Phase I-II Clinical Trial on Tolerability and Bioavailability of Utidelone Capsule in Patients With Advanced Solid Tumors
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 入组人数
- 84
- 试验地点
- 11
- 主要终点
- Maximum Tolerated Dose, MTD
研究概览
简要总结
This study has three parts. Part 1 is a dose-escalation trial, Part 2 is a pharmacokinetic comparison and food effect study, and Part 3 is extended trial of combination of utidelone capsule and capecitabine. The primary objectives are 1. To evaluate the safety and tolerability of utidelone capsules in patients with advanced solid tumors and to determine the Maximum Tolerated Dose (MTD) and Dose Limiting Toxicity (DLT). 2. To evaluate the objective response rate in patients with advanced metastatic breast cancer treated with the combination of utidelone capsule and capecitabine. The secondary objectives are: 1. to evaluate the absolute bioavailability of utidelone capsules relative to utidelone injection; 2. to evaluate the pharmacokinetic profile of utidelone capsules in patients with advanced solid tumors; 3. to preliminarily evaluate the efficacy and safety of utidelone capsules in patients with advanced solid tumors; and 4. to recommend doses and dosing regimens for subsequent clinical trials. 5. To evaluate the Progression-Free Survival (PFS), safety and pharmacokinetics of utidelone capsule combined with capecitabine in the treatment of patients with advanced metastatic breast cancer.
详细描述
Part 1 is a dose-escalation trial, and it's an open design; Part 2 is a pharmacokinetic comparison and food effect study, and it's an open, controlled study;Part 3: Extended trial of combination of utidelone capsule and capecitabine.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •All inclusion criteria must be met for enrollment:
- •Patients who have fully understood the objectives, content, process of the study and possible adverse events, voluntarily serves as a participant and signs the informed consent form.
- •Part 1 and Part 2: Patients with definitive histopathological diagnosis of advanced solid tumors. Part 3: Patients were diagnosed with advanced metastatic breast cancer by pathology and/or cytology.
- •Part 1 and Part 2: Male or female participants aged ≥18 and ≤65, Part 3: Male or female participants aged ≥18 and ≤70, with ECOG performance status scored 0-
- •Expected survival time ≥ 12 weeks;
- •At least one measurable lesion present according to RECIST 1.1 criteria.
- •Baseline routine blood tests within 1 week prior to enrollment is normal (not received blood transfusions or hematopoietic-stimulating factors within 14 days), with CTCAE grade ≤1 (based on normal values at each site's laboratory): a) Neutrophil count (ANC) ≥ 1.5 × 109/L; b) platelet count (PLT ) ≥ 100 × 109/L; c) Hemoglobin ≥9.0 g/dL.
- •Liver and kidney function test results are normal within 1 week prior to enrollment, with CTCAE grade ≤1 (based on normal values at each site's laboratory): a) Total bilirubin (TBIL) ≤ 1.5× the upper limit of normal value (ULN); b) Serum Glutamic Pyruvic Transaminase/Alanine Aminotransferease (SGPT /ALT) ≤ 2.5× ULN (Part 3 allowed ≤5×ULN in patients with liver metastases); c) Serum Glutamic-oxaloacetic Transaminase/Aspartate Aminotransferase (SGOT /AST) ≤ 2.5× ULN (Part 3 allowed ≤5×ULN in patients with liver metastases); d) Creatinine clearance (Ccr) ≥60 ml/min.
- •Patients with no functional disorders of major organs.
- •Fertile males and females of childbearing potential must agree to use effective contraception (so do their partners, using hormonal or barrier contraception, or abstinence) during the study and within at least 6 months after the last dose. The blood or urine pregnancy test for female patients of childbearing potential prior to enrollment must be negative.
- •Part 3: breast cancer patients who had received ≤4 previous chemotherapy regimens (adjuvant chemotherapy/neoadjuvant chemotherapy was considered as one chemotherapy regimen);
- •Part 3: history of prior treatment with at least one anthracycline or one taxane as neoadjuvant/adjuvant or advance therapy or both.
排除标准
- •Meet any exclusion criteria will be excluded from the study:
- •Patients who have received non-investigational anti-tumor therapies (such as chemotherapy, radiotherapy, immunotherapy, biological therapy or traditional Chinese medicine treatment) within 4 weeks prior to study drug administration.
- •Nitrosoureas or mitomycin C: within 6 weeks prior to study drug administration;
- •Oral fluoropyrimidines and small molecule targeted agents: within 2 weeks or 5 half lives of the drug prior to study drug administration (whichever is longer);
- •Traditional Chinese medicine with anti tumor indications and endocrine therapy for breast cancer: within 2 weeks prior to study drug administration.
- •Participants with severe hypersensitivity to castor oil (this criteria is applicable to Part 2 of the study), and Participants who had hypersensitivity reaction caused by previous anti-microtubule drugs.
- •Patients with uncontrollable brain metastases (brain metastatic lesion confirmed by examination within 2 months after radiotherapy or other localized treatment); patients with uncontrollable bone metastases (patients who have had fracture or have the risk of fracture in recent days, patients who need surgery or localized radiotherapy in recent days, patients with other critical conditions)
- •Patients with serious comorbidities, such as severe heart disease, cerebrovascular disease, uncontrolled diabetes, uncontrolled hypertension, severe infections, active peptic ulcers, etc.
- •Patients with mental illnesses which are hard to control, patients who lack legal capacity or have limited legal capacity.
- •Patients with gastrointestinal diseases such as esophageal obstruction, pyloric obstruction, intestinal obstruction, or who are post-operative of gastrointestinal resection, or who have difficulty in swallowing due to other factors, interfering with oral administration and absorption of the drug.
- •Patients with active hepatitis B infections.
- •Patients with peripheral neuropathy grade>1 within 4 weeks prior to enrollment (NCI CTCAE 5.0).
- •Patients who still experience ≥ Grade 2 acute toxicities caused by previous anti-tumor therapies (e.g. chemotherapy, radiotherapy, immunotherapy, biological therapy or TCM treatment) prior to enrollment (NCI-CTCAE 5.0, except alopecia).
- •Patients who have undergone any major surgery or have major trauma within 4 weeks prior to administration of the investigational product or are expected to undergo major surgery during the treatment.
- •Patients who have participated in another clinical trial or have received other investigational treatments within 4 weeks prior to administration of the investigational product.
- •Patients who, in the opinion of the investigator, are not suitable to participate in this study.
- •Part 3: other malignant tumors within 5 years before enrollment, excluding cured cervical carcinoma in situ, skin basal cell carcinoma or skin squamous cell carcinoma, thyroid papillary carcinoma;
- •Part 3: previous or current capecitabine therapy (except if capecitabine was used in neoadjuvant/adjuvant therapy and progression occurred > 12 months after completion of treatment, inclusion was allowed);
- •Part 3: patients with previous fluorouracil medication history with severe allergy or known dihydropyrimidine dehydrogenase (DPD) deficiency;
- •Part 3: previous or current use of utidelone (including utidelone injection and utidelone capsule); 17) Part 3: pregnant or lactating patients; 18) Part 3: uncontrolled pleural effusion, pericardial effusion or ascites (drainage once a month or more); 19) Part 3: a history of immunodeficiency, including positive HIV antibody test, other acquired or congenital immunodeficiency diseases, or a history of organ transplantation.
研究组 & 干预措施
Utidelone Capsule combination with Capecitabine
Dosage:
Utidelone capsule: 60 mg/m2/d, administered once a day on an empty stomach, continuously for 5 days from day 1 to day 5, with a treatment cycle of 21 days.
Capecitabine: 1000mg/m2, twice a day (daily dose 2000mg/m2), once in the morning and once in the evening, taken orally within 30 minutes after meals. It is administered continuously for 14 days from day 1 to day 14, with a 21 day treatment cycle.
干预措施: Utidelone Capsule (Part 3) (Drug)
Utidelone Capsule combination with Capecitabine
Dosage:
Utidelone capsule: 60 mg/m2/d, administered once a day on an empty stomach, continuously for 5 days from day 1 to day 5, with a treatment cycle of 21 days.
Capecitabine: 1000mg/m2, twice a day (daily dose 2000mg/m2), once in the morning and once in the evening, taken orally within 30 minutes after meals. It is administered continuously for 14 days from day 1 to day 14, with a 21 day treatment cycle.
干预措施: Capecitabine (Drug)
Utidelone Capsule (Part 1)
Utidelone Capsule, available as 10 mg/capsule and 15 mg /capsule. Doses between 50 mg/m2/d and 120 mg/m2/d administered orally will be explored. Patients will be dosed for 5/7 consecutive days in a 21 day cycle.
干预措施: Utidelone Capsule (Part 1) (Drug)
结局指标
主要结局
Maximum Tolerated Dose, MTD
时间窗: 8 months
The maximum tolerated dose (MTD) is defined as the highest dose tested in which none or only one patient experienced DLT attributable to the study drug(s), when 6 patients were treated at that dose and are evaluable for toxicity. The MTD is one dose level below the lowest dose tested in which 2 or more patients experienced DLT attributable to the study drug(s).
Dose-Limiting Toxicity, DLT
时间窗: 8 months
DLT is observed during Cycle 1 in the dose escalation trial. Any toxicity meeting the criteria outlined in the protocol, at least possibly related to study drug (i.e. definitely, probably, or possibly attributed), will be considered a DLT.
Objective Response Rate, ORR
时间窗: 6 weeks
To evaluate the objective response rate (ORR) of utidelone capsule combined with capecitabine in the treatment of patients with advanced metastatic breast cancer
次要结局
- Time to peak drug concentration-Tmax(8 months)
- the time required for plasma concentration of a drug to decrease by 50%-t1/2(8 months)
- Objective Response Rate-ORR(12 months)
- Treatment-related Adverse Event-TRAE(12 months)
- Progression-Free Survival, PFS(6 weeks)
- Bioavailability of Utidelone Capsule(8 months)
- Maximum (or peak) serum concentration-Cmax(8 months)
- the area under the concentration-time curve from dosing (time 0) to time t-AUC0-t(8 months)