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

Study Overview
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Brief Summary
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This phase I trial studies how well giving accelerated hypofractionated (ACRT) 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.

Detailed Description
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PRIMARY OBJECTIVE: 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.

Official Title
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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)

Conditions
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Localized Lung Carcinoma, Locally Advanced Lung Non-Small Cell Carcinoma, 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, Unresectable Lung Non-Small Cell Carcinoma

Intervention / Treatment
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* Radiation: Accelerated Hypofractionated Radiation Therapy
* Biological: Durvalumab
* Radiation: Radiation Therapy


Participation Criteria
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Eligibility Criteria
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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 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 Body weight > 30 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) Glomerular filtration rate (GFR) >= 40 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. 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) 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

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 |
| --- | --- |
| Experimental: Arm I (Durvalumab and ACRT)<br>Given Durvalumab every 4 weeks for a year starting two weeks before accelerated hypofractionated radiation therapy (ACRT). | Radiation: Accelerated Hypofractionated Radiation Therapy<br>* 160 Gy given as one 4 Gy fraction per day, 5 days per week for 15 fractions.<br>* Other names: AHRT;Biological: Durvalumab<br>* 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.<br>* Other names: MEDI4736;|
| Experimental: Arm II (Durvalumab and standard RT)<br>Given Durvalumab every 4 weeks for a year starting two weeks before standard fractionated radiation therapy (RT). | Biological: Durvalumab<br>* 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.<br>* Other names: MEDI4736;Radiation: Radiation Therapy<br>* 60 gy given as one 2 Gy fraction per day, 5 days per week for 30 fractions<br>* Other names: Therapy, Radiation;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| Distribution of Participants by Highest Grade Adverse Event | Common Terminology Criteria for Adverse Events (CTCAE) v 5.0 grades adverse event severity from 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild AE, Grade 2 Moderate AE, Grade 3 Severe AE, Grade 4 Life-threatening or disabling AE, Grade 5 Death related to AE. Summary data is provided in this outcome measure; see Adverse Events Module for specific adverse event data. | From registration to last follow-up. Schedule: weekly during RT, every 4 weeks post-RT durvalumab, every 3 months for year 1 from end of durvalumab, every 4 months for year 2 from end of durvalumab. Maximum follow-up at time of analysis was 23.2 months | 
| Percentage of Participants Experiencing a Grade 4 or Higher Non-hematologic Adverse Event | Common Terminology Criteria for Adverse Events (CTCAE) v 5.0 grades adverse event severity from 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild AE, Grade 2 Moderate AE, Grade 3 Severe AE, Grade 4 Life-threatening or disabling AE, Grade 5 Death related to AE. Summary data is provided in this outcome measure; see Adverse Events Module for specific adverse event data. | From registration to last follow-up. Schedule: weekly during RT, every 4 weeks post-RT durvalumab, every 3 months for year 1 from end of durvalumab, every 4 months for year 2 from end of durvalumab. Maximum follow-up at time of analysis was 23.2 months. | 
| Progression-free Survival | Progression is defined by the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 as an increase >= 20% of the sum of longest diameters of target lesions compared with nadir (minimum 5 mm) or progression of non-target lesions or new lesion. Progression-free survival time is defined as time from registration to the date of first progression, death, or last known follow-up (censored). Progression-free survival rates are estimated using the Kaplan-Meier method. | From registration to last follow-up. Data collection: weekly during RT, then every 4 weeks post-RT durvalumab, then every 3 months for year 1 from end of durvalumab, then every 4 months for year 2 from end of durvalumab |