Proton Based Cardiac Sparing Accelerated Fractionated RadioTherapy in Unresectable NSCLC

All study participants will receive the same study intervention, which will consist of proton
based external beam radiation therapy with concurrent Durvalumab starting one week before RT.
Radiation will be delivered using cardiac sparing accelerated fractionated proton radiation.
Radiation will have two dose escalation schemes followed by an expansion cohort for a total
of approximately 24 participants enrolled at University Hospitals Cleveland Medical Center.

The objectives of this study are to evaluate the safety and feasibility of combination of
durvalumab with two different schemes for accelerated fractionation proton radiation in
participants who are unable to tolerate concurrent chemoradiation therapy. This will also
include the evaluation of adverse events resulting from these treatment schemes.

Inclusion Criteria:

- 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.