Efficacy, Safety, and Pharmacokinetic of MSC2156119J in Asian Participants With Hepatocellular Carcinoma

NCT01988493 | Completed Phase 1 Results DMC

• 1 other identifier: 200095-004
• Study Type: interventional
• Target: 117
• Locations: 3 countries
• Sites: 43

Brief Summary

This is an open-label, integrated, Phase 1b/2 trial to determine the recommended Phase 2 dose (RP2D) and to evaluate the efficacy, safety, and pharmacokinetic of MSC2156119J as first-line treatment versus sorafenib in subjects with MET+, Barcelona Clinic Liver Cancer (BCLC) Stage C, systemic treatment naive advanced hepatocellular carcinoma (HCC) and Child-Pugh class A liver function.

Conditions

Carcinoma, Hepatocellular

Keywords

Carcinoma, Hepatocellular; MSC2156119J; Sorafenib; Recommended Phase 2 dose

Outcome Measures

Primary Outcomes (3)

• Phase 1b: Number of Participants Experiencing Dose Limiting Toxicity

  Dose limiting toxicity (DLT) was defined as toxicities at any dose level and judged to be related to the study treatment by investigator and/or the sponsor. DLTs included Grade 4 neutropenia for more than 7 days; Grade greater than or equal to (\>=) 3 febrile neutropenia for more than 1 day; Grade 4 thrombocytopenia or Grade 3 thrombocytopenia with non-traumatic bleeding; Grade \>= 3 uncontrolled nausea/vomiting and/or diarrhea despite adequate and optimal treatment and Grade \>= 3 any non-hematological adverse event (AE), except the aforementioned gastrointestinal events and alopecia. Number of participants who experienced DLT during phase 1b were reported.

  Day 1 to Day 21 of Cycle 1 (each cycle is 21 days)

• Phase 1b: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs

  An AE was defined as any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug. A serious AE was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. Treatment-emergent are events between first dose of study drug and assessed up to 94 weeks. TEAEs include both Serious TEAEs and non-serious TEAEs.

  Baseline up to Day 30 after the last dose of study treatment, assessed up to 94 weeks

• Phase 2: Time to Progression (TTP) Based on Tumor Assessment by an Independent Review Committee (IRC)

  TTP was defined as the time in months from randomization to date of the observation of radiological progressive disease (PD) (based on Response Evaluation Criteria in Solid Tumors \[RECIST\] v1.1) assessed by an IRC. PD is defined as at least 20 percent (%) increase in sum of diameters of target lesions, taking as reference as smallest sum on study; and/or unequivocal progression of existing non-target lesions and/or the presence of new lesions. The sum must demonstrate an absolute increase of at least 5 millimeter (mm).

  From randomization to date of the observation of radiological progressive disease, assessed up to maximum 3.8 years

Secondary Outcomes (21)

• Phase 2: Progression Free Survival (PFS) Time Based on Tumor Assessment by the Independent Review Committee (IRC)

  Up to 2.8 years

• Phase 2: Overall Survival (OS)

  Time from randomization to the date of death or up to 6.9 years

• Phase 2: Time to Progression (TTP) Based on Tumor Assessment by Investigator

  From randomization to date of the observation of radiological progressive disease, assessed up to maximum 2.8 years

• Phase 1b: Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC0-infinity) of Tepotinib

  Predose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours postdose; Day 1 and Day 15 of Cycle 1 (each Cycle is 21 days)

• Phase 1b: Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC 0-t) of Tepotinib

  Predose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours postdose; Day 1 and Day 15 of Cycle 1 (each Cycle is 21 days)

Study Arms (5)

Phase 1b: Tepotinib 300 mg

EXPERIMENTAL

Participants received Tepotinib 300 milligram (mg) orally once daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal.

Drug: Tepotinib 300 mg

Phase 1b: Tepotinib 500 mg

EXPERIMENTAL

Participants received Tepotinib 500 mg orally once daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal.

Drug: Tepotinib 500 mg

Phase 1b: Tepotinib 1000 mg

EXPERIMENTAL

Participants received Tepotinib 1000 mg orally once daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal.

Drug: Tepotinib 1000 mg

Phase 2: Tepotinib

EXPERIMENTAL

Participants randomized to receive Tepotinib recommended Phase 2 dose (RP2D) determined from Phase 1b over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal.

Drug: Tepotinib

Phase 2 Sorafenib

EXPERIMENTAL

Participants randomized to receive Sorafenib 400 mg orally twice daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal.

Drug: Sorafenib

Interventions

Tepotinib 300 mg DRUG

Participants received Tepotinib 300 milligram (mg) orally once daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal.

Phase 1b: Tepotinib 300 mg

Tepotinib 500 mg DRUG

Participants received Tepotinib 500 mg orally once daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal.

Phase 1b: Tepotinib 500 mg

Tepotinib 1000 mg DRUG

Participants received Tepotinib 1000 mg orally once daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal

Phase 1b: Tepotinib 1000 mg

Tepotinib DRUG

Participants randomized to receive Tepotinib recommended Phase 2 dose (RP2D) determined from Phase 1b over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal.

Phase 2: Tepotinib

Sorafenib DRUG

Participants randomized to receive Sorafenib 400 mg orally twice daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal.

Phase 2 Sorafenib

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Histologically or cytologically confirmed HCC
• Participants were either intermediate HCC of BCLC Stage B, who were not eligible for surgical and/or local-regional therapies or who had progressive disease (PD) after surgical and/or local-regional therapies (note: the local-regional therapy must not contain sorafenib), or advanced HCC of BCLC Stage C
• Participants who had disease progression on or were intolerant to the prior standard treatment for advanced HCC (phase Ib Korean subjects only)
• A tumor biopsy was required for determining MET status
• MET+ status (Phase 2 only), as determined by the central laboratory (Phase 1b retrospectively, Phase 2 for participant selection) were defined in the protocol
• Child-Pugh class A with no encephalopathy according to the screening assessment
• Asian male or female, 18 years of age or older
• Measurable disease in accordance with RECIST v1.1 (Phase 2 only)
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 to 2
• Eligible for treatment with sorafenib, was assessed by investigators according to the Package Insert and clinical judgment (Phase 2 only)
• Signed and dated informed consent indicating that the participants had 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 was judged by the investigator of at least 3 months

You may not qualify if:

• Prior systemic anticancer treatment for advanced HCC, included targeted therapy (for example, sorafenib), chemotherapy, or any other investigational agent (Phase 2 only)
• Prior treatment with any agent targeting the hepatocyte growth factor (HGF)/c-Met pathway
• Prior local-regional therapy within 4 weeks prior to Day 1 of trial treatment
• Prior history of liver transplant
• Laboratory index at baseline were defined in the protocol
• Past or current history of neoplasm other than HCC, except for curatively treated non-melanoma skin cancer, in situ carcinoma of the cervix, or other cancer curatively treated and with no evidence of disease for at least 5 years
• Known central nervous system (CNS) or brain metastasis that is either symptomatic or untreated
• Medical history of difficulty swallowing, malabsorption, or other chronic gastrointestinal disease, or conditions that may hamper compliance and/or absorption of the tested products
• Clinically significant gastrointestinal bleeding within 4 weeks before trial entry
• Peripheral neuropathy Grade greater than or equal to 2 (Common Terminology Criteria for Adverse Events \[CTCAE\] v4.0)
• Impaired cardiac function was defined in the protocol
• Hypertension uncontrolled by standard therapies
• Participants with a family history of long QT syndrome or who take any agent that is known to prolong QT/QTc interval
• Known human immunodeficiency virus (HIV) infection
• Particpants who had acute pancreatitis and/or chronic pancreatitis, with elevated lipase and/or amylase, clinical symptoms, and/or imaging studies that are indicative of the diagnosis (Mainland Chinese participants only)

Sponsors & Collaborators

• Merck KGaA, Darmstadt, Germany: lead

Study Sites (43)

307 Hosptial of PLA

Beijing, Beijing Municipality, 100071, China

Location

Peking University Cancer Hospital

Beijing, Beijing Municipality, 100142, China

Location

Fuzhou General Hospital of Nanjing Military Area Command of Chinese PLA

Fuzhou, Fujian, 350025, China

Location

Sun Yat-sen University, Cancer Center

Guangzhou, Guangdong, 510060, China

Location

Nanfang Hospital

Guangzhou, Guangdong, 510515, China

Location

Harbin Medical University Cancer Hospital

Harbin, Heilongjiang, 150081, China

Location

The Third Xiangya Hospital of Central South University

Changsha, Hu'nan, 410013, China

Location

Nanjing Bayi Hospital

Nanjing, Jiangsu, 210002, China

Location

Nanjing First Hospital Affiliated to Nanjing Medical University

Nanjing, Jiangsu, 210029, China

Location

Jilin Cancer Hospital

Changchun, Jilin, 130012, China

Location

Shanghai Cancer Hospital, Fudan University

Shanghai, Shanghai Municipality, 200032, China

Location

Zhongshan Hospital Fudan University

Shanghai, Shanghai Municipality, 200032, China

Location

Cancer Hospital, Tianjin Medical University

Tianjin, Zhejiang, 300060, China

Location

Sir Run Run Shaw Hospital, Zhejiang University, School of Medicine

Zhejiang, Zhejiang, 310016, China

Location

Beijing Friendship Hospital, Capital Medical University

Beijing, 100050, China

Location

Dong-A University Hospital

Busan, 602-715, South Korea

Location

Pusan National University Hospital

Busan, 602-739, South Korea

Location

Keimyung University Dongsan Hospital

Daegu, 41931, South Korea

Location

Kyungpook National University Hospital

Daegu, 700-721, South Korea

Location

National Cancer Center

Goyang-si, 10408, South Korea

Location

CHA Bundang Medical Center, CHA University

Seongnam-si, 13496, South Korea

Location

Seoul National University Bundang Hospital

Seongnam-si, 13620, South Korea

Location

Kyung Hee University Hospital

Seoul, 02447, South Korea

Location

Korea University Anam Hospital

Seoul, 02841, South Korea

Location

Severance Hospital, Yonsei University

Seoul, 03722, South Korea

Location

Asan Medical Center

Seoul, 05505, South Korea

Location

Gangnam Severance Hospital, Yonsei University Health System

Seoul, 06273, South Korea

Location

Samsung Medical Center

Seoul, 06351, South Korea

Location

The Catholic University of Korea, Seoul St. Mary's Hospital

Seoul, 06591, South Korea

Location

Korea University Guro Hospital

Seoul, 08308, South Korea

Location

Seoul National University Hospital

Seoul, 110744, South Korea

Location

Ajou University Hospital

Suwon, 443-380, South Korea

Location

Pusan National University Yangsan Hospital

Yangsan, 626-770, South Korea

Location

Changhua Christian Hospital

Changhua, 50004, Taiwan

Location

Kaohsiung Medical University Chung-Ho Memorial Hospital

Kaohsiung City, 807, Taiwan

Location

Kaohsiung Chang Gung Memorial Hospital

Kaohsiung City, 83301, Taiwan

Location

Taichung Veterans General Hospital

Taichung, 40705, Taiwan

Location

National Cheng Kung University Hospital

Tainan, 704, Taiwan

Location

Chi Mei Medical Center, Liou Ying

Tainan, 736, Taiwan

Location

National Taiwan University Hospital

Taipei, 100, Taiwan

Location

Mackay Memorial Hospital

Taipei, 10449, Taiwan

Location

Taipei Veterans General Hospital

Taipei, 11217, Taiwan

Location

Chang Gung Memorial Hospital, Linkou

Taoyuan District, 333, Taiwan

Location

Related Publications (2)

• Ryoo BY, Cheng AL, Ren Z, Kim TY, Pan H, Rau KM, Choi HJ, Park JW, Kim JH, Yen CJ, Lim HY, Zhou D, Straub J, Scheele J, Berghoff K, Qin S. Randomised Phase 1b/2 trial of tepotinib vs sorafenib in Asian patients with advanced hepatocellular carcinoma with MET overexpression. Br J Cancer. 2021 Jul;125(2):200-208. doi: 10.1038/s41416-021-01380-3. Epub 2021 May 10.

  PMID: 33972742 RESULT

• 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.

  PMID: 35771259 DERIVED

Related Links

• Trial Awareness and Transparency website
• Redacted Clinical study report, redacted clinical study protocol and redacted statistical analysis plan for this study is also available at the HC-PRCI portal (Health Canada-Public release of clinical information)

MeSH Terms

Conditions

Carcinoma, Hepatocellular

Interventions

tepotinib; Sorafenib

Condition Hierarchy (Ancestors)

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Liver Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Digestive System Diseases; Liver Diseases

Intervention Hierarchy (Ancestors)

Phenylurea Compounds; Urea; Amides; Organic Chemicals; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Niacinamide; Nicotinic Acids; Acids, Heterocyclic; Heterocyclic Compounds; Pyridines; Heterocyclic Compounds, 1-Ring

Results Point of Contact

• Title: Communication Center
• Organization: Merck KGaA Darmstadt, Germany

service@emdgroup.com

+49-6151-72-5200

Study Officials

• Medical Responsible

  Merck KGaA, Darmstadt, Germany

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 1, 2013
• First Posted: November 20, 2013
• Study Start: January 6, 2014
• Primary Completion: February 5, 2018
• Study Completion: December 3, 2020
• Last Updated: August 24, 2022
• Results First Posted: July 24, 2019

Record last verified: 2022-08

Locations

CN (15); TW (10); KR (18)