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Accelerated Hypofractionated or Conventionally Fractionated Radiotherapy and Durvalumab in Treating Patients With Stage II-III Non-small Cell Lung Cancer

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ClinicalTrials.gov Identifier: NCT03801902
Recruitment Status : Recruiting
First Posted : January 14, 2019
Last Update Posted : September 10, 2019
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Brief Summary:
This phase I trial studies how well giving accelerated hypofractionated or conventionally fractionated radiation therapy and durvalumab works in treating patients with stage II-III non-small cell lung cancer. 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. Conventionally fractionated radiation therapy delivers smaller doses of radiation therapy over time and may kill more tumor cells and have fewer side effects. Immunotherapy with monoclonal antibodies, such as durvalumab, may help the body's immune system attack the tumor, and may interfere with the ability of tumor cells to grow and spread. It is not yet known whether giving accelerated hypofractionated radiation therapy or conventionally fractionated radiation therapy with durvalumab will work better in treating patients with non-small cell lung cancer.

Condition or disease Intervention/treatment Phase
Lung Non-Small Cell Carcinoma PD-L1 Overexpression Recurrent Lung Carcinoma Stage II Lung Cancer AJCC v8 Stage IIA Lung Cancer AJCC v8 Stage IIB Lung Cancer AJCC v8 Stage III Lung Cancer AJCC v8 Stage IIIA Lung Cancer AJCC v8 Stage IIIB Lung Cancer AJCC v8 Stage IIIC Lung Cancer AJCC v8 Biological: Durvalumab Radiation: Fractionated Stereotactic Radiation Therapy Radiation: Hypofractionated Radiation Therapy Phase 1

Detailed Description:

PRIMARY OBJECTIVES:

I. To evaluate if the addition of MEDI4736 (durvalumab) to two schedules of radiation therapies (60 Gy in 30 fractions or 60 Gy in 15 fractions) is safe.

SECONDARY OBJECTIVES:

I. To examine if the addition of MEDI4736 (durvalumab) to radiation therapy is feasible.

II. To assess toxicities associated with the addition of MEDI4736 (durvalumab) to radiation therapy.

III. To obtain preliminary estimates of progression-free survival (PFS), using Response Evaluation Criteria in Solid Tumors (RECIST) guidelines, in patients who received MEDI4736 (durvalumab) added to radiation.

EXPLORATORY OBJECTIVES:

I. To assess the impact the addition of MEDI4736 (durvalumab) has on progression-free survival, using immune-related response criteria (irRC) guidelines.

II. To assess the changes in circulating tumor cells (CTCs) and various immune parameters during treatment with durvalumab and radiotherapy and changes after completion of treatment.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive durvalumab intravenously (IV) over 60 minutes on day 1 starting 2 weeks prior to radiation therapy. Treatment repeats every 4 weeks for 13 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo accelerated hypofractionated radiation therapy (ACRT) 1 fraction per day, 5 days per week for 15 fractions.

ARM II: Patients receive durvalumab as in Arm I. Patients also undergo conventionally fractionated radiation therapy 1 fraction per day, 5 days per week for 30 fractions.

After completion of study treatment, patients are followed up every 3 months for 1 year and then every 4 months for 1 year.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 24 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I Trial of Accelerated or Conventionally Fractionated Radiotherapy Combined With MEDI4736 (Durvalumab) in PD-L1 High Locally Advanced Non-Small Cell Lung Cancer (NSCLC) (ARCHON-1)
Actual Study Start Date : January 4, 2019
Estimated Primary Completion Date : July 28, 2020
Estimated Study Completion Date : July 28, 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Lung Cancer
Drug Information available for: Durvalumab

Arm Intervention/treatment
Experimental: Arm I (durvalumab, ACRT)
Patients receive durvalumab IV over 60 minutes on day 1 starting 2 weeks prior to radiation therapy. 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.
Biological: Durvalumab
Given IV
Other Names:
  • Imfinzi
  • Immunoglobulin G1, Anti-(Human Protein B7-H1) (Human Monoclonal MEDI4736 Heavy Chain), Disulfide with Human Monoclonal MEDI4736 Kappa-chain, Dimer
  • MEDI-4736
  • MEDI4736

Radiation: Hypofractionated Radiation Therapy
Undergo ACRT
Other Names:
  • Hypofractionated Radiotherapy
  • hypofractionation

Active Comparator: Arm II (durvalumab, standard RT)
Patients receive durvalumab as in Arm I. Patients also undergo conventionally fractionated radiation therapy 1 fraction per day, 5 days per week for 30 fractions.
Biological: Durvalumab
Given IV
Other Names:
  • Imfinzi
  • Immunoglobulin G1, Anti-(Human Protein B7-H1) (Human Monoclonal MEDI4736 Heavy Chain), Disulfide with Human Monoclonal MEDI4736 Kappa-chain, Dimer
  • MEDI-4736
  • MEDI4736

Radiation: Fractionated Stereotactic Radiation Therapy
Undergo conventionally fractionated radiation therapy
Other Name: Fractionated Stereotactic Radiotherapy




Primary Outcome Measures :
  1. Incidence of adverse events [ Time Frame: Up to 2 years ]
    All adverse events will be graded according to Common Terminology Criteria for Adverse Events version 5.0.


Secondary Outcome Measures :
  1. Feasibility of giving durvalumab in combination with radiation therapy [ Time Frame: Up to 8 weeks ]
    Feasibility is based on an evaluation of the percentage of patients who received at least 80% of the planned dose of MEDI4736 (durvalumab) therapy during the first 8 weeks following initial dose of MEDI4736 (durvalumab).

  2. Incidence of adverse events (AEs) [ Time Frame: Up to 2 years ]
    Will be assessed by Common Terminology Criteria for Adverse Events version 5.0. Counts of all AEs by grade will be provided by treatment arm. Counts and frequencies will be provided for the worst grade AE experienced by the patient by treatment arm and within the subset of AEs related to treatment. Severe AEs will be any grade 4 or greater non-hematologic toxicities and will be summarized by frequency tables by treatment arm. No formal statistical testing will be performed on these summary data.

  3. Progression free survival [ Time Frame: Time from registration to progressive disease or death, whichever occurs first, assessed up to 2 years ]
    Will be assessed by Response Evaluation Criteria in Solid Tumors. Will be estimated using the Kaplan Meier method. Plots and descriptive statistics will be provided for both treatment arms but no formal testing performed due to lack of statistical power


Other Outcome Measures:
  1. Progression free survival [ Time Frame: Time from registration to progressive disease or death, whichever occurs first, assessed up to 2 years ]
    Will be assessed by immune-related response criteria. Will be estimated using the Kaplan Meier method. Plots and descriptive statistics will be provided for both treatment arms but no formal testing performed due to lack of statistical power.

  2. Change in circulating tumor cells [ Time Frame: Baseline up to 2 years ]
    Circulating tumor cells will be collected and analyzed at the time of progression.

  3. Change in immune parameter [ Time Frame: Baseline up to 2 years ]
    Will focus on descriptive statistics and change from baseline to subsequent collection times.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 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 platform) 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
  • Body weight > 30 kg
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 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)
  • Glomerular filtration rate (GFR) >= 60 mL/min/1.73 m^2 (within 30 days prior to registration)
  • Total bilirubin =< 1.5 x upper limit of normal (ULN) with the following exception (within 30 days prior to registration):

    • Patients with known Gilbert disease who have serum bilirubin level =< 3 x ULN may be enrolled
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x ULN (within 30 days prior to registration)
  • Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-menopausal patients, obtained within 14 days prior to registration. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply:

    • Women < 50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy).
    • Women >= 50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses > 1 year ago, had chemotherapy-induced menopause with last menses > 1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy)
  • Patients who are human immunodeficiency virus (HIV) positive may participate IF they meet the following eligibility requirements:

    • They must be stable on their anti-retroviral regimen, and they must be healthy from an HIV perspective.
    • They must have a CD4 count of greater than 250 cells/mcL.
    • They must not be receiving prophylactic therapy for an opportunistic infection
  • The patient or a legally authorized representative must provide study-specific informed consent prior to study entry

Exclusion Criteria:

  • 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
  • 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
  • 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)
  • Pregnancy or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception during treatment and for 3 months after the last dose of MEDI4736 (durvalumab); this exclusion is necessary because the treatment involved in this study may be significantly teratogenic. Women who are breastfeeding are also excluded
  • Any unresolved toxicity National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) grade >= 2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria:

    • 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
  • Major surgical procedure (as defined by the investigator) within 28 days prior to the first dose of investigational product (IP). Note: Local surgery of isolated lesions for palliative intent is acceptable
  • History of allogenic organ transplantation
  • History of leptomeningeal carcinomatosis
  • History of active primary immunodeficiency
  • Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab. The following are exceptions to this criterion:

    • Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection);
    • Systemic corticosteroids at physiologic doses not to exceed <<10 mg/day>> of prednisone or its equivalent;
    • Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication)
  • Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. Note: Patients, if enrolled, should not receive live vaccine whilst receiving IP and up to 30 days after the last dose of IP
  • Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03801902


  Show 32 Study Locations
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Steven H Lin NRG Oncology

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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT03801902     History of Changes
Other Study ID Numbers: NCI-2019-00176
NCI-2019-00176 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
NRG-LU004 ( Other Identifier: NRG Oncology )
NRG-LU004 ( Other Identifier: CTEP )
U10CA180868 ( U.S. NIH Grant/Contract )
First Posted: January 14, 2019    Key Record Dates
Last Update Posted: September 10, 2019
Last Verified: March 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page
URL: https://grants.nih.gov/policy/sharing.htm

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Carcinoma
Lung Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Lung Diseases
Respiratory Tract Diseases
Durvalumab
Antibodies, Monoclonal
Antineoplastic Agents, Immunological
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs