Inclusion Criteria:

- Subjects must be 18 years of age or greater with histologically or cytologically
confirmed non-small cell lung cancer that is advanced and cannot be treated
adequately by radiotherapy or surgery; or metastatic or recurrent disease after at
least one prior chemotherapy regimen

- Prior invasive malignancies are allowed, provided at least five years has elapsed
since the completion of therapy and enrollment on this protocol.

- All participants must have received at least one prior chemotherapy regimen for
metastatic NSCLC; prior adjuvant or neoadjuvant chemotherapy for NSCLC will also be
allowed, but will NOT be counted toward the number of regimens for metastatic disease
unless patients develop evidence of metastatic disease within six months of the
initiation of the adjuvant chemotherapy, indicating resistance to platinum-based
therapy. There is no limit on the number of prior regimens allowed, provided the
patient meets all other eligibility criteria. Patients who may best benefit from the
application of specific targeted therapies (i.e., erlotinib for EGFR exon 19 or 21
activating mutations, or crizotinib for EML4-ALK translocations) will be eligible for
this protocol only after documented progression through such targeted therapy AND a
platinum-based doublet regimen

- All participants must have the appropriate phenotype on pretreatment screening of
tumor tissue or sputa, consisting of ISG15-positive cells by immunohistochemistry
(staining score of 4-12, as defined in section 4.2), performed by the UK Department
of Pathology, and must agree to have their tissues evaluated for ISG15 expression (a
separate informed consent will be requested). Potential participants who have no
available tissue for assessment will be offered sputum assessment or tissue biopsy if
it can be performed safely, potential disease sites can be safely approached, and
only if it is the opinion or their attending physician that participation in this
protocol represents their best treatment option at this time. Subjects with
assessable material will not be required to undergo a separate biopsy solely for
participation in this protocol.

- Subjects must have the following baseline laboratory values (bone marrow, renal,
hepatic):

- Adequate bone marrow function:

- Absolute neutrophil count >1000/μL

- Platelet count >100'000/μL

- Serum creatinine < 2.0 mg/dL

- Bilirubin <1.5x normal

- Serum calcium < 12 mg/dl

- Signed Informed Consent

- ECOG Performance Status <2

- Life expectancy > 16 weeks

- Patients must have measurable disease, defined as at least one lesion that can be
accurately measured in at least one dimension (longest diameter to be recorded for
non-nodal lesions and short axis for nodal lesions) as >20 mm with conventional
techniques or as >10 mm with spiral CT scan, MRI, or calipers by clinical exam. See
Section 11 for the evaluation of measurable disease.

- Patients of childbearing potential must be using an effective means of contraception.

The effects of Irinotecan on the developing human fetus are unknown. For this reason and
because camptothecins are known to be teratogenic, 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 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
irinotecan administration.

Exclusion Criteria:

- Prior therapy with irinotecan, topotecan, or other camptothecin analog

- Patients whose tumor harbors an EGFR exon 19 or 21 mutation who has not yet received
prior therapy with an EGFR-specific tyrosine kinase inhibitor such as erlotinib or
gefitinib

- Patients whose tumor harbors an EML4/ALK translocation and who has not yet received
crizotinib

- Pregnant or lactating females

- Myocardial infarction or ischemia, or active cerebrovascular disease, within the 6
months before Cycle 1' Day 1

- Uncontrolled clinically significant dysrhythmia

- Prior radiotherapy to an indicator lesion unless there is objective evidence of tumor
growth in that lesion

- Uncontrolled metastatic disease of the central nervous system (previously treated,
stable disease is allowable on this protocol)

- Radiotherapy within the 2 weeks before registration

- Surgery within the 2 weeks before registration

- Any co morbid condition that' in the view of the attending physician' renders the
patient at high risk from treatment complications

- Patients who have had chemotherapy within 4 weeks (6 weeks for nitrosoureas or
mitomycin C) prior to entering the study or those who have not recovered from adverse
events due to agents administered more than 4 weeks earlier.

- Patients who are receiving any other investigational agents.

- Patients with known untreated brain metastases should be excluded from this clinical
trial because of their poor prognosis and because they often develop progressive
neurologic dysfunction that would confound the evaluation of neurologic and other
adverse events.

- Pregnant women are excluded from this study because Irinotecan is a camptothecin with
the potential for teratogenic or abortifacient effects. Because there is an unknown
but potential risk for adverse events in nursing infants secondary to treatment of
the mother with Irinotecan, breastfeeding should be discontinued if the mother is
treated with Irinotecan.

- HIV-positive patients on combination antiretroviral therapy are ineligible because of
the potential for pharmacokinetic interactions with Irinotecan. In addition, these
patients are at increased risk of lethal infections when treated with
marrow-suppressive therapy. Appropriate studies will be undertaken in patients
receiving combination antiretroviral therapy when indicated.