= 1,500/mm^3 - Platelet count >= 100,000/mm^3 - Calculated (Calc.) creatinine clearance >= 45 mL/min - Total bilirubin =< 1.5 x upper limit of normal (ULN) - Aspartate aminotransferase (AST) / alanine aminotransferase (ALT) =< 2.5 x upper limit of normal (ULN)

Study Design


Intervention

Procedure:
Biopsy
Undergo tissue biopsy
Biospecimen Collection
Undergo blood sample collection
Computed Tomography
Undergo CT
Echocardiography
Undergo ECHO
Biological:
Ipilimumab
Given IV
Procedure:
Magnetic Resonance Imaging
Undergo MRI
Biological:
Nivolumab
Given IV
Procedure:
Positron Emission Tomography
Undergo PET
Other:
Quality-of-Life Assessment
Ancillary studies
Radiation:
Stereotactic Body Radiation Therapy
Undergo SBRT

Locations

Country Name City State
United States Summa Health System - Akron Campus Akron Ohio
United States The Don and Sybil Harrington Cancer Center Amarillo Texas
United States Mary Greeley Medical Center Ames Iowa
United States McFarland Clinic - Ames Ames Iowa
United States Trinity Health Saint Joseph Mercy Hospital Ann Arbor Ann Arbor Michigan
United States UM Sylvester Comprehensive Cancer Center at Aventura Aventura Florida
United States Alta Bates Summit Medical Center-Herrick Campus Berkeley California
United States Saint Luke's Cancer Institute - Boise Boise Idaho
United States Trinity Health IHA Medical Group Hematology Oncology - Brighton Brighton Michigan
United States Trinity Health Medical Center - Brighton Brighton Michigan
United States Roswell Park Cancer Institute Buffalo New York
United States Trinity Health IHA Medical Group Hematology Oncology - Canton Canton Michigan
United States Trinity Health Medical Center - Canton Canton Michigan
United States Saint Francis Medical Center Cape Girardeau Missouri
United States Christiana Care Health System-Concord Health Center Chadds Ford Pennsylvania
United States Medical University of South Carolina Charleston South Carolina
United States West Virginia University Charleston Division Charleston West Virginia
United States Chelsea Hospital Chelsea Michigan
United States Trinity Health IHA Medical Group Hematology Oncology - Chelsea Hospital Chelsea Michigan
United States Northwestern University Chicago Illinois
United States University of Chicago Comprehensive Cancer Center Chicago Illinois
United States University of Illinois Chicago Illinois
United States Mercy Cancer Center-West Lakes Clive Iowa
United States Mission Cancer and Blood - West Des Moines Clive Iowa
United States Memorial Hospital North Colorado Springs Colorado
United States UCHealth Memorial Hospital Central Colorado Springs Colorado
United States UM Sylvester Comprehensive Cancer Center at Coral Gables Coral Gables Florida
United States Greater Regional Medical Center Creston Iowa
United States Carle at The Riverfront Danville Illinois
United States Geisinger Medical Center Danville Pennsylvania
United States Decatur Memorial Hospital Decatur Illinois
United States UM Sylvester Comprehensive Cancer Center at Deerfield Beach Deerfield Beach Florida
United States Northwestern Medicine Cancer Center Kishwaukee DeKalb Illinois
United States Mercy Medical Center - Des Moines Des Moines Iowa
United States Mission Cancer and Blood - Laurel Des Moines Iowa
United States City of Hope Comprehensive Cancer Center Duarte California
United States Duke University Medical Center Durham North Carolina
United States Marshfield Medical Center-EC Cancer Center Eau Claire Wisconsin
United States Carle Physician Group-Effingham Effingham Illinois
United States Crossroads Cancer Center Effingham Illinois
United States Parkland Health Center - Farmington Farmington Missouri
United States Genesys Hurley Cancer Institute Flint Michigan
United States Hurley Medical Center Flint Michigan
United States Cancer Care and Hematology-Fort Collins Fort Collins Colorado
United States Poudre Valley Hospital Fort Collins Colorado
United States Beebe South Coastal Health Campus Frankford Delaware
United States Saint Luke's Cancer Institute - Fruitland Fruitland Idaho
United States Northwestern Medicine Cancer Center Delnor Geneva Illinois
United States Northwestern Medicine Glenview Outpatient Center Glenview Illinois
United States Northwestern Medicine Grayslake Outpatient Center Grayslake Illinois
United States UCHealth Greeley Hospital Greeley Colorado
United States Ingalls Memorial Hospital Harvey Illinois
United States Penn State Milton S Hershey Medical Center Hershey Pennsylvania
United States City of Hope at Irvine Lennar Irvine California
United States Bronson Methodist Hospital Kalamazoo Michigan
United States West Michigan Cancer Center Kalamazoo Michigan
United States Gundersen Lutheran Medical Center La Crosse Wisconsin
United States Mayo Clinic Health System-Franciscan Healthcare La Crosse Wisconsin
United States Northwestern Medicine Lake Forest Hospital Lake Forest Illinois
United States Northwell Health/Center for Advanced Medicine Lake Success New York
United States City of Hope Antelope Valley Lancaster California
United States University of Michigan Health - Sparrow Lansing Lansing Michigan
United States Cancer Centers of Southwest Oklahoma Research Lawton Oklahoma
United States Geisinger Medical Oncology-Lewisburg Lewisburg Pennsylvania
United States Saint Joseph Hospital East Lexington Kentucky
United States University of Kentucky/Markey Cancer Center Lexington Kentucky
United States Trinity Health Saint Mary Mercy Livonia Hospital Livonia Michigan
United States Medical Center of the Rockies Loveland Colorado
United States Marshfield Medical Center-Marshfield Marshfield Wisconsin
United States Fremont - Rideout Cancer Center Marysville California
United States Carle Physician Group-Mattoon/Charleston Mattoon Illinois
United States Saint Luke's Cancer Institute - Meridian Meridian Idaho
United States University of Miami Miller School of Medicine-Sylvester Cancer Center Miami Florida
United States Hennepin County Medical Center Minneapolis Minnesota
United States Marshfield Clinic-Minocqua Center Minocqua Wisconsin
United States ProHealth D N Greenwald Center Mukwonago Wisconsin
United States Saint Luke's Cancer Institute - Nampa Nampa Idaho
United States Providence Queen of The Valley Napa California
United States UC Comprehensive Cancer Center at Silver Cross New Lenox Illinois
United States Lenox Hill Hospital New York New York
United States Manhattan Eye Ear and Throat Hospital New York New York
United States Mount Sinai Chelsea New York New York
United States Mount Sinai Hospital New York New York
United States Mount Sinai West New York New York
United States Helen F Graham Cancer Center Newark Delaware
United States Medical Oncology Hematology Consultants PA Newark Delaware
United States CTCA at Southeastern Regional Medical Center Newnan Georgia
United States ProHealth Oconomowoc Memorial Hospital Oconomowoc Wisconsin
United States Mercy Hospital Oklahoma City Oklahoma City Oklahoma
United States University of Oklahoma Health Sciences Center Oklahoma City Oklahoma
United States University of Chicago Medicine-Orland Park Orland Park Illinois
United States Upstate Cancer Center at Oswego Oswego New York
United States Mayo Clinic Hospital in Arizona Phoenix Arizona
United States Michigan Healthcare Professionals Pontiac Pontiac Michigan
United States Trinity Health Saint Joseph Mercy Oakland Hospital Pontiac Michigan
United States Duke Raleigh Hospital Raleigh North Carolina
United States Beebe Health Campus Rehoboth Beach Delaware
United States Marshfield Medical Center-Rice Lake Rice Lake Wisconsin
United States VCU Massey Cancer Center at Stony Point Richmond Virginia
United States Virginia Commonwealth University/Massey Cancer Center Richmond Virginia
United States North Memorial Medical Health Center Robbinsdale Minnesota
United States Mayo Clinic in Rochester Rochester Minnesota
United States Delbert Day Cancer Institute at PCRMC Rolla Missouri
United States University of California Davis Comprehensive Cancer Center Sacramento California
United States Missouri Baptist Medical Center Saint Louis Missouri
United States Regions Hospital Saint Paul Minnesota
United States Sainte Genevieve County Memorial Hospital Sainte Genevieve Missouri
United States MaineHealth Cancer Care Center of York County Sanford Maine
United States Lewis Cancer and Research Pavilion at Saint Joseph's/Candler Savannah Georgia
United States Maine Medical Center- Scarborough Campus Scarborough Maine
United States City of Hope South Pasadena South Pasadena California
United States Maine Medical Partners - South Portland South Portland Maine
United States Memorial Medical Center Springfield Illinois
United States Southern Illinois University School of Medicine Springfield Illinois
United States Springfield Clinic Springfield Illinois
United States Marshfield Medical Center-River Region at Stevens Point Stevens Point Wisconsin
United States Missouri Baptist Sullivan Hospital Sullivan Missouri
United States BJC Outpatient Center at Sunset Hills Sunset Hills Missouri
United States State University of New York Upstate Medical University Syracuse New York
United States SUNY Upstate Medical Center-Community Campus Syracuse New York
United States Gene Upshaw Memorial Tahoe Forest Cancer Center Truckee California
United States Saint Luke's Cancer Institute - Twin Falls Twin Falls Idaho
United States City of Hope Upland Upland California
United States Carle Cancer Center Urbana Illinois
United States Upstate Cancer Center at Verona Verona New York
United States Northwestern Medicine Cancer Center Warrenville Warrenville Illinois
United States MedStar Washington Hospital Center Washington District of Columbia
United States UW Cancer Center at ProHealth Care Waukesha Wisconsin
United States Mercy Medical Center-West Lakes West Des Moines Iowa
United States Marshfield Medical Center - Weston Weston Wisconsin
United States Geisinger Wyoming Valley/Henry Cancer Center Wilkes-Barre Pennsylvania
United States Wake Forest University Health Sciences Winston-Salem North Carolina
United States Trinity Health IHA Medical Group Hematology Oncology Ann Arbor Campus Ypsilanti Michigan

Sponsors (1)

Lead Sponsor Collaborator
National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type Measure Description Time frame Safety issue
Primary Progression-free survival (PFS) (Phase II) Will be performed on an intent-to-treat (ITT) basis. From randomization to disease progression or death of all causes, whichever comes first, assessed up to 5 years
Primary Overall survival (OS) (Phase III) Will be performed on an ITT basis. The comparison of the distributions of OS between treatment arms will be done with a one-sided stratified log-rank test). The rates at various time points (e.g., every 6 months after randomization) and medians of OS for each arm will be estimated using the Kaplan-Meier estimator. The associated 95% confidence interval (CI) will be calculated using Greenwood's formula and based on a log-log transformation applied on the survival function. Hazard ratios will be estimated using a stratified Cox regression model. The final phase III analysis of OS will be considered as "positive" if the stratified log-rank test statistics Z-value greater than the critical value adjusted for type 1 error using group sequential methods. Multivariable Cox models will be used to evaluate the treatment effect on survival time and its interaction with baseline covariates, including stage, systemic therapy, histology and performance status. From randomization and death of all causes, assessed up to 5 years
Secondary PFS Assessed per Response Evaluation Criteria in Solid Tumors (RECIST). From randomization to disease progression or death of all causes, whichever comes first, assessed up to 5 years
Secondary Objective response rate (ORR) Assessed per RECIST for both irradiated and un-irradiated areas. The ORRs between treatments will be compared with Fisher's exact test. The difference of ORR between treatments will be estimated by the Miettinen-Nurminen method and its 95% CI will be given. Multivariable logistic regression will be used to evaluate the treatment effect on ORR while adjusting for significant baseline covariates. Up to 5 years
Secondary Quality of life Up to 5 years
Secondary Incidence of treatment-related adverse events Treatment-related toxicity will be summarized by grade, type, and system organ class. Comparisons of the percentages of patients experiencing an adverse event between Arm A and Arm B will be performed using Fisher's exact test. Up to 5 years
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