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

 The thyroid is a gland at the base of the throat. Thyroid cancer is a disease that people get
 when abnormal cells begin to grow in this gland. Researchers believe a new drug called
 CUDC-907 may be able to help people with thyroid cancer that has spread or has gotten worse.

 Objective:

 To see if CUDC-907 will shrink tumors in people with advanced thyroid cancer.

 Eligibility:

 People at least 18 years old who have been diagnosed with locally advanced and metastatic
 thyroid cancer.

 Design:

 Participants will be screened with:

 Medical history

 Physical exam

 Blood and urine tests

 Electrocardiogram (ECG) heart test.

 Review of their symptoms and how they perform normal activities

 A scan will be performed. Some will have a computed tomographic scan (CT) that takes pictures
 of the body using a small amount of radiation. Some will have magnetic resonance imaging
 (MRI) that uses a magnetic field to take pictures.

 Bone scan (some participants)

 Fludeoxyglucose (FDG) positron emission tomography (PET) scan to produce a tumor image.

 A sample of their tumor from a previous surgery. They may have a biopsy of their tumor if a
 tumor sample is not available from a previous surgery.

 Participants will be given CUDC-907 in tablet form. They will take it by mouth once a day for
 5 days, then take 2 days off, each week.

 While taking the study drug, participants will have study visits that repeat the screening
 tests.

 After they stop treatment, participants will have 3 follow-up visits over a year. They will
 repeat some tests. Then participants will be contacted by phone or e-mail every 6 months....
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.