Clinical trial NCT02115373: c-Met Second-Line Hepatocellular Carcinoma
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Carcinoma, Hepatocellular
Keywords: Hepatocellular Carcinoma
c-Met inhibitor
Phase 1b
Sorafenib
MSC2156119J
Lead sponsor: Merck KGaA, Darmstadt, Germany
Sponsor class: INDUSTRY
First posted: 2014-04-16
Enrollment: 66
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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

Primary outcomes:
measure: 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
timeFrame: Day 1 to Day 21 of Cycle 1 (each cycle was 21 days)
measure: 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
timeFrame: At 12 weeks post first-dose in Phase 2
Secondary outcomes:
measure: Phase 1b and Phase 2: Time to Progression According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1
timeFrame: 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)
measure: Phase 1b and Phase 2: Progression-free Survival (PFS) Time According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1
timeFrame: From randomization up to first observation of PD or death, assessed maximum up to 1369 days
measure: Phase 1b and Phase 2: Progression-free Survival (PFS) Time According to Modified Response Evaluation Criteria in Solid Tumors (mRECIST) for Hepatocellular Carcinoma (HCC)
timeFrame: From randomization up to first observation of PD or death, assessed maximum up to 1369 days
measure: Phase 2: Time-to-symptomatic Progression (TTSP)
timeFrame: From date of randomization up to 1369 days
measure: Phase 1b and Phase 2: Overall Survival (OS) Time
timeFrame: From date of randomization up to the date of death, assessed maximum up to 1369 days
measure: Phase 1b and Phase 2: Percentage of Participants With Best Overall Tumor Assessment of CR or PR According to RECIST v1.1
timeFrame: From date of randomization up to first occurrence of PD, assessed maximum up to 1369 days
measure: Phase 1b and Phase 2: Percentage of Participants With Disease Control
timeFrame: From date of randomization up to first occurrence of PD, assessed maximum up to 1369 days
measure: Phase 1b and Phase 2: Percentage of Participants With Biological Response
timeFrame: Baseline up to Cycle 3 (each cycle is 21 days)
measure: 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
timeFrame: 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)
measure: 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
timeFrame: 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)
measure: Phase 1b: Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC0-inf) of Tepotinib
timeFrame: 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)
measure: Phase 1b: Maximum Observed Plasma Concentration (Cmax) of Tepotinib
timeFrame: 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)
measure: Phase 1b: Dose Normalized Maximum Observed Plasma Concentration (Cmax) of Tepotinib
timeFrame: 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)
measure: Phase 1b: Minimum Observed Plasma Concentration (Cmin) of Tepotinib
timeFrame: 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)
measure: Phase 1b: Time to Reach Maximum Plasma Concentration (Tmax) of Tepotinib
timeFrame: 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)
measure: Phase 1b: Average Plasma Concentration at Steady State (Cav) of Tepotinib
timeFrame: 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)
measure: Phase 1b: Apparent Total Body Clearance From Plasma (CL/f) of Tepotinib
timeFrame: 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)
measure: Phase 1b: Apparent Volume of Distribution During the Terminal Phase (Vz/f) of Tepotinib
timeFrame: 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)
measure: Phase 1b: Apparent Volume of Distribution During the Steady State (Vss/f) of Tepotinib
timeFrame: 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)
measure: Phase 1b: Apparent Terminal Elimination Rate Constant (λz) of Tepotinib
timeFrame: 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)
measure: Phase 1b: Apparent Terminal Half-life (t1/2) of Tepotinib
timeFrame: 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)
measure: Phase 1b: Time Prior to the First Quantifiable (Non-zero) Concentration (Tlag) of Tepotinib
timeFrame: 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)
measure: Phase 1b: Percentage Peak-Trough Fluctuation (PTF) Post First Dose of Tepotinib
timeFrame: 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)
measure: Phase 1b: Accumulation Ratio of Cmax (Racc (Cmax))
timeFrame: 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)
measure: Phase 1b: Accumulation Ratio of AUC (Racc (AUC)
timeFrame: 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)
Other outcomes:
Locations:
city: Darmstadt
country: Germany
facility: Please contact the Merck KGaA Communication Center located in
Study officials:
affiliation: Merck KGaA, Darmstadt, Germany
name: Medical Responsible
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.