A Phase I Study of TL32711 In Combination With Gemcitabine in Patients With Advanced Solid Tumors
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 21
- 试验地点
- 2
- 主要终点
- MTD of smac mimetic TL32711
研究概览
简要总结
The purpose of this study is to determine the dose of smac mimetic TL32711 that is safe and tolerated when given with gemcitabine hydrochloride to patients with advanced cancer
详细描述
PRIMARY OBJECTIVES:
I. To determine the maximum tolerated dose (MTD) and recommended Phase II dose of TL32711 (smac mimetic TL32711) in combination with gemcitabine (gemcitabine hydrochloride) in patients with advanced solid tumors.
SECONDARY OBJECTIVES:
I. To determine the toxicity and safety profile of TL32711 in combination with gemcitabine in patients with advanced solid tumors.
II. To determine the pharmacokinetic profile of TL32711 and gemcitabine when administered in combination.
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
- •Histologically or cytologically confirmed solid tumors that are advanced or metastatic that gemcitabine-based treatment is considered standard therapy
- •Patient must consent to the use of their archival tumor tissue for protocol use if available
- •Patient with at least one measurable site of disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 that has not been previously irradiated
- •Eastern Cooperative Oncology Group (ECOG) Performance Status =< 1
- •Life expectancy >= 3 months
- •Absolute neutrophil count (ANC) >= 1,500 cells/mm^3 (system international [SI] units 1.5 x 10^6/L)
- •Platelets >= 100,000 cells/m^3 (SI units 100 x 10^6/L)
- •Hemoglobin >= 9.0 g/dL (SI units 90 g/L) (in the absence of transfusion within 24 hours prior to dosing)
- •Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGPT) and alanine aminotransferase (ALT)/serum glutamate pyruvate transaminase (SGPT) =< 3 x Upper Limit of Normal (ULN); In patients with known hepatic involvement, AST and ALT < 5 x ULN are allowed
- •Total bilirubin =< 1.5 x ULN; in patients with known hepatic involvement, total bilirubin =< 1.5 x ULN is allowed
- •Serum creatinine =< 1.5 x ULN, or 24-hr urine creatinine clearance calculation >= 60 mL/min
- •Willing and able to comply with scheduled visits, treatment plan and laboratory tests
- •Ability to understand and willingness to sign a written informed consent; a signed informed consent must be obtained prior to any study specific procedures
- •Women of childbearing potential must have a negative serum pregnancy test at screening and negative (serum or urine) pregnancy test within 48 hours prior to the first dose of the first cycle of study treatment
- •Women of childbearing potential must agree to use 2 methods of adequate contraception (i.e., hormonal and barrier method) prior to enrollment, during the study, and for a period of 30 days following the last dose of study drug(s); males who are sexually active must agree to use a condom during the study for a period of 30 days following the last dose of study drug(s), and if their partner is of childbearing potential, she must agree to use a secondary method of contraception (i.e., hormonal, intrauterine device, barrier) during the study and for a period of 30 days following the last dose of study drug(s)
排除标准
- •Patients who have receive recent anti-cancer therapy defined by:
- •Chemotherapy, immunotherapy, hormonal therapy and monoclonal antibodies (but excluding nitrosourea, mitomycin-C, targeted therapy and radiation) =< 4 weeks prior to starting study drug, or who have not recovered from side effects of such therapy
- •Last administration of nitrosourea or mitomycin-C =< 6 weeks prior to starting study drug, or who have not recovered from the side effects of such therapy; or
- •Targeted therapy (e.g. sunitinib, sorafenib, pazopanib) =< 2 weeks prior to starting study drug, or who have not recovered from the side effects of such therapy; or
- •Radiotherapy =< 4 weeks prior to starting study drug, or =< 2 weeks prior to starting study drug in the case of localized radiotherapy (e.g. for analgesic purpose or for lytic lesions at risk of fracture), or who have not recovered from radiotherapy toxicities
- •Patients who have undergone major surgery (e.g. intra-thoracic, intra-abdominal or intra-pelvic), open biopsy or significant traumatic injury =< 4 weeks prior to starting study treatment, or patients who have had minor procedures, percutaneous biopsies or placement of vascular access device =< 1 week prior to starting study drug, or who have not recovered from side effects of such procedure or injury
- •Uncontrolled concurrent illness, including but not limited to ongoing or active serious infection requiring systemic antimicrobials (within 2 weeks prior to first dose of TL32711), arterial hypertension (> 160/100 mm/Hg on antihypertensive medications), uncontrolled endocrine diseases, altered mental status or psychiatric illness/social situations that would limit compliance with protocol requirements and/or obscure study results
- •Known or suspected diagnosis of human immunodeficiency virus (HIV) or chronic active Hepatitis B or C; viral testing is not required
- •Inability to start prophylactic anti-viral medication
- •Clinically significant pulmonary illness resulting in Grade >= 2 hypoxia (National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE, v4]) or any requirement for supplemental oxygen, or pulse oximetry less than 90% saturation on room air
- •Symptomatic or uncontrolled brain metastases requiring current treatment (less than 4 weeks from last cranial radiation or 4 weeks from last steroids)
- •Impaired cardiac function or clinically significant cardiac disease including the following:
- •Clinically significant arrhythmias (except chronic well controlled atrial fibrillation)
- •New York Heart Association (NYHA) grade II, III, or IV congestive heart failure
- •Angina pectoris =< 6 months prior to dosing with TL32711
- •Myocardial infarction within the last 12 months prior to dosing with TL32711
- •QT interval corrected for heart rate (QTc) > 480 msec (including patients on medication); patients with a ventricular pacemaker for whom QT interval is not measurable may be eligible for enrollment after consultation with the Sponsor and the documentation of approval
- •Ongoing auto-immune disease or with history of an auto-immune disease within the past 5 years; a patient with a history of auto-immune disease that is currently in remission must not be receiving medication designed to control the disease and must not have experienced an exacerbation of the disease requiring treatment with immunomodulatory agents in the last 5 years; auto-immune disease includes but are not limited to systemic lupus erythematosis, scleroderma, rheumatoid arthritis, psoriasis, psoriatic arthritis, ulcerative colitis and regional enteritis (Crohn's disease)
- •Systemic or chronic topical corticosteroids or immunosuppressive therapy within 4 weeks prior to study entry or anticipated need of systemic corticosteroids or immunosuppressive therapy during study participation
- •Patients with a healing or open wound
- •Skin lesions of Grade >= 2 severity (NCI CTCAE v4), except alopecia
- •Lack of recovery or prior adverse events to Grade =< 1 severity (NCI CTCAE v4) (except alopecia) due to medications administered prior to the first dose of TL32711
- •Patients with prior history of Bell's Palsy
- •Any other condition or finding that in the opinion of the investigator may render the patient at excessive risk for treatment complications or may not be able to provide evaluable outcome information
- •Pregnant or breast-feeding women
- •Known allergy to any of the formulation components of TL32711 including citric acid monohydrate, sodium citrate dehydrate, and sodium chloride
研究组 & 干预措施
Treatment (enzyme inhibitor therapy)
Patients receive gemcitabine hydrochloride IV over 30 minutes and smac mimetic TL32711 IV over 30 minutes once weekly for 2 weeks. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity.
干预措施: pharmacological study (Other)
Treatment (enzyme inhibitor therapy)
Patients receive gemcitabine hydrochloride IV over 30 minutes and smac mimetic TL32711 IV over 30 minutes once weekly for 2 weeks. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity.
干预措施: Smac mimetic TL32711 (Drug)
Treatment (enzyme inhibitor therapy)
Patients receive gemcitabine hydrochloride IV over 30 minutes and smac mimetic TL32711 IV over 30 minutes once weekly for 2 weeks. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity.
干预措施: gemcitabine hydrochloride (Drug)
Treatment (enzyme inhibitor therapy)
Patients receive gemcitabine hydrochloride IV over 30 minutes and smac mimetic TL32711 IV over 30 minutes once weekly for 2 weeks. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity.
干预措施: laboratory biomarker analysis (Other)
Treatment (enzyme inhibitor therapy)
Patients receive gemcitabine hydrochloride IV over 30 minutes and smac mimetic TL32711 IV over 30 minutes once weekly for 2 weeks. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity.
干预措施: biopsy (Procedure)
结局指标
主要结局
MTD of smac mimetic TL32711
时间窗: During the first course (21 days)
Defined as the highest dose level at which less than 2 of 6 patients experience study treatment-related dose-limiting toxicity. Summarized with frequencies and descriptive measures, and tabulated according to body system, severity and relation to treatment.
次要结局
- Response rates according to the RECIST v1.1 (solid tumor/dose-finding cohort)(Up to 4 weeks post-treatment)
- Overall toxicity profile characterized by type, frequency, severity (according to the NCI CTCAE version 4.0), timing, seriousness, and relationship to study treatment(Up to 4 weeks post-treatment)
- Progression-free survival(Up to 2 years)
- Plasma pharmacokinetic parameters of smac mimetic TL32711, gemcitabine hydrochloride and its metabolites(Days 1 and 8 of course 1 and then day 1 of course 2 (day 22))