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.
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.
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