Mithramycin for Lung, Esophagus, and Other Chest Cancers

Background:

Increasing evidence indicates that activation of stem cell gene expression is a common
mechanism by which environmental carcinogens mediate initiation and progression of thoracic
malignancies. Similar mechanisms appear to contribute to extra-thoracic malignancies that
metastasize to the chest. Utilization of pharmacologic agents, which target gene regulatory
networks mediating stemness may be novel strategies for treatment of these neoplasms. Recent
studies performed in the Thoracic Epigenetics Laboratory, TOSB/NCI, demonstrate that under
exposure conditions potentially achievable in clinical settings, mithramycin diminishes stem
cell gene expression and markedly inhibits growth of lung and esophageal cancer and MPM cells
in vitro and in vivo. These finding add to other recent preclinical studies demonstrating
impressive anti-tumor activity of mithramycin in epithelial malignancies and sarcomas that
frequently metastasize to the thorax.

Primary Objective:

-To assess clinical response rates of mithramycin administered as 6 hour intravenous
infusions in patients with malignancies involving lungs, esophagus, pleura, or mediastinum.

Eligibility:

- Patients with measurable inoperable, histologically confirmed primary lung and
esophageal carcinomas, thymic neoplasms, germ cell tumors, malignant pleural
mesotheliomas or chest wall sarcomas, as well as patients with gastric, colorectal or
renal cancers and sarcomas metastatic to the thorax are eligible.

- Patients with germline SNPs in ABCB4, ABCB11, RALBP or CYP851 that are associated with
resistance to mithramycin-induced hepatotoxicity.

- Patients must have had or refused first-line standard therapy for their malignancies.

- Patients must be 18 years or older with an ECOG performance status of 0 2, without
evidence of unstable or decompensated myocardial disease. Patients must have adequate
pulmonary reserve evidenced by FEV1 and DLCO equal to or greater than 30% predicted;
oxygen saturation greater than or equal to 92% on room air. ABG will be drawn if
clinically indicated.

- Patients must have a platelet count greater than 100,000, an ANC equal to or greater
than 1500 without transfusion or cytokine support, a normal PT/PTT, and adequate hepatic
function as evidenced by a total bilirubin of <1.5 times upper limits of normal (ULN)
and AST/ALT less than or equal to 3 x ULN. Serum creatinine less than 3 or equal to 1.6
mg/ml, or creatinine clearance greater than 70 ml/min/1.73m^2.

Design:

- Simon Optimal Two Stage Design for Phase II Clinical Trials targeting an objective
response rate (RECIST) of 30%.

- Patients will be stratified based on location of primary disease (thoracic vs.
extra-thoracic).

- Patients will receive 6 hour infusions of mithramycin at 30 -50 mcg/kg every day for 7
days, every 21 days (1 cycle). Three cycles will constitute one course of therapy. Those
patients tolerating 30 mcg/kg infusions during the first cycle will receive subsequent
cycles of mithramycin at a dose of 50 mcg/kg using the same infusion schedule.

- Following each course of therapy, patients will undergo restaging studies. Patients
exhibiting objective response to therapy or stable disease by RECIST criteria will be
offered an additional course of therapy.

- Patients exhibiting disease progression will be removed from study.

- Biopsies of index lesions will be obtained at baseline and on day 8 of the second cycle
of

therapy for analysis of molecular end-points.

-Pharmacokinetics will be assessed during cycle 1 and cycle 2 of the first course of therapy.

- INCLUSION CRITERIA:

- Diagnosis: Patients with measurable inoperable, histologically confirmed primary lung
and esophageal carcinomas, thymic neoplasms, germ cell tumors, malignant pleural
mesotheliomas or chest wall sarcomas, as well as patients with gastric, colorectal or
renal cancers and sarcomas metastatic to the thorax are eligible

- Histologic confirmation of disease in the Laboratory of Pathology, CCR, NCI, NIH.

- Disease amenable to biopsy via percutaneous approach or other minimally invasive
procedures such as thoracoscopy, bronchoscopy, laparoscopy, or GI endoscopy

- Age >18

- ECOG status 0-2.

- Patients must have had or refused first-line standard chemotherapy for their
inoperable malignancies.

- Patients must have had no chemotherapy, biologic therapy, or radiation therapy for
their malignancy for at least 30 days prior to treatment. Patients may have received
localized radiation therapy to non-target lesions provided that the radiotherapy is
completed 14 days prior to commencing therapy, and the patient has recovered from any
toxicity. At least 3 half-lives must have elapsed since monoclonal antibody treatment.
At least six weeks must have elapsed between mitomycin C or nitrosourea treatment.

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

a) Hematologic and Coagulation Parameters:

i. Peripheral ANC greater than or equal to 1500/mm^3

ii. Platelets greater than or equal to 100,000/ mm^3 (transfusion independent)

iii. Hemoglobin greater than or equal to 8 g/dL (PRBC transfusions permitted)

iv. PT/PTT within normal limits (patient may be eligible for trial if abnormality is deemed
clinically insignificant and cleared for protocol therapy by Hematology Consult Service)

b) Hepatic Function

i. Bilirubin (total) < 1.5 times upper limit of normal (ULN)

ii. ALT (SGPT) less than or equal to 3.0 times ULN

iii. Albumin > 2 g/dL

c) Renal Function

i. Creatinine within normal institutional limits or creatinine clearance greater than or
equal to 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal.

ii. Normal ionized calcium, magnesium and phosphorus (can be on oral supplementation)

- Cardiac Function: Left ventricular ejection fraction (EF) >40% by Echocardiogram,
MUGA, or cardiac MR.

- Ability of subject to understand, and be willing to sign informed consent.

- Female and male patients (and when relevant their partners) must be willing to
practice birth control (including abstinence) during and for two months after
treatment, if of childbearing potential during sexual contact with a female of
childbearing potential.

- Patients must be willing to undergo 2 tumor biopsies

EXCLUSION CRITERIA:

- Patients with ABCB4, ABCB11, RALBP or CYP851 genotypes associated with
mithramycin-mediated hepatotoxicity.

- Clinically significant systemic illness (e.g. serious active infections or significant
cardiac, pulmonary, hepatic or other organ dysfunction), that in the judgment of the
PI would compromise the patient s ability to tolerate protocol therapy or
significantly increase the risk of complications

- Patients with cerebral metastases

- Patients with any of the following pulmonary function abnormalities will be excluded:
FEV, < 30% predicted; DLCO, < 30% predicted (post-bronchodilator); Oxygen saturation
greater than 92% on room air. Arterial blood gas will be drawn if clinically
indicated.

- Patients with evidence of active bleeding, intratumoral hemorrhage or history of
bleeding diatheses, unless specifically occurring as an isolated incident during
reversible chemotherapy induced thrombocytopenia

- Patients on therapeutic anticoagulation. Note: prophylactic anticoagulation (i.e.
intralumenal heparin) for venous or arterial access devices is allowed

- Patients who are concurrently receiving or requiring any of the following agents,
which may increase the risk for mithramycin related toxicities, such as hemorrhage:

- Thrombolytic agents

- Aspirin or salicylate-containing products, which may increase risk of hemorrhage

- Dextran

- Dipyridamole

- Sulfinpyrazone

- Valproic acid

- Clopidogrel

- Lactating or pregnant females (due to risk to fetus or newborn, and lack of testing
for excretion in breast milk)

- Patients with history of HIV, HBV or HCV due to potentially increased risk of
mithramycin toxicity in this population

- Hypersensitivity to mithramycin

- Patients who in the opinion of the investigator may not be able to comply with the
safety monitoring requirements of the study