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Testing the Addition of Radiation Therapy to the Usual Treatment (Immunotherapy With or Without Chemotherapy) for Stage IV Non-Small Cell Lung Cancer Patients Who Are PD-L1 Negative

Sponsor
National Cancer Institute (NCI) (NIH)
Overall Status
Recruiting
CT.gov ID
NCT04929041
Collaborator
(none)
100
Enrollment
55
Locations
2
Arms
72.3
Anticipated Duration (Months)
1.8
Patients Per Site
0
Patients Per Site Per Month

Study Details

Study Description

Brief 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 has spread to nearby tissue or lymph nodes (advanced) or has spread 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 and pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Chemotherapy drugs, such as carboplatin, pemetrexed, paclitaxel and nab-paclitaxel, 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. 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.

Condition or Disease Intervention/Treatment Phase
Phase 2/Phase 3

Detailed Description

PRIMARY OBJECTIVE:
  1. 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:

  1. 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.

  2. To summarize and compare progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors (RECIST) between the arms.

  3. 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:
  1. To assess the health-related QOL in both treatment arms.
CORRELATIVE SCIENCE OBJECTIVE:
  1. To evaluate changes in the peripheral immune microenvironment between the arms.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM A: Patients receive 1 of 6 treatment options.

Some patients receive immunotherapy alone whether they have squamous or non-squamous histology.

OPTION 1: 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.

Patients with non-squamous histology receive 1 of 2 options.

OPTION 2: Patients receive pembrolizumab IV over 30 minutes on day 1 of each cycle, carboplatin IV on days 1 and 22 of cycles 1 and 2, and pemetrexed IV over 10 minutes on days 1 and 22 of each cycle. Cycles repeat every 6 weeks for 24 months in the absence of disease progression or unacceptable toxicity.

OPTION 3: Patients receive nivolumab IV over 30 minutes on days 1 and 22 and ipilimumab IV over 30 minutes on day 1 of each cycle. Patients also receive carboplatin IV on days 1 and 22 of cycle 1 and pemetrexed IV over 10 minutes on days 1 and 22 of cycle 1. Cycles repeat every 6 weeks for 24 months in the absence of disease progression or unacceptable toxicity.

Patients with squamous histology receive 1 of 3 options.

OPTION 4: Patients receive pembrolizumab IV over 30 minutes on day 1 of each cycle. Patients also receive carboplatin IV and paclitaxel IV over 1-96 hours on days 1 and 22 of cycles 1 and 2. Cycles repeat every 6 weeks for 24 months in the absence of disease progression or unacceptable toxicity.

OPTION 5: Patients receive pembrolizumab IV over 30 minutes on day 1 of each cycle. Patients also receive carboplatin IV on days 1 and 22 of cycles 1 and 2, and nab-paclitaxel IV over 30 minutes on days 1, 8, 15, 22, 29 and 36 of cycles 1 and 2. Cycles repeat every 6 weeks for 24 months in the absence of disease progression or unacceptable toxicity.

OPTION 6: Patients receive nivolumab IV over 30 minutes on days 1 and 22 and ipilimumab IV over 30 minutes on days 1 of each cycle. Patients also receive carboplatin IV and paclitaxel IV over 1-96 hours on days 1 and 22 of cycle 1. Cycles repeat every 6 weeks for 24 months in the absence of disease progression or unacceptable toxicity.

Arm B: Patients receive 1 of 6 treatment options as in Arm A. Patients also undergo 3 fractions of SBRT every other day.

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.

Study Design

Study Type:
Interventional
Anticipated Enrollment :
100 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Randomized Phase II/III Trial of Modern Immunotherapy Based Systemic Therapy With or Without SBRT for PD-L1-Negative, Advanced Non-Small Cell Lung Cancer
Actual Study Start Date :
Dec 21, 2021
Anticipated Primary Completion Date :
Dec 31, 2027
Anticipated Study Completion Date :
Dec 31, 2027

Arms and Interventions

Arm Intervention/Treatment
Experimental: Arm A (immunotherapy, +/- chemotherapy)

See Detailed Description

Drug: Carboplatin
Given IV
Other Names:
  • Blastocarb
  • Carboplat
  • Carboplatin Hexal
  • Carboplatino
  • Carboplatinum
  • Carbosin
  • Carbosol
  • Carbotec
  • CBDCA
  • Displata
  • Ercar
  • JM-8
  • Nealorin
  • Novoplatinum
  • Paraplatin
  • Paraplatin AQ
  • Paraplatine
  • Platinwas
  • Ribocarbo

    • Biological: Ipilimumab
    Given IV
    Other Names:
  • Anti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody
  • BMS-734016
  • Ipilimumab Biosimilar CS1002
  • MDX-010
  • MDX-CTLA4
  • Yervoy

    • Drug: Nab-paclitaxel
    Given IV
    Other Names:
  • ABI 007
  • ABI-007
  • Abraxane
  • Albumin-bound Paclitaxel
  • Albumin-Stabilized Nanoparticle Paclitaxel
  • Nanoparticle Albumin-bound Paclitaxel
  • Nanoparticle Paclitaxel
  • Paclitaxel Albumin
  • paclitaxel albumin-stabilized nanoparticle formulation
  • Protein-bound Paclitaxel

    • Biological: Nivolumab
    Given IV
    Other Names:
  • BMS-936558
  • CMAB819
  • MDX-1106
  • NIVO
  • Nivolumab Biosimilar CMAB819
  • ONO-4538
  • Opdivo

    • Drug: Paclitaxel
    Given IV
    Other Names:
  • Anzatax
  • Asotax
  • Bristaxol
  • Praxel
  • Taxol
  • Taxol Konzentrat

    • Biological: Pembrolizumab
    Given IV
    Other Names:
  • Keytruda
  • Lambrolizumab
  • MK-3475
  • SCH 900475

    • Drug: Pemetrexed
    Given IV
    Other Names:
  • MTA
  • Multitargeted Antifolate
  • Pemfexy

    • Other: Quality-of-Life Assessment
    Ancillary studies
    Other Names:
  • Quality of Life Assessment

    		•
    Experimental: Arm B ( immunotherapy, +/- chemotherapy, SBRT)

    Patients receive 1 of 6 treatment options as in Arm A. Patients also undergo 3 fractions of SBRT every other day.

    Drug: Carboplatin
    Given IV
    Other Names:
  • Blastocarb
  • Carboplat
  • Carboplatin Hexal
  • Carboplatino
  • Carboplatinum
  • Carbosin
  • Carbosol
  • Carbotec
  • CBDCA
  • Displata
  • Ercar
  • JM-8
  • Nealorin
  • Novoplatinum
  • Paraplatin
  • Paraplatin AQ
  • Paraplatine
  • Platinwas
  • Ribocarbo

    • Biological: Ipilimumab
    Given IV
    Other Names:
  • Anti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody
  • BMS-734016
  • Ipilimumab Biosimilar CS1002
  • MDX-010
  • MDX-CTLA4
  • Yervoy

    • Drug: Nab-paclitaxel
    Given IV
    Other Names:
  • ABI 007
  • ABI-007
  • Abraxane
  • Albumin-bound Paclitaxel
  • Albumin-Stabilized Nanoparticle Paclitaxel
  • Nanoparticle Albumin-bound Paclitaxel
  • Nanoparticle Paclitaxel
  • Paclitaxel Albumin
  • paclitaxel albumin-stabilized nanoparticle formulation
  • Protein-bound Paclitaxel

    • Biological: Nivolumab
    Given IV
    Other Names:
  • BMS-936558
  • CMAB819
  • MDX-1106
  • NIVO
  • Nivolumab Biosimilar CMAB819
  • ONO-4538
  • Opdivo

    • Drug: Paclitaxel
    Given IV
    Other Names:
  • Anzatax
  • Asotax
  • Bristaxol
  • Praxel
  • Taxol
  • Taxol Konzentrat

    • Biological: Pembrolizumab
    Given IV
    Other Names:
  • Keytruda
  • Lambrolizumab
  • MK-3475
  • SCH 900475

    • Drug: Pemetrexed
    Given IV
    Other Names:
  • MTA
  • Multitargeted Antifolate
  • Pemfexy

    • Other: Quality-of-Life Assessment
    Ancillary studies
    Other Names:
  • Quality of Life Assessment

    • Radiation: Stereotactic Body Radiation Therapy
    Undergo SBRT
    Other Names:
  • SABR
  • SBRT
  • Stereotactic Ablative Body Radiation Therapy

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Progression-free survival (PFS) (Phase II) [From randomization to disease progression or death of all causes, whichever comes first, assessed up to 5 years]

      Will be performed on an ITT basis.

    2. Overall survival (OS) (Phase III) [From randomization and death of all causes, assessed up to 5 years]

      Will be performed on an intent-to-treat (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.

    Secondary Outcome Measures

    1. PFS [From randomization to disease progression or death of all causes, whichever comes first, assessed up to 5 years]

      Assessed per Response Evaluation Criteria in Solid Tumors (RECIST).

    2. Objective response rate (ORR) [Up to 5 years]

      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.

    3. Quality of life [Up to 5 years]

    4. Incidence of treatment-related adverse events [Up to 5 years]

      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.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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 stereotactic body radiation therapy (SBRT)

    • Age >= 18 years

    • Eastern Cooperative Oncology Group (ECOG) performance status 0-2

    • No prior systemic chemotherapy or immunotherapy for advanced NSCLC

    • No prior treatment with checkpoint inhibitors for metastatic lung cancer

    • Chemotherapy for non-metastatic disease (e.g., adjuvant therapy) or immunotherapy for locally advanced stage III disease is allowed if terminated at least 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

    • = 1 week 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

    • 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) 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)

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Mayo Clinic Hospital in Arizona Phoenix Arizona United States 85054
    2 Alta Bates Summit Medical Center-Herrick Campus Berkeley California United States 94704
    3 City of Hope Antelope Valley Lancaster California United States 93534
    4 University of California Davis Comprehensive Cancer Center Sacramento California United States 95817
    5 City of Hope Upland Upland California United States 91786
    6 Beebe South Coastal Health Campus Frankford Delaware United States 19945
    7 Helen F Graham Cancer Center Newark Delaware United States 19713
    8 Medical Oncology Hematology Consultants PA Newark Delaware United States 19713
    9 Beebe Health Campus Rehoboth Beach Delaware United States 19971
    10 Saint Luke's Cancer Institute - Boise Boise Idaho United States 83712
    11 Saint Luke's Cancer Institute - Fruitland Fruitland Idaho United States 83619
    12 Saint Luke's Cancer Institute - Meridian Meridian Idaho United States 83642
    13 Saint Luke's Cancer Institute - Nampa Nampa Idaho United States 83686
    14 Saint Luke's Cancer Institute - Twin Falls Twin Falls Idaho United States 83301
    15 Carle on Vermilion Danville Illinois United States 61832
    16 Carle Physician Group-Effingham Effingham Illinois United States 62401
    17 Ingalls Memorial Hospital Harvey Illinois United States 60426
    18 Carle Physician Group-Mattoon/Charleston Mattoon Illinois United States 61938
    19 Carle Cancer Center Urbana Illinois United States 61801
    20 Mary Greeley Medical Center Ames Iowa United States 50010
    21 McFarland Clinic PC - Ames Ames Iowa United States 50010
    22 Medical Oncology and Hematology Associates-West Des Moines Clive Iowa United States 50325
    23 Mercy Cancer Center-West Lakes Clive Iowa United States 50325
    24 Greater Regional Medical Center Creston Iowa United States 50801
    25 Medical Oncology and Hematology Associates-Laurel Des Moines Iowa United States 50314
    26 Mercy Medical Center - Des Moines Des Moines Iowa United States 50314
    27 Mercy Medical Center-West Lakes West Des Moines Iowa United States 50266
    28 MaineHealth Cancer Care Center of York County Sanford Maine United States 04073
    29 Maine Medical Center- Scarborough Campus Scarborough Maine United States 04074
    30 Maine Medical Partners - South Portland South Portland Maine United States 04106
    31 Saint Joseph Mercy Hospital Ann Arbor Michigan United States 48106
    32 Saint Joseph Mercy Brighton Brighton Michigan United States 48114
    33 Trinity Health IHA Medical Group Hematology Oncology - Brighton Brighton Michigan United States 48114
    34 Saint Joseph Mercy Canton Canton Michigan United States 48188
    35 Trinity Health IHA Medical Group Hematology Oncology - Canton Canton Michigan United States 48188
    36 Saint Joseph Mercy Chelsea Chelsea Michigan United States 48118
    37 Trinity Health IHA Medical Group Hematology Oncology - Chelsea Hospital Chelsea Michigan United States 48118
    38 Genesys Hurley Cancer Institute Flint Michigan United States 48503
    39 Hurley Medical Center Flint Michigan United States 48503
    40 Trinity Health Saint Mary Mercy Livonia Hospital Livonia Michigan United States 48154
    41 Trinity Health IHA Medical Group Hematology Oncology Ann Arbor Campus Ypsilanti Michigan United States 48197
    42 Roswell Park Cancer Institute Buffalo New York United States 14263
    43 Mount Sinai Hospital New York New York United States 10029
    44 Upstate Cancer Center at Oswego Oswego New York United States 13126
    45 State University of New York Upstate Medical University Syracuse New York United States 13210
    46 SUNY Upstate Medical Center-Community Campus Syracuse New York United States 13215
    47 Summa Health System - Akron Campus Akron Ohio United States 44304
    48 University of Oklahoma Health Sciences Center Oklahoma City Oklahoma United States 73104
    49 Christiana Care Health System-Concord Health Center Chadds Ford Pennsylvania United States 19317
    50 Medical University of South Carolina Charleston South Carolina United States 29425
    51 Gundersen Lutheran Medical Center La Crosse Wisconsin United States 54601
    52 Mayo Clinic Health System-Franciscan Healthcare La Crosse Wisconsin United States 54601
    53 ProHealth D N Greenwald Center Mukwonago Wisconsin United States 53149
    54 ProHealth Oconomowoc Memorial Hospital Oconomowoc Wisconsin United States 53066
    55 UW Cancer Center at ProHealth Care Waukesha Wisconsin United States 53188

    Sponsors and Collaborators

    • National Cancer Institute (NCI)

    Investigators

    • Principal Investigator: Steven E Schild, Alliance for Clinical Trials in Oncology

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    National Cancer Institute (NCI)
    ClinicalTrials.gov Identifier:
    NCT04929041
    Other Study ID Numbers:
    • NCI-2021-06042
    • NCI-2021-06042
    • A082002
    • A082002
    • U10CA180821
    First Posted:
    Jun 18, 2021
    Last Update Posted:
    Aug 23, 2022
    Last Verified:
    Jul 1, 2022
    Individual Participant Data (IPD) Sharing Statement:
    Yes
    Plan to Share IPD:
    Yes
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Additional relevant MeSH terms:
    Carcinoma
    Lung Neoplasms
    Carcinoma, Non-Small-Cell Lung
    Adenocarcinoma
    Adenocarcinoma of Lung
    Carcinoma, Adenosquamous
    Paclitaxel
    Albumin-Bound Paclitaxel
    Carboplatin
    Pembrolizumab
    Nivolumab
    Pemetrexed
    Ipilimumab

    Study Results

    No Results Posted as of Aug 23, 2022