c-Met Second-Line Hepatocellular Carcinoma
2022年8月22日 更新者：Merck KGaA, Darmstadt, Germany
A Multicenter, Single Arm, Phase Ib/II Study to Evaluate Efficacy, Safety, and PK of MSC2156119J as Monotherapy in Subjects With MET+ Advanced Hepatocellular Carcinoma With Child Pugh Class A Liver Function Who Have Failed Sorafenib Treatment
This is a Phase 1b/2, multicenter, single arm trial to assess the efficacy, safety, and pharmacokinetics (PK) of MSC2156119J as monotherapy in subjects with MET+ advanced hepatocellular carcinoma (HCC) with child Pugh Class A liver function who have failed sorafenib treatment.
調査の概要
研究の種類
介入
入学 (実際)
66
段階
- フェーズ2
- フェーズ 1
連絡先と場所
このセクションには、調査を実施する担当者の連絡先の詳細と、この調査が実施されている場所に関する情報が記載されています。
研究場所
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Darmstadt、ドイツ
- Please contact the Merck KGaA Communication Center located in
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参加基準
研究者は、適格基準と呼ばれる特定の説明に適合する人を探します。これらの基準のいくつかの例は、人の一般的な健康状態または以前の治療です。
適格基準
就学可能な年齢
18年歳以上 (大人、高齢者)
健康ボランティアの受け入れ
いいえ
受講資格のある性別
全て
説明
Inclusion Criteria:
- Histologically confirmed HCC
- Child Pugh Class A liver function score
- For Phase 2 only: MET+ status
- Male or female, 18 years of age or older
- Measurable disease in accordance with Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1
- Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1 (inclusive)
- Availability of a pretreatment tumor biopsy (excluding fine needle aspiration and cytology samples) taken after the subject has discontinued sorafenib and within 28 days before the day of first dosing with MSC2156119J. From the pretreatment biopsy either a formalin-fixed (formalin fixation is mandatory) paraffin-embedded block with tumor tissue (preferred) or at least 15 unstained slides must be sent to the central laboratory prior to enrollment. An associated pathology report must also be sent with the sample
- Previously treated with sorafenib for greater than or equal to 4 weeks and discontinued sorafenib treatment at least 14 days prior to Day 1 due to either intolerance or radiographic progression
- Signed and dated informed consent indicating that the subject (or legally acceptable representative if applicable by local laws) has been informed of all the pertinent aspects of the trial prior to enrollment
- Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests and other trial procedures
- Life expectancy of at least 3 months as judged by the investigator
Exclusion Criteria:
- Prior systemic anticancer treatment for advanced HCC (except for sorafenib as described in the inclusion criteria)
- Prior treatment with any agent targeting the hepatocyte growth factor (HGF)/c-Met pathway
- Local-regional therapy within 4 weeks before Day 1
- Impaired cardiac function
- Other protocol defined exclusion criteria could apply
研究計画
このセクションでは、研究がどのように設計され、研究が何を測定しているかなど、研究計画の詳細を提供します。
研究はどのように設計されていますか？
デザインの詳細
- 主な目的：処理
- 割り当て：非ランダム化
- 介入モデル：並列代入
- マスキング：なし（オープンラベル）
武器と介入
参加者グループ / アーム |
介入・治療 |
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実験的：Phase 1b: Tepotinib 300 mg
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Participants received a single oral dose of Tepotinib 300 milligram (mg) in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.
他の名前：
Participants received a single oral dose of Tepotinib 500 mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.
他の名前：
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実験的：Phase 1b: Tepotinib 500 mg
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Participants received a single oral dose of Tepotinib 300 milligram (mg) in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.
他の名前：
Participants received a single oral dose of Tepotinib 500 mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.
他の名前：
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実験的：Phase 2: Tepotinib 500 mg
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Participants received a single oral dose of Tepotinib 300 milligram (mg) in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.
他の名前：
Participants received a single oral dose of Tepotinib 500 mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.
他の名前：
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この研究は何を測定していますか？
主要な結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
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Phase 1b: Number of Participants Experiencing Dose Limiting Toxicity (DLT) According to National Cancer Institute Common Toxicity Criteria (NCI-CTCAE) for Adverse Events (AEs) Version 4.0
時間枠：Day 1 to Day 21 of Cycle 1 (each cycle was 21 days)
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DLT: defined using NCI-CTCAE for AEs Version 4.0, as any of following toxicities: Grade 4 neutropenia for more than 7 days; greater than or equal to (>=) Grade 3 febrile neutropenia for more than 1 day; Grade 4 or Grade 3 thrombocytopenia with nontraumatic bleeding; >=Grade 3 uncontrolled nausea/vomiting and/or diarrhoea despite adequate treatment for more than 3 days; >=Grade 3 any non-hematological AE. (DLT defined specifically for following cases: >=Grade 3 liver AE requiring recovery period of more than 7 days or to Grade 1 or less or Grade 2 with liver metastases ; >=Grade 3 lipase and/or amylase elevation with confirmation of pancreatitis.
An isolated lipase and/or amylase elevation of >=Grade 3 without clinical/radiological evidence of pancreatitis was not classified as DLT); and AEs assessed by investigators to be exclusively related to the participant's underlying disease or medical condition/concomitant treatment are not considered as DLTs.
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Day 1 to Day 21 of Cycle 1 (each cycle was 21 days)
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Phase 2: Number of Participants Who Were Progression-free at 12 Weeks (PFS Status) as Assessed by the Investigator According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1
時間枠：At 12 weeks post first-dose in Phase 2
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PFS status was evaluated by the number of participants who were progression-free at 12 weeks according to RECIST Version 1.1.
Participants were considered to be progression-free if the participant had a tumor assessment of Complete Response (CR) defined as disappearance of all target and non-target lesions and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 millimeter (mm).
Partial response (PR) defined as at least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum diameters, or Stable Disease (SD) defined as any cases that do not qualify for either partial response or progressive disease (an increase of at least 20% in the sum of the diameters of target lesions, taking as reference the smallest sum of the diameters of target lesions recorded since treatment started)12 weeks after start of treatment or later.
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At 12 weeks post first-dose in Phase 2
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二次結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
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Phase 1b and Phase 2: Time to Progression According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1
時間枠：Time from first study drug administration to the date of first occurrence of radiological progressive disease (PD), assessed up to 12 months after last participant's first dose (assessed maximum up to 1369 days)
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TTP was the time (in months) from the date of first study drug administration to the date of radiological confirmation of PD performed according to RECIST Version 1.1.
PD was defined as an increase of at least 20% in the sum of the diameters of target lesions, taking as reference the smallest sum of the diameters of target lesions recorded since treatment started.
The descriptive data represents the number of participants with progression.
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Time from first study drug administration to the date of first occurrence of radiological progressive disease (PD), assessed up to 12 months after last participant's first dose (assessed maximum up to 1369 days)
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Phase 1b and Phase 2: Progression-free Survival (PFS) Time According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1
時間枠：From randomization up to first observation of PD or death, assessed maximum up to 1369 days
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PFS time was defined as the time from date of randomization until date of the first observation of progressive disease (PD) or death due to any cause within 12 weeks of the last tumor assessment in the absence of documented PD, whichever occurs first.
PFS was assessed as per RECIST v1.1 as adjudicated by independent endpoint review committee (IERC).
PD was defined as an increase of at least 20% in the sum of the diameters of target lesions, taking as reference the smallest sum of the diameters of target lesions recorded since treatment started.
The descriptive data represents number of participants with death or progressive disease.
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From randomization up to first observation of PD or death, assessed maximum up to 1369 days
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Phase 1b and Phase 2: Progression-free Survival (PFS) Time According to Modified Response Evaluation Criteria in Solid Tumors (mRECIST) for Hepatocellular Carcinoma (HCC)
時間枠：From randomization up to first observation of PD or death, assessed maximum up to 1369 days
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PFS time was defined as the time from date of randomization until date of the first observation of progressive disease (PD) or death due to any cause within 12 weeks of the last tumor assessment in the absence of documented PD, whichever occurs first.
PFS was assessed as per mRECIST for HCC as adjudicated by independent endpoint review committee (IERC).
PD was defined as an increase of at least 20% in the sum of the diameters of viable (enhancing) target lesions, taking as reference the smallest sum of the diameters of target lesions recorded since treatment started.
The descriptive data represents number of participants with death or progressive disease.
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From randomization up to first observation of PD or death, assessed maximum up to 1369 days
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Phase 2: Time-to-symptomatic Progression (TTSP)
時間枠：From date of randomization up to 1369 days
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Time-to-symptomatic progression was defined as time (in months) from first study drug administration to the date of deterioration of symptoms assessed by Functional Assessment of Cancer Therapy Hepatobiliary Symptom Index 8 (FHSI-8) (defined as at least a 4-point increase, i.e., higher score, compared with baseline value), or deterioration to Eastern Cooperative Oncology Group (ECOG) performance score 4, or death.
FHSI-8 assesses hepatobiliary cancer symptoms with total score ranges from 0 to 32 (0 = the best quality of life; 32 = the worst quality of life with severe symptoms).
ECOG assess participant's performance status on a scale of 0 to 5, where 0=fully active and 5=dead.
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From date of randomization up to 1369 days
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Phase 1b and Phase 2: Overall Survival (OS) Time
時間枠：From date of randomization up to the date of death, assessed maximum up to 1369 days
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The OS time was defined as the time from randomization to the date of death.
The participants who were still alive at the time of data analysis or who were lost to follow-up OS time was censored at the last recorded date that the participant was known to be alive before the data cutoff date.
The descriptive data represents number of participants who had an event of death.
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From date of randomization up to the date of death, assessed maximum up to 1369 days
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Phase 1b and Phase 2: Percentage of Participants With Best Overall Tumor Assessment of CR or PR According to RECIST v1.1
時間枠：From date of randomization up to first occurrence of PD, assessed maximum up to 1369 days
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Percentage of participants with best overall tumor assessment of (CR or PR) according to RECIST Version 1.1 was reported.
CR defined as disappearance of all target and non-target lesions and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm.
PR defined as at least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum diameters.
PD was defined as an increase of at least 20% in the sum of the diameters of target lesions, taking as reference the smallest sum of the diameters of target lesions recorded since treatment started.
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From date of randomization up to first occurrence of PD, assessed maximum up to 1369 days
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Phase 1b and Phase 2: Percentage of Participants With Disease Control
時間枠：From date of randomization up to first occurrence of PD, assessed maximum up to 1369 days
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Disease control was defined as CR, PR, or SD as the best overall response according to RECIST Version 1.1.
Complete Response (CR) defined as disappearance of all target and non-target lesions and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm.
Partial response (PR) defined as at least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum diameters, or Stable Disease (SD) defined as any cases that do not qualify for either partial response or progressive disease (an increase of at least 20% in the sum of the diameters of target lesions, taking as reference the smallest sum of the diameters of target lesions recorded since treatment started)12 weeks after start of treatment or later.
Percentage of Participants With Disease Control were reported.
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From date of randomization up to first occurrence of PD, assessed maximum up to 1369 days
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Phase 1b and Phase 2: Percentage of Participants With Biological Response
時間枠：Baseline up to Cycle 3 (each cycle is 21 days)
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Percentage of participants with biological response was measured by serum Alpha-Fetoprotein (AFP), defined as a greater than 20% decrease in AFP level by Cycle 3 (each cycle is of 21 days) compared with baseline.
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Baseline up to Cycle 3 (each cycle is 21 days)
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Phase 1b: Area Under the Plasma Concentration-Time Curve From Time Zero to Last Sampling Time at Which the Concentration is at or Above the Lower Limit of Quantification (AUC0-t) of Tepotinib
時間枠：Pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10 and 24 hours Post-dose on Day 1 and Day 15 of Treatment Cycle 1 (each cycle was 21 days)
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Pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10 and 24 hours Post-dose on Day 1 and Day 15 of Treatment Cycle 1 (each cycle was 21 days)
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Phase 1b: Dose Normalized Area Under the Plasma Concentration-Time Curve From Zero to Last Sampling Time at Which the Concentration is at or Above the Lower Limit of Quantification (AUC0-t) of Tepotinib
時間枠：Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours post-dose; Day 1 and Day 15 of Cycle 1 (each Cycle is 21 days)
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Dose normalized was calculated as area under the plasma concentration versus time curve from time zero to the last sampling time t at which the concentration is at or above the lower limit of quantification (LLQ) divided by the dose.
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Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours post-dose; Day 1 and Day 15 of Cycle 1 (each Cycle is 21 days)
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Phase 1b: Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC0-inf) of Tepotinib
時間枠：Pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10 and 24 hours Post-dose on Day 1 and Day 15 of Treatment Cycle 1 (each cycle was 21 days)
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Pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10 and 24 hours Post-dose on Day 1 and Day 15 of Treatment Cycle 1 (each cycle was 21 days)
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Phase 1b: Maximum Observed Plasma Concentration (Cmax) of Tepotinib
時間枠：Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours post-dose; Day 1 and Day 15 of Cycle 1 (each Cycle is 21 days)
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Cmax is the maximum observed plasma concentration obtained directly from the concentration versus time curve.
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Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours post-dose; Day 1 and Day 15 of Cycle 1 (each Cycle is 21 days)
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Phase 1b: Dose Normalized Maximum Observed Plasma Concentration (Cmax) of Tepotinib
時間枠：Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours post-dose; Day 1 and Day 15 of Cycle 1 (each Cycle is 21 days)
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Dose normalized was calculated as maximum observed plasma concentration obtained directly from the concentration versus time curve divided by dose.
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Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours post-dose; Day 1 and Day 15 of Cycle 1 (each Cycle is 21 days)
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Phase 1b: Minimum Observed Plasma Concentration (Cmin) of Tepotinib
時間枠：Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours post-dose; Day 15 of Cycle 1 (each Cycle is 21 days)
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Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours post-dose; Day 15 of Cycle 1 (each Cycle is 21 days)
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Phase 1b: Time to Reach Maximum Plasma Concentration (Tmax) of Tepotinib
時間枠：Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours post-dose; Day 1 and Day 15 of Cycle 1 (each Cycle is 21 days)
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Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours post-dose; Day 1 and Day 15 of Cycle 1 (each Cycle is 21 days)
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Phase 1b: Average Plasma Concentration at Steady State (Cav) of Tepotinib
時間枠：Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours post-dose; Day 15 of Cycle 1 (each Cycle is 21 days)
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Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours post-dose; Day 15 of Cycle 1 (each Cycle is 21 days)
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Phase 1b: Apparent Total Body Clearance From Plasma (CL/f) of Tepotinib
時間枠：Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours post-dose; Day 15 of Cycle 1 (each Cycle is 21 days)
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Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours post-dose; Day 15 of Cycle 1 (each Cycle is 21 days)
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Phase 1b: Apparent Volume of Distribution During the Terminal Phase (Vz/f) of Tepotinib
時間枠：Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours post-dose; Day 1 and Day 15 of Cycle 1 (each Cycle is 21 days)
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Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours post-dose; Day 1 and Day 15 of Cycle 1 (each Cycle is 21 days)
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Phase 1b: Apparent Volume of Distribution During the Steady State (Vss/f) of Tepotinib
時間枠：Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours post-dose; Day 1 and Day 15 of Cycle 1 (each Cycle is 21 days)
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Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours post-dose; Day 1 and Day 15 of Cycle 1 (each Cycle is 21 days)
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Phase 1b: Apparent Terminal Elimination Rate Constant (λz) of Tepotinib
時間枠：Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours post-dose; Day 1 and Day 15 of Cycle 1 (each Cycle is 21 days)
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Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours post-dose; Day 1 and Day 15 of Cycle 1 (each Cycle is 21 days)
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Phase 1b: Apparent Terminal Half-life (t1/2) of Tepotinib
時間枠：Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours post-dose; Day 1 and Day 15 of Cycle 1 (each Cycle is 21 days)
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Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours post-dose; Day 1 and Day 15 of Cycle 1 (each Cycle is 21 days)
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Phase 1b: Time Prior to the First Quantifiable (Non-zero) Concentration (Tlag) of Tepotinib
時間枠：Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours post-dose; Day 1 Cycle 1 (each Cycle is 21 days)
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Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours post-dose; Day 1 Cycle 1 (each Cycle is 21 days)
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Phase 1b: Percentage Peak-Trough Fluctuation (PTF) Post First Dose of Tepotinib
時間枠：Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours post-dose; Day 15 of Cycle 1 (each Cycle is 21 days)
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The peak trough fluctuation within complete dosing interval at steady state, calculated as PTF (%) = ([Cmax - Cmin]/Cav ) multiplied by 100
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Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours post-dose; Day 15 of Cycle 1 (each Cycle is 21 days)
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Phase 1b: Accumulation Ratio of Cmax (Racc (Cmax))
時間枠：Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours post-dose; Day 1 and Day 15 of Cycle 1 (each Cycle is 21 days)
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Accumulation ratio for Cmax was calculated as Cmax, after dosing on Day 15 divided by Cmax, after dosing on day 1 of cycle 1.
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Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours post-dose; Day 1 and Day 15 of Cycle 1 (each Cycle is 21 days)
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Phase 1b: Accumulation Ratio of AUC (Racc (AUC)
時間枠：Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours post-dose; Day 1 and Day 15 of Cycle 1 (each Cycle is 21 days)
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Accumulation ratio for AUC was calculated as AUC, after dosing on Day 15 divided by AUC, after dosing on day 1 of cycle 1.
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Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours post-dose; Day 1 and Day 15 of Cycle 1 (each Cycle is 21 days)
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協力者と研究者
ここでは、この調査に関係する人々や組織を見つけることができます。
出版物と役立つリンク
研究に関する情報を入力する責任者は、自発的にこれらの出版物を提供します。これらは、研究に関連するあらゆるものに関するものである可能性があります。
一般刊行物
- Xiong W, Hietala SF, Nyberg J, Papasouliotis O, Johne A, Berghoff K, Goteti K, Dong J, Girard P, Venkatakrishnan K, Strotmann R. Exposure-response analyses for the MET inhibitor tepotinib including patients in the pivotal VISION trial: support for dosage recommendations. Cancer Chemother Pharmacol. 2022 Jul;90(1):53-69. doi: 10.1007/s00280-022-04441-3. Epub 2022 Jun 30.
- Decaens T, Barone C, Assenat E, Wermke M, Fasolo A, Merle P, Blanc JF, Grando V, Iacobellis A, Villa E, Trojan J, Straub J, Bruns R, Berghoff K, Scheele J, Raymond E, Faivre S. Phase 1b/2 trial of tepotinib in sorafenib pretreated advanced hepatocellular carcinoma with MET overexpression. Br J Cancer. 2021 Jul;125(2):190-199. doi: 10.1038/s41416-021-01334-9. Epub 2021 Apr 6. Erratum In: Br J Cancer. 2021 Jun 2;:
研究記録日
これらの日付は、ClinicalTrials.gov への研究記録と要約結果の提出の進捗状況を追跡します。研究記録と報告された結果は、国立医学図書館 (NLM) によって審査され、公開 Web サイトに掲載される前に、特定の品質管理基準を満たしていることが確認されます。
主要日程の研究
研究開始 (実際)
2014年5月18日
一次修了 (実際)
2018年2月14日
研究の完了 (実際)
2018年2月14日
試験登録日
最初に提出
2014年4月14日
QC基準を満たした最初の提出物
2014年4月14日
最初の投稿 (見積もり)
2014年4月16日
学習記録の更新
投稿された最後の更新 (実際)
2022年8月24日
QC基準を満たした最後の更新が送信されました
2022年8月22日
最終確認日
2022年8月1日
詳しくは
この情報は、Web サイト clinicaltrials.gov から変更なしで直接取得したものです。研究の詳細を変更、削除、または更新するリクエストがある場合は、register@clinicaltrials.gov。 までご連絡ください。 clinicaltrials.gov に変更が加えられるとすぐに、ウェブサイトでも自動的に更新されます。