Hypofractionated Boost Before Chemoradiation for Patients With Stage II-III Non-small Cell Lung Cancer Unsuitable for Surgery

PRIMARY OBJECTIVES:

I. To estimate the primary tumor control rate at 12 months.

SECONDARY OBJECTIVES:

I. To further establish safety and tolerability of this regimen. II. To estimate the rates of
regional, distant control as well as progression-free survival and overall survival.

III. To evaluate the objective response rate (ORR) to this regimen. IV. To evaluate the
response of tumors to stereotactic (high-dose) radiation using magnetic resonance tumor
perfusion imaging modalities (magnetic resonance [MR]-dynamic contrast-enhanced
[DCE]/perfusion weighted imaging [PWI], MR-diffusion, blood oxygenation level dependent
[BOLD] sequences).

OUTLINE:

Patients will receive a hypofractionated boost to the primary tumor over 2 fractions (at
least 40 hours apart) during week 1. Beginning week 2, patients receive cisplatin
intravenously (IV) on days 8, 15, 36, and 43; and etoposide IV over 60 minutes on days 8-12
and 36-40. If carboplatin and paclitaxel is administered concurrently with radiotherapy, 2
cycles of carboplatin (AUC=6 mg/min/mL IV on day 1, 22) and paclitaxel (200 mg/m2 IV on day
1, 22) consolidation chemotherapy are required, to be administered starting 4-6 weeks after
concurrent chemoradiation has ended. Each cycle is 21 days long. If cisplatin and etoposide
is administered concurrently with radiotherapy, consolidation chemotherapy is not allowed.
Patients also undergo standard conformal radiation therapy once daily (QD) 5 days a week for
a total of 30 fractions. Treatment continues for 6 weeks in the absence of disease
progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years and
then every 6 months for 3 years.

Inclusion Criteria:

- All prior treatment-related toxicities must be Common Terminology Criteria for Adverse
Events (CTCAE) (version 4.0) =< grade 1 (except alopecia) at the time of enrollment

- Adequate baseline organ function obtained within 30 days of study registration

- Absolute neutrophil count >= 1.5 x 10^9/L

- Hemoglobin >= 9 g/dL

- Platelets >= 100 x 10^9/L

- Total bilirubin =< 1.5 x upper limit of normal (ULN)

- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x ULN

- Creatinine =< 1.5 ULN AND

- Calculated creatinine >= 50 mL/min (calculated by the Cockcroft-Gault formula) or

- 24-hour urine creatinine clearance >= 50 mL/min

- Non-small cell lung cancer (NSCLC), histologically and/or cytologically proven

- Clinical American Joint Committee on Cancer (AJCC) stage (7th edition) IIA-IIIB NSCLC
(T1-4N1-3M0)

- Patients must be considered unresectable or medically-inoperable

- Patients must have primary tumor =< 6 cm as defined by CT largest axial dimension

- Within 60 days of registration: patients must have fludeoxyglucose F 18 (FDG)-positron
emission tomography (PET)-CT scan (or CT chest/abdomen/pelvis with IV contrast), and
magnetic resonance imaging (MRI) brain with IV contrast (or CT scan of the brain with
contrast); a non-contrast MRI scans of the chest/abdomen/pelvis or brain are permitted
for workup if patient has allergy to CT contrast or renal insufficiency

- Within 90 days of registration: pulmonary function tests (PFTs) including FEV-1 and
DLCO.

- Within 30 days of registration: patients must have vital signs, history/physical
examination, laboratory studies (complete blood count panel [CBCP] with differential,
chemistries including liver function tests, creatinine clearance [CrCl] assessment,
pregnancy test if needed within 14 days of registration)

- If a pleural effusion is present and visible on both CT scan AND chest x-ray, the
investigator should exclude malignant disease by pleurocentesis to confirm
cytologically-negative pleural fluid; if fluid is exudative or cytologically positive
for tumor cells, patient is excluded

- Patients with effusions that are minimal (i.e. not visible on chest x-ray) and that
are too small to safely tap are eligible.

- Life expectancy of at least 12 weeks in the opinion of investigator

- Patient has an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
within 30 days of registration

- Patients must have measurable primary tumor (undetectable NSCLC primary tumor is
ineligible)

- Patients must be a minimum of 3 weeks from thoracotomy (if performed) and well-healed
before starting treatment

- Ability to provide written informed consent obtained prior to participation in the
study and any related procedures being performed

- Women of child-bearing potential (WOCBP) must have a negative pregnancy test within 14
days of registration; urine human gonadotropin (HCG) is an acceptable pregnancy
assessment

- Nursing women may participate only if nursing is discontinued

- Women/men of reproductive potential must be counseled on contraception/abstinence
while receiving the study treatment

Exclusion Criteria:

- Patients with contralateral hilar involvement (greater than 1.5 cm on short axis or
positive on PET scan, or biopsy-proven)

- Documented or pathologically-proven metastatic disease

- Presence of nodules considered neoplastic in the same lobe or other ipsilateral lobe
as the primary tumor (stage T3-4), unless the nodule can be encompassed in the
stereotactic boost (gross tumor volume [GTV]boost) without exceeding a total GTVboost
size of 6 cm as defined by CT largest axial dimension

- Presence of nodules considered neoplastic in contralateral lobes (M1a)

- Patients with history of pneumonectomy

- Prior cytotoxic chemotherapy or molecularly-targeted agents (e.g. erlotinib,
crizotinib), unless > 2 years prior

- Any concurrent malignancy other than non-melanoma skin cancer, non-invasive bladder
cancer, or carcinoma in situ of the cervix; patients with a previous malignancy
without evidence of disease for >= 3 years will be allowed to enter the trial

- History of active connective tissue disease (scleroderma) or idiopathic pulmonary
fibrosis

- History of previous radiation therapy which would result in overlapping radiation
fields

- Uncontrolled neuropathy grade 2 or greater, regardless of cause

- Subjects who are breast-feeding and plan to continue breast-feeding during therapy, or
have a positive pregnancy test will be excluded from the study; should a woman become
pregnant or suspect she is pregnant while participating in this study, she should
inform her treating physician immediately

- Medical contraindication to MR imaging (e.g. pacemakers, metallic implants, aneurysm
clips, known contrast allergy to Gadolinium contrast, pregnancy, nursing mothers,
weight greater than 350 pounds) [first 10 patients]

- Any serious and/or unstable pre-existing medical disorder (aside from malignancy
exception above), psychiatric disorder, or other conditions that could interfere with
subject's safety, obtaining informed consent or compliance to the study procedures, in
the opinion of the Investigator; this could include severe, active co-morbidities such
as:

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

- Transmural myocardial infarction within the last 6 months

- Acquired immune deficiency syndrome (AIDS) based upon the current CDC definition;
note, however, that HIV testing is not required for entry to protocol. The need
to exclude patients with AIDS from this protocol is necessary because the
treatments involved may be significantly immunosuppressive

- Chronic obstructive pulmonary disease exacerbation or other respiratory illness
requiring hospitalization or precluding study therapy within 30 days of
registration

- Hepatic insufficiency resulting in jaundice and/or coagulation defects