A Phase I Dose Escalation-Expansion Trial of Sunitinib Malate Plus Lutetium Lu 177 Dotatate (Lutathera) in Somatostatin Receptor Positive Pancreatic Neuroendocrine Tumors
概览
- 阶段
- 1 期
- 干预措施
- Lutetium Lu 177 Dotatate
- 疾病 / 适应症
- Metastatic Pancreatic Neuroendocrine Tumor
- 发起方
- National Cancer Institute (NCI)
- 入组人数
- 24
- 试验地点
- 19
- 主要终点
- Incidence of adverse events (AEs)
- 状态
- 招募中
- 最后更新
- 11天前
概览
简要总结
This phase I trial tests the safety, side effects, and best dose of sunitinib malate in combination with lutetium Lu 177 dotatate in treating patients with pancreatic neuroendocrine tumors. Sunitinib malate is in a class of medications called kinase inhibitors and a form of targeted therapy that blocks the action of abnormal proteins called VEGFRs that signal tumor cells to multiply. This helps stop or slow the spread of tumor cells. Radioactive drugs, such as lutetium Lu 177 dotatate, may carry radiation directly to tumor cells and not harm normal cells. It is also a form of targeted therapy because it works by attaching itself to specific molecules (receptors) on the surface of tumor cells, known as somatostatin receptors, so that radiation can be delivered directly to the tumor cells and kill them. Giving sunitinib malate and lutetium Lu 177 dotatate in combination may be safer and more effective in treating pancreatic neuroendocrine tumors than giving either drug alone.
详细描述
PRIMARY OBJECTIVE: I. To evaluate the safety and maximum tolerated dose (MTD) for the combination of sunitinib malate with lutetium Lu 177 dotatate in metastatic unresectable pancreatic neuroendocrine tumors (NETS). SECONDARY OBJECTIVES: I. To observe and record anti-tumor activity. II. To assess objective response rate (ORR) of the combination by the Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1. III. To assess progression-free survival (PFS) and overall survival (OS) of the combination. IV. To determine the duration of response (DOR) from the combination. V. To determine lutetium Lu 177 dotatate dosimetry in the combination. VI. To associate somatostatin receptor (SSR) positron emission tomography (PET) triage imaging with lutetium Lu 177 dotatate dosimetry. VII. To assess the correlation of chromogranin A (CgA) with disease response in patients being treated with lutetium Lu 177 dotatate. OUTLINE: This is a dose-escalation study of sunitinib malate followed by a dose-expansion study. Patients receive sunitinib malate orally (PO) daily (QD) from day 1 of lutetium 177 dotatate therapy to 28 days after the last dose of lutetium 177 dotatate in the absence of unacceptable toxicity. Patients also receive lutetium Lu 177 dotatate intravenously (IV) over 30 minutes on day 1 of each cycle. Cycles repeat every 8 weeks (Q8W) for 4 cycles in the absence of unacceptable toxicity. Patients undergo a computed tomography (CT) scan and/or magnetic resonance imaging (MRI) throughout the trial. Patients also undergo a SSR PET/CT scan during screening and blood sample collection on study. After completion of study treatment, patients are followed for up to 4 weeks.
研究者
入排标准
入选标准
- •Patients must have histologically or cytologically confirmed metastatic or unresectable well- or moderately-differentiated pancreatic neuroendocrine tumors (PNETs) of all grades (Grade 1, grade 2 and grade 3)
- •Patients with measurable disease per RECIST 1.1 appropriate for lutetium Lu 177 dotatate treatment, as determined by positive screening with SSR PET/CT and appropriate theranostics consultation (nuclear medicine or radiation oncology consultation)
- •Patients may be treatment naïve or have disease progression on or intolerance of up to one line of systemic therapy other than somatostatin analog therapy (somatostatin analog therapy is not considered a line of systemic therapy). Systemic therapy is considered therapy for unresectable or metastatic disease. Any prior adjuvant therapy with curative intent will not be considered a line unless relapse occurs within 6 months. Prior and/or concurrent use of somatostatin analogs are allowed
- •Patients who have have received a prior line of therapy must have documented disease progression per RECIST 1.1 within 12 months of initiation of the study protocol
- •Age \>= 18 years. Because no dosing or adverse event data are currently available on the use of sunitinib malate in combination with lutetium Lu 177 dotatate in patients \< 18 years of age, children are excluded from this study
- •Eastern Cooperative Oncology Group (ECOG) performance status =\< 2 (Karnofsky \>= 60%)
- •Absolute neutrophil count \>= 1,000/mcL
- •Platelets \>= 75,000/mcL
- •Total bilirubin =\< 1.5 institutional upper limit of normal (ULN)
- •Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase \[SGPT\]) =\< 3 × institutional ULN
排除标准
- •Patients who have not recovered from acute clinically significant adverse events due to prior anti-cancer therapy (i.e., have residual toxicities \> grade 1) with the exception of alopecia
- •Patients who are receiving any other investigational agents
- •History of allergic reactions attributed to compounds of similar chemical or biologic composition to sunitinib malate or lutetium Lu 177 dotatate
- •Patients who require use of therapeutic doses of coumarin-derivative anticoagulants such as warfarin are excluded, although doses of up to 2 mg daily are permitted for prophylaxis of thrombosis. Note: Low molecular weight heparin is permitted provided the patient's INR is =\< 1.5 and is the preferred anticoagulant in this trial. Other non-coumarin-derivative anticoagulants including direct oral anticoagulants may be used with caution
- •Patients with any condition (e.g., gastrointestinal tract disease resulting in an inability to take oral medication or a requirement for IV alimentation, prior surgical procedures affecting absorption, or active peptic ulcer disease) that impairs their ability to swallow and retain sunitinib tablets are excluded
- •Patients with any of the following conditions are excluded:
- •Serious or non-healing wound, ulcer, or bone fracture
- •History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 28 days of treatment
- •Any history of cerebrovascular accident (CVA) or transient ischemic attack within 12 months prior to study entry
- •History of myocardial infarction, cardiac arrhythmia, stable/unstable angina, symptomatic congestive heart failure, or coronary/peripheral artery bypass graft or stenting within 12 months prior to study entry
研究组 & 干预措施
Treatment (sunitinib malate, lutetium Lu 177 dotatate)
Patients receive sunitinib malate PO QD from day 1 of lutetium 177 dotatate therapy to 28 days after the last dose of lutetium 177 dotatate in the absence of unacceptable toxicity. Patients also receive lutetium Lu 177 dotatate IV over 30 minutes on day 1 of each cycle. Cycles repeat Q8W for 4 cycles in the absence of unacceptable toxicity. Patients undergo a CT scan and/or MRI throughout the trial. Patients also undergo a SSR PET/CT scan during screening and blood sample collection on study.
干预措施: Lutetium Lu 177 Dotatate
Treatment (sunitinib malate, lutetium Lu 177 dotatate)
Patients receive sunitinib malate PO QD from day 1 of lutetium 177 dotatate therapy to 28 days after the last dose of lutetium 177 dotatate in the absence of unacceptable toxicity. Patients also receive lutetium Lu 177 dotatate IV over 30 minutes on day 1 of each cycle. Cycles repeat Q8W for 4 cycles in the absence of unacceptable toxicity. Patients undergo a CT scan and/or MRI throughout the trial. Patients also undergo a SSR PET/CT scan during screening and blood sample collection on study.
干预措施: Magnetic Resonance Imaging
Treatment (sunitinib malate, lutetium Lu 177 dotatate)
Patients receive sunitinib malate PO QD from day 1 of lutetium 177 dotatate therapy to 28 days after the last dose of lutetium 177 dotatate in the absence of unacceptable toxicity. Patients also receive lutetium Lu 177 dotatate IV over 30 minutes on day 1 of each cycle. Cycles repeat Q8W for 4 cycles in the absence of unacceptable toxicity. Patients undergo a CT scan and/or MRI throughout the trial. Patients also undergo a SSR PET/CT scan during screening and blood sample collection on study.
干预措施: Positron Emission Tomography
Treatment (sunitinib malate, lutetium Lu 177 dotatate)
Patients receive sunitinib malate PO QD from day 1 of lutetium 177 dotatate therapy to 28 days after the last dose of lutetium 177 dotatate in the absence of unacceptable toxicity. Patients also receive lutetium Lu 177 dotatate IV over 30 minutes on day 1 of each cycle. Cycles repeat Q8W for 4 cycles in the absence of unacceptable toxicity. Patients undergo a CT scan and/or MRI throughout the trial. Patients also undergo a SSR PET/CT scan during screening and blood sample collection on study.
干预措施: Computed Tomography
Treatment (sunitinib malate, lutetium Lu 177 dotatate)
Patients receive sunitinib malate PO QD from day 1 of lutetium 177 dotatate therapy to 28 days after the last dose of lutetium 177 dotatate in the absence of unacceptable toxicity. Patients also receive lutetium Lu 177 dotatate IV over 30 minutes on day 1 of each cycle. Cycles repeat Q8W for 4 cycles in the absence of unacceptable toxicity. Patients undergo a CT scan and/or MRI throughout the trial. Patients also undergo a SSR PET/CT scan during screening and blood sample collection on study.
干预措施: Biospecimen Collection
Treatment (sunitinib malate, lutetium Lu 177 dotatate)
Patients receive sunitinib malate PO QD from day 1 of lutetium 177 dotatate therapy to 28 days after the last dose of lutetium 177 dotatate in the absence of unacceptable toxicity. Patients also receive lutetium Lu 177 dotatate IV over 30 minutes on day 1 of each cycle. Cycles repeat Q8W for 4 cycles in the absence of unacceptable toxicity. Patients undergo a CT scan and/or MRI throughout the trial. Patients also undergo a SSR PET/CT scan during screening and blood sample collection on study.
干预措施: Sunitinib Malate
结局指标
主要结局
Incidence of adverse events (AEs)
时间窗: Within the first cycle (8 weeks)
Dose-limiting toxicities (DLTs) during the first 8 weeks of the combination of sunitinib malate plus lutetium Lu 177 dotatate and incidence of treatment-emergent AEs during DLT observation period. DLTs will be defined as grade 3 or worse hematologic and non-hematologic toxicity that is considered clinically significant and at least possibly related to lutetium Lu 177 dotatate and sunitinib malate within the first cycle (8 weeks). Safety endpoints will be listed for each dose level and the tabulations of adverse events will also be produced by severity and by relationship to study drug
次要结局
- Progression-free survival (PFS)(The time from first dose to the earlier date of assessment of progression or death by any cause, assessed up to 4 weeks)
- Overall survival (OS)(From the date of first dose to the date of death by any cause, assessed up to 4 weeks)
- Intensity of tumor uptake(Up to 4 weeks)
- Chromogranin A levels(Up to 4 weeks)
- Objective response (ORR)(Up to 4 weeks)
- Duration of response(The time from first documentation of response (CR or PR) until the time of first documentation of disease progression by RECIST v1.1, assessed up to 4 weeks)