Phase 0 Pharmacodynamic Study of the Effects of Itraconazole on Tumor Angiogenesis and the Hedgehog Pathway in Early-stage Non-small Cell Lung Cancer
试验速览
- 阶段
- 早期 1 期
- 状态
- 已完成
- 入组人数
- 13
- 试验地点
- 1
- 主要终点
- Changes in Tumor Tissue Microvessel Density [MVD] From Baseline
研究概览
简要总结
The purpose of this study is to determine the pharmacodynamics effects of itraconazole in early-stage non-small cell lung cancer.
详细描述
This is a phase 0 clinical trial. While clinical data including safety will be recorded, the principal outcomes are pharmacodynamic endpoints. Specifically, the investigators seek to identify: (1) effects of itraconazole on tumor angiogenesis, (2) effects of itraconazole on the Hh pathway, (3) biomarker predictors of these effects, (4) the correlation between itraconazole pharmacokinetics and these effects, (5) the correlation between different biomarkers.
Up to 15 eligible patients with previously diagnosed or suspected NSCLC planned for resection will undergo a study-specific core needle biopsy, imaging (dynamic contrast enhanced [DCE]-, diffusion weighted imaging [DWI]-, and arterial spin labeling [ASL] magnetic resonance imaging [MRI]), skin punch biopsy, and collection of peripheral blood. Subjects will then receive itraconazole 600 mg PO daily for 7-10 days, following which they will undergo repeat imaging, skin biopsy, and blood collection. Subsequently they will undergo surgical resection. Due to the safety profile of itraconazole when used as an antifungal agent , all histologic subtypes of NSCLC will be eligible for the trial. The itraconazole dose of 600 mg, higher than an anti-angiogenic dose, has been shown to inhibit the Hedgehog (Hh) pathway.
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 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Histologically or cytologically proven NSCLC planned for surgical resection. All NSCLC histologic subtypes are eligible. Alternatively, patients in whom a diagnosis of NSCLC is highly suspected based on history and imaging studies and who are, therefore, scheduled for diagnostic biopsy and/or surgical resection will also be eligible for screening, enrollment, and study treatment if they meet all additional eligibility criteria. In the event that biopsies do not confirm NSCLC, such patients will be removed from study but monitored for any adverse events resulting from study participation.
- •No prior therapy but planned for surgical resection
- •Age ≥ 18 years.
- •ECOG (Eastern Cooperative Oncology Group) 0-2 performance status
- •Adequate organ function as defined below:
- •total bilirubin within normal institutional limits
- •AST (Aspartate Aminotransferase) (SGOT)/ALT (Alanine Aminotransferase) (SPGT) ≤ 2.5 X institutional upper limit of normal
- •creatinine ≤ 2 X institutional upper limit of normal
- •Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 90 days following completion of therapy. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.
- •6.1 A female of child-bearing potential is any woman (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria:
- •Has not undergone a hysterectomy or bilateral oophorectomy; or
- •Has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months).
- •Ability to understand and willingness to sign a written informed consent.
排除标准
- •Subjects may not be receiving any investigational agents that would confound interpretation of study pharmacodynamic endpoints.
- •History of allergic reactions attributed to itraconazole or to compounds of similar chemical or biologic composition to itraconazole.
- •Uncontrolled, concurrent medical illness.
- •Active hepatitis or symptomatic liver disease.
- •History of or current evidence of uncontrolled cardiac ventricular dysfunction (congestive heart failure) or NYHA (New York Heart Association) Class III or IV heart failure.
- •Current use of medications significantly affecting metabolism of itraconazole (certain anti-convulsants, corticosteroids). See 3.5 Drug Interactions in protocol.
- •Current evidence of hyperthyroidism (which would increase metabolism of itraconazole).
- •Pregnant or lactating female or any female trying to get pregnant.
- •Claustrophobia that would interfere with MRI studies anticipated to last 45-50 minutes.
- •Metal implants deemed at risk for migration during MRI studies.
- •CrCl (Creatinine clearance) < 45 mL/min (increased risk of nephrogenic systemic fibrosis [NSF] from MRI Gadolinium contrast).
- •Known allergy to MRI contrast.
研究组 & 干预措施
Itraconazole
600 mg twice daily for 10-14 days
干预措施: Itraconazole (Drug)
结局指标
主要结局
Changes in Tumor Tissue Microvessel Density [MVD] From Baseline
时间窗: Baseline and Post Treatment (after 7-10 days of itraconazole bid)
Images of DAPI (4',6-Diamidino-2-Phenylindole) , CD31 (cluster of differentiation 31 ), and CD34 (cluster of differentiation 34) were taken from the same field of view and then merged.
次要结局
- Change in HIF1α From Baseline(Baseline and Post Treatment (after 7-10 days of itraconazole bid))
- Change in VEGFR2 From Baseline(Baseline and Post Treatment (after 7-10 days of itraconazole bid))
- Change in Phospho-VEGFR2 From Baseline(Baseline and Post Treatment (after 7-10 days of itraconazole bid))
- Mean Percent Change in Other Plasma Cytokine From Baseline to Post-Treatment(Baseline and Post Treatment (after 7-10 days of itraconazole bid))
- Mean Percent Change in Angiogenic Cytokines From Baseline(Baseline and Post Treatment (after 7-10 days of itraconazole bid))
- Changes in Perfusion (Ktrans)(Baseline and Post Treatment (after 7-10 days of itraconazole bid))
- Number of Participants With Tumor SMO (Smoothened) Gene Mutations, GLI2 and CCND1 Copy Number, PI3K-mTOR Pathway Activation(Baseline and Post Treatment (after 7-10 days of itraconazole bid))
- Change in Tumor Tissue GLI1, SHH and PTCH1 Levels From Baseline(Baseline and Post Treatment (after 7-10 days of itraconazole bid))
- Change in Skin Biopsy GLI1 Levels From Baseline(Baseline and Post Treatment (after 7-10 days of itraconazole bid))
- Change in Skin Biopsy SHH Levels From Baseline(Baseline and Post Treatment (after 7-10 days of itraconazole bid))
- Change in Skin Biopsy PTCH1 Levels From Baseline(Baseline and Post Treatment (after 7-10 days of itraconazole bid))
- Number of Participants With Tumor Cell Proliferation/Apoptosis(Baseline and Post Treatment (after 7-10 days of itraconazole bid))
- Itraconazole Levels in Post-treatment Serum(Post Treatment (after 7-10 days of itraconazole bid))
- Itraconazole Levels in Tumor Tissue(Baseline and Post Treatment (after 7-10 days of itraconazole bid))
- Itraconazole Levels in Skin Biopsy(Baseline and Post Treatment (after 7-10 days of itraconazole bid))
研究者
David E Gerber
Professor of Medicine
University of Texas Southwestern Medical Center