Proton Based Cardiac Sparing Accelerated Fractionated RadioTherapy in Unresectable NSCLC

• ECOG performance status 0-2
• Body Weight >30kg
• Must have anticipated life expectancy of at least 12 weeks
• Must be histologically or cytologically confirmed to be non-small cell lung cancer (NSCLC) confirmed by biopsy within 90 days of registration.
• Any tumor PD-L1 expression is allowed (including 0% to 100%, or unknown at time of study enrollment)
• AJCC 8th Stage IIA-IIIC.
• Must be deemed by Specialist or tumor board decision to not be a candidate for surgical resection or the participant refuses resection. Being deemed unresectable can be for any reason, including but not limited to: tumor location, tumor characteristics, operative risks, poor participant lung function, participant age or medical comorbidity.
• Must be deemed by Medical Oncologist or tumor board decision to not be a candidate for or able to tolerate standard cisplatinum based doublet concurrent chemoradiation therapy or the participant refuses chemotherapy. Being deemed not a chemotherapy candidate can be for any reason, including but not limited to: age, medical comorbidity, end organ dysfunction.
• Pulmonary function testing performed within 365 days prior to registration. . Sufficient lung function as judged by the primary investigator based on anticipated radiation fields, with a minimum of FEV1 ≥ 0.7 Liter or ≥ 30% and DLCO ≥ 30% with or without bronchodilator within 365 days prior to registration.
• Adequate normal organ and marrow function as defined below:
• Haemoglobin ≥9.0 g/dL
• Absolute neutrophil count (ANC) 1.5 (or 1.0) x (> 1500 per mm3)
• Platelet count ≥75 x 109/L (>75,000 per mm3)
• Serum bilirubin ≤1.5 x institutional upper limit of normal (ULN). This will not apply to participants 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.
• AST (SGOT)/ALT (SGPT) ≤2.5 x institutional upper limit of normal
• Measured creatinine clearance (CL) >30 mL/min or Calculated creatinine CL>30 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance:
• Males:

Creatinine CL (mL/min) = (Weight (kg) x (140 - Age)) / (72 x serum creatinine (mg/dL))

• Females:

Creatinine CL (mL/min) = (Weight (kg) x (140 - Age)) / (72 x serum creatinine (mg/dL)) x 0.85

• Subjects must have the ability to understand and the willingness to sign a written informed consent document.
• Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-menopausal participants. 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).
• Participant 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 large field thoracic radiation therapy is not allowed except for at the discretion of the primary investigator. Prior SBRT to contralateral lung, or breast radiation greater than 3 years prior is allowed. Other prior thoracic radiation is allowed at the discretion of the primary investigator.
• Prior radiation therapy, or immunotherapy for current diagnosis of NSCLC
• 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
• Female participants who are pregnant or breastfeeding or male or female participants of reproductive potential who are not willing to employ effective birth control from screening to 90 days after the last dose of durvalumab monotherapy.
• History of another primary malignancy except for:
• Malignancy treated with curative intent and with no known active disease ≥2 years before the first dose of IP and of low potential risk for recurrence
• Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
• Adequately treated carcinoma in situ (i.e. breast) without evidence of disease
• Low risk prostate cancer which has been treated or is undergoing active surveillance.
• Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria
• Participants with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after consultation with the Study Physician.
• Participants 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 IP.
• Judgment by the investigator that the participant is unsuitable to participate in the study and the participant is unlikely to comply with study procedures, restrictions and requirements

Medication Specific Exclusion Criterion:

• History of primary immunodeficiency
• 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:
• Participants with vitiligo or alopecia
• Participants with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement
• Any chronic skin condition that does not require systemic therapy
• Participants without active disease in the last 5 years may be included but only after consultation with the study physician
• Participants with celiac disease controlled by diet alone
• Participants with prior allogeneic bone marrow transplantation or prior solid organ transplantation
• Treatment with systemic immunosuppressive medications (including but not limited to prednisone > 10 mg daily, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor [TNF] agents) within 2 weeks prior to Cycle 1, Day 1. However, the use of inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone) for participants with orthostatic hypotension or adrenocortical insufficiency is allowed.
• Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients.
• 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 AEs or compromise the ability of the participant to give written informed consent
• Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and tuberculosis testing in line with local practice), hepatitis B (known positive hepatitis B surface antigen [HBsAg] result), hepatitis C, or human immunodeficiency virus (positive human immunodeficiency virus [HIV] 1/2 antibodies). Participants with a past or resolved hepatitis B (HBV) infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Participants positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
• Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. Note: Participants, if enrolled, should not receive live vaccine whilst receiving IP and up to 30 days after the last dose of IP.
• Prior randomisation or treatment in a previous durvalumab and/or tremelimumab clinical study regardless of treatment arm assignment.