Trial of LBH589 in Metastatic Thyroid Cancer

Medullary thyroid cancer (MTC) is a neuroendocrine tumor and accounts for 3-5% of cases of
thyroid cancer. The majority of patients with MTC do not present with early stage disease.
Differentiated thyroid cancer (DTC) accounts for >90% of all thyroid cancers. In a sub-set
of patients, thyroid cells become resistant to I-131 radioiodine therapy and subsequently
develop distant metastases. In both MTC and DTC, systemic chemotherapy for metastatic
disease is largely ineffective.

LBH589 is a histone deacetylase (HDAC) with recently demonstrated activity to inhibit the
Notch1 signaling pathway in MTC cancer cells and suppress tumor cell proliferation in DTC
cancer cells. This clinical trial will evaluate the tumor response rate of LBH589 in
patients with metastatic MTC or radioactive iodine resistant DTC.

Inclusion Criteria:

- Histologically confirmed metastatic medullary or differentiated thyroid cancer.
Diagnosis must be confirmed at University of Wisconsin

- Patients must have measurable disease as defined by RECIST.

- At least 3 weeks from the completion of major surgery, chemotherapy, or other
systemic therapy or local liver therapy to study registration

- No concurrent chemotherapy or radiation therapy

- ECOG Performance Status of ≤ 2

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

- Adequate bone marrow, kidney, liver function

- Left ventricular ejection fraction ≥ the lower limit of the institutional normal

- Those with differentiated thyroid cancer must have radioactive iodine resistant
disease, defined by failure to incorporate 131-Iodine after therapy, FDG-avidity on a
PET scan, or progression of measurable disease after 131-Iodine therapy or an allergy
to radioactive iodine

- Hypertension must be well controlled (to less than 150/90 mmHg) on a stable regimen
of anti-hypertensive therapy

Exclusion Criteria:

- Prior HDAC, DAC, HSP90 inhibitors or valproic acid for the treatment of cancer

- Patients who will need valproic acid for any medical condition during the study or
within 5 days prior to first LBH589 treatment

- Impaired cardiac function

- Concomitant use of drugs with a risk of causing torsades de pointes

- Patients with unresolved diarrhea > CTCAE grade 1

- Impairment of gastrointestinal (GI) function or GI disease that may significantly
alter the absorption of oral LBH589

- Other concurrent severe and/or uncontrolled medical conditions

- Women who are pregnant or breast feeding or women of childbearing potential (WOCBP)
not willing to use a double barrier method of contraception during the study and 3
months after last study drug administration. Women of childbearing potential must
have a negative serum pregnancy test within 7 days of the first administration of
oral LBH589.

- Male patients whose sexual partners are WOCBP not using a double method of
contraception during the study and 3 months after the end of treatment

- Patients with a history of another primary malignancy that, in the opinion of the
investigator, would interfere with the assessment of the primary endpoints of the
study

- Patients with known positivity for human immunodeficiency virus (HIV) or hepatitis C

- Patients with any significant history of non-compliance to medical regimens or with
inability to grant a reliable informed consent