A Phase II Study of Ponatinib in Advanced or Metastatic Medullary Thyroid Cancer
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 入组人数
- 3
- 试验地点
- 1
- 主要终点
- Overall Response Rate.
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 99 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- 未提供
排除标准
- 未提供
研究组 & 干预措施
RET mutation positive participants
Rearranged during transfection (RET) mutation positive
干预措施: Ponatinib (Drug)
RET mutation negative participants
Rearranged during transfection (RET) mutation negative
干预措施: Ponatinib (Drug)
结局指标
主要结局
Overall Response Rate.
时间窗: 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.
次要结局
- Progression Free Survival(2-4 months)
- Number of Participants With Adverse Events(17 months and 19 days)
- Molecular Differences in Advanced Medullary Thyroid Cancer (MTC)(Prior to the first dose of ponatinib)
- Changes in Serum Levels of MTC Tumor Markers Calcitonin (CTN) and Its Relation With Clinical Response(Baseline to 4 weeks)
- Objective Response to Ponatinib(up to 4 cycles of treatment with ponatinib)
- Changes in Serum Levels of MTC Tumor Markers Carcinoemybryonic Antigen (CEA) and Its Relation With Clinical Response(Baseline to 4 weeks)
- Overall Survival(up to 6 months)
研究者
James Gulley, M.D.
Principal Investigator
National Institutes of Health Clinical Center (CC)