Methoxyamine, Pemetrexed Disodium, Cisplatin, and Radiation Therapy in Treating Patients With Stage IIIA-IV Non-small Cell Lung Cancer

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) of methoxyamine (TRC102) in combination with
pemetrexed (pemetrexed disodium)-cisplatin and thoracic radiotherapy.

SECONDARY OBJECTIVES:

I. To (descriptively) assess the toxicity profile of methoxyamine (TRC102) in combination
with pemetrexed-cisplatin and thoracic radiotherapy.

II. To (descriptively) assess the short-term progression-free survival at 6 months (PFS6) in
the patients treated on this protocol.

III. To observe and record anti-tumor activity.

OUTLINE: This is a dose-escalation study of methoxyamine.

COURSES 1-2: Patients receive pemetrexed disodium intravenously (IV) over 10 minutes and
methoxyamine orally (PO) day 1; and cisplatin IV over 0.5-24 hours on day 3. Patients also
undergo 3-dimensional (3-D) conformal radiation therapy (RT) or intensity-modulated radiation
therapy (IMRT) once daily (QD) 5 days a week (3 days of week 1 and 4 days of week 4) for 30
fractions total.

COURSES 3-4: Beginning at least 10 days after RT completion, patients receive pemetrexed
disodium IV over 10 minutes and cisplatin IV over 0.5-24 hours on day 1.

Treatment repeats every 21 days for 4 courses in the absence of disease progression or
unacceptable toxicity.

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

Inclusion Criteria:

- Patients must have pathologic diagnosis of adenocarcinoma or large cell carcinoma of
the lung with confirmation by immunohistochemistry (e.g., transcription termination
factor 1 [TTF-1] positivity) (histologic tissue diagnosis is recommended, but cytology
is acceptable); stage IIIA/IIIB or oligometastatic stage IV in which the patient is
still considered an appropriate candidate for aggressive chemoradiotherapy for the
primary tumor; oligometastatic disease is defined as =< 5 metastatic sites (=< 3
lesions per organ); for intracranial metastasis, the patient should have asymptomatic
disease that is stable on steroids or 1 to 3 symptomatic metastatic lesions treated
with stereotactic radiosurgery (SRS)

- Eastern Cooperative Oncology Group (ECOG) performance status < 2

- Life expectancy of greater than 12 months

- Ability to swallow and retain orally-administered medication and does not have any
clinically significant gastro-intestinal abnormalities (e.g., malabsorption syndrome
or major resection of the stomach or bowel)

- Leukocytes >= 3,000/mcL

- Absolute neutrophil count >= 1,500/mcL

- Platelets >= 100,000/mcL

- Total bilirubin within normal institutional limits

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) =<
2.5 x institutional upper limit of normal

- Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x
institutional upper limit of normal

- Creatinine within normal institutional limits OR

- Creatinine clearance >= 60 mL/min/1.73 m^2 for patients with creatinine levels above
institutional normal

- Hemoglobin >= 9 g/dL without transfusion within 7 days prior to enrollment

- Women of child-bearing potential and men must agree to use adequate contraception
(hormonal or barrier method of birth control; abstinence) prior to study entry and for
the duration of study participation; should a woman become pregnant or suspect she is
pregnant while she or her partner is participating in this study, she should inform
her treating physician immediately; men and women treated or enrolled on this protocol
must also agree to use adequate contraception prior to the study, for the duration of
study participation, and 4 months after completion of methoxyamine administration

- Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

- Patients who have had prior chemotherapy or any other investigational drug within 30
days of registration or prior radiotherapy to the study treatment volume; prior
surgery is allowed; there must be at least 6 weeks between mitomycin or nitrosoureas
and any new therapy

- Patients who are receiving any other investigational agents

- Patients with a history of any active malignancy requiring on-going treatment, except
basal cell carcinoma or squamous cell carcinoma of the skin

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to methoxyamine or to pemetrexed or cisplatin

- Undetectable haptoglobin or evidence of glucose-6-phophate dehydrogenase (G6PD)
deficiency, pyruvate kinase deficiency, hemoglobinopathy, hereditary spherocytosis,
thalassemia or other disorder associated with hemolysis

- Patients receiving any medications or substances that are inhibitors or inducers of
nonsteroidal anti-inflammatory drugs (NSAIDS), probenecid, salicylates, sulfonamides
are ineligible; concomitant drugs that are sensitive CYP450 substrates or strong and
moderate CYP450 inducers and inhibitors should be avoided; as part of the
enrollment/informed consent procedures, the patient will be counseled on the risk of
interactions with other agents, and what to do if new medications need to be
prescribed or if the patient is considering a new over-the-counter medicine or herbal
product

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements

- Pregnant women are excluded from this study; breastfeeding should be discontinued if
the mother is treated with methoxyamine

- Patients who are known to be human immunodeficiency positive (HIV)-positive and are on
combination antiretroviral therapy are ineligible