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临床试验/NCT01833546
NCT01833546已完成1 期

A Japanese Single Center, Open-label, Phase I Trial of TH-302 Given Intravenously to Subjects With Solid Tumors as Monotherapy or to Subjects With Advanced Pancreatic Cancer in Combination With Gemcitabine

Merck KGaA, Darmstadt, Germany1 个研究点 分布在 1 个国家目标入组 20 人开始时间: 2013年4月18日最近更新:
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适应症
干预措施
相关药物

试验速览

阶段
1 期
状态
已完成
入组人数
20
试验地点
1
主要终点
Number of Participants Who Experienced Any Dose-Limiting Toxicity (DLT) During First Cycle - Day 1 to 28
研究概览研究设计入排标准研究组 & 干预措施结局指标研究者研究点记录与标识符相似试验

研究概览

简要总结

This is a Japanese Phase 1, open-label, and dose-escalating trial of TH-302 as monotherapy in subjects with solid tumors and in combination with gemcitabine in subjects with pancreatic cancer.

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
20 Years 至 —（Adult, Older Adult）
性别
All
接受健康志愿者
否

入选标准

  • •At least 20 years of age
  • •Signed written informed consent form
  • •Histologically or cytologically confirmed advanced or metastatic solid tumor previously treated with one or more standard treatment regimen(s) or for which no effective therapy is available
  • •Histologically or cytologically confirmed locally advanced unresectable or metastatic pancreatic adenocarcinoma previously untreated with chemotherapy or systemic therapy
  • •Recovered from toxicities of prior anti-cancer treatment to Grade 1 or less
  • •Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
  • •Life expectancy of at least 3 months
  • •Acceptable liver function, renal function, hematologic status and coagulation status as defined in the protocol
  • •No clinically significant abnormalities in urinalysis
  • •Effective contraception for both male and female subjects if the risk of conception exists
  • •Other inclusion criteria apply

排除标准

  • •Prior anti-cancer treatment with more than 3 myelosuppressive cytotoxic chemotherapy regimens
  • •Prior treatment with gemcitabine for their advanced or metastatic pancreatic cancer, except for radiosensitizing doses of gemcitabine
  • •Prior radiotherapy to more than 30 percent of the bone marrow within 6 months prior to the trial entry
  • •Cardiac disease with New York Heart Association (NYHA) Class 3 or 4, within 6 months prior to the trial entry
  • •Clinically significant (that is, active) cardiovascular disease
  • •Seizure disorders requiring anticonvulsant therapy
  • •Known brain, leptomeningeal or epidural metastases (unless previously treated and well controlled for at least 3 months at the trial entry)
  • •Previously treated malignancies other than the current disease for at least 5 years at the trial entry
  • •Severe chronic obstructive or other pulmonary disease major surgery, within 4 weeks prior to the trial entry, without complete recovery
  • •Active, uncontrolled bacterial, viral, or fungal infections, requiring systemic therapy
  • •Anti-cancer treatment prior to trial entry
  • •Participation in an investigational drug or device trial within 4 weeks prior to the trial entry
  • •Known infection with human immunodeficiency virus (HIV), Hepatitis B, or Hepatitis C
  • •A history of allergic reactions
  • •Taking a medication that is either moderate or strong inhibitor or inducer of cytochrome P450 (CYP)3A4 or is a sensitive substrate of other cytochrome P450
  • •Pregnancy or lactation period
  • •Concomitant disease or condition that could interfere with the conduct of the trial, or that would, in the opinion of the Investigator, pose an unacceptable risk to the subject in this trial
  • •Unwillingness or inability to comply with the trial protocol for any reason
  • •Legal incapacity or limited legal capacity
  • •Other exclusion criteria apply

研究组 & 干预措施

Evofosfamide 240 mg

Experimental

干预措施: Evofosfamide (Drug)

Evofosfamide 340 mg

Experimental

干预措施: Evofosfamide (Drug)

Evofosfamide 480 mg

Experimental

干预措施: Evofosfamide (Drug)

Evofosfamide 340 mg + Gemcitabine

Experimental

干预措施: Evofosfamide (Drug)

Evofosfamide 340 mg + Gemcitabine

Experimental

干预措施: Gemcitabine (Drug)

结局指标

主要结局

Number of Participants Who Experienced Any Dose-Limiting Toxicity (DLT) During First Cycle - Day 1 to 28

时间窗: Day 1 up to Day 28 of Cycle 1

A DLT was defined as any of the following toxicities at any dose level that occurred during the first cycle, and were considered to be related to the study drug by the Investigator or the Sponsor: - Grade 3 or Grade 4 non-hematological toxicity, except for Grade 3 or Grade 4 nausea, vomiting and diarrhea, - Grade 3 or higher skin reactions or mucosal toxicities, - Febrile neutropenia, - Grade 3 alanine aminotransferase (ALT)/aspartate aminotransferase (AST) elevation lasting more than 7 days, - Grade 4 neutropenia lasting more than 5 days, - Grade 4 thrombocytopenia, - Grade 4 anemia, - Any non-preexisting Grade 2 or higher non-hematologic toxicity which, in the judgment of the Investigator and the Sponsor, was considered a DLT, - Any Grade 2 or higher non-hematologic toxicity that did not resolve to Grade 0 or Grade 1 toxicity by the start of the next cycle which, in the judgment of the Investigator and the Sponsor, was considered a DLT.

次要结局

  • Maximum Observed Plasma Concentration (Cmax) of Evofosfamide and Its Metabolite (Bromo-isophosphoramide Mustard [Br-IPM])(Monotherapy: pre-dose, 0.25, 0.5, 0.58, 0.75, 1, 1.08, 1.25, 1.5, 2, 2.5, 3.5, 4.5, 6.5, 8.5, 12.5 hours post-dose on Day 1 and 15; Combination therapy: pre-dose, 0.5, 0.66, 1, 2, 2.5, 3, 3.5, 4, 4.5, 6.5, 8, 10.5, 26.5 hours post-dose on Day 1 and 15)
  • Number of Participants With Treatment-Emergent Adverse Events (TEAE), Serious TEAEs, TEAEs Leading to Death(Baseline up to 33 months)
  • Time to Reach Maximum Plasma Concentration (Tmax) of Evofosfamide and Its Metabolite (Bromo-isophosphoramide Mustard [Br-IPM])(Monotherapy: pre-dose, 0.25, 0.5, 0.58, 0.75, 1, 1.08, 1.25, 1.5, 2, 2.5, 3.5, 4.5, 6.5, 8.5, 12.5 hours post-dose on Day 1 and 15; Combination therapy: pre-dose, 0.5, 0.66, 1, 2, 2.5, 3, 3.5, 4, 4.5, 6.5, 8, 10.5, 26.5 hours post-dose on Day 1 and 15)
  • Time to Reach Maximum Plasma Concentration (Tmax) of Gemcitabine and Its Metabolite (2',2'-Difluorodeoxyuridine [dFdU])(Pre-dose, 0.5, 1, 2, 4, 8, and 24 hours post-dose on Day 1 and 15)
  • Maximum Observed Plasma Concentration (Cmax) of Gemcitabine and Its Metabolite (2',2'-Difluorodeoxyuridine [dFdU])(Pre-dose, 0.5, 1, 2, 4, 8, and 24 hours post-dose on Day 1 and 15)
  • Terminal Rate Constant Associated With the Terminal Elimination Phase (λz) of Evofosfamide and Its Metabolite (Bromo-isophosphoramide Mustard [Br-IPM])(Monotherapy: pre-dose, 0.25, 0.5, 0.58, 0.75, 1, 1.08, 1.25, 1.5, 2, 2.5, 3.5, 4.5, 6.5, 8.5, 12.5 hours post-dose on Day 1 and 15; Combination therapy: pre-dose, 0.5, 0.66, 1, 2, 2.5, 3, 3.5, 4, 4.5, 6.5, 8, 10.5, 26.5 hours post-dose on Day 1 and 15)
  • Terminal Rate Constant Associated With the Terminal Elimination Phase (λz) of Gemcitabine and Its Metabolite (2',2'-Difluorodeoxyuridine [dFdU])(Pre-dose, 0.5, 1, 2, 4, 8, and 24 hours post-dose on Day 1 and 15)
  • Apparent Terminal Half-life (t1/2) of Evofosfamide and Its Metabolite (Bromo-isophosphoramide Mustard [Br-IPM])(Monotherapy: pre-dose, 0.25, 0.5, 0.58, 0.75, 1, 1.08, 1.25, 1.5, 2, 2.5, 3.5, 4.5, 6.5, 8.5, 12.5 hours post-dose on Day 1 and 15; Combination therapy: pre-dose, 0.5, 0.66, 1, 2, 2.5, 3, 3.5, 4, 4.5, 6.5, 8, 10.5, 26.5 hours post-dose on Day 1 and 15)
  • Apparent Terminal Half-life (t1/2) of of Gemcitabine and Its Metabolite (2',2'-Difluorodeoxyuridine [dFdU])(Pre-dose, 0.5, 1, 2, 4, 8, and 24 hours post-dose on Day 1 and 15)
  • Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero to Sampling Time With Concentration at or Above the Lower Limit of Quantitation (AUC[0-t]) of Evofosfamide and Its Metabolite (Bromo-isophosphoramide Mustard [Br-IPM])(Monotherapy: pre-dose, 0.25, 0.5, 0.58, 0.75, 1, 1.08, 1.25, 1.5, 2, 2.5, 3.5, 4.5, 6.5, 8.5, 12.5 hours post-dose on Day 1 and 15; Combination therapy: pre-dose, 0.5, 0.66, 1, 2, 2.5, 3, 3.5, 4, 4.5, 6.5, 8, 10.5, 26.5 hours post-dose on Day 1 and 15)
  • Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero to Sampling Time With Concentration at or Above the Lower Limit of Quantitation (AUC[0-t]) of Gemcitabine and Its Metabolite (2',2'-Difluorodeoxyuridine [dFdU])(Pre-dose, 0.5, 1, 2, 4, 8, and 24 hours post-dose on Day 1 and 15)
  • Area Under the Plasma Concentration-Time Curve From Time 0 to Infinity (AUC [0-infinity]) of Evofosfamide and Its Metabolite (Bromo-isophosphoramide Mustard [Br-IPM])(Monotherapy: pre-dose, 0.25, 0.5, 0.58, 0.75, 1, 1.08, 1.25, 1.5, 2, 2.5, 3.5, 4.5, 6.5, 8.5, 12.5 hours post-dose on Day 1 and 15; Combination therapy: pre-dose, 0.5, 0.66, 1, 2, 2.5, 3, 3.5, 4, 4.5, 6.5, 8, 10.5, 26.5 hours post-dose on Day 1 and 15)
  • Area Under the Plasma Concentration-Time Curve From Time 0 to Infinity (AUC [0-infinity]) of Gemcitabine and Its Metabolite (2',2'-Difluorodeoxyuridine [dFdU])(Pre-dose, 0.5, 1, 2, 4, 8, and 24 hours post-dose on Day 1 and 15)
  • Apparent Total Body Clearance of (CL) of Evofosfamide(Monotherapy: pre-dose, 0.25, 0.5, 0.58, 0.75, 1, 1.08, 1.25, 1.5, 2, 2.5, 3.5, 4.5, 6.5, 8.5, 12.5 hours post-dose on Day 1 and 15; Combination therapy: pre-dose, 0.5, 0.66, 1, 2, 2.5, 3, 3.5, 4, 4.5, 6.5, 8, 10.5, 26.5 hours post-dose on Day 1 and 15)
  • Apparent Total Body Clearance of (CL) of Gemcitabine(Pre-dose, 0.5, 1, 2, 4, 8, and 24 hours post-dose on Day 1 and 15)
  • Apparent Volume of Distribution at Steady State (Vss) of Evofosfamide(Monotherapy: pre-dose, 0.25, 0.5, 0.58, 0.75, 1, 1.08, 1.25, 1.5, 2, 2.5, 3.5, 4.5, 6.5, 8.5, 12.5 hours post-dose on Day 1 and 15; Combination therapy: pre-dose, 0.5, 0.66, 1, 2, 2.5, 3, 3.5, 4, 4.5, 6.5, 8, 10.5, 26.5 hours post-dose on Day 1 and 15)
  • Apparent Volume of Distribution at Steady State (Vss) of Gemcitabine(Pre-dose, 0.5, 1, 2, 4, 8, and 24 hours post-dose on Day 1 and 15)
  • Apparent Volume of Distribution During Terminal Phase (Vz) of Evofosfamide(Monotherapy: pre-dose, 0.25, 0.5, 0.58, 0.75, 1, 1.08, 1.25, 1.5, 2, 2.5, 3.5, 4.5, 6.5, 8.5, 12.5 hours post-dose on Day 1 and 15; Combination therapy: pre-dose, 0.5, 0.66, 1, 2, 2.5, 3, 3.5, 4, 4.5, 6.5, 8, 10.5, 26.5 hours post-dose on Day 1 and 15)
  • Apparent Volume of Distribution During Terminal Phase (Vz) of Gemcitabine(Pre-dose, 0.5, 1, 2, 4, 8, and 24 hours post-dose on Day 1 and 15)
  • Cumulative Amount of Evofosfamide Excreted From Time Zero to Time After Dosing (Ae0-t)(Monotherapy: pre-dose, 0.25, 0.5, 0.58, 0.75, 1, 1.08, 1.25, 1.5, 2, 2.5, 3.5, 4.5, 6.5, 8.5, 12.5 hours post-dose on Day 1 and 15; Combination therapy: pre-dose, 0.5, 0.66, 1, 2, 2.5, 3, 3.5, 4, 4.5, 6.5, 8, 10.5, 26.5 hours post-dose on Day 1 and 15)
  • Renal Clearance (CL) for Evofosfamide(Monotherapy: pre-dose, 0.25, 0.5, 0.58, 0.75, 1, 1.08, 1.25, 1.5, 2, 2.5, 3.5, 4.5, 6.5, 8.5, 12.5 hours post-dose on Day 1 and 15; Combination therapy: pre-dose, 0.5, 0.66, 1, 2, 2.5, 3, 3.5, 4, 4.5, 6.5, 8, 10.5, 26.5 hours post-dose on Day 1 and 15)
  • Best Overall Response (BOR)(Time from first treatment to final assessment at 33 months)
  • Number of Participants With Objective Response(Time from first treatment to final assessment at 33 months)
  • Number of Participants With Disease Control(Time from first treatment to final assessment at 33 months)
  • Number of Participants With Clinical Significant Laboratory Abnormalities and Vital Signs Abnormalities Reported as Treatment Emergent Adverse Events(Baseline up to 33 months)
  • Number of Participants With Abnormal Electrocardiogram (ECG) Findings Reported as Treatment Emergent Adverse Events (TEAEs)(Baseline up to 33 months)
  • Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status Score of 2 or Higher Than 2(Baseline up to 33 months)

研究者

申办方类型
Industry
责任方
Sponsor

研究点 (1)

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