An Open-label, Multi-center, Phase I, Dose Finding Study of Oral TNO155 in Adult Patients With Advanced Solid Tumors
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 227
- 试验地点
- 23
- 主要终点
- Number of participants with adverse events and serious adverse events
研究概览
简要总结
The purpose of this first in human (FIH) trial was to characterize the safety and tolerability of the SHP2 inhibitor TNO155 alone and in combination with EGF816 (nazartinib) and identify a recommended dose for future studies in adult patients with advanced solid tumors in selected indications.
详细描述
This study has been designed as a Phase I, open-label, dose finding study with a dose escalation part and a dose expansion part in adult patients with selected advanced solid tumors. The study treatment, TNO155 alone or in combination with EGF816 (nazartinib), was taken until the patient experienced unacceptable toxicity, progressive disease and/or treatment was discontinued at the discretion of the investigator or the patient or due to withdrawal of consent.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 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 99 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Able to understand and voluntarily sign the ICF and able to comply with the study visit schedule and the other protocol requirements.
- •Patient (male or female) ≥18 years of age willing to agree to not father a child/become pregnant and comply with effective contraception criteria.
- •Must have progressed following standard therapy, or for whom, in the opinion of the Investigator, no effective standard therapy exists, is tolerated or is appropriate.
- •ECOG (Eastern cooperative oncology group) performance status ≤2
- •Additional criteria only appying to TNO155 in combination with EGF816 (nazartinib):
- •Patients must be screened for Hepatitis B virus and Hepatitis C virus
排除标准
- •Tumors harboring known activating KRAS, NRAS, HRAS, BRAF or PTPN11 (SHP2) mutations. (Exceptions are KRAS G12-mutant NSCLC's)
- •History or current evidence of retinal vein occlusion (RVO) or current risk factors for RVO.
- •Any medical condition that would, in the investigator's judgment, prevent the patient's participation in the clinical study due to safety concerns or compliance with clinical study procedures.
- •Clinically significant cardiac disease.
- •Active diarrhea or inflammatory bowel disease
- •Insufficient bone marrow function
- •Insufficient hepatic and renal function.
- •Additional criteria only appying to TNO155 in combination with EGF816 (nazartinib):
- •Patients with a known history of human immunodeficiency virus (HIV) seropositivity.
- •Patients receiving concomitant immunosuppressive agents or chronic corticosteroids use at the time of study entry.
- •Patients who have undergone a bone marrow or solid organ transplant
- •Patients with a history or presence of interstitial lung disease or interstitial pneumonitis
- •Bullous and exfoliative skin disorders at screening of any grade
- •Presence of clinically significant ophthalmological abnormalities that might increase the risk of corneal epithelial injury
研究组 & 干预措施
TNO155
TNO155 for oral administration
干预措施: TNO155 (Drug)
TNO155 in combination with EGF816 (nazartinib)
TNO155 in combination with EGF816 (nazartinib) in patients with advanced EGFR mutant NSCLC
干预措施: TNO155 in combination with EGF816 (nazartinib) (Drug)
结局指标
主要结局
Number of participants with adverse events and serious adverse events
时间窗: up to 5 years; at least once per treatment cycle
All patients participating in this study will be assessed for incidence and severity of adverse events (AEs) and serious AEs, including changes in laboratory values, vital signs, electrocardiograms and cardiac biomarkers
Number of participants with dose limiting toxicities
时间窗: up to 28-day cycle
Incidence and nature of dose limiting toxicities (DLTs) in the dose escalation part. A DLT is defined as an adverse event or abnormal laboratory value assessed as unrelated to disease, disease progression, inter-current illness, or concomitant medications that occurs within the first treatment cycle (either 21 days or 28 days, depending on the cohort's treatment schedule) with TNO155 or with TNO155 in combination with EGF816 (nazartinib)
Number of participants with dose interruptions and reductions
时间窗: Up to 5 years
Assessment of tolerability. For patients who do not tolerate the protocol-specified dosing schedule, dose adjustments may be permitted in order to allow patients to continue the study treatment
Dose intensity of study drugs
时间窗: Up to 5 years
Dose intensity is computed as the ratio of actual cumulative dose received to actual duration of exposure
次要结局
- Overall response rate (ORR) per RECIST v1.1(From start of treatment for 60 months)
- Disease control rate (DCR) per RECIST v1.1(From start of treatment for 60 months)
- Progression-free survival (PFS) per RECIST v1.1(Up to 5 years)
- Duration of response (DOR) per RECIST v1.1(Up to 5 years)
- Change from baseline in DUSP6 in tumor samples(At screening and between Cycle 1 and Cycle 3. One cycle=either 21 days or 28 days, depending on the cohort's treatment schedule.)
- Area under the plasma concentration-time curve (AUC) of study drugs(From pre-dose up to 48 hours post-dose on Cycle 1 Day 1 and from pre-dose up to 24 hours post-dose on Cycle 1 Day 14. One cycle=21 days or 28 days, depending on the dosing schedule.)
- Peak plasma concentration (Cmax) of study drugs(From pre-dose up to 48 hours post-dose on Cycle 1 Day 1 and from pre-dose up to 24 hours post-dose on Cycle 1 Day 14. One cycle=21 days or 28 days, depending on the dosing schedule.)
- Time to reach peak plasma concentration (Tmax) of study drugs(From pre-dose up to 48 hours post-dose on Cycle 1 Day 1 and from pre-dose up to 24 hours post-dose on Cycle 1 Day 14. One cycle=21 days or 28 days, depending on the dosing schedule.)
- Apparent terminal elimination half-life of study drugs(From pre-dose up to 48 hours post-dose on Cycle 1 Day 1 and from pre-dose up to 24 hours post-dose on Cycle 1 Day 14. One cycle=21 days or 28 days, depending on the dosing schedule.)