CUDC-907 Treatment in People With Metastatic and Locally Advanced Thyroid Cancer

Background:

- There are no standard or effective systemic therapies for metastatic or locally advanced
poorly differentiated and undifferentiated thyroid cancer.

- Poorly differentiated and undifferentiated thyroid cancer are aggressive, with high
mortality.

- CUDC-907 is a first-in-class dual inhibitor of histone deacetylase (HDAC) and PI3K
signaling.

- Approximately 80% of poorly differentiated and undifferentiated thyroid cancers have
driver mutations in the PI3K/AKT pathway or activation of the pathway.

- HDAC2 is upregulated in poorly differentiated and undifferentiated thyroid cancer, and
aggressive variants of differentiated thyroid cancer, and CUDC-907 treatment reduces
HDAC2 levels in thyroid cancer cells.

- CUDC-907 inhibits thyroid cancer cell growth, invasion and migration in vitro.

- In addition to inhibiting the PI3K/AKT signaling pathway, CUDC-907 inhibits the
EGFR/RAS/RAF/MEK/ERK signaling pathway, which is also activated in poorly differentiated
and undifferentiated thyroid cancer.

- CUDC-907 inhibits growth and metastases in a mouse model of metastatic thyroid cancer.

- We hypothesize that CUDC-907 will cause cancer regression in patients with metastatic
and locally advanced poorly differentiated and undifferentiated thyroid cancer, and
aggressive variants of differentiated thyroid cancer.

Objective:

-To determine response to CUDC-907 treatment by Response Evaluation Criteria in Solid Tumors
(RECIST) criteria in patients with locally advanced and metastatic poorly differentiated and
undifferentiated thyroid cancer, and aggressive variants of differentiated thyroid cancer.

Eligibility:

- Age greater than or equal to 18 years

- Thyroid cancer that is refractory to or relapsed after standard treatment.

- Aggressive thyroid cancer confirmed on histology or cytologic analysis.

- Measurable disease.

- Last dose of chemotherapy or last radiotherapy treatment more than 4 weeks prior to
starting treatment with this protocol, except for subjects with
anaplastic/undifferentiated thyroid cancer who may enroll immediately after
discontinuation of previous therapy.

Design:

- Open label, phase II trial to determine response to CUDC-907 treatment.

- Patients will be given 60 mg of CUDC-907 orally for 5 consecutive days followed by 2
days off (5/2 schedule).

- One cycle is 21 days. Patients may continue on treatment if there is no disease
progression.

- Initial anatomic and functional imaging will be performed at enrollment and after 2
cycles of treatment. Thereafter, anatomic imaging will be performed every two cycles of
treatment.

- INCLUSION CRITERIA:

- Subjects greater than or equal to 18 years of age.

- Thyroid cancer histology or cytology that is aggressive (anaplastic/undifferentiated
thyroid cancer, poorly differentiated thyroid cancer, Hurthle cell carcinoma,
tall-cell variant of papillary thyroid cancer, sclerosing variant of papillary thyroid
cancer).

- Measurable disease.

- Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.

- Absolute neutrophil count greater than or equal to 1,000/microL

- Platelets greater than or equal to 75,000/microL

- Creatinine less than or equal to 1.5 times upper limit of normal (ULN) or creatinine
clearance > 60ml for patients with creatinine levels 1.5 times above institutional ULN
(calculated based on age, weight and sex

- Total bilirubin less than or equal to 1.5 times ULN; aspartate aminotransferase
(AST)/alanine aminotransferase (ALT) less than or equal to 2.5 times ULN. For subjects
with documented liver metastases, the AST/ALT may be less than or equal to 5 times
ULN.

- Recovery to Grade 1 or baseline of any toxicity due to prior anticancer therapies
(excluding alopecia).

- Platelet transfusions to help patients meet eligibility criteria are not allowed
within 3 days prior to screening complete blood count (CBC) or Cycle 1, Day 1
treatment.

- Women of child bearing potential must have a negative serum pregnancy test.

- The effects of CUDC-907 on the developing human fetus are unknown. For this reason,
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, for
the duration of study participation and for 30 days following the last study
treatment.

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.

-Able to provide written informed consent and to follow protocol requirements.

EXCLUSION CRITERIA:

- Systemic anticancer therapy within 4 weeks of study entry, except for subjects with
anaplastic/undifferentiated thyroid cancer who may be enrolled immediately after
discontinuation of previous therapy.

- Other investigational agents within 4 weeks prior to study treatment except for
subjects with anaplastic/undifferentiated thyroid cancer who may be enrolled
immediately of discontinuation of previous therapy.

- Pregnant women are excluded from this study because the potential risk of teratogenic
or abortifacient effects of CUDC-907 is unknown. Because there is an unknown but
potential risk for adverse events in nursing infants secondary to treatment of the
mother with CUDC-907, breastfeeding should be discontinued if the mother is treated
with CUDC-907. These potential risks may also apply to other agents used in this
study.

- Diabetes mellitus that is not controlled with medication.

- Serious infection requiring intravenous antibiotic therapy within 14 days prior to
study treatment.

- Evidence of central nervous system metastasis.

- Uncontrolled or severe cardiovascular disease, including myocardial infarction,
unstable angina, or atrial fibrillation (AFib) within 6 months prior to study
treatment, New York Heart Association (NYHA) Class II or greater congestive heart
failure, serious arrhythmias requiring medication for treatment, clinically
significant pericardial disease, cardiac amyloidosis, or corrected QT interval (QTc)
with Fridericia's (QTcF) correction that is unmeasurable or greater than or equal to
480 msec on screening electrocardiogram (ECG). (Note: for QTcF greater than or equal
to 480 sec on the screening ECG, the ECG may be repeated twice at least 24 hours
apart; the mean QTcF from the three screening ECGs must be < 480 msec in order to meet
eligibility for trial participation).

- Gastrointestinal disease or disorder that could interfere with the swallowing, oral
absorption, or tolerance of CUDC-907. This includes uncontrolled diarrhea (> 1 watery
stool/day), major abdominal surgery, significant bowel obstruction and/or
gastrointestinal diseases that could alter the assessment of pharmacokinetics or
safety, including but not limited to: irritable bowel syndrome, ulcerative colitis,
Crohn's disease and hemorrhagic coloproctitis.

- Unstable or clinically significant concurrent medical condition that would, in the
opinion of the investigator, jeopardize the safety of a subject and/or compliance with
the protocol.

- Second primary malignancy within 2 years of study entry other than adequately treated
non-melanoma skin or superficial bladder cancer, curatively treated carcinoma in situ
of the cervix or other curatively treated solid tumor deemed by the investigator to be
at low risk for recurrence.