Drug- Drug Interaction Study of JI-101 & Everolimus in Advanced Solid Tumors, Expansion Pharmacodynamic Study of JI-101 in Advanced Low Grade Endocrine Tumors, Ovarian Cancers or K-RAS Mutant Colon Cancers
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 19
- 试验地点
- 1
- 主要终点
- Effect of JI 101 on Pharmacokinetics Area Under Curve (AUC) (0-inf) of RAD001
研究概览
简要总结
The study consists of two parts: Drug Interaction (Pharmacokinetic) Phase and Pharmacodynamic Phase
The primary study objective for the Drug Interaction Study is to determine the pharmacokinetic interactions between RAD001 and JI-101.
The primary study objective for the Pharmacodynamic Study is progression-free survival at 2 moths, evaluated separately in each of the three cohorts.
These will include a determination of tumor response using Response Evaluation Criteria in Solid Tumors (RECIST) Criteria and an assessment of ephrinB4 expression in blood samples.
Secondary objectives are to determine safety and tolerability of JI-101. The investigational products are everolimus (42-O-(2-hydroxyethyl) rapamycin) and JI-101 (1-[1-(2-amino-pyridin-4-ylmethyl)-1H-indol-4-yl]-3-(5-bromo-2 methoxy-phenyl)-urea)
Eligible patients meeting all study entry criteria will be enrolled in the study. For the Drug Interaction study, patients with solid tumors will receive a single dose (10 mg) of Everolimus by mouth on Day 1 and Day 8 and JI-101 capsules (200 mg) by mouth on Day 8 and Day 15. For the Pharmacodynamic Study, all patients will receive JI-101 capsules by mouth (200 mg BID) for 28 day treatment cycles.
详细描述
This is a multi-center, non-randomized, open-label study to evaluate the safety and efficacy of RAD001 and JI-101 in patients with solid tumors.
Patients will complete all Screening evaluations within 21 days of Study Cycle 1Day 1. All patients will provide written Informed consent and Health Insurance Portability and Accountability Act (HIPAA) authorization before any procedures or assessments are initiated for the purposes of the protocol.
For the Drug Interaction Study, Everolimus will be administered to eligible patients at Cycle 1 Day 1 and blood will be drawn for pharmacokinetic analyses prior to dosing and at 0.5, 1, 2, 4, 6, 8, 10, and 24 hours after dosing. On Day 8, Everolimus and JI-101 will be administered and blood will be drawn for pharmacokinetic analyses prior to dosing and at 0.5, 1, 2, 4, 6, 8, 10, and 24 hours after dosing. On Day 15, JI-101 will be administered and blood will be drawn for pharmacokinetic analyses prior to dosing and at 0.5, 1, 2, 4, 6, 8, 10, and 24 hours after dosing. Patients will continue to receive JI-101(200 mg BID) for 28 day treatment cycles. Patients in the Drug Interaction Study will also receive CT scans prior to screening and every 2 treatment cycles.
For the Pharmacodynamic Study, JI-101 will be dispensed to eligible patients at Cycle 1 Day 1. JI-101 will be administered (200 mg BID) for 28 day treatment cycles. PET and CT scans will be performed prior to commencing treatment if it is standard of care. A CT scan will be performed otherwise. Patients will return to the study site every 2 cycles to complete safety assessments with radiologic tumor assessments (CT and/or PET). Adverse events will be monitored following the first administration of investigational product for the duration of the patient's participation in this study. Archival tissue will be collected for detection of mutations in relevant pathways and development of assays to study modulation of pathways that are targeted by JI-101.
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 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Male or female, ≥18 years of age
- •For the Pharmacokinetic Drug Interaction Study: Histologically or cytologically confirmed advanced solid tumors that are refractory to all standard of care therapy or for whom no standard therapy is available, or for whom other standard therapies the patient has denied. For the Pharmacodynamic Study: Histologically or cytologically confirmed metastatic/advanced ovarian carcinoma or metastatic/advanced KRAS mutant colorectal cancer or metastatic/advanced Head and neck squamous cell cancer (HNSCC) that are refractory to all standard therapies therapy or for whom no standard therapy is available, or for whom other standard therapies the patient has denied.
- •At least one measurable tumor as defined by RECIST
- •Minimum of 4 weeks since any major surgery, completion of radiation, or completion of all prior systemic anticancer therapy
- •Eastern Cooperative Oncology Group (ECOG) of 0 to 2
- •Organ &marrow function as defined in the protocol.
- •No evidence of preexisting uncontrolled hypertension as documented by two baseline blood pressure readings taken at least 1 hour apart
- •Clinically euthyroid
- •Normal range cardiac function
- •For female patients of child-bearing potential, a negative serum pregnancy test at Screening.
- •Current use of an acceptable form of double-barrier birth control
- •Have provided written informed consent
排除标准
- •Known brain or other central nervous system metastases metastases that are not stable for 3 months or longer
- •Active peptic ulcer disease, inflammatory bowel disease, ulcerative colitis, or other gastrointestinal conditions with increased risk of perforation.
- •Major surgery, radiotherapy, chemotherapy, or cytokine therapy within 28 days of Study Day 0;
- •History of intratumoral bleeding or evidence of bleeding diathesis or coagulopathy
- •Female patients who are pregnant, planning a pregnancy, or who are breastfeeding
- •Known allergy or hypersensitivity to JI-101 or everolimus or any component of the investigational products
- •Use of an investigational drug/device/biologic within 28 days of Study Day 0
- •Current drug or alcohol abuse or history of drug or alcohol abuse within the past two years
- •Known history of or serologic positivity for the Hepatitis B Virus (HBV), or the Hepatitis C Virus (HCV), or for the human immunodeficiency virus (HIV)
- •History of cardiac abnormalities
- •Gastrointestinal (GI) abnormalities
- •Use of concomitant medications that prolong the QT/QTc interval within 14 days prior to Study Day 0
- •History of cerebrovascular accident including transient ischemic attack within the past 6 months
- •History of pulmonary embolism or deep vein thrombosis within the past 6 months
- •History of significant retinopathy or any progressive eye disease that could lead to severe loss of visual acuity or visual field loss during the study period
- •Treatment with heparin or heparin analogs
- •Inability or unwillingness to meet the requirements of the study
- •Other current active malignancy or history of malignancy within the past five years, except for cervical carcinoma in situ, basal cell carcinoma that has been surgically removed, or prostate cancer that is being managed with watchful waiting.
- •Any clinically significant abnormal finding at screening that the investigator judges would interfere with study participation
研究组 & 干预措施
Pharmacokinetic Arm
Patients going on Pharmacokinetic arm will receive JI-101 & Everolimus (4 patients only)
干预措施: JI-101 (Drug)
Pharmacokinetic Arm
Patients going on Pharmacokinetic arm will receive JI-101 & Everolimus (4 patients only)
干预措施: Everolimus (Drug)
Pharmacodynamic arm
Patients going on the Pharmacodynamic study will receive JI-101 only.
干预措施: JI-101 (Drug)
结局指标
主要结局
Effect of JI 101 on Pharmacokinetics Area Under Curve (AUC) (0-inf) of RAD001
时间窗: pre-dose and at 0.5, 1, 2, 4, 6, 8, 10, and 24 hours after dosing (Cycle 1 Day 1 for RAD001 alone and Cycle 1 Day 8 for RAD001 + JI-101
Determine the mean percent change that JI-101 has on the peak concentration as determined by calculating the AUC (0-inf) of RAD001 in the presence and absence of JI-101
Effect of RAD001 on Pharmacokinetics AUC(0-inf) of JI-101
时间窗: pre-dose and at 0.5, 1, 2, 4, 6, 8, 10, and 24 hours after dosing (Cycle 1 Day 8 for RAD001 + JI101 and Cycle 1 Day 15 for JI-101 alone
Determine the mean percent change that RAD001 has on the peak concentration as determined by calculating the AUC (0-inf) of JI101 in the presence and absence of RAD001
Progression Free-Survival in the Ovarian Cancer Cohort
时间窗: 2 months
progression-free survival at 2 months. We define progression as using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), to detect a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
Tumor Response in the Ovarian Cancer Cohort
时间窗: 2 years
Response Rate determined by the sum of patients achieving complete or partial response to JI-101 as defined by Response Evaluation Criteria in Solid Tumors
次要结局
- Safety and Tolerability of JI-101(2 years)
- Tumor Response(2 years)