Ponatinib for Advanced Medullary Thyroid Cancer
- Registration Number
- NCT01838642
- Brief Summary
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 with 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.
- Detailed Description
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.
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 3
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description RET mutation positive participants Ponatinib Rearranged during transfection (RET) mutation positive RET mutation negative participants Ponatinib Rearranged during transfection (RET) mutation negative
- Primary Outcome Measures
Name Time Method Overall Response Rate. 2-4 months Defined as the percentage of participants with a best response (complete response (CR) + partial response (PR)) recorded from the start of the treatment until disease progression/recurrence assessed by the Response Evaluation Criteria in Solid Tumors (RECIST). Complete response (CR) is the disappearance of all target lesions. Any pathological lymph nodes (Whether target or non-target) must have reduction in short axis to \<10 mm. Partial response (PR) is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters.
- Secondary Outcome Measures
Name Time Method Progression Free Survival 2-4 months Progression free survival is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first.
Number of Participants With Adverse Events 17 months and 19 days Here is the number of participants with adverse events. For a detailed list of adverse events, see the adverse event module.
Molecular Differences in Advanced Medullary Thyroid Cancer (MTC) Prior to the first dose of ponatinib Compare the molecular profile of tumor deoxyribonucleic acid (DNA) prior to treatment with the molecular profile at the time of progression. Prior to the first dose of ponatinib and at time of progression, subjects were to undergo a biopsy of the primary tumor or any metastatic site for analysis of tumor DNA for rearranged during transfection (RET) or rat sarcoma (RAS) mutation. Progression is assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) and is defined as at least a 20% decrease in the sum of diameters of target lesions, taking as reference the smallest sum on study.
Changes in Serum Levels of MTC Tumor Markers Calcitonin (CTN) and Its Relation With Clinical Response Baseline to 4 weeks Responders are those subjects with a best biomarker response of complete response (CR) or partial response (PR) and who achieve a clinical response of CR or PR assessed by the following criteria. Biomarker: complete response (CR) is normalization (\</= upper limit of normal (ULN)) of CTN (i.e., normal \<10 pg/mL) following treatment, confirmed with a repeat CTN level at least 4 weeks apart. Partial response (PR) is a \>/=50% decrease in the CTN level relative to baseline level, confirmed with a repeat CTN level at least 4 weeks apart. Clinical: complete response (CR) is an average of 0-2 formed stools per day for a period of at least 4 weeks. Partial response (PR) is a \>50% decrease in the average stool frequency relative to baseline and a change in stool consistency from watery to loose (partially formed) for a period of at least 4 weeks.
Objective Response to Ponatinib up to 4 cycles of treatment with ponatinib Objective response was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST). Complete response (CR) is the disappearance of all target lesions. Any pathological lymph nodes (Whether target or non-target) must have reduction in short axis to \<10 mm. Partial response (PR) is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters. Progressive disease (PD) is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5mm. Stable disease (SD) is neither shrinkage to qualify for PR nor sufficient increase to qualify for PD.
Changes in Serum Levels of MTC Tumor Markers Carcinoemybryonic Antigen (CEA) and Its Relation With Clinical Response Baseline to 4 weeks Responders are those subjects with a best biomarker response of complete response (CR) or partial response (PR) and who achieve a clinical response of CR or PR assessed by the following criteria. Biomarker: complete response (CR) is normalization (\</= upper limit of normal (ULN)) of CTN (i.e., normal 0-2.5 mcg/L) following treatment, confirmed with a repeat CEA level at least 4 weeks apart. Partial response (PR) is a \>/=50% decrease in the CEA level relative to baseline level, confirmed with a repeat CEA level at least 4 weeks apart. Clinical: complete response (CR) is an average of 0-2 formed stools per day for a period of at least 4 weeks. Partial response (PR) is a \>50% decrease in the average stool frequency relative to baseline and a change in stool consistency from watery to loose (partially formed) for a period of at least 4 weeks.
Overall Survival up to 6 months Overall survival is defined as the time between the first day of treatment to the day of disease progression.
Trial Locations
- Locations (1)
National Institutes of Health Clinical Center, 9000 Rockville Pike
🇺🇸Bethesda, Maryland, United States