Clinical Trials /

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

NCT03916419

Description:

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.

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

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: 201905035
  • NCT ID: NCT03916419

Conditions

  • Stage IIB Non-Small Cell Lung Carcinoma
  • Stage IIIA Non-small Cell Lung Cancer

Interventions

DrugSynonymsArms
PaclitaxelTaxolSafety lead-in: Chemoradiation + Durvalumab
Carboplatin AUCParaplatinSafety lead-in: Chemoradiation + Durvalumab
DurvalumabImfinziSafety lead-in: Chemoradiation + Durvalumab

Purpose

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.

Trial Arms

NameTypeDescriptionInterventions
Safety lead-in: Chemoradiation + DurvalumabExperimentalThe 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.
  • Paclitaxel
  • Carboplatin AUC
  • Durvalumab
Phase II: Chemoradiation + DurvalumabExperimental-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.
  • Paclitaxel
  • Carboplatin AUC
  • Durvalumab

Eligibility Criteria

        Inclusion Criteria:

          -  Histologically or cytologically proven diagnosis of non-small cell lung cancer.

          -  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

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

Primary Outcome Measures

Measure: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 Issue:
Description: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.

Secondary Outcome Measures

Measure:Number of acute toxicities
Time Frame:Up to 14 months, to include the 3 week chemoradiation and 12 week immunotherapy components
Safety Issue:
Description: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.
Measure:Number of late toxicities
Time Frame:Up to 24 months
Safety Issue:
Description: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.
Measure:Tumor response rate
Time Frame:Up to 24 months
Safety Issue:
Description:-Tumor response is defined as achieving a partial or complete response per RECIST criteria.
Measure:Distant recurrence rate
Time Frame:Up to 24 months
Safety Issue:
Description:-Distant recurrence is defined as development of metastatic, non-local, and non-regional disease.
Measure:Incidence of brain metastases
Time Frame:Up to 24 months
Safety Issue:
Description:
Measure:Progression-free survival (PFS)
Time Frame:Up to 24 months
Safety Issue:
Description: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
Measure:Disease-free survival
Time Frame:Up to 24 months
Safety Issue:
Description:Disease-free survival is defined as survival with no evidence of recurrent (local, regional or distant) disease or death
Measure:Overall survival
Time Frame:Up to 24 months
Safety Issue:
Description:

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Washington University School of Medicine

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