Ponatinib for Advanced Medullary Thyroid Cancer

Background:

- Medullary thyroid cancer (MTC) represents 5% of thyroid cancers and presents as a
hereditary (25% of cases) or sporadic (75% of cases) neuroendocrine malignancy.

- MTC arises from the parafollicular C-cells of the thyroid.

- Germline mutations in the rearranged during transfection (RET) proto-oncogene occur in
virtually all of hereditary MTC cases, and somatic RET mutations occur in 50% of
sporadic cases.

- Drugs targeting RET kinase such as vandetanib and cabozantinib have shown efficacy in
the treatment of advanced or metastatic MTC, however, more effective RET inhibitors are
needed for previously untreated patients as well as patients who have become refractory
to other molecular targeted therapeutics (MTTs).

- Ponatinib, a drug that is Food and Drug Administration (FDA) approved as a therapy for
chronic myelogenous leukemia

(CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL), is a
potent inhibitor of RET kinase.

Primary Objective:

-To determine the objective overall response rate (complete response [CR] + partial response
[PR] by Response Evaluation Criteria in Solid Tumors (RECIST) to ponatinib in the treatment
of patients with advanced or metastatic MTC previously treated cabozantinib and vandetanib
who: 1) have tumors with RET mutations and 2) have tumors without RET mutations.

Eligibility:

- Patients must have histologically confirmed, unresectable, locally advanced or
metastatic MTC, with measurable disease by RECIST criteria.

- Patients must have disease amenable to biopsy and be willing to undergo biopsy for
molecular analysis, and also have adequate archival material from their thyroidectomy
or from a tumor biopsy obtained prior to beginning any systemic therapy.

- Patients must have failed or been intolerant to prior treatment with both cabozantinib
and vandetanib.

- The last dose of prior systemic therapy must be more than 28 days prior to the first
dose of ponatinib.

- Radiation therapy is permitted if the last treatment was received more than 28 days
prior to the first dose of ponatinib.

Design:

- Open label phase II trial with 2 treatment groups:

- RET mutation positive MTC, previously treated with vandetanib and cabozantinib

- RET mutation negative MTC, previously treated with vandetanib and cabozantinib

- Patients will receive ponatinib 30 mg orally daily until disease progression or until
the development of intolerable side effects.

- Tumor response will be assessed by RECIST 1.1 criteria at 8 weeks and then every 12
weeks thereafter. After one year on study, tumor response will be assessed every 16
weeks.

- Patients will have a biopsy of their MTC for molecular analysis prior to initiating
treatment with ponatinib. Patients will also have a biopsy of their MTC at the time of
tumor progression, should that occur.

- INCLUSION CRITERIA:

- Diagnosis of localized or metastatic unresectable medullary thyroid cancer (MTC). The
histological diagnosis of MTC must be confirmed on review of submitted tumor tissue
by the Laboratory of Pathology in the National Cancer Institute

- Measurable disease, defined as at least one lesion that can be accurately measured in
at least one dimension (longest diameter to be recorded for non-nodal lesions and
short axis for nodal lesions) as greater than or equal to 20 mm with conventional
techniques or as greater than or equal to 10 mm with spiral computed tomography (CT)
scan.

- Disease amenable to biopsy and agree to undergo biopsy for molecular analysis

- The last dose of previous therapy targeting rearranged during transfection (RET)
kinase must be given at least 4 weeks prior to the first dose of ponatinib.

- Previous treatment with cytotoxic chemotherapy, immunotherapy, or radiotherapy are
permitted, if the last dose was given at least 4 weeks prior to the first dose of
ponatinib

- Patient must have failed (progressed on or been intolerant of) prior treatment with
cabozantinib and vandetanib.

- Age greater than or equal to 18 years old

- Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2

- Normal organ and marrow function as defined below:

- Leukocytes greater than or equal to microL

- Absolute neutrophil count 1,500/microL

- Platelet count greater than or equal to 100,000 microL

- Total bilirubin < 1.5 times upper limit of normal (ULN)

- Aspartate aminotransferase (AST) serum glutamic oxaloacetic
transaminase(SGOT)/alanine aminotransferase (ALT) serum glutamic pyruvic
transaminase (SGPT) < 2.5 times institutional ULN or < 5 times ULN if liver
involvement

- Prothrombin Time < 1.5 times ULN

- Creatinine < 1.5 times ULN

- Lipase less than or equal to 1.5 times ULN

- Negative pregnancy test for women of childbearing potential. The effects of ponatinib
on the developing human fetus are unknown. For this reason, women of childbearing
potential and men must agree to use adequate contraception (hormonal or barrier
method of birth control; abstinence) prior to study entry and for the duration of
study participation. 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.

- Normal QT interval corrected (Fridericia) (QTcF) on screening electrocardiogram (ECG)
evaluation, defined as QTcF of less than or equal to 450 ms in males or less than or
equal to 470 ms in females.

- Ability to understand and the willingness to sign a written informed consent document
and follow the guidelines of the clinical protocol including visits to National
Cancer Institute (NCI), Bethesda, Maryland for treatment and follow up visits.

EXCLUSION CRITERIA:

- Patients who are receiving any other investigational agent.

- Patients with brain metastases or spinal cord compression unless they completed
radiation therapy greater than or equal to 4 weeks prior to the first dose of
ponatinib and are stable without steroids or anti-convulsant therapy for greater than
or equal to 10 days.

- Medications that are known to be associated with Torsades de Pointes.

- Uncontrolled hypertension (systolic blood pressure > 150 or diastolic blood pressure
> 100

- Significant or active cardiovascular disease, specifically including but not
restricted to:

- History of myocardial infarction

- History of atrial or ventricular arrhythmia

- Unstable angina within 6 months prior to first dose of ponatinib

- History of congestive heart failure

- Left ventricular ejection fraction fraction (LVEF) less than lower limit of
normal

- History of peripheral arterial occlusive disease

- History of cerebrovascular accident or transient ischemic attack

- Venous thromboembolism including deep venous thrombosis or pulmonary embolism
within 6 months prior to enrollment

- A history of pancreatitis or alcohol abuse

- Uncontrolled hypertriglyceridemia (> 450 mg/dL)

- Major surgery (with the exception of minor surgical procedures, such as catheter
placement or tumor biopsy) within 28 days prior to the first dose of ponatinib

- Ongoing or active infection including known history of human immunodeficiency virus
[HIV], hepatitis B virus [HBV], or hepatitis C virus[HCV]. Testing for these viruses
is not required in the absence of a history of infection.

- Suffer from any condition or illness that, in the opinion of the investigator, would
compromise patient safety or interfere with the evaluation of the safety of the study
drug

- Evidence of a bleeding diathesis that cannot be corrected with standard therapy or
factor replacement

- Presence of another primary malignancy within the past 2 years (except for
nonmelanoma skin cancer or cervical cancer in situ. Prior prostate cancer is also
permitted if prostatic specific antigen (PSA) is now undetectable.)

- Pregnant or lactating