NCT04198818终止1 期
A First-in-Human, Open Label, Phase I/II Study to Evaluate the Safety, Tolerability and Pharmacokinetics of HH2710 in Patients With Advanced Tumors
Haihe Biopharma Co., Ltd.3 个研究点 分布在 2 个国家目标入组 37 人开始时间: 2020年1月7日最近更新:
适应症
干预措施
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 发起方
- 入组人数
- 37
- 试验地点
- 3
- 主要终点
- MTD (Maximum Tolerated Dose)
研究概览
简要总结
This is a First-in-Human, Open Label, Phase I/II Study to Evaluate the Safety, Tolerability and Pharmacokinetics of HH2710 in Patients with Advanced Tumors, composed of a Phase I dose escalation and dose expansion stage and a Phase II dose extension stage.
详细描述
HH2710 is developed by Shanghai Haihe Pharmaceutical Co., Ltd. HH2710 is a highly potent, selective, reversible, ATP-competitive ERK1/2 inhibitor. This is a first-in-human study of HH2710 and is designed as an open-label, multicenter, Phase I/II study which is composed of a Phase I dose escalation and dose expansion stage and a Phase II dose extension stage.
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
- •Provide signed and dated informed consent prior to initiation of any study-related procedures.
- •Male or female patients aged ≥ 18 years.
- •Phase I dose escalation stage: Patients who have been diagnosed with histologically or cytological documented, unresectable/metastatic tumors that are refractory or intolerant to standard therapy or for whom no curative standard therapy exists.
- •For LCH/ECD: Eligible patients must have multifocal disease and the diagnosis must be confirmed by pathological evaluation of the affected tissue.
- •Phase I expansion stage and Phase II stage: Histologically or cytologically documented unresectable/metastatic tumors with evidence of genetic mutations affecting MAPK pathway is required. Patients with a BRAF V600 mutation must have progressed on or after standard therapy, including BRAF and/or MEK inhibitors (≤3 lines). Patients entering the Phase 2 portion of the trial will be enrolled in Cohorts 1-4 depending upon their tumor type.
- •Cohort 1: Patients with BRAF/NRAS (mutation sites as follows: NRAS G13V, NRAS Q61, BRAF V600, BRAF G469A, L485W, L597Q, T599dup) mutated melanoma;
- •Cohort 2: Patients with BRAF/NRAS (mutation sites as follows: NRAS G13V, NRAS Q61, BRAF V600, BRAF G469A, L485W, L597Q, T599dup) mutated non-small cell lung cancer;
- •Cohort 3: Patients with BRAF V600 mutated Langerhans Cell Histiocytosis Syndrome (LCH)/ Erdheim-Chester disease (ECD);
- •For LCH/ECD: Eligible patients must have multifocal disease and the diagnosis must be confirmed by pathological evaluation of the affected tissue.
- •Cohort 4: Patients with RAS/RAF/MEK/ERK mutated tumor types that are not included in other cohorts.
- •Patients in the Phase I dose escalation portion of the trial may have measurable (per RECIST v1.1) or evaluable disease. Patients in the Phase I expansion and Phase II portions of the trial must have measurable disease per RECIST v1.
- •Eastern Cooperative Oncology Group (ECOG) performance status≤
- •Predicted life expectancy ≥ 3 months;
- •Adequate renal function defined as a creatinine clearance ≥ 60 mL/min;
- •Adequate hepatic function [total bilirubin ≤ 1.5 x UNL; AST (aspartate aminotransferase) and ALT (alanine aminotransferase) ≤ 3 x UNL or ≤ 5 x UNL if due to liver involvement by tumor];
- •Adequate cardiac function, > institutional lower limit of normal e.g., left ventricular ejection fraction (LVEF) of ≥ 50% as assessed by ultrasound/echocardiography (ECHO) or multi-gated acquisition (MUGA) ; corrected QT interval (QTcF) < 460 ms (male patients), < 470 ms (female patients) (using QTc Fridericia's formula.
- •Adequate bone marrow function, patients must not have required blood transfusion or growth factor support ≤ 7 days before sample collection for the following ：
- •Absolute neutrophil count ≥ 1.5 × 109/L; • Hemoglobin ≥ 9 g/dL; • Platelet count ≥100 × 109/L; • International normalized ratio (INR) ≤ 1.5; • Activated partial prothrombin time (APTT) ≤ 1.5 × ULN;
- •Willing and able to participate in the trial and comply with all study requirements;
排除标准
- •Gastrointestinal condition which could impair absorption of study medication;
- •Congenital long QT syndrome, or any known history of torsade de pointes (TdP), or family history of unexplained sudden death;
- •Clinically uncontrolled hypertension (after standard antihypertensive treatment, systolic blood pressure ≥ 140 mmHg and/or diastolic blood pressure ≥ 90 mmHg);
- •Undergone a bone marrow or solid organ transplant;
- •Any toxicities from prior treatment that have not recovered to ≤ CTCAE Grade 1 before the start of study drug, with the exception of hair loss or fatigue;
- •Patients who have previously participated in clinical trials of ERK inhibitors drug;
- •Allergic to similar drugs or their excipients;
- •HIV (human immunodeficiency virus) infection, active hepatitis B or hepatitis C patients (HBsAg positive patients also detected HBV (hepatitis B virus) DNA ≥ 103 copies or ≥ 200 IU/ml; HCV antibody test results are positive, and HCV (hepatitis C virus) RNA PCR test results are positive);
- •Uncontrolled or severe intercurrent medical condition:
- •Unstable angina pectoris ≤3 months prior to starting study drug;
- •Acute myocardial infarction ≤3 months prior to starting study drug;
- •Symptomatic CNS metastases that are neurologically unstable or requiring increasing doses of steroids to control CNS disease. Note: Controlled CNS metastases are allowed. Radiotherapy or surgery for CNS metastases must have been completed >2 weeks prior to study entry. No new neurologic deficits on clinical examination and no new findings on CNS imaging are permitted. Steroid use for management of CNS metastases must be at a stable dose for two weeks preceding study entry;
- •Any cancer-directed therapy (chemotherapy, radiotherapy, hormonal therapy, biologic or immunotherapy, Chinese medicine/Chinese patent medicine with anti-tumor effect, etc.) within 28 days or 5 half-lives, whichever is shorter;
- •Major surgery within 4 weeks prior to first dose;
- •Any use of an investigational drug within 28 days or 5 half-lives (whichever is shorter) prior to the first dose of HH2710;
- •Pregnant or breast-feeding women;
- •Severe chronic or active infections requiring systemic antibacterial, antifungal or antiviral therapy, including tuberculosis infection, etc.
- •Severe infections within 4 weeks prior to the first dose, including but not limited to hospitalization for complications of infection, bacteremia, or severe pneumonia.
- •Received therapeutic oral or IV antibiotics within 2 weeks prior to the first dose of study drug.
- •Any important or severe medical illness or abnormal laboratory finding that would increase the risk of participating in this study;
- •A history or current evidence/risk of retinal vein occlusion, central serous retinopathy or choroidneovascularization (CNV) ;
- •Concurrent therapy with any other investigational agent;
- •Concomitant malignancies or previous malignancies with less than 2 years disease-free interval at the time of enrollment; (But basal cell carcinoma skin cancer, cervical CIS(carcinoma in situ), CIS of the breast, localized or low Gleason grade prostate cancer, and < T2 bladder cancer can be included);
- •Current treatment with agents including vitamins, supplements, and herbal supplements that are metabolized solely through CYP3A4;
- •Severe chronic obstructive pulmonary disease, severe asthma, pneumoconiosis, asbestosis and other occupational lung diseases.
- •A history of acute or chronic pancreatitis, surgery of the pancreas, or any risk factors that may increase the risk of pancreatitis;
- •Contraception: Patients who do not meet the following conditions will be excluded, - For women: Negative pregnancy test for females of child-bearing potential; must be surgically sterile, postmenopausal (defined as no menstrual cycle for at least 12 consecutive months), or compliant with an acceptable contraceptive regimen (2 highly effective forms, such as oral contraceptives, condom with spermicide, etc.) during and for 6 months after the treatment period. Abstinence is not considered an adequate contraceptive regimen; - For men: Must be surgically sterile, or compliant with a contraceptive regimen (as above) during and for a minimum of 6 months after the treatment period.
研究组 & 干预措施
Dose escalation study of HH2710
Experimental
to determine the MTD of HH2710 and/or Recommended Phase II dose (RP2D).
干预措施: HH2710 (Drug)
结局指标
主要结局
MTD (Maximum Tolerated Dose)
时间窗: Up to 1 cycle (21 days)
MTD estimation: After the escalation is completed, select the MTD based on the isotonic regression. Specifically, select the MTD for which the isotonic estimate of the toxicity rate is closest to the target toxicity rate. If there are ties, select the higher dose level when the isotonic estimate is lower than the target toxicity rate and select the lower dose level when the isotonic estimate is greater than or equal to the target toxicity rate.
Number of Participants Who Experienced DLT (Dose Limiting Toxicities)
时间窗: Up to 1 cycle (21 days)
DLT is defined as: any toxicity meeting the specified criteria and considered at least possibly related to HH2710 (i.e., any toxicity for which a clear alternative etiology such as disease progression has not been identified) should be considered a DLT per National Cancer Institute Common Terminology Criteria for Adverse events (NCI-CTCAE V5.0) standard, which met any of the following, NCI-CTCAE V5.0 will be used for all grading, and compliance of 80% (i.e. 17 of 21 days) in Cycle 1 is required for a patient to be included in the DLT evaluation. For the purpose of dose-escalation decisions, DLTs will be considered and included in the BOIN.
Tumor Objective Response Rate (ORR)
时间窗: Up to 1 cycle (21 days)
ORR=CR+PR. ORR was defined as the percentage of patients who had at least one confirmed response of CR or PR defined by RECIST version 1.1 prior to any evidence of progression, and was calculated and summarized by the treatment group, along with the 95% confidence interval (CI) calculated by the Clopper-Pearson method.
次要结局
- Pharmacokinetic Measures - Plasma Concentration Timecurve From Time 0 to Time (t) (AUC0-t)(C1D1,pre-dose,15min,30min,1h,2h,3h,4h,6h,8h,12h;C1D2, pre-dose and 24h; C1D7,C1D10, pre-dose.C1D15 at pre-dose,15min,30min,1h,2h,3h,4h,6h,8h,12h, C1D16 pre-dose and 24h,C1D22 pre-dose,and C2D1,C3D1,C5D1,C7D1,C9D1 pre-dose.)
- Pharmacokinetic Measures - Plasma Clearance Rate Constant, Lambda z (λz)(Single dose, C1D1,pre-dose,15min,30min,1h,2h,3h,4h,6h,8h,12h(if available),C1D2, pre-dose(if available))
- Pharmacokinetic Measures - Apparent Volume of Distribution (Vz/F)(Single dose, C1D1,pre-dose,15min,30min,1h,2h,3h,4h,6h,8h,12h(if available),C1D2, pre-dose(if available))
- Pharmacokinetic Measures - Peak Plasma Concentration (Cmax)(C1D1,pre-dose,15min,30min,1h,2h,3h,4h,6h,8h,12h;C1D2, pre-dose and 24h; C1D7,C1D10, pre-dose.C1D15 at pre-dose,15min,30min,1h,2h,3h,4h,6h,8h,12h, C1D16 pre-dose and 24h,C1D22 pre-dose,and C2D1,C3D1,C5D1,C7D1,C9D1 pre-dose.)
- Pharmacokinetic Measures -Plasma Elimination Half-life (t1/2)(Single dose, C1D1,pre-dose,15min,30min,1h,2h,3h,4h,6h,8h,12h(if available),C1D2, pre-dose(if available))
- Pharmacokinetic Measures - Apparent Clearance (CL/F)(C1D1,pre-dose,15min,30min,1h,2h,3h,4h,6h,8h,12h ;C1D2, pre-dose and 24h; C1D7,C1D10, pre-dose.C1D15 at pre-dose,15min,30min,1h,2h,3h,4h,6h,8h,12h, C1D16 pre-dose and 24h,C1D22 pre-dose,and C2D1,C3D1,C5D1,C7D1,C9D1 pre-dose.)
- Pharmacokinetic Measures - Peak Time (Tmax)(C1D1,pre-dose,15min,30min,1h,2h,3h,4h,6h,8h,12h;C1D2, pre-dose and 24h; C1D7,C1D10, pre-dose.C1D15 at pre-dose,15min,30min,1h,2h,3h,4h,6h,8h,12h, C1D16 pre-dose and 24h,C1D22 pre-dose,and C2D1,C3D1,C5D1,C7D1,C9D1 pre-dose.)
研究者
研究点 (3)
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