Testing the Safety of Adding Either Monalizumab (IPH2201) or Oleclumab (MEDI9447) to Durvalumab (MEDI4736) Plus Standard Radiation Therapy for Locally Advanced Non-small Cell Lung Cancer (NSCLC), ARCHON-1 Trial

NCT03801902 | Completed Phase 1 Results FDA Drug

• 3 other identifiers: NCI-2019-00176NRG-LU004U10CA180868
• Study Type: interventional
• Target: 26
• Locations: 1 country
• Sites: 56

Brief Summary

This phase I trial studies the safety of adding durvalumab to accelerated hypofractionated radiation therapy (ACRT) or conventionally fractionated radiation therapy, as well as the safety of adding either monalizumab or oleclumab to durvalumab plus conventionally fractionated radiation therapy in treating patients with non-small cell lung cancer that has spread to nearby tissue or lymph nodes (locally advanced). Accelerated hypofractionated radiation therapy delivers higher doses of radiation therapy over a shorter period of time and may kill more tumor cells and have fewer side effects. Immunotherapy with monoclonal antibodies, such as durvalumab and monalizumab, may help the body's immune system attack the tumor, and may interfere with the ability of tumor cells to grow and spread. Oleclumab is in a class of medications called monoclonal antibodies. It binds to a protein called CD73, which is found on some types of tumor cells. Oleclumab may block CD73 and help the immune system kill tumor cells. It is not yet known whether adding durvalumab to ACRT or adding monalizumab or oleclumab to durvalumab plus conventionally fractionated radiation therapy will work better in treating patients with non-small cell lung cancer.

Conditions

Locally Advanced Lung Non-Small Cell Carcinoma; Locally Recurrent Lung Non-Small Cell Carcinoma; Stage II Lung Cancer AJCC v8; Stage III Lung Cancer AJCC v8; Unresectable Lung Non-Small Cell Carcinoma

Outcome Measures

Primary Outcomes (1)

• Number of Participants Experiencing a Safety Event

  Safety event is defined as one of the following: * Grade 4-5 non-hematologic protocol-defined serious adverse event (SAE) possibly, probably, or definitely related to protocol treatment occurring within 90 days from radiation therapy (RT) start for Arm 1 or within 8 weeks from RT start for Arm 2; * Any adverse event possibly, probably, or definitely related to protocol treatment that leads to missing at least 2 doses of durvalumab within 90 days from RT start for Arm 1 or within 8 weeks from RT start for Arm 2; * Permanent discontinuation of durvalumab due to an adverse event possibly, probably, or definitely related to protocol treatment within the first 30 days of starting durvalumab; or * SAEs possibly, probably, or definitely related to RT that cause either an interruption or early termination of RT. Adverse events are graded according to the Common Terminology Criteria for Adverse Events version 5.0, which assigns a grade according to severity from 1=mild to 5=death.

  From start of study treatment to 90 (ACRT) or 56 (standard RT) days from the end of radiation treatment. (Approximately 104 or 70 days, respectively, from start of study treatment)

Secondary Outcomes (5)

• Percentage of Participants Who Received at Least 80% of Planned Durvalumab Dose During First 8 Weeks Following Initial Dose

  From start of durvalumab to 8 weeks

• Percentage of Participants Who Received at Least 80% of Planned Dose of Monalizumab or Oleclumab During the First 8 Weeks Following the Initial Dose (Feasibility)

  From start of monalizumab or oleclumab to 8 weeks

• Distribution of Participants by Highest Grade Adverse Event

  From registration to last follow-up at time of initial analysis. Maximum follow-up was 23.2 months

• Percentage of Participants Experiencing a Grade 4 or Higher Non-hematologic Adverse Event

  From registration to last follow-up at time of initial analysis. Maximum follow-up was 23.2 months.

• Progression-free Survival

  From registration to two years after protocol treatment, which lasted up to 12 months. Maximum follow-up was 38.3 months.

Study Arms (4)

Arm I (CLOSED) (Durvalumab and ACRT)

EXPERIMENTAL

Starting 2 weeks prior to radiation therapy, patients receive durvalumab IV over 60 minutes on day 1 of each cycle. Treatment repeats every 4 weeks for 13 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo ACRT 1 fraction per day, 5 days per week for 15 fractions. Patients also undergo brain MRI or CT scan during screening and as clinically indicated, chest CT scans on study and during follow up, and collection of blood samples during screening and on study.

Radiation: Accelerated Hypofractionated Radiation Therapy; Procedure: Biospecimen Collection; Procedure: Computed Tomography; Biological: Durvalumab; Procedure: Magnetic Resonance Imaging of the Brain with and without Contrast

Arm II (CLOSED) (Durvalumab and standard RT)

EXPERIMENTAL

Starting 2 weeks prior to radiation therapy, patients receive durvalumab IV over 60 minutes on day 1 of each cycle. Treatment repeats every 4 weeks for 13 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo conventionally fractionated radiation therapy 1 fraction per day, 5 days per week for 30 fractions. Patients also undergo brain MRI or CT scan during screening and as clinically indicated, chest CT scans on study and during follow up, and collection of blood samples during screening and on study.

Procedure: Biospecimen Collection; Procedure: Computed Tomography; Biological: Durvalumab; Procedure: Magnetic Resonance Imaging of the Brain with and without Contrast; Radiation: Radiation Therapy

Arm III (durvalumab, monalizumab, standard RT)

EXPERIMENTAL

Starting 2 weeks prior to radiation therapy, patients receive durvalumab IV over 60 minutes and monalizumab IV over 60 minutes on day 1 of each cycle. Treatment repeats every 4 weeks for 13 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo conventionally fractionated radiation therapy 1 fraction per day, 5 days per week for 30 fractions. Patients also undergo brain MRI or CT scan during screening and as clinically indicated, chest CT scans on study and during follow up, and collection of blood samples during screening and on study.

Procedure: Biospecimen Collection; Procedure: Computed Tomography; Biological: Durvalumab; Procedure: Magnetic Resonance Imaging of the Brain with and without Contrast; Biological: Monalizumab; Radiation: Radiation Therapy

Arm IV (durvalumab, oleclumab, standard RT)

EXPERIMENTAL

Starting 2 weeks prior to radiation therapy, patients receive durvalumab IV over 60 minutes on day 1 of each cycle. Patients also receive oleclumab IV over 60 minutes on days 1 and 15 of cycles 1-2, then on day 1 of cycles thereafter. Treatment repeats every 4 weeks for 13 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo conventionally fractionated radiation therapy 1 fraction per day, 5 days per week for 30 fractions. Patients also undergo brain MRI or CT scan during screening and as clinically indicated, chest CT scans on study and during follow up, and collection of blood samples during screening and on study.

Procedure: Biospecimen Collection; Procedure: Computed Tomography; Biological: Durvalumab; Procedure: Magnetic Resonance Imaging of the Brain with and without Contrast; Biological: Oleclumab; Radiation: Radiation Therapy

Interventions

Accelerated Hypofractionated Radiation Therapy RADIATION

160 Gy given as one 4 Gy fraction per day, 5 days per week for 15 fractions.

Also known as: AHF-RT, AHRT

Arm I (CLOSED) (Durvalumab and ACRT)

Biospecimen Collection PROCEDURE

Undergo collection of blood samples

Also known as: Biological Sample Collection, Biospecimen Collected, Specimen Collection

Arm I (CLOSED) (Durvalumab and ACRT); Arm II (CLOSED) (Durvalumab and standard RT); Arm III (durvalumab, monalizumab, standard RT); Arm IV (durvalumab, oleclumab, standard RT)

Computed Tomography PROCEDURE

Undergo brain CT and chest CT

Also known as: 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

Arm I (CLOSED) (Durvalumab and ACRT); Arm II (CLOSED) (Durvalumab and standard RT); Arm III (durvalumab, monalizumab, standard RT); Arm IV (durvalumab, oleclumab, standard RT)

Durvalumab BIOLOGICAL

Administered intravenously (IV) as a 1500 mg fixed dose over 60 minutes for 13 cycles (1 cycle = 4 weeks), until disease progression or toxicity or death, whichever comes first.

Also known as: Imfinzi, Immunoglobulin G1, Anti-(Human Protein B7-H1) (Human Monoclonal MEDI4736 Heavy Chain), Disulfide with Human Monoclonal MEDI4736 Kappa-chain, Dimer, MEDI 4736, MEDI-4736, MEDI4736

Arm I (CLOSED) (Durvalumab and ACRT); Arm II (CLOSED) (Durvalumab and standard RT); Arm III (durvalumab, monalizumab, standard RT); Arm IV (durvalumab, oleclumab, standard RT)

Magnetic Resonance Imaging of the Brain with and without Contrast PROCEDURE

Undergo brain MRI

Also known as: Brain Magnetic Resonance Imaging with and without Contrast, Brain MRI, Brain MRI with and without Contrast, Head MRI with and without Contrast

Arm I (CLOSED) (Durvalumab and ACRT); Arm II (CLOSED) (Durvalumab and standard RT); Arm III (durvalumab, monalizumab, standard RT); Arm IV (durvalumab, oleclumab, standard RT)

Monalizumab BIOLOGICAL

Administered IV as a 1500 mg fixed dose over 60 minutes (+/- 10 minutes)

Also known as: Immunoglobulin G4-kappa, Anti-(Homo sapiens KLRC1 (Killer Cell Lectin-like Receptor Subfamily C Member 1, NKG2-a, NKG2a, CD159A, CD94)), Humanized Monoclonal Antibody, IPH-2201, IPH2201, NN-8765, NN8765, NN8765-3658

Arm III (durvalumab, monalizumab, standard RT)

Oleclumab BIOLOGICAL

Administered IV 3000 mg over 60 minutes (+/- 10 minutes)

Also known as: Anti-CD73 Monoclonal Antibody MEDI9447, MEDI9447

Arm IV (durvalumab, oleclumab, standard RT)

Radiation Therapy RADIATION

60 gy given as one 2 Gy fraction per day, 5 days per week for 30 fractions

Also known as: Cancer Radiotherapy, Energy Type, ENERGY_TYPE, Irradiate, Irradiated, Irradiation, Radiation, Radiation Therapy, NOS, Radiotherapeutics, Radiotherapy, RT, Therapy, Radiation

Arm II (CLOSED) (Durvalumab and standard RT); Arm III (durvalumab, monalizumab, standard RT); Arm IV (durvalumab, oleclumab, standard RT)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Pathologic (cytological or histological) proof of diagnosis of stage II-III (American Joint Committee on Cancer \[AJCC\] 8th edition \[ed.\]) unresectable or inoperable, non-metastatic non-small cell lung cancer (NSCLC) within 60 days prior to registration, with no liver or renal end organ damage, as determined by normal laboratory values noted below. Locally recurrent, N1-N3 disease following surgery without prior radiation therapy is eligible. Patients with N1 to N3 and undetectable primary lung tumors (T0) are eligible
• Pathological diagnosis of PD-L1 high expressing tumors (\>= 50%) within 60 days prior to registration (using Dako 22C3 immunohistochemistry \[IHC\] antibody or the Ventana SP263 antibody platforms) performed at a Clinical Laboratory Improvement Act (CLIA)-certified lab
• Appropriate stage for study entry based on the following diagnostic workup:
• History/physical examination within 30 days prior to registration;
• Positron emission tomography (PET)/computed tomography (CT) scan for staging within 30 days prior to registration (note: if CT portion of PET/CT scan is not of diagnostic quality, then a separate CT scan with contrast is required);
• Magnetic resonance imaging (MRI) scan of the brain with contrast; if medically contraindicated, then CT scan of the brain with contrast (unless medically contraindicated) is acceptable, within 30 days prior to registration;
• Sufficient lung function with forced expiratory volume in 1 second (FEV1) \>= 0.8 liter or \>= 35% predicted and carbon monoxide diffusing capability (DLCO) \>= 40% with or without bronchodilator within 30 days prior to registration;
• Patients who meet the criterion above without oxygen (O2), but who need acute (started within 10 days prior to registration) supplemental oxygen due to tumor-caused obstruction/hypoxia are eligible, provided the amount of the O2 needed has been stable
• Age ≥ 18
• Minimum body weight \>= 40 kg
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 within 30 days prior to registration
• Absolute neutrophil count (ANC) \>= 1500 cells/mm\^3 (within 30 days prior to registration)
• Lymphocyte count \>= 500 cells/mm\^3 (within 30 days prior to registration)
• Platelet count \>= 100,000 cells/mm\^3 (within 30 days prior to registration)
• Hemoglobin \>= 9.0 g/dL (within 30 days prior to registration) (Note: The use of transfusion or other intervention to achieve hemoglobin \[Hgb\] \>= 9.0 g/dl is acceptable)

You may not qualify if:

• Definitive clinical or radiologic evidence of metastatic disease
• Prior invasive malignancy (except those with a negligible risk of metastasis or death and with expected curative outcome \[such as adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, localized prostate cancer treated surgically with curative intent, or ductal carcinoma in situ treated surgically with curative intent\] or undergoing active surveillance per standard-of-care management \[e.g., chronic lymphocytic leukemia (CLL) Rai stage 0, prostate cancer with Gleason score =\< 6, and prostate specific antigen (PSA) =\< 10 mg/mL\]) unless disease free for a minimum of 3 years
• Prior chemotherapy or systemic therapy for the study cancer; note that prior chemotherapy for a different cancer is allowable
• Prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields so that cumulative composite dose combining previous plan and current plan to be within 80 Gy to the trachea, major blood vessels, esophagus, and heart, and 55 Gy to the spinal cord (if such patients are being considered, this will need to be centrally reviewed). Prior chest radiation without overlap is permissible
• Prior history of myocardial infarction, stroke, or transient ischemic attack in the past 3 months
• History of autoimmune disease, including but not limited to systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjogren's syndrome, Guillain-Barre syndrome, multiple sclerosis, vasculitis, or glomerulonephritis. Patients with a history of treated autoimmune thyroid disease requiring thyroid replacement but not immunosuppressives, as well as type 1 diabetes, are permitted. Patients with vitiligo, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll
• History of idiopathic pulmonary fibrosis, pneumonitis (including drug induced), organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia, etc.), or evidence of active pneumonitis on chest PET/CT or CT scan
• Severe, active co-morbidity defined as follows:
• Known clinically significant liver disease, including active viral, alcoholic, or other hepatitis, cirrhosis, fatty liver, and inherited liver disease;
• Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the patient at high risk from treatment complications;
• Active tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and tuberculosis \[TB\] testing in line with local practice);
• Active hepatitis B (chronic or acute) or hepatitis C infection. Patients with past or resolved hepatitis B infection defined as having a negative hepatitis B surface antigen (HBsAg) test, a positive anti-HBc (antibody to hepatitis B core antigen), and a negative viral deoxyribonucleic acid (DNA) test (only obtained if HBsAg is found positive) are eligible. Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV ribonucleic acid (RNA)
• Women who are breastfeeding and unwilling to discontinue
• Patients with grade \>= 2 neuropathy will be evaluated on a case-by-case basis after consultation with the study physician.
• Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab may be included only after consultation with the study physician

Sponsors & Collaborators

• National Cancer Institute (NCI): lead
• NRG Oncology: collaborator

Study Sites (56)

Grady Health System

Atlanta, Georgia, 30303, United States

Location

Emory University Hospital Midtown

Atlanta, Georgia, 30308, United States

Location

Emory University Hospital/Winship Cancer Institute

Atlanta, Georgia, 30322, United States

Location

Emory Saint Joseph's Hospital

Atlanta, Georgia, 30342, United States

Location

Augusta University Medical Center

Augusta, Georgia, 30912, United States

Location

Saint Alphonsus Cancer Care Center-Boise

Boise, Idaho, 83706, United States

Location

Saint Alphonsus Cancer Care Center-Caldwell

Caldwell, Idaho, 83605, United States

Location

Saint Alphonsus Cancer Care Center-Nampa

Nampa, Idaho, 83687, United States

Location

University of Kansas Cancer Center-West

Kansas City, Kansas, 66112, United States

Location

University of Kansas Cancer Center

Kansas City, Kansas, 66160, United States

Location

University of Kansas Cancer Center-Overland Park

Overland Park, Kansas, 66210, United States

Location

University of Kansas Hospital-Westwood Cancer Center

Westwood, Kansas, 66205, United States

Location

Saint Elizabeth Healthcare Edgewood

Edgewood, Kentucky, 41017, United States

Location

University of Maryland/Greenebaum Cancer Center

Baltimore, Maryland, 21201, United States

Location

UM Upper Chesapeake Medical Center

Bel Air, Maryland, 21014, United States

Location

Central Maryland Radiation Oncology in Howard County

Columbia, Maryland, 21044, United States

Location

UM Baltimore Washington Medical Center/Tate Cancer Center

Glen Burnie, Maryland, 21061, United States

Location

McLaren Cancer Institute-Bay City

Bay City, Michigan, 48706, United States

Location

McLaren Cancer Institute-Clarkston

Clarkston, Michigan, 48346, United States

Location

Michigan Healthcare Professionals Clarkston

Clarkston, Michigan, 48346, United States

Location

Wayne State University/Karmanos Cancer Institute

Detroit, Michigan, 48201, United States

Location

Michigan Healthcare Professionals Farmington

Farmington Hills, Michigan, 48334, United States

Location

Weisberg Cancer Treatment Center

Farmington Hills, Michigan, 48334, United States

Location

McLaren Cancer Institute-Flint

Flint, Michigan, 48532, United States

Location

Singh and Arora Hematology Oncology PC

Flint, Michigan, 48532, United States

Location

Karmanos Cancer Institute at McLaren Greater Lansing

Lansing, Michigan, 48910, United States

Location

Mid-Michigan Physicians-Lansing

Lansing, Michigan, 48912, United States

Location

McLaren Cancer Institute-Lapeer Region

Lapeer, Michigan, 48446, United States

Location

McLaren Cancer Institute-Macomb

Mount Clemens, Michigan, 48043, United States

Location

McLaren Cancer Institute-Northern Michigan

Petoskey, Michigan, 49770, United States

Location

McLaren-Port Huron

Port Huron, Michigan, 48060, United States

Location

Michigan Healthcare Professionals Troy

Troy, Michigan, 48098, United States

Location

Siteman Cancer Center at Saint Peters Hospital

City of Saint Peters, Missouri, 63376, United States

Location

Siteman Cancer Center at West County Hospital

Creve Coeur, Missouri, 63141, United States

Location

University of Kansas Cancer Center - North

Kansas City, Missouri, 64154, United States

Location

University of Kansas Cancer Center - Lee's Summit

Lee's Summit, Missouri, 64064, United States

Location

University of Kansas Cancer Center at North Kansas City Hospital

North Kansas City, Missouri, 64116, United States

Location

Washington University School of Medicine

St Louis, Missouri, 63110, United States

Location

Siteman Cancer Center-South County

St Louis, Missouri, 63129, United States

Location

Siteman Cancer Center at Christian Hospital

St Louis, Missouri, 63136, United States

Location

Benefis Sletten Cancer Institute

Great Falls, Montana, 59405, United States

Location

Logan Health Medical Center

Kalispell, Montana, 59901, United States

Location

Nebraska Methodist Hospital

Omaha, Nebraska, 68114, United States

Location

Ohio State University Comprehensive Cancer Center

Columbus, Ohio, 43210, United States

Location

University of Oklahoma Health Sciences Center

Oklahoma City, Oklahoma, 73104, United States

Location

Legacy Mount Hood Medical Center

Gresham, Oregon, 97030, United States

Location

Legacy Good Samaritan Hospital and Medical Center

Portland, Oregon, 97210, United States

Location

Thomas Jefferson University Hospital

Philadelphia, Pennsylvania, 19107, United States

Location

Lankenau Medical Center

Wynnewood, Pennsylvania, 19096, United States

Location

MD Anderson in The Woodlands

Conroe, Texas, 77384, United States

Location

M D Anderson Cancer Center

Houston, Texas, 77030, United States

Location

MD Anderson West Houston

Houston, Texas, 77079, United States

Location

MD Anderson League City

League City, Texas, 77573, United States

Location

MD Anderson in Sugar Land

Sugar Land, Texas, 77478, United States

Location

Legacy Salmon Creek Hospital

Vancouver, Washington, 98686, United States

Location

West Virginia University Healthcare

Morgantown, West Virginia, 26506, United States

Location

MeSH Terms

Conditions

Lung Neoplasms

Interventions

Specimen Handling; durvalumab; Immunoglobulin G; Disulfides; Contrast Media; monalizumab; NK Cell Lectin-Like Receptor Subfamily C; Antibodies, Monoclonal, Humanized; Radiotherapy; Radiation

Condition Hierarchy (Ancestors)

Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Investigative Techniques; Immunoglobulin Isotypes; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Sulfides; Anions; Ions; Electrolytes; Inorganic Chemicals; Hydrogen Sulfide; Sulfur Compounds; Organic Chemicals; Diagnostic Uses of Chemicals; Pharmacologic Actions; Chemical Actions and Uses; Specialty Uses of Chemicals; Receptors, NK Cell Lectin-Like; Receptors, Natural Killer Cell; Receptors, Immunologic; Receptors, Cell Surface; Membrane Proteins; Antibodies, Monoclonal; Therapeutics; Physical Phenomena

Limitations and Caveats

The study opened with 2 cohorts. Results were entered in 01-2022 and approved, after which the protocol was amended to add 2 cohorts such that the primary completion date (PCD) was changed to a future date, requiring entered results to be removed. The new cohorts opened accrual 01-2024. About a year later the decision was made to permanently close accrual. There was no accrual to the new cohorts, therefore PCD reverted to the prior date and the original outcome measure results were re-entered.

Results Point of Contact

• Title: Wendy Seiferheld
• Organization: NRG Oncology

seiferheldw@nrgoncology.org

215-574-3208

Study Officials

• Steven H Lin

  NRG Oncology

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 11, 2019
• First Posted: January 14, 2019
• Study Start: October 28, 2019
• Primary Completion: October 26, 2021
• Study Completion: September 4, 2025
• Last Updated: September 23, 2025
• Results First Posted: June 19, 2025

Record last verified: 2025-09

Data Sharing

• IPD Sharing: Will share

Locations

US (56)