ADMIRAL Trial: Adaptive Mediastinal Radiation With Chemo-Immunotherapy
ADMIRAL Trial: Adaptive Mediastinal Radiation With Chemo-Immunotherapy
This phase II trial studies two questions in patients with stage III NSCLC: 1) does it
 improve cancer control to add the drug Durvalumab, a type of immunotherapy, earlier in the
 treatment course; and 2) by intensifying treatment with durvalumab, is it possible to avoid
 mediastinal radiation to decrease side effects, without decreasing cancer control?
OUTLINE:

 Patients will receive platinum doublet chemotherapy per standard of care with durvalumab for
 8 weeks, concurrent with a short course of radiation to the primary lung tumor. Patients will
 then undergo repeat evaluation of the mediastinal lymph nodes. If there is no cancer in the
 lymph nodes, patients will receive 2 years of adjuvant durvalumab. If there is still cancer
 in the lymph nodes, patients will receive 6 weeks of radiation to the mediastinal lymph
 nodes, and 2 years of adjuvant durvalumab.

 After the completion of study treatment, patients are followed up for 12 months.
Inclusion Criteria:

 -  Histologically or cytologically documented non-small cell lung cancer (NSCLC)

 -  Stage III NSCLC according to American Joint Committee on Cancer (AJCC) staging version
 (v)8

 -  At least one mediastinal site of disease that is discontiguous from all other visible
 sites of disease and can be excluded from primary tumor site radiation (i.e. at least
 10 mm separation between tumors)

 -  A maximum of 20 patients with bulky mediastinal disease will be allowed on this trial,
 defined as at least one contiguous mediastinal mass with minimum diameter > 2 cm, that
 is not contiguous with the primary tumor (and therefore would not be irradiated during
 radiation to the primary tumor)

 -  No surgery for lung cancer for at least 3 years

 -  No other malignancies for at least 3 years, excluding low grade or non-invasive
 malignancies such as skin cancers, prostate cancers, and ductal breast carcinoma in
 situ (DCIS)

 -  Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

 -  Life expectancy of >= at least 3 months

 -  Body weight > 30 kg

 -  Hemoglobin >= 9.0 g/dL

 -  Absolute neutrophil count (ANC) 1.5 (or 1.0) x (>= 1500 per mm^3)

 -  Platelet count >= 100,000 per mm^3

 -  Serum bilirubin =< 1.5 x institutional upper limit of normal (ULN). This will not
 apply to patients with confirmed Gilbert's syndrome (persistent or recurrent
 hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or
 hepatic pathology), who will be allowed only in consultation with their physician

 -  Aspartate transaminase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine
 transferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x
 institutional upper limit of normal unless liver metastases are present, in which case
 it must be =< 5 x upper limit of normal (ULN)

 -  Measured creatinine clearance (CL) > 60 mL/min or calculated creatinine CL > 50 mL/min
 by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine
 collection for determination of creatinine clearance

 -  Capable of giving signed informed consent which includes compliance with the
 requirements and restrictions listed in the informed consent form (ICF) and in this
 protocol. Written informed consent and any locally required authorization (eg, Health
 Insurance Portability and Accountability Act) obtained from the patient/legal
 representative prior to performing any protocol-related procedures, including
 screening evaluations

 -  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)

 -  Patient is willing and able to comply with the protocol for the duration of the study
 including undergoing treatment and scheduled visits and examinations including follow
 up

 Exclusion Criteria:

 -  Prior anti-CTLA-4, PD-1 or PD-L1 antibodies including durvalumab

 -  Prior chemotherapy in the past 3 years from consent

 -  Any unresolved toxicity National Cancer Institute (NCI) 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

 -  Prior thoracic radiation that would preclude curative-intent radiation dose as
 outlined in this study

 -  Concurrent enrolment in another clinical study, unless it is an observational
 (non-interventional) clinical study or during the follow-up period of an
 interventional study

 -  History of allogenic organ transplantation

 -  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

 -  Uncontrolled intercurrent illness, including but not limited to, ongoing or active
 infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable
 angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic
 gastrointestinal conditions associated with diarrhea, or psychiatric illness/social
 situations that would limit compliance with study requirement, substantially increase
 risk of incurring adverse events (AEs) or compromise the ability of the patient to
 give written informed consent

 -  History of leptomeningeal carcinomatosis

 -  History of active primary immunodeficiency

 -  Active infection including tuberculosis (clinical evaluation that includes clinical
 history, physical examination and radiographic findings, and tuberculosis (TB) testing
 in line with local practice), hepatitis B (known positive hepatitis B virus [HBV]
 surface antigen [HBsAg] result), hepatitis C. Patients with a past or resolved HBV
 infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence
 of HBsAg) are eligible. Patients positive for hepatitis C (hepatitis C virus [HCV])
 antibody are eligible only if polymerase chain reaction is negative for HCV
 ribonucleic acid (RNA)

 -  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., computed
 tomography [CT] scan premedication)

 -  Receipt of live attenuated vaccine within 30 days prior to the first dose of
 investigational product (IP). Note: Patients, if enrolled, should not receive live
 vaccine whilst receiving IP and up to 30 days after the last dose of IP

 -  Female patients who are pregnant or breastfeeding or male or female patients of
 reproductive potential who are not willing to employ effective birth control from
 screening to 90 days after the last dose of durvalumab monotherapy

 -  Known allergy or hypersensitivity to any of the study drugs or any of the study drug
 excipients