| Eligibility |
Inclusion Criteria:
1.1 Pathologically (histologically or cytologically) proven diagnosis of NSCLC with,
medically inoperable (or patients who refuse resection) stage IIIA or stage IIIB disease
(AJCC 8th edition);
1.1.1 Inoperable Stage IIIA disease is defined by multiple and/or bulky N2 mediastinal
lymph nodes on computed tomography (CT) scan such that, in the opinion of the treating
investigator, the patient was not a candidate for surgical resection.
1.1.2 N2 disease must have been documented by biopsy, or at a minimum by fluorodeoxyglucose
positron emission tomography (PET) or CT if nodes were more than 2 cm in short axis
diameter.
1.1.3 T4 disease is often considered resectable at the discretion of a thoracic surgeon.
Patients with T4N0 or T4N1 disease can be enrolled if their case is reviewed by a thoracic
surgeon and felt to be unresectable or if they are either medically inoperable or refuse
surgery.
1.1.4 Stage IIIB patients have N3 or T4N2 status. N3 status must have been documented by
the presence of a contralateral (to the primary tumor) mediastinal lymph node or
supraclavicular or scalene lymph node proven by biopsy, or at a minimum by
fluorodeoxyglucose uptake on PET or more than 2 cm in short axis diameter on CT scan.
Patients with disease extending into the cervical region (defined as disease extending
above cricoid cartilage) are not eligible.
1.2 Appropriate stage for study entry based on the following diagnostic workup:
1.2.1 History/physical examination, including documentation of height, weight and vital
signs, within 30 days prior to registration;
1.2.2 CT scan with IV contrast (CT scan without contrast acceptable if IV contrast is
medically contraindicated) of the lung and upper abdomen through the adrenal glands within
60 days prior to registration (recommended within 30 days prior to registration);
1.2.3 MRI of the brain with contrast (or CT with contrast if MRI is medically
contraindicated) within 60 days prior to registration; note: the use of intravenous
contrast is required for the MRI or CT (unless medically contra-indicated).
1.2.4 Whole-body FDG-PET/CT within 60 days prior to registration;
1.3 Age = 18 years;
1.4 Life expectancy = 12 weeks
1.5 Zubrod Performance Status of 0-1 within 30 days prior to registration;
1.6 Adequate respiratory function within 180 days prior to registration defined as follows:
FEV1 > 1.2 liters; DLCO = 50% predicted;
1.7 Patients with post-obstructive pneumonia are eligible provided they no longer require
intravenous antibiotics at registration;
1.8 Patients with a pleural effusion that is transudative, cytologically negative and
non-bloody, are eligible if the radiation oncologist feels the tumor can be encompassed
within a reasonable field of radiotherapy; if pleural fluid is too small a volume to
effectively sample by thoracentesis and does not show increased metabolic activity on
CT/PET imaging, the patient will be remain eligible.
1.9 Allowable type and amount of prior therapy
1.10 Adequate organ and marrow function as defined below
1.10.1 Absolute neutrophil count >1.5 × 10^9/L
1.10.2 Platelet count >100 × 10^9/L
1.10.3 Baseline or post-transfusion Hemoglobin =9.0 g/dL
1.10.4 Serum bilirubin= 1.5x upper limit of normal (ULN). This will not apply to patients
with confirmed Gilbert's syndrome, who will be allowed in consultation with their
physician.
1.10.5 Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) = 2.5x ULN.
1.10.6 Measured creatinine clearance (CL) >40 mL/min or calculated CL >40 mL/min as
determined by Cockcroft-Gault (using actual body weight);
Males:
Creatinine CL = (Weight (kg) × (140 - Age)) / ((mL/min) 72 × serum creatinine (mg/dL))
Females:
Creatinine CL = (Weight (kg) × (140 - Age) × 0.85) / ((mL/min) 72 × serum creatinine
(mg/dL))
1.11 Negative serum pregnancy test within three days prior to registration for women of
childbearing potential.
1.12 Women of child-bearing potential and men must agree to use adequate contraception
(hormonal or barrier method of birth control; abstinence) prior to study entry, for the
duration of study participation, and for 90 days following completion of therapy. Should a
woman become pregnant or suspect she is pregnant while participating in this study, she
should inform her treating physician immediately.
1.12.1 A female of child-bearing potential is any woman (regardless of sexual orientation,
having undergone a tubal ligation, or remaining celibate by choice) who meets the following
criteria:
- Has not undergone a hysterectomy or bilateral oophorectomy; or
- Has not been naturally postmenopausal for at least 12 consecutive months (i.e., has
had menses at any time in the preceding 12 consecutive months).
1.12.2 Evidence of post-menopausal status or negative urinary or serum pregnancy test for
female pre-menopausal patients. 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).
1.13 Ability to understand and the willingness to sign a written informed consent.
Exclusion Criteria:
2.1 Definitive clinical or radiologic evidence of metastatic disease;
2.2 Subjects may not be receiving any other investigational agents for the treatment of the
cancer under study.
2.3 Current invasive malignancy (except non-melanomatous skin cancer, localized bladder and
prostate cancer). Carcinoma in situ of the breast, oral cavity, or cervix are permissible
regardless of timing;
2.4 Prior radiotherapy to the region of the study cancer that would result in overlap of
radiation therapy fields. For example, patients with prior breast radiotherapy treatments
would likely be excluded;
2.5 Prior systemic treatment with chemotherapy, targeted therapy or an anti-PD-1,
anti-PD-L1 including durvalumab, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or
drug specifically targeting T-cell costimulation or immune checkpoint pathways for NSCLC;
2.6 A condition requiring systemic treatment with either corticosteroids (> 10 mg daily
prednisone equivalents) or other immunosuppressive medications within 7 days of study drug
administration. Inhaled or topical steroids and adrenal replacement doses > 10 mg daily
prednisone equivalents are permitted in the absence of active autoimmune disease;
2.7 Severe, active co-morbidity defined as follows:
2.7.1 Major surgical procedure (as defined by the Investigator) within 28 days prior to the
first dose of IP. Note: Local surgery of isolated lesions for palliative intent is
acceptable.
2.7.2 Active or prior documented autoimmune or inflammatory disorders (including
inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with the
exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or
Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis,
hypophysitis, uveitis, etc]). The following are exceptions to this criterion:
- Patients with vitiligo or alopecia
- Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone
replacement
- Any chronic skin condition that does not require systemic therapy
- Patients without active disease in the last 5 years may be included but only after
consultation with the study physician
- Patients with celiac disease controlled by diet alone
2.7.3 Active infection including tuberculosis, hepatitis B, hepatitis C.
2.7.4 History of allogenic organ transplantation.
2.7.5 History of symptomatic or previously established interstitial lung disease;
2.7.6 History of severe hypersensitivity reaction to any monoclonal antibody or allergy to
study drug components;
2.7.7 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.
2.8 Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that, in the opinion of the
investigator, would limit compliance with study requirements.
2.9 Pregnancy, nursing females, or women of childbearing potential and men who are sexually
active and not willing/able to use medically acceptable forms of contraception; this
exclusion is necessary because the treatment involved in this study may be significantly
teratogenic.
2.10 Patients whose radiation treatment plans are likely to encompass a volume of whole
lung receiving = 35% of lung volume. V20s up to 37% will be permitted and viewed as a minor
deviation, provided that the treating radiation oncologist believes this level of exposure
is within patient tolerance.
2.11 Planned radiation cardiac dose V50 >25%.
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