Perfusion-Induced Hyperthermia for Metastatic Carcinoma

One potential candidate for a new approach to advanced cancer therapy is hyperthermia because
cancer cells are thermo-sensitive, with significantly reduced heat shock protein (HSP)
expression. Moreover, hyperthermia (42°C) causes repression of genes involved in the cell
cycle and cellular growth and proliferation. Upon exposure to hyperthermic conditions, HSP
expression is increased in normal cells. However, when cancer cells are exposed to
hyperthermia, they initially express significantly less HSPs than normal cells, which
sensitizes them to hyperthermia. Mild hyperthermia (43°C for less than two hours) induces
extensive double-stranded DNA fragmentation and, at a later time, apoptosis in murine
thymocytes. In cells with irreparable levels of DNA damage, apoptosis is the means of
elimination.

Inclusion Criteria:

- Patients must have histologically or cytologically confirmed diagnosis of Stage IIIB
or Stage IV of non-small cell lung cancer and have received at least two lines of
FDA-approved or National Comprehensive Cancer Network (NCCN) accepted systemic therapy
and progressed through, or not tolerated, such therapy.

- Subjects whose tumors harbor an exon 19 deletion or exon 21L858R EGFR mutation
must have progressed on or had intolerance to EGFR tyrosine kinase inhibitor.

- Subjects whose tumors harbor an AKL translocation must have progressed on or had
intolerance to crizotinib (or any FDA approved ALK inhibitor).

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

- Have histologically confirmed malignancy that is metastatic or unresectable and
for which standard curative or palliative measures do not exist or are no longer
effective

Must have undergone at least 2 prior regimens for treatment of recurrent or metastatic
disease

- Life expectancy of greater than 3 months.

- Age ≥22 years.

- There is no restriction on the number of prior therapies allowed for this disease and
prior radiation and chemotherapy is allowed, provided the subject has recovered from
all grade 2 or greater toxicity prior to enrollment.

- Patient understands the nature of the procedure, is willing to comply with associated
follow-up evaluations, and provide written informed consent prior to the procedure

Exclusion Criteria:

- Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for
nitrosoureas or mitomycin C, or monoclonal antibodies such as bevacizumab, cetuximab
or panitumumab) prior to entering the study or those who have not recovered to < grade
2 adverse events due to agents administered more than 4 weeks earlier.

- Patients with stroke or TIA within 90 days prior to enrollment; or peripheral vascular
disease requiring intervention within the 90 days prior to enrollment; or any known
hemodynamically significant lesion or embolic plaque.

- Patients must have normal organ and marrow function as defined below:

- leukocytes ≥3,000/mcL

- absolute neutrophil count ≥1,500/mcL

- total Bilirubin, AST(SGOT)/ALT(SGPT) ≤2.5 × institutional upper limit of normal

- glomerular filtration rate (GFR)> 60 as defined by the Modification of Diet in
Renal Disease (MDRD) formula

- Thromboplastin Time (PTT) < 35 sec)

- Patients with uncontrolled seizure disorder, spinal cord compression or carcinomatous
meningitis.

- Patients with a mental disorder, psychiatric illness/social or concussion which would
inhibit their ability to provide informed consent or prevent compliance with
follow-up.

- Patients with high risk of cardiovascular event such as severe uncontrolled
hypertension (>170/110 systemic blood pressure on therapy), or pulmonary hypertension
(greater than .5 systolic blood pressure

- ST elevation myocardial infarction within 30 days prior to enrollment; unstable angina
or significant, untreated arrhythmias within 30 days prior to enrollment.

- Patients with moderate to severe heart failure, New York Heart Association (NYHA)
class III or IV, liver dysfunction with total bilirubin >2. 5 upper limit of normal,
or serum creatinine >2.5 mg/dL or any form of dialysis; within 30 days prior to
enrollment.

- Patients with a major surgical procedure or other investigational agents within 30
days before study enrollment.

- Patients with known, untreated or progressive brain metastases will 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

- Patients with documented contraindication to anticoagulation therapy such as heparin
induced thrombocytopenia or a documented coagulopathy or hematologic disorder that
would contraindicated undergoing treatment and use of the associated anticoagulant
agents required during treatment.

- Patients with documented active bacterial, viral or fungal infection, untreated
systematic peptic ulcer disease, uncontrolled diabetes mellitus or serious concurrent
medical disease that could limit survival to less than 3 months.

- HIV-positive patients on combination antiretroviral therapy are ineligible because of
the potential for harm when exposed to hyperthermia, as well as negative interactions
of these medications with hyperthermia.