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

NCT03801902

Description:

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.

Related Conditions:
  • Non-Small Cell Lung Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: NCI-2019-00176
  • SECONDARY ID: NCI-2019-00176
  • SECONDARY ID: NRG-LU004
  • SECONDARY ID: NRG-LU004
  • SECONDARY ID: U10CA180868
  • NCT ID: NCT03801902

Conditions

  • 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

Interventions

DrugSynonymsArms
DurvalumabImfinzi, Immunoglobulin G1, Anti-(Human Protein B7-H1) (Human Monoclonal MEDI4736 Heavy Chain), Disulfide with Human Monoclonal MEDI4736 Kappa-chain, Dimer, MEDI-4736, MEDI4736Arm I (durvalumab, ACRT)

Purpose

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.

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.
    

Trial Arms

NameTypeDescriptionInterventions
Arm I (durvalumab, ACRT)ExperimentalPatients 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.
  • Durvalumab
Arm II (durvalumab, standard RT)Active ComparatorPatients receive durvalumab as in Arm I. Patients also undergo conventionally fractionated radiation therapy 1 fraction per day, 5 days per week for 30 fractions.
  • Durvalumab

Eligibility 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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of adverse events
Time Frame:Up to 2 years
Safety Issue:
Description:All adverse events will be graded according to Common Terminology Criteria for Adverse Events version 5.0.

Secondary Outcome Measures

Measure:Feasibility of giving durvalumab in combination with radiation therapy
Time Frame:Up to 8 weeks
Safety Issue:
Description: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).
Measure:Incidence of adverse events (AEs)
Time Frame:Up to 2 years
Safety Issue:
Description: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.
Measure:Progression free survival
Time Frame:Time from registration to progressive disease or death, whichever occurs first, assessed up to 2 years
Safety Issue:
Description: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

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

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