A Pilot Study of HIF-Mediated Gene Expression Changes in Casdatifan-Treated Refractory Renal Cell Carcinoma
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 12
- 试验地点
- 2
- 主要终点
- To determine the change in expression of predefined HIF2-regulated target genes in metastatic tumor tissue following casdatifan therapy in a refractory ccRCC population.
研究概览
简要总结
This is a single-institution, pilot study of oral casdatifan, a selective HIF-2α inhibitor, in patients with metastatic clear cell renal cell carcinoma refractory to prior IO- and VEGF-based therapies. This phase I trial evaluates the effects of casdatifan on certain genes linked to kidney cancer growth and tests it for the treatment of clear cell renal cell cancer that has not responded to previous treatment (refractory) and that has spread from where it first started (primary site) to other places in the body (metastatic).
Casdatifan may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
详细描述
PRIMARY OBJECTIVE:
I. To determine the change in expression of predefined HIF2-regulated target genes in metastatic tumor tissue following casdatifan therapy in a refractory clear cell renal cell carcinoma (ccRCC) population.
SECONDARY OBJECTIVES:
I. To assess changes in global tumor gene expression following casdatifan treatment.
II. To identify differences in baseline and on-treatment HIF-mediated gene expression between objective responders and non-responders.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 100 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Signed and dated written informed consent.
- •Male or female ≥ 18 years of age on the day of signing informed consent.
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
- •Histologically confirmed metastatic clear cell renal cell carcinoma (ccRCC)
- •Patients must have received at least one immune oncology (IO) agent and at least one VEGF-targeted therapy (alone or in combination)
- •Measurable tumor burden which can be followed by computed tomography (CT) scan or magnetic resonance imaging (MRI), based on RECIST 1.1 as assessed by the local site investigator
- •At least one metastatic lesion that is amenable to percutaneous biopsy
- •Adequate organ and bone marrow function resulted ≤ 28 days prior to first dose of protocol-indicated treatment:
- •Absolute neutrophil count (ANC) ≥ 1500/µL.
- •Platelets ≥ 100,000/µL.
- •Hemoglobin ≥ 10.0 g/dL or ≥ 6.2 mmol/L.
- •Estimated glomerular filtration rate (eGFR) ≥ 30 mL/min (as calculated by the Cockcroft-Gault Formula or calculated/measured by an alternative established institutional standard consistently applied across participants).
- •Total bilirubin ≤ 1.5 times institutional upper limit of normal (ULN), or direct bilirubin ≤ ULN for participants with total bilirubin > 1.5 xULN.
- •AST (SGOT) and ALT (SGPT) ≤ 2.5 times institutional upper limit of normal (ULN)
- •Women must not be breastfeeding and further agree to not breastfeed during study treatment; and for at least 7 days after patient's final dose of casdatifan.
- •A woman of childbearing potential (WOCBP) - see Appendix 3 for definition of WOCBP - must have a negative serum or urine pregnancy test during screening within 28 days prior to receiving first dose of protocol-indicated treatment, and must agree to follow instructions for using acceptable contraception (Appendix 3) from the time of signing consent, and until at least 7 days after her final dose of casdatifan.
- •Men must refrain from donating sperm for at least 7 days after patient's final dose of casdatifan.
- •A man able to father children (see Appendix 3 for definition) who is sexually active with a WOCBP must agree to follow instructions for using acceptable contraception (Appendix 3), from the time of signing consent, and until at least 7 days after his final dose of casdatifan.
- •No exercise-induced desaturation on a 6-minute walk test, defined as a blood oxygen saturation by pulse oximetry ≤ 88%.
- •No active pneumonitis at screening as assessed by CT scan.
- •No medical history of severe chronic obstructive pulmonary disease (COPD).
- •If a participant has CNS metastases the participant must meet the following criteria:
- •Participants with previously treated brain metastases may participate provided they are clinically stable and without steroid treatment for at least 14 days prior to the first dose of study treatment. Participants with carcinomatous meningitis are excluded.
排除标准
- •Prior treatment with HIF 2α inhibitors (e.g. belzutifan or related agents)
- •Is currently participating in or within 2 weeks prior to receiving first dose of study treatment in a study of an investigational agent or investigational device.
- •Participants who have entered the follow-up phase of an investigational study may participate as long as it has been 2 weeks after the last dose or last exposure to the previous investigational agent or investigational device.
- •Known severe hypersensitivity (≥ Grade 3) to any of the excipients of casdatifan.
- •History of myocarditis or pericarditis or other known underlying heart disease that is clinically significant by investigator judgment (for example, cardiomyopathy, congestive heart failure with New York Heart Association [NYHA] functional classification III or IV, symptomatic arrhythmia not controlled by medication, unstable angina, history of acute myocardial infarction). History of cerebrovascular accident (including TIA) within the past 6 months (24 weeks) prior to starting study treatment.
- •Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection/sepsis, interstitial lung disease, recent hospitalizations with unresolved symptoms, poorly controlled hypertension, or psychiatric illness/social situations that would limit compliance with study requirements.
- •Inability to swallow study treatment.
- •Contraindications to biopsy (e.g. bleeding diathesis, uncorrectable coagulopathy)
研究组 & 干预措施
Casdatifan
Casdatifan will be taken orally at a fixed dose of 100 mg once daily, with or without food, on a continuous schedule beginning on Cycle 1, Day 1. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan or MRI, tumor biopsy and blood sample collection throughout the study.
干预措施: casdatifan (Drug)
结局指标
主要结局
To determine the change in expression of predefined HIF2-regulated target genes in metastatic tumor tissue following casdatifan therapy in a refractory ccRCC population.
时间窗: 1 year (From baseline to on-treatment biopsy)
A serial biopsy design, incorporating biopsies at baseline, on-treatment, and disease progression, enables longitudinal evaluation of the HIF-2α transcriptional program and characterization of adaptive or resistance-associated gene expression changes emerging during therapy.
To determine the change in expression of predefined HIF2-regulated target genes in metastatic tumor tissue following casdatifan therapy in a refractory ccRCC population.
时间窗: 1 year
A serial biopsy design, incorporating biopsies at baseline, on-treatment, and disease progression, enables longitudinal evaluation of the HIF-2α transcriptional program and characterization of adaptive or resistance-associated gene expression changes emerging during therapy.
次要结局
- To assess changes in global tumor gene expression following casdatifan treatment.(1 year (From baseline to on-treatment biopsy))
- To identify differences in baseline and on-treatment HIF-mediated gene expression between objective responders and non-responders.(1 year (From baseline to on-treatment biopsy))
- To assess changes in global tumor gene expression following casdatifan treatment.(1 year)
- To identify differences in baseline and on-treatment HIF-mediated gene expression between objective responders and non-responders.(1 year)
研究者
Brian Rini
Assistant Professor of Medicine
Vanderbilt-Ingram Cancer Center