A Phase I, Open-Label, Dose-finding Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Intravenously Infused SNB-101(as SN-38) in Patients With Advanced Solid Tumors
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 21
- 试验地点
- 3
- 主要终点
- Number of participants with clinically meaningful changes in Vital signs from baseline
研究概览
简要总结
SNB-101 is a novel nano-particle formulation of SN-38, the active metabolite of irinotecan(CPT-11). Study SNB101P01 is a multicenter, open-label, dose escalation, phase 1 study of SNB 101 with its active ingredient SN-38, in participants with advanced solid tumors. Dose escalation will occur using a modified accelerated titration design (ATD).
All participants will receive SNB 101 in different cohorts. SNB 101 will be administered intravenously to participants on day 1 and day 15 of each 28 day treatment cycle until progressive disease, unacceptable toxicity, death, or withdrawal of consent, whichever occurs first.
A Safety Review Committee will determine dose escalation, de-escalation, and modification and the MTD/RP2D based on DLTs and other safety information.
详细描述
Each participant will undergo a screening period, a treatment period, and a follow-up period. Participants will be followed until death, withdrawal of consent, or end of study, whichever occurs first.
During the treatment period, participants will receive SNB-101 (dose range: 5 mg/m2 to 50 mg/m2) intravenously on day 1 and day 15 of each 28 day cycle.
Dose reductions are permitted after the DLT observation period, which occurs during the first 28 days of treatment (cycle 1). Participants may permanently or temporarily (at the investigator's discretion) discontinue SNB-101. If a participant experiences a DLT or unacceptable toxicity, SNB-101 treatment should be interrupted until the observed toxicity returns to baseline or ≤ grade 1 toxicity. The start of the next cycle can be delayed up to 2 weeks at the investigator's discretion.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 19 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients with a histologically or cytologically confirmed, locally advanced or metastatic disease, has progressed after systemic standard of care treatment for advanced disease and is not suitable for complete surgical resection.
- •Patients with measurable or evaluable disease consistent with Response Evaluation Criteria in Solid Tumors version 1.
- •Patients ambulatory with an Eastern Cooperative Oncology Group performance score of 0 or
- •Patients with adequate hematological, renal, and liver function(CTCAE V5.0 grade 1 or lower).
- •Patients with the life expectancy of 3 months or longer.
排除标准
- •Patients homozygous for UGT1A1*28 or UGT1A1*6 alleles.
- •Patients known or suspected intolerance or hypersensitivity to main ingredient or any of the excipients of SNB-
- •Patients with unintentional weight loss >10% within 3 months prior to screening.
- •Patients who are on dialysis.
- •Patients who are positive for HIVs.
- •Patients with a QT interval with Fridericia's correction outside of normal.
- •Patients with intestinal palsy or bowel obstruction.
- •Patients with chronic inflammatory bowel disease.
- •Patients who may require administration of neuromuscular blockers, peripheral muscle relaxants, etc. during the study.
- •Patients who may require lapatinib during the study.
- •Patients who may require attenuated vaccine during the study.
- •Patients who are taking any medication that in the judgement of the investigator could have an effect on the action of SNB-
- •Patients unable to participate in the study as judged by the investigator.
研究组 & 干预措施
Cohort 3
SNB-101 20/32mg/m2 Q2W IV
干预措施: SNB-101 (Drug)
Cohort 1
SNB-101 5/8mg/m2 Q2W IV
干预措施: SNB-101 (Drug)
Cohort 2
SNB-101 10/16mg/m2 Q2W IV
干预措施: SNB-101 (Drug)
Cohort 4
SNB-101 30/48mg/m2 Q2W IV
干预措施: SNB-101 (Drug)
Cohort 5
SNB-101 40/64mg/m2 Q2W IV
干预措施: SNB-101 (Drug)
Cohort 6
SNB-101 45/72mg/m2 Q2W IV
干预措施: SNB-101 (Drug)
Cohort 7
SNB-101 50/80mg/m2 Q2W IV
干预措施: SNB-101 (Drug)
结局指标
主要结局
Number of participants with clinically meaningful changes in Vital signs from baseline
时间窗: up to 18 months(depending on safety variable)
* Vital signs include blood pressure(sitSBP/sitDBP), heart rate, respiratory rate, and body temperature. Change from baseline or previous visit will be described. * After each infusion of SNB-101, vital signs will be monitored every 30 minutes for 3 hours on an outpatient basis. * Descriptive statistics for continuous variables, frequency and percentage for categorical variables
Permanent discontinuation of SNB-101 and dose reduction due to adverse events(AEs)
时间窗: up to 18 months(depending on safety variable)
Definition of permanent discontinuation of SNB-101: 1. Experiencing a DLT or intolerable toxicity during the DLT observation period. 2. Experiencing life-threatening Grade 4 adverse events (AE). 3. Experiencing Grade 2 interstitial lung disease or Grade 4 infusion related reaction/ hypersensitivity. * Descriptive statistics for continuous variables, frequency and percentage for categorical variables
Number of participants with clinically meaningful changes in Laboratory test results from baseline
时间窗: up to 18 months(depending on safety variable)
* Hematology: RBC count, WBC count, hemoglobin, hematocrit, platelets, mean cell volume, mean cell hemoglobin, mean cell hemoglobin concentration, WBC differential count, ANC. * Serum biochemistry: BUN, creatinine, glucose (random), aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, total bilirubin, total protein, albumin, Ca, P, K, Na, Cl, CO2, GGT, and LDH. * Coagulation: prothrombin time and international normalized ratio. * Viral serology: viral serology test for HIV antibody, hepatitis B surface antigen (HBsAg), and hepatitis C virus antibody. The test can be waived for participants who have results within 28 days prior to screening. * Urinalysis: specific gravity, protein, pH, blood, and ketones. * Descriptive statistics for continuous variables, frequency and percentage for categorical variables
Electrocardiogram(ECG) results
时间窗: up to 18 months(depending on safety variable)
* ECG data will be collected at screening, C1D1, C3D1 and EOT. * ECG measurement at C1D1 and C3D1 will be performed after PK sampling at the end of the infusion (90 min.), 2.5 hours and 24 hours after drug administration. * ECG QT interval will be assessed for the safety endpoint(e.g. QTc prolongation) * Descriptive statistics for continuous variables, frequency and percentage for categorical variables
Number of clinically significant Chest radiograph findings(chest x-ray, CXR)
时间窗: up to 18 months(depending on safety variable)
* Number of clinically significant chest radiograph findings from chest x-ray. * Descriptive statistics for continuous variables, frequency and percentage for categorical variables
Dose-limiting toxicity(DLT)
时间窗: up to 18 months(depending on safety variable)
* All participants who take at least 1 dose of SNB-101 will be assessed. * DLTs will be presented by dose group and the MTD determined. \*DLTs : 1\) Hematological toxicity * Grade 4 thrombocytopenia * Grade 3 thrombocytopenia with clinically significant bleeding * Grade 4 neutropenia lasting \> 7 days * ≥ grade 3 febrile neutropenia 2\) Nonhematological toxicity * Any ≥ grade 3 nonhematological toxicity 3\) Liver function abnormalities * Patients who have bone or liver metastasis with the following increases will be considered a DLT: 1. Baseline AST or ALT = 2.5 to 5× ULN, then AST or ALT that increases to \>8× ULN 2. Baseline ALP = 2.5 to 5×ULN, then ALP increases to \>8×ULN 4\) Any toxicity related to SNB-101 that results in a treatment delay of more than 2 weeks.
次要结局
- Volume of distribution(Vd)(4 months)
- Elimination rate constant(4 months)
- Terminal half-life(t1/2)(4 months)
- Time to Cmax(Tmax)(4 months)
- Clearance(CL)(4 months)
- Overall survival(OS)(up to 18 months(depending on subject cycles))
- The objective response rate(ORR)(up to 18 months(depending on subject cycles))
- Progression-free survival(PFS)(up to 18 months(depending on subject cycles))
- Disease control rate(DCR)(up to 18 months(depending on subject cycles))
- Time to progression(TTP)(up to 18 months(depending on subject cycles))
- Area under the plasma concentration-time curve(AUC)(4 months)
- Maximum plasma concentration(Cmax)(4 months)