Working…
COVID-19 is an emerging, rapidly evolving situation.
Get the latest public health information from CDC: https://www.coronavirus.gov.

Get the latest research information from NIH: https://www.nih.gov/coronavirus.
ClinicalTrials.gov
ClinicalTrials.gov Menu

c-Met Second-Line Hepatocellular Carcinoma

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02115373
Recruitment Status : Completed
First Posted : April 16, 2014
Results First Posted : August 9, 2019
Last Update Posted : August 9, 2019
Sponsor:
Information provided by (Responsible Party):
Merck KGaA, Darmstadt, Germany

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.

Condition or disease Intervention/treatment Phase
Carcinoma, Hepatocellular Drug: Tepotinib Phase 1 Phase 2

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 66 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : May 18, 2014
Actual Primary Completion Date : February 14, 2018
Actual Study Completion Date : February 14, 2018

Arm Intervention/treatment
Experimental: Phase 1b: Tepotinib 300 mg Drug: Tepotinib
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.
Other Name: MSC2156119J

Experimental: Phase 1b: Tepotinib 500 mg Drug: Tepotinib
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.
Other Name: MSC2156119J

Experimental: Phase 2: Tepotinib 500 mg Drug: Tepotinib
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.
Other Name: MSC2156119J




Primary Outcome Measures :
  1. 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 [ Time Frame: Day 1 to Day 21 of Cycle 1 (each cycle was 21 days) ]
    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.

  2. 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 [ Time Frame: At 12 weeks post first-dose in Phase 2 ]
    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.


Secondary Outcome Measures :
  1. Phase 1b and Phase 2: Time to Progression According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 [ Time Frame: 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) ]
    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.

  2. Phase 1b and Phase 2: Progression-free Survival (PFS) Time According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 [ Time Frame: From randomization up to first observation of PD or death, assessed maximum up to 1369 days ]
    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.

  3. Phase 1b and Phase 2: Progression-free Survival (PFS) Time According to Modified Response Evaluation Criteria in Solid Tumors (mRECIST) for Hepatocellular Carcinoma (HCC) [ Time Frame: From randomization up to first observation of PD or death, assessed maximum up to 1369 days ]
    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.

  4. Phase 2: Time-to-symptomatic Progression (TTSP) [ Time Frame: From date of randomization up to 1369 days ]
    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.

  5. Phase 1b and Phase 2: Overall Survival (OS) Time [ Time Frame: From date of randomization up to the date of death, assessed maximum up to 1369 days ]
    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.

  6. Phase 1b and Phase 2: Percentage of Participants With Best Overall Tumor Assessment of CR or PR According to RECIST v1.1 [ Time Frame: From date of randomization up to first occurrence of PD, assessed maximum up to 1369 days ]
    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.

  7. Phase 1b and Phase 2: Percentage of Participants With Disease Control [ Time Frame: From date of randomization up to first occurrence of PD, assessed maximum up to 1369 days ]
    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.

  8. Phase 1b and Phase 2: Percentage of Participants With Biological Response [ Time Frame: Baseline up to Cycle 3 (each cycle is 21 days) ]
    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.

  9. 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 [ Time Frame: 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) ]
  10. 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 [ Time Frame: 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) ]
    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.

  11. Phase 1b: Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC0-inf) of Tepotinib [ Time Frame: 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) ]
  12. Phase 1b: Maximum Observed Plasma Concentration (Cmax) of Tepotinib [ Time Frame: 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) ]
    Cmax is the maximum observed plasma concentration obtained directly from the concentration versus time curve.

  13. Phase 1b: Dose Normalized Maximum Observed Plasma Concentration (Cmax) of Tepotinib [ Time Frame: 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) ]
    Dose normalized was calculated as maximum observed plasma concentration obtained directly from the concentration versus time curve divided by dose.

  14. Phase 1b: Minimum Observed Plasma Concentration (Cmin) of Tepotinib [ Time Frame: 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) ]
  15. Phase 1b: Time to Reach Maximum Plasma Concentration (Tmax) of Tepotinib [ Time Frame: 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) ]
  16. Phase 1b: Average Plasma Concentration at Steady State (Cav) of Tepotinib [ Time Frame: 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) ]
  17. Phase 1b: Apparent Total Body Clearance From Plasma (CL/f) of Tepotinib [ Time Frame: 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) ]
  18. Phase 1b: Apparent Volume of Distribution During the Terminal Phase (Vz/f) of Tepotinib [ Time Frame: 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) ]
  19. Phase 1b: Apparent Volume of Distribution During the Steady State (Vss/f) of Tepotinib [ Time Frame: 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) ]
  20. Phase 1b: Apparent Terminal Elimination Rate Constant (λz) of Tepotinib [ Time Frame: 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) ]
  21. Phase 1b: Apparent Terminal Half-life (t1/2) of Tepotinib [ Time Frame: 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) ]
  22. Phase 1b: Time Prior to the First Quantifiable (Non-zero) Concentration (Tlag) of Tepotinib [ Time Frame: 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) ]
  23. Phase 1b: Percentage Peak-Trough Fluctuation (PTF) Post First Dose of Tepotinib [ Time Frame: 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) ]
    The peak trough fluctuation within complete dosing interval at steady state, calculated as PTF (%) = ([Cmax - Cmin]/Cav ) multiplied by 100

  24. Phase 1b: Accumulation Ratio of Cmax (Racc (Cmax)) [ Time Frame: 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) ]
    Accumulation ratio for Cmax was calculated as Cmax, after dosing on Day 15 divided by Cmax, after dosing on day 1 of cycle 1.

  25. Phase 1b: Accumulation Ratio of AUC (Racc (AUC) [ Time Frame: 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) ]
    Accumulation ratio for AUC was calculated as AUC, after dosing on Day 15 divided by AUC, after dosing on day 1 of cycle 1.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02115373


Locations
Layout table for location information
Germany
Please contact the Merck KGaA Communication Center located in
Darmstadt, Germany
Sponsors and Collaborators
Merck KGaA, Darmstadt, Germany
Investigators
Layout table for investigator information
Study Director: Medical Responsible Merck KGaA, Darmstadt, Germany
  Study Documents (Full-Text)

Documents provided by Merck KGaA, Darmstadt, Germany:
Study Protocol  [PDF] June 13, 2016
Statistical Analysis Plan  [PDF] March 15, 2018

Layout table for additonal information
Responsible Party: Merck KGaA, Darmstadt, Germany
ClinicalTrials.gov Identifier: NCT02115373    
Other Study ID Numbers: EMR 200095_005
2013-002053-30 ( EudraCT Number )
First Posted: April 16, 2014    Key Record Dates
Results First Posted: August 9, 2019
Last Update Posted: August 9, 2019
Last Verified: June 2019
Keywords provided by Merck KGaA, Darmstadt, Germany:
Hepatocellular Carcinoma
c-Met inhibitor
Phase 1b
Sorafenib
MSC2156119J
Additional relevant MeSH terms:
Layout table for MeSH terms
Carcinoma
Carcinoma, Hepatocellular
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Adenocarcinoma
Liver Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Liver Diseases