Comparing Photon Therapy To Proton Therapy To Treat Patients With Lung Cancer

PRIMARY OBJECTIVES:

I. To compare the overall survival (OS) in patients with stage II-IIIB non-small cell lung
cancer (NSCLC) after image guided, motion-managed photon radiotherapy (Arm 1) or after image
guided, motion-managed proton radiotherapy (Arm 2) both given with concurrent platinum- based
chemotherapy.

II. To compare the cardiac toxicity and lymphocyte reduction (lymphopenia) definitely,
probably, or possibly related to treatment between the 2 arms.

SECONDARY OBJECTIVES:

I. To compare 2-year progression-free survival (PFS) between the 2 arms. II. To compare the
development of grade 3 or higher adverse events not included above that are definitely,
probably, or possibly related to treatment.

III. To compare differences between the two arms in quality of life (QOL) based primarily on
the development of shortness of breath at 6 months and secondarily on the development of sore
throat at the end of chemoradiotherapy (chemoRT) (as measured by the lung cancer module of
the MD Anderson Symptom Inventory [MDASI-Lung]), as well as breathing related functioning
impairments as measured by the Shortness Breath Questionnaire [SOBQ].

IV. To compare cost-effectiveness outcomes between the 2 arms. V. To compare pulmonary
function changes by treatment arms and response. VI. To explore the most appropriate and
clinically relevant technological parameters to ensure quality and effectiveness throughout
radiation therapy processes, including imaging, simulation, patient immobilization, target
and critical structure definition, treatment planning, image guidance and delivery.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients undergo photon beam radiation therapy 5 days per week for a total of 35
fractions and receive either paclitaxel* intravenously (IV) over 1 hour and carboplatin* IV
weekly during radiation therapy or etoposide IV on days 1-5 and 29-33 and cisplatin IV on
days 1, 8, 29, and 36. Patients with non-squamous cell cancera may receive pemetrexed IV and
carboplatin IV on every 21 days.

ARM II: Patients undergo proton beam radiation therapy 5 days per week for a total of 35
fractions and receive either paclitaxel* and carboplatin*, etoposide and cisplatin, or
pemetrexed and carboplatin (for non-squamous cell cancer patients only) as in Arm I.

*In both arms, patients who receive paclitaxel and carboplatin must complete 2 courses of
consolidation therapy.

CONSOLIDATION THERAPY: Beginning 3-6 weeks after chemoradiotherapy, patients receive either
paclitaxel IV over 3 hours and carboplatin IV on day 1 or durvalumab IV every 2 weeks.
Treatment repeats every 21 days for 2 courses or every 2 weeks for up to 12 months for
durvalumab in the absence of disease progression or unacceptable toxicity. Patients with
non-squamous cell carcinoma may receive durvalumab or pemetrexed IV and carboplatin IV on day
1 every 21 days for up to 4 courses.

After completion of study treatment, patients are followed up at 4-8 weeks, every 3 months
for 1 year, every 6 months for 1 year, and then annually thereafter.

Inclusion Criteria:

- Histologically or cytologically proven diagnosis of non-small cell lung cancer

- Clinical American Joint Committee on Cancer (AJCC) (AJCC, 7th ed.) II, IIIA or IIIB
(with non-operable disease; non-operable disease will be determined by a
multi-disciplinary treatment team within 60 days prior to registration; note: for
patients who are clearly nonresectable, the case can be determined by the treating
radiation oncologist and/or a medical oncologist or pulmonologist

- Patients who present with N2 or N3 disease and an undetectable NSCLC primary
tumor are eligible

- Patients who refuse surgery are eligible

- Patients who develop local recurrence after surgery and rendered candidate for
definitive concurrent chemoradiation are also eligible

- Patients who have received systemic treatment (up to 4 cycles of induction
chemotherapy, or up to 6 months of targeted therapy) are eligible

- Appropriate stage for protocol entry, including no distant metastases, based upon the
following minimum diagnostic workup:

- History/physical examination within 30 days prior to registration including
resting heart rate;

- Fludeoxyglucose F 18 (FDG)-positron emission tomography (PET)/computed tomography
(CT) scan for staging within 60 days prior to registration

- Magnetic resonance imaging (MRI) scan with contrast of the brain (preferred) or
CT scan of the brain with contrast within 60 days prior to registration;

- Forced expiratory volume in one second (FEV1) >= 0.8 liter or >= 35% predicted
with or without bronchodilator within 90 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

- Zubrod performance status 0-1 within 30 days prior to registration

- Absolute neutrophil count (ANC) >= 1,500 cells/mm^3 obtained within 30 days prior to
registration

- Platelets >= 100,000 cells/mm^3 obtained within 30 days prior to registration

- Hemoglobin >= 9.0 g/dl (note: the use of transfusion or other intervention to achieve
hemoglobin [Hgb] >= 9.0 g/dl is acceptable), obtained within 30 days prior to
registration

- Serum glutamic oxaloacetic transaminase (SGOT) or serum glutamate pyruvate
transaminase (SGPT) within 30 days prior to registration

- It is highly recommended but not required that SGOT or SGPT be =< 1.5 upper limit
of normal

- Total bilirubin =< 1.5 within 30 days prior to registration

- It is highly recommended but not required that total bilirubin be =< 1.5 upper
limit of normal

- Serum creatinine < 1.5 mg/dL or calculated creatinine clearance >= 50 mL/min within 30
days prior to registration estimated by the Cockcroft-Gault formula

- Peripheral neuropathy =< grade 1 at the time of registration

- Patients with non-malignant pleural effusion are eligible

- If a pleural effusion is present, the following criteria must be met to exclude
malignant involvement:

- When pleural fluid is visible on both the CT scan and on a chest x-ray, a
pleuracentesis is required to confirm that the pleural fluid is
cytologically negative

- Exudative pleural effusions are excluded, regardless of cytology

- Effusions that are minimal (i.e, not visible on chest x-ray) that are too
small to safely tap are eligible

- Patients must have measurable or evaluable disease

- Women of childbearing potential must have a negative serum pregnancy test within 14
days prior to registration

- Women of childbearing potential and male participants must practice adequate
contraception

- Patient must provide study-specific informed consent prior to study entry

Exclusion Criteria:

- Prior invasive malignancy unless disease free for a minimum of 3 years; however, skin
cancer and in situ carcinomas of the breast, oral cavity, cervix, and other organs and
are permissible

- Patients with prior history of either small cell lung cancer or NSCLC regardless of
the treatment received, other than patients who have recurrent disease following
resection

- Prior systemic chemotherapy for the study cancer, if more than 4 cycles of induction
chemotherapy or more than 6 months of targeted therapy; 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

- Severe, active co-morbidity, defined as follows:

- Unstable angina and/or congestive heart failure requiring hospitalization within
the last 6 months;

- Transmural myocardial infarction within the last 6 months;

- Chronic obstructive pulmonary disease exacerbation or other respiratory illness
other than the diagnosed lung cancer requiring hospitalization or precluding
study therapy within 30 days before registration;

- Acquired immune deficiency syndrome (AIDS) based upon current Centers for Disease
Control and Prevention (CDC) definition; note, however, that human
immunodeficiency virus (HIV) testing is not required for entry into this protocol

- Unintentional weight loss > 10% within 30 days prior to registration

- Pregnancy or women of childbearing potential and men who are sexually active and not
willing/able to use medically acceptable forms of contraception