Clofarabine Therapy in Patients With Locally Advanced or Metastatic Urothelial Carcinoma: a Phase 1/2 Dose-Escalation Study
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- 入组人数
- 50
- 试验地点
- 1
- 主要终点
- Determining the maximum tolerated dose (MTD)
研究概览
简要总结
This phase 1/2 study will evaluate the maximum tolerated dose, efficacy, and safety of clofarabine in patients with advanced or metastatic urothelial cancer.
详细描述
Clofarabine is an antimetabolite chemotherapeutic agent used as a subsequent line of treatment in pediatric patients with leukemia. In preclinical studies, it showed promising results, surpassing the effectiveness of the current standard of care. The study aims to define the maximum tolerated dose of clofarabine in patients with metastatic or locally advanced urothelial carcinoma. It also seeks to characterize the pharmacokinetics of clofarabine and assess the efficacy, safety, and tolerability of the treatment. The study population consists of patients with histologically confirmed urothelial carcinoma and radiologically documented metastatic or unresectable locally advanced disease, who have already received standard-of-care treatment. The study will be performed using a dose-escalation regimen.
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
- •Patients with histologically or cytologically confirmed urothelial carcinoma, radiologically documented metastatic or unresectable locally advanced disease
- •Patients who have already received standard treatment and did not benefit from it, or patients who have refused standard therapy
- •Age ≥ 18 years
- •Eastern Cooperative Oncology Group (ECOG) performance status 0-2
- •Absolute neutrophil count (ANC) greater than or equal to
- •White blood cell (WBC) count greater than 3.
- •Platelets greater than or equal to
- •Hemoglobin greater than 9.0 g/dL.
- •Adequate hepatobiliary function as indicated by the following laboratory values: Total bilirubin ≤ 1.5 x upper limit of normal (ULN); Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN
- •Adequate renal function as indicated by the following laboratory values: Serum creatinine ≤ 1.0 mg/dL; if serum creatinine > 1.0 mg/dL, then the estimated glomerular filtration rate (GFR) must be > 60 mL/min/1.73 m^2 as calculated by the Modification of Diet in Renal Disease (MDRD) equation
- •Adequate cardiac function (NYHA cardiac III-IV excluded)
- •Male and female patients must use an effective contraceptive method during the study and for a minimum of 6 months after study treatment
- •Female patients of childbearing potential must have a negative serum pregnancy test within 2 weeks prior to enrollment
- •Willing and able to provide informed consent
排除标准
- •Received previous treatment with clofarabine
- •Current concomitant chemotherapy, radiation therapy, or immunotherapy
- •Prior radiation therapy to the pelvis
- •Currently participation in other investigational drug studies or having received other investigational drugs within the previous 30 days
- •Have any other severe concurrent disease, or have a history of serious organ dysfunction or disease involving the heart, kidney, liver, or other organ system that may place the patient at undue risk to undergo treatment. In particular: a) New York Heart Association classification stage II, III, or IV congestive heart failure; b) Coronary artery disease or arteriosclerotic cardiovascular disease (angina, myocardial infraction) within 3 months of first dose of study drug; c) Any other primary cardiac disease that, in the opinion of the investigator, increases the risk of ventricular arrhythmia.
- •Patients with a systemic fungal, bacterial, viral, or other infection not controlled (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment).
- •Any medical condition that requires chronic use of oral high-dose corticosteroids (in excess of 1 mg/kg/day) (low-dose corticosteroid for pre-medication purposes are allowed).
- •Any significant concurrent disease, illness, or psychiatric disorder that would compromise patient safety or compliance, interfere with consent, study participation, follow up, or interpretation of study results
- •Diagnosis of another malignancy, unless the patient has been disease-free for at least 5 years following the completion of curative intent therapy with the following exceptions: Patients with treated non-melanoma skin cancer, in-situ carcinoma or cervical intraepithelial neoplasia regardless of disease-free duration are eligible for this study if definitive treatment for the condition has been completed; Patients with organ-confined prostate cancer with no evidence of recurrent or progressive disease based on PSA value are eligible for this study if hormonal therapy has been initiated or a radical prostatectomy has been performed
- •Had currently active gastrointestinal disease, or prior surgery that might affect the ability of the participants to absorb oral Clofarabine.
- •Had prior treatment with a known nephrotoxic drug within 2 weeks of the first dose of study drug, unless the participants had a calculated GFR >30 at 2 time points no <7 days apart during the 2- week period prior to the first dose of study drug.
- •Positive human immunodeficiency virus (HIV) test.
- •Female patients who are pregnant/breastfeeding.
研究组 & 干预措施
Patients with urothelial carcinoma treated with clofarabine
干预措施: Clofarabine (Drug)
结局指标
主要结局
Determining the maximum tolerated dose (MTD)
时间窗: From the start of study drug administration through the first 28 days of dosing (Cycle 1), based on the observed incidence of dose-limiting toxicity (DLT) and evaluation of maximum tolerated dose (MTD)
The objective of the dose selection phase is to determine the maximum tolerated dose (MTD) or confirm that the start dose level of clofarabine is safe. The MTD is defined as the highest dose at which the probability of toxicity remains below the target toxicity threshold. MTD estimation will be based on the observed dose-dependent incidence rate of dose-limiting toxicity (DLT) within the first 28 days of dosing (Cycle 1). Patients eligible for MTD evaluation include: * Those who completed Cycle 1 and took at least 80% of the required total dose of the study drug (protocol-defined dose reductions will not be considered noncompliance). * Those who discontinued during Cycle 1 due to a DLT.
次要结局
- Objective response rate (ORR)(From the date of study treatment start until the date of the best documented objective response (for a maximum duration of 36 months).)
- Duration of response (DOR)(From the date of the first documented objective response of PR or CR, whichever is noted earlier, to disease progression or death (for a maximum duration of 36 months).)
- Progression-free survival (PFS)(From the date of study treatment start until the date of the first observed progression or date of death due to any cause, if death occurs before progression is documented (for a maximum duration of 36 months).)
- Overall survival (OS)(From the date of study treatment start until the date of death due to any cause (for a maximum duration of 36 months).)
- Safety and tolerability endpoints(Day 1 up to 90 days after last dose of study drug.)
- Area under the concentration-time curve (AUC)(Day 1 up to the date of the last dose of study drug.)
- Maximum serum concentration (Cmax) of Clofarabine(Day 1 up to the date of the last dose of study drug.)
研究者
Ekaterina Laukhtina
Dr. Sponsor-Investigator
Medical University of Vienna