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Magnetic Resonance-Guided Hypofractionated Adaptive Radiation Therapy With Concurrent Chemotherapy and Consolidation Durvalumab for Inoperable Stage IIB and IIIA Non-small Cell Lung Cancer

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03916419
Recruitment Status : Active, not recruiting
First Posted : April 16, 2019
Last Update Posted : May 7, 2020
Sponsor:
Information provided by (Responsible Party):
Washington University School of Medicine

Brief Summary:
Building upon the clinical experience of the investigators with the magnetic resonance (MR)-guided radiation therapy system and applying principals of hypofractionation toward the current treatment paradigm of concurrent chemoradiation and consolidation immunotherapy for locally advanced non-small cell lung cancer (NSCLC), this prospective, single-arm Phase II clinical trial with safety lead-in will test the feasibility and outcomes of this approach.

Condition or disease Intervention/treatment Phase
Stage IIB Non-Small Cell Lung Cancer Stage IIIA Non-small Cell Lung Cancer Stage IIIB Non-small Cell Lung Cancer Device: ViewRay MR-Linear Accelerator Radiation: Radiation therapy Drug: Paclitaxel Drug: Carboplatin AUC Biological: Durvalumab Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 27 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Single-Arm Phase II Study With a Safety Lead-in of Magnetic Resonance-Guided Hypofractionated Adaptive Radiation Therapy With Concurrent Chemotherapy and Consolidation Durvalumab for Inoperable Stage IIB, IIIA, and Select IIIB Non-small Cell Lung Cancer
Actual Study Start Date : June 20, 2019
Estimated Primary Completion Date : December 31, 2024
Estimated Study Completion Date : December 31, 2024

Resource links provided by the National Library of Medicine

Drug Information available for: Durvalumab

Arm Intervention/treatment
Experimental: Safety lead-in: Chemoradiation + Durvalumab
  • The first 6 patients enrolled on study will comprise the Safety Lead-In cohort and will be closely monitored for toxicity related specifically to the experimental chemoradiation portion of the study treatment. After these 6 patients have been enrolled, accrual will temporarily be suspended for a minimum of 6 months after completion of chemoradiation to allow for the evaluation of adverse events.
  • Patients will receive concurrent chemoradiation over the course of 3 weeks (15 fractions of radiation with online adaptive treatment planning at fractions 6, 9, and 12 and weekly carboplatin + paclitaxel). Four to 6 weeks after the end of chemoradiation, durvalumab immunotherapy will administered every two weeks for up to 12 months.
Device: ViewRay MR-Linear Accelerator
-Radiation will be delivered by this machine

Radiation: Radiation therapy
-60Gy in 15 fractions

Drug: Paclitaxel
-50 mg/m^2 intravenous
Other Name: Taxol

Drug: Carboplatin AUC
-2 mg/mL/min intravenous over 30 minutes
Other Name: Paraplatin

Biological: Durvalumab
-10 mg/kg
Other Name: Imfinzi

Experimental: Phase II: Chemoradiation + Durvalumab
-Patients will receive concurrent chemoradiation over the course of 3 weeks (15 fractions of radiation with online adaptive treatment planning at fractions 6, 9, and 12 and weekly carboplatin + paclitaxel). Four to 6 weeks after the end of chemoradiation, durvalumab immunotherapy will administered every two weeks for up to 12 months.
Device: ViewRay MR-Linear Accelerator
-Radiation will be delivered by this machine

Radiation: Radiation therapy
-60Gy in 15 fractions

Drug: Paclitaxel
-50 mg/m^2 intravenous
Other Name: Taxol

Drug: Carboplatin AUC
-2 mg/mL/min intravenous over 30 minutes
Other Name: Paraplatin

Biological: Durvalumab
-10 mg/kg
Other Name: Imfinzi




Primary Outcome Measures :
  1. Safety lead-in only: Number of participants with dose limiting toxicities (DLTs) [ Time Frame: Through 6 months after completion of concurrent chemoradiation (estimated to be 6 months and 3 weeks) ]
    • Safety of hypofractionated MRI-guided adaptive radiotherapy (60Gy/15 fractions) with concurrent chemotherapy (carboplatin and paclitaxel) and consolidation durvalumab is defined as <2/6 participants experiencing dose limiting toxicities
    • DLT is defined as any possibly, probably, or definitely related to concurrent chemoradiation grade 3 toxicity that cannot be managed with maximal supportive care within 2 weeks, or any grade > 4 toxicity that occurs during treatment
    • The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for all toxicity reporting.

  2. Local and/or regional control rate [ Time Frame: Up to 24 months ]
    -Local and/or regional failure will be defined as clinical and/or radiographic evidence of progression of disease at the primary (local) site or previously involved or uninvolved hilar and/or mediastinal nodal (regional) sites.


Secondary Outcome Measures :
  1. Number of acute toxicities [ Time Frame: Up to 14 months, to include the 3 week chemoradiation and 12 week immunotherapy components ]
    • The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for all toxicity reporting.
    • Possibly, probably, definitely related to treatment = Grade 3-5 cardiac arrhythmia/cardiac general (pericardial effusion, pericarditis, restrictive cardiomyopathy). Grade 3-5 hemorrhage/bleeding (pulmonary/upper respiratory excluding nose, larynx, pharynx). Grade 3-5 neurologic: (brachial plexopathy, laryngeal nerve dysfunction, myelitis, phrenic nerve dysfunction). Grade 3-5 pulmonary/upper respiratory: (atelectasis (grade 4-5 only), fistula, hypoxia (provided grade 3 is worse than baseline), obstruction/stenosis of the airway, pleural effusion, pneumonitis, pulmonary fibrosis). Grade 4-5 gastrointestinal (dysphagia, esophagitis, esophageal fistula/obstruction/perforation/stricture/stenosis/ulcer/hemorrhage). Grade 4-5 skin. Any Grade 5.

  2. Number of late toxicities [ Time Frame: Up to 24 months ]
    • The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for all toxicity reporting.
    • Possibly, probably, definitely related to treatment = Grade 3-5 cardiac arrhythmia/cardiac general (pericardial effusion, pericarditis, restrictive cardiomyopathy). Grade 3-5 hemorrhage/bleeding (pulmonary/upper respiratory excluding nose, larynx, pharynx). Grade 3-5 neurologic: (brachial plexopathy, laryngeal nerve dysfunction, myelitis, phrenic nerve dysfunction). Grade 3-5 pulmonary/upper respiratory: (atelectasis (grade 4-5 only), fistula, hypoxia (provided grade 3 is worse than baseline), obstruction/stenosis of the airway, pleural effusion, pneumonitis, pulmonary fibrosis). Grade 4-5 gastrointestinal (dysphagia, esophagitis, esophageal fistula/obstruction/perforation/stricture/stenosis/ulcer/hemorrhage). Grade 4-5 skin. Any Grade 5.

  3. Tumor response rate [ Time Frame: Up to 24 months ]
    -Tumor response is defined as achieving a partial or complete response per RECIST criteria.

  4. Distant recurrence rate [ Time Frame: Up to 24 months ]
    -Distant recurrence is defined as development of metastatic, non-local, and non-regional disease.

  5. Incidence of brain metastases [ Time Frame: Up to 24 months ]
  6. Progression-free survival (PFS) [ Time Frame: Up to 24 months ]
    • Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progressions).
    • PFS is defined as survival with no evidence of disease progression (local, regional, or distant) or death

  7. Disease-free survival [ Time Frame: Up to 24 months ]
    Disease-free survival is defined as survival with no evidence of recurrent (local, regional or distant) disease or death

  8. Overall survival [ Time Frame: Up to 24 months ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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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:

  • Histologically or cytologically proven diagnosis of non-small cell lung cancer.
  • Inoperable or patient has refused surgery
  • Clinical AJCC stage IIB or IIIA (AJCC, 8th ed.) with plans to be treated with concurrent chemoradiotherapy.

    • Recurrent non-small cell lung cancer is allowed, provided the intent of the current treatment is curative and there has been no prior radiation to the thorax (except prior SBRT per the protocol)
    • Prior chemotherapy, immunotherapy, or targeted therapy is permitted as long as patients have recovered from prior toxicities to grade ≤ 1
    • Clinical AJCC stage IIIB with plans to be treated with concurrent chemoradiotherapy are eligible if T3N2M0 or T4N2M0 (with T4 by size criteria (> 7 cm); T4 due to invasion or nodules in other ipsilateral lobe are excluded).
  • Appropriate stage for protocol entry based upon the following minimum diagnostic workup:

    • History/physical examination within 30 days prior to registration
    • FDG-PET/CT scan and CT chest with or without contrast for staging within 60 days prior to registration
    • MRI scan with contrast of the brain (preferred) or CT scan of the brain with contrast within 60 days prior to registration
  • Zubrod Performance Status 0-2 within 30 days prior to registration.
  • Age ≥ 18 years.
  • CBC/differential obtained within 30 days prior to registration, with adequate bone marrow function defined as follows:

    • Absolute neutrophil count (ANC) ≥ 1,500 cells/mm3
    • Platelets ≥ 100,000 cells/mm3
    • Hemoglobin ≥ 8.0 g/dl (Note: The use of transfusion or other intervention to achieve Hgb ≥ 8.0 g/dl is acceptable.)
  • AST and ALT ≤ 1.5 upper limit of normal within 30 days prior to registration.
  • Total bilirubin ≤ 1.5 upper limit of normal within 30 days prior to registration.
  • Serum creatinine < 1.5 mg/dL or calculated creatinine clearance ≥ 50 mL/min within 30 days prior to registration estimated by the Cockcroft-Gault formula:

Creatinine Clearance (male) = [(140 - age) x (wt in kg)] [(Serum Creatinine mg/dl) x (72)] Creatinine Clearance (female) = 0.85 x Creatinine Clearance (male)

  • Peripheral neuropathy ≤ grade 1 at the time of registration.
  • Presence of measurable or evaluable disease by RECIST 1.1.
  • Negative serum or urine pregnancy test within 2 weeks prior to registration for women of childbearing potential.
  • Women of childbearing potential and male participants must agree to use a medically effective means of birth control throughout their participation in the treatment phase of the study.
  • Able to understand and willing to sign an IRB-approved informed consent document.

Exclusion Criteria:

  • Severe, active comorbidity, defined as follows:

    • Unstable angina, history of myocardial infarction and/or congestive heart failure requiring hospitalization within the last 6 months
    • Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration;
    • Chronic Obstructive Pulmonary Disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of registration
    • Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects; note, however, that laboratory tests for liver function and coagulation parameters are not required for entry into this protocol
    • Acquired Immune Deficiency Syndrome (AIDS) based upon current CDC definition; note, however, that HIV testing is not required for entry into this protocol. The need to exclude patients with AIDS from this protocol is necessary because the treatments involved in this protocol may be significantly immunosuppressive. Protocol-specific requirements may also exclude immuno-compromised patients
  • Prior radiotherapy to the thorax. An exception can be made for prior stereotactic body radiation therapy (SBRT) if there is no overlap with the protocol PTV and OAR constraints can still be achieved with a composite plan.
  • Evidence of a concurrent primary malignancy, or any history of metastatic cancer.
  • Currently receiving any other investigational agents.
  • Pregnant or breastfeeding.
  • Medical contraindication to receiving MRI imaging (including presence of a cardiac pacemaker).
  • Autoimmune disease requiring active treatment, including but not limited to systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, Wegener's granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome, multiple sclerosis, autoimmune thyroid disease, vasculitis, or glomerulonephritis. Specific instances of autoimmune disease are eligible and allowed on study, as below:

    • Patients with a history of autoimmune hypothyroidism on a stable dose of thyroid replacement hormone
    • Patients with controlled type 1 diabetes mellitus on a stable insulin regimen.
    • Patients with eczema or psoriasis with dermatologic manifestations only, provided that the disease is well controlled at baseline and only requiring topical steroids, with no acute exacerbations within the last 12 months (requiring psoralen, ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, high potency or oral steroids
  • 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 screening chest CT scan.
  • Chronic oral steroid use (greater than prednisone 10 mg orally once daily, or its equivalent) for any indication.

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): NCT03916419


Locations
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United States, Missouri
Washington University School of Medicine
Saint Louis, Missouri, United States, 63110
Sponsors and Collaborators
Washington University School of Medicine
Investigators
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Principal Investigator: Gregory Vlacich, M.D, Ph.D. Washington University School of Medicine
Additional Information:
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Responsible Party: Washington University School of Medicine
ClinicalTrials.gov Identifier: NCT03916419    
Other Study ID Numbers: 201905035
First Posted: April 16, 2019    Key Record Dates
Last Update Posted: May 7, 2020
Last Verified: May 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: Yes
Product Manufactured in and Exported from the U.S.: No
Additional relevant MeSH terms:
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Lung Neoplasms
Carcinoma, Non-Small-Cell Lung
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
Carcinoma, Bronchogenic
Bronchial Neoplasms
Paclitaxel
Carboplatin
Durvalumab
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents, Immunological