A Phase II Study of Ponatinib in Advanced or Metastatic Medullary Thyroid Cancer
- 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 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 FDA approved as a therapy for chronic myelogenous leukemia
(CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL), has been
well tolerated in clinical trials, and is a potent inhibitor of RET kinase.
-To determine the objective overall response rate (complete response [CR] + partial response
[PR] by RECIST) to ponatinib in the treatment of patients with advanced or metastatic MTC
who: 1) have tumors with RET mutations and have been previously treated with a RET
inhibitor; 2) have tumors with RET mutations and have NOT been previously treated with a
RET inhibitor; and 3) have tumors without RET mutations, whether or not they have received
a prior RET inhibitor.
- 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.
- Prior treatment with systemic therapy is permitted if the last dose was received 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.
- Open label phase II trial with 3 treatment groups:
- RET mutation positive MTC, previously treated with a RET inhibitor
- RET mutation positive MTC, previously untreated with a RET inhibitor
- RET mutation negative MTC, whether treated or not with a RET inhibitor
- Patients will receive ponatinib 45 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
- 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.
Allocation: Non-Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
To determine the objective overall response rate (complete response [CR] + partial response [PR] by RECIST) to ponatinib
Ann W Gramza, M.D.
National Cancer Institute (NCI)
United States: Federal Government
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