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

Stage IIIB Non-small Cell Lung Cancer Clinical Trial

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 and IIIC Non-small Cell Lung Cancer

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03916419
• Other study ID #: 201905035
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: June 20, 2019
• Est. completion date: September 30, 2025

Study information

• Verified date: November 2023
• Source: Washington University School of Medicine
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 26
• Est. completion date: September 30, 2025
• Est. primary completion date: September 30, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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 any of the following apply: (1) T3N2M0, (2) T4N2M0 (with T4 by size criteria (> 7 cm); T4 due to invasion or nodules in other ipsilateral lobe are excluded), (3) T1-2N3M0 where N3 disease is confined to no more than 2 contiguous nodal stations in the contralateral mediastinum. N3 disease with either contralateral hilar adenopathy, multistation contralateral mediastinal adenopathy that is either non-contiguous or >2 contiguous nodal stations, or any scalene or supraclavicular adenopathy are not eligible.

• Clinical AJCC stage IIIC (T3-4N3M0) are eligible if N3 disease is confined to no more than 2 contiguous nodal stations in the contralateral mediastinum as above and, if applicable, T4 is due only to size >7 cm as above.

• 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. Patients without capacity to make an informed consent decision must have a legally authorized representative sign the IRB-approved informed consent document on their behalf.

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.

Related Conditions & MeSH terms

• Carcinoma, Non-Small-Cell Lung
• Lung Neoplasms
• Stage IIB Non-Small Cell Lung Cancer
• Stage IIIA Non-small Cell Lung Cancer
• Stage IIIB Non-small Cell Lung Cancer
• Stage IIIC Non-Small Cell Lung Cancer

Intervention

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
• Carboplatin AUC
-2 mg/mL/min intravenous over 30 minutes

Biological:
• Durvalumab
-10 mg/kg

Locations

Country	Name	City	State
United States	Washington University School of Medicine	Saint Louis	Missouri

Sponsors (1)

Lead Sponsor	Collaborator
Washington University School of Medicine

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Safety lead-in only: Number of participants with dose limiting toxicities (DLTs)	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.	Through 6 months after completion of concurrent chemoradiation (estimated to be 6 months and 3 weeks)
Primary	Local control rate (Phase II only)	-Clinical and/or radiographic evidence of progression of disease at the primary (local) site	Through 2 years after start of chemoradiation (estimated to be 2 years and 3 weeks)
Primary	Regional control rate (Phase II only)	-Clinical and/or radiographic evidence of progression of disease at the previously involved or uninvolved hilar and/or mediastinal nodal (regional) sites	Through 2 years after start of chemoradiation (estimated to be 2 years and 3 weeks)
Secondary	Number of acute toxicities	-Only those that are considered possibly/probably/definitely related to radiation therapy or chemoradiation	From start of chemoradiation through 60 days
Secondary	Number of late toxicities	-Only those that are considered possibly/probably/definitely related to radiation therapy or chemoradiation	From 61 days after start of chemoradiation through 2 years after the start of chemoradiation
Secondary	Tumor response rate	-Tumor response is defined as achieving a partial or complete response per RECIST criteria.	Through completion of treatment (estimated to be 12 months and 3 weeks)
Secondary	Distant recurrence rate	-Distant recurrence is defined as development of metastatic, non-local, and non-regional disease.	Through 2 years after start of chemoradiation (estimated to be 2 years and 3 weeks)
Secondary	Incidence of brain metastases	-Defined as development of brain metastasis.	Through 2 years after start of chemoradiation (estimated to be 2 years and 3 weeks)
Secondary	Progression-free survival (PFS)	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	Through 2 years after start of chemoradiation (estimated to be 2 years and 3 weeks)
Secondary	Disease-free survival	Disease-free survival is defined as survival with no evidence of recurrent (local, regional or distant) disease or death	Through 2 years after start of chemoradiation (estimated to be 2 years and 3 weeks)
Secondary	Overall survival	-Defined as survival with no evidence of death.	Through 2 years after start of chemoradiation (estimated to be 2 years and 3 weeks)

External Links

•   Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine