Hyperpolarized C-13 Pyruvate as a Biomarker of PI3K/mTOR Pathway Inhibition in Patients With Advanced Solid Tumor Malignancies
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 23
- 试验地点
- 1
- 主要终点
- Signal-to-noise Ratio (Part A)
研究概览
简要总结
This is a single center prospective imaging study investigating the utility of hyperpolarized C-13 pyruvate as a Biomarker of PI3K/mTOR pathway inhibition in patients with advanced solid tumor malignancies. The current protocol will serve as a companion imaging biomarker study paired with therapeutic trials of PI3K/mTOR pathway inhibitors (e.g. CUDC-907, BYL719), as well as a stand-alone protocol for patients treated with standard-of-care therapies inhibiting the PI3K/mTOR signaling pathway (eg. everolimus).
详细描述
This is a single center prospective imaging study investigating the utility of hyperpolarized C-13 pyruvate/metabolic magnetic resonance (MR) imaging. The current protocol will serve as a companion imaging biomarker study paired with therapeutic trials of PI3K/mTOR pathway inhibitors (e.g. CUDC-907, BYL719), as well as a stand-alone protocol for patients treated with standard-of-care therapies inhibiting the PI3K/mTOR signaling pathway (eg. everolimus).
In Part A (run-in feasibility phase), patients will undergo imaging at a single time point, without paired tumor biopsy. There will be no follow up imaging or requirement for treatment with PI3K/mTOR pathway inhibitor. Iterative adjustment of radiofrequency coil geometry and imaging sequences will be undertaken to optimize intra-tumoral hyperpolarized pyruvate/lactate signal-to-noise ratio.
In Part B, patients will undergo paired baseline hyperpolarized C-13 pyruvate imaging + tumor biopsy,then initiate treatment with agent inhibiting the PI3K/mTOR pathway. After 21 days (+/- 14 days), patients will undergo repeat hyperpolarized C-13 pyruvate MR imaging + tumor biopsy. Patients will subsequently be treated with PI3K/mTOR pathway inhibitor until disease progression, unacceptable toxicity, or patient/physician decision to discontinue therapy.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Diagnostic
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Presence of at least one target liver or other intra-abdominal lesion detected by standard staging scans that, in the judgment of Study Investigators, would be amenable to hyperpolarized C-13 pyruvate/metabolic MR imaging: Target lesion must measure >=1.0 cm in long axis diameter on CT or MRI
- •The subject is able and willing to comply with study procedures and provide signed and dated informed consent.
- •Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or
- •Adequate organ function, including creatinine < 1.5 x ULN or estimated creatinine clearance >=500 mL/min (by the Cockcroft Gault equation) and total bilirubin <3x upper limit of normal (ULN).
- •Part B only:
- •No prior local therapy to target lesion.
- •If patient agrees to optional biopsy:
- •Presence of at least one target lesion amenable to percutaneous tumor biopsy in the judgment of Interventional Radiology
- •No history of bleeding diathesis.
- •Patients on anti-coagulation they must be able to safely stop treatment for purposes of tumor biopsy.
- •Planned treatment with agent targeting PI3K/mTOR pathway (either standard of care or investigational agent)
排除标准
- •Patients who because of age, general medical or psychiatric condition, or physiologic status cannot give valid informed consent.
- •Patients unwilling or unable to undergo MR imaging, including patients with contra-indications to MRI, such as cardiac pacemakers or non-compatible intracranial vascular clips.
- •Metallic implant or device that distorts local magnetic field and compromises the quality of MR imaging.
- •Poorly controlled hypertension, defined as systolic blood pressure at study entry greater than 160 mm Hg or diastolic blood pressure greater than 100 mm Hg. The addition of anti-hypertensives to control blood pressure is allowed.
- •Congestive heart failure or New York Heart Association (NYHA) status ≥
- •A history of clinically significant EKG abnormalities, including QT prolongation (QTcF > 500 ms), a family history of prolonged QT interval syndrome, or myocardial infarction (MI) within 6 months of study entry. Patients with rate-controlled atrial fibrillation/flutter will be allowed on study.
- •Any condition that, in the opinion of the Principal Investigator, would impair the patient's ability to comply with study procedures.
研究组 & 干预措施
Part A: Feasibility Run-In
Patients with advanced solid tumor malignancies with at least one liver metastasis will be enrolled with iterative adjustment of coil design to optimize imaging parameters including spatial resolution and signal-to-noise ratio (SNR) of hyperpolarized pyruvate / lactate within the target metastatic lesion(s).
干预措施: Pyruvate (13C) (Drug)
Part A: Feasibility Run-In
Patients with advanced solid tumor malignancies with at least one liver metastasis will be enrolled with iterative adjustment of coil design to optimize imaging parameters including spatial resolution and signal-to-noise ratio (SNR) of hyperpolarized pyruvate / lactate within the target metastatic lesion(s).
干预措施: MRI (Device)
Part B: Biomarker Cohort
Patients with advanced solid tumor malignancies and the presence of at least one liver metastasis amenable to hyperpolarized C-13 pyruvate metabolic MR imaging who are planning on being treated with agent targeting PI3K/mTOR pathway will be enrolled.
干预措施: Pyruvate (13C) (Drug)
Part B: Biomarker Cohort
Patients with advanced solid tumor malignancies and the presence of at least one liver metastasis amenable to hyperpolarized C-13 pyruvate metabolic MR imaging who are planning on being treated with agent targeting PI3K/mTOR pathway will be enrolled.
干预措施: MRI (Device)
结局指标
主要结局
Signal-to-noise Ratio (Part A)
时间窗: 1 day
The Signal-to-noise ratio with respect to intra-tumoral hyperpolarized (HP) C-13 Lactate/Pyruvate (lac/pyr) ratio detected within target liver or other intra-abdominal metastasis in patients with advanced solid tumor malignancies enrolled in the feasibility cohort will be determined
Mean Percent Change From Baseline in Peak Intra-tumoral Hyperpolarized Lactate/Pyruvate Ratio (Part B)
时间窗: Up to 24 months
Descriptive statistics will be used to characterize the mean change from baseline in intra-tumoral HP pyruvate/lactate ratio after initiation of treatment with PI3K/mTOR pathway inhibitor for participants enrolled in the biomarker cohort, along with 95% confidence interval.
次要结局
- Number of Participants With Reported Treatment-related Adverse Events(Up to 24 months)
- Association Between Percent Change From Baseline in Peak Intra-humoral HP Lactate/Pyruvate Ratio on Metabolic MR Imaging With Progression-free Survival (Part B)(Up to 24 months)
- Association Between Percent Change From Baseline in Peak Intra-tumoral Hyperpolarized Lactate/Pyruvate Ratio on Metabolic MR Imaging With Clinical Benefit Rate (Part B)(Up to 24 months)
研究者
Rahul Aggarwal
Assistant Professor
University of California, San Francisco