A Phase I, First-in-human, Open-label, Dose-escalation, Safety, Pharmacokinetic, and Pharmacodynamic Study of Oral TP-0184 Administered Once Weekly for 4 Weeks to Patients With Advanced Solid Tumors
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 24
- 试验地点
- 5
- 主要终点
- Incidence of dose-limiting toxicities (DLTs) and treatment emergent adverse events
研究概览
简要总结
TP-0184 is a potent inhibitor of ALK2 or ACRV1 kinase, a constitutively active serine/threonine receptor kinase due to activating mutations or upregulated upstream signaling pathways. This is a Phase 1, open-label, dose-escalation, safety, pharmacokinetics, and pharmacodynamic study, with a purpose of determining the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of oral TP-0184 administered once weekly for 4 weeks in patients with advanced solid tumors.
详细描述
Primary Objective:
• To determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of oral TP-0184 administered once weekly for 4 weeks, over a range of doses in patients with advanced solid tumors.
Secondary Objectives:
- To establish the pharmacokinetics of orally administered TP-0184
- To observe patients for any evidence of antitumor activity of TP-0184 by objective radiographic assessment
- To study the pharmacodynamics of TP-0184 therapy
- To establish the Recommended Phase 2 Dose (RP2D) for future studies with TP-0184
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
- •Have a histologically confirmed diagnosis of advanced metastatic or progressive solid tumor
- •Be refractory to, or intolerant of, established therapy known to provide clinical benefit for their condition.
- •Have one or more tumors measurable or evaluable as outlined by modified RECIST v1.1
- •Have an Eastern Cooperative Oncology Group (ECOG) (World Health Organization [WHO]) performance of ≤1
- •Have a life expectancy ≥3 months
- •Be ≥18 years of age
- •Have a negative pregnancy test (if female of childbearing potential)
- •Have acceptable liver function:
- •Bilirubin ≤1.5x upper limit of normal (ULN)
- •Aspartate aminotransferase (AST/SGOT), alanine aminotransferase (ALT/SGPT) and alkaline phosphatase ≤2.5x upper limit of normal (ULN) *If liver metastases are present, then ≤5x ULN is allowed.
- •Have acceptable renal function: Calculated creatinine clearance ≥ 30 mL/min
- •Have acceptable hematologic status:
- •Granulocyte ≥1500 cells/mm3
- •Platelet count ≥100,000 (plt/mm3)
- •Hemoglobin ≥8 g/dL (Patients may not have received prior transfusions within 2 weeks of the first dose of TP-0184)
- •Have acceptable coagulation status:
- •Prothrombin time (PT) within 1.5x normal limits
- •Activated partial thromboplastin time (aPTT) within 1.5x normal limits
- •Be nonfertile or agree to use an adequate method of contraception. Sexually active patients and their partners must use an effective method of contraception (hormonal or barrier method of birth control; or abstinence) prior to study entry and for the duration of study participation and for at least 3 months (males) and 6 months (females) after the last study drug dose. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.
- •Have read and signed the Institutional Review Board (IRB)-approved informed consent form (ICF) prior to any study related procedure. (In the event that the patient is re-screened for study participation or a protocol amendment alters the care of an ongoing patient, a new ICF must be signed.)
排除标准
- •History of congestive heart failure (CHF); cardiac disease, myocardial infarction within the past 6 months prior to Cycle 1 Day 1; left ventricular ejection fraction (LVEF) <45% by echocardiogram (ECHO), unstable arrhythmia, or evidence of ischemia on electrocardiogram (ECG) within 14 days prior to Cycle 1 Day 1
- •Have a corrected QT interval (using Fridericia's correction formula) (QTcF) of >450 msec in men and >470 msec in women
- •Have a seizure disorder requiring anticonvulsant therapy
- •Presence of symptomatic central nervous system metastatic disease or disease that requires local therapy such as radiotherapy, surgery, or increasing dose of steroids within the prior 2 weeks
- •Have severe chronic obstructive pulmonary disease with hypoxemia (defined as resting O2 saturation of ≤90% breathing room air)
- •Have undergone major surgery, other than diagnostic surgery, within 2 weeks prior to Cycle 1 Day 1
- •Have active, uncontrolled bacterial, viral, or fungal infections, requiring systemic therapy
- •Are pregnant or nursing
- •Received treatment with radiation therapy, surgery, chemotherapy, or investigational therapy within 28 days or 5 half lives, whichever occurs first, prior to study entry (6 weeks for nitrosoureas or Mitomycin C)
- •Are unwilling or unable to comply with procedures required in this protocol
- •Have known infection with human immunodeficiency virus (HIV), hepatitis B, or hepatitis C. Patients with history of chronic hepatitis that is currently not active are eligible.
- •Have a serious nonmalignant disease (eg, hydronephrosis, liver failure, or other conditions) that could compromise protocol objectives in the opinion of the investigator and/or the sponsor
- •Are currently receiving any other investigational agent
- •Have exhibited allergic reactions to a similar structural compound, biological agent, or formulation
- •Have undergone significant surgery to the gastrointestinal tract that could impair absorption or that could result in short bowel syndrome with diarrhea due to malabsorption
- •Have hemochromatosis or a transferrin saturation (TS) >50% in men or >45% in women at baseline or noted during the study via scheduled iron panel monitoring
研究组 & 干预措施
Single Arm TP-0184
Weekly dose of TP-0184 by oral administration
干预措施: TP-0184 (Drug)
结局指标
主要结局
Incidence of dose-limiting toxicities (DLTs) and treatment emergent adverse events
时间窗: Day 1 - 28
A DLT is defined as any one of the following events observed within Cycle 1 regardless of investigator attribution unless there is a clear alternative explanation: * Grade 3 or greater febrile neutropenia * Grade 4 neutropenia for ≥7 consecutive days * Grade 4 thrombocytopenia or Grade 3 thrombocytopenia with clinically significant bleeding or that requires a platelet transfusion * Grade 3 or 4 nonhematologic AEs including nausea, vomiting, diarrhea, and electrolyte imbalances persisting for more than 48 hours despite optimal medical management * Dosing delays ≥1 week due to treatment emergent adverse events or related severe laboratory test values
Determine maximum tolerated dose (MTD)
时间窗: 20 months
If a patient experiences a DLT, up to three additional patients will be treated at that dose level. If no additional DLTs are observed in the expanded six-patient cohort, the dose will be escalated in a new cohort of three patients. If two or more patients at a given dose level experience a DLT during the first cycle, then the MTD will have been exceeded and up to a total of six patients will be treated at the next lower dose level. If 0 or 1 of 6 patients experiences a DLT at this previous lower dose level, this dose will be declared the MTD.
次要结局
- Determine antitumor activity of TP-0184(20 months)
- Recommended Phase 2 Dose of TP-0184(23 months)