Efficacy, Safety, and Pharmacokinetic of MSC2156119J in Asian Participants With Hepatocellular Carcinoma
Sponsor
Merck KGaA, Darmstadt, Germany (Industry)
Overall Status
Completed
CT.gov ID
NCT01988493
Collaborator
(none)
117
43
5
82.9
2.7
0
Study Details
Study Description
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 1/Phase 2 |
Study Design
Study Type:
Interventional
Actual Enrollment
:
117 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Multicenter, Randomized, Phase Ib/II Trial to Evaluate the Efficacy, Safety, and Pharmacokinetics of MSC2156119J as Monotherapy Versus Sorafenib in Asian Subjects With MET+ Advanced Hepatocellular Carcinoma and Child-Pugh Class A Liver Function
Actual Study Start Date
:
Jan 6, 2014
Actual Primary Completion Date
:
Feb 5, 2018
Actual Study Completion Date
:
Dec 3, 2020
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Phase 1b: Tepotinib 300 mg 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
Participants received Tepotinib 300 milligram (mg) orally once daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal.
|
| Experimental: Phase 1b: Tepotinib 500 mg 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
Participants received Tepotinib 500 mg orally once daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal.
|
| Experimental: Phase 1b: Tepotinib 1000 mg 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
Participants received Tepotinib 1000 mg orally once daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal
|
| Experimental: Phase 2: Tepotinib 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
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.
|
| Experimental: Phase 2 Sorafenib 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
Participants randomized to receive Sorafenib 400 mg orally twice daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal.
|
Outcome Measures
Primary Outcome Measures
- Phase 1b: Number of Participants Experiencing Dose Limiting Toxicity [Day 1 to Day 21 of Cycle 1 (each cycle is 21 days)]
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.
- Phase 1b: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs [Baseline up to Day 30 after the last dose of study treatment, assessed up to 94 weeks]
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.
- Phase 2: Time to Progression (TTP) Based on Tumor Assessment by an Independent Review Committee (IRC) [From randomization to date of the observation of radiological progressive disease, assessed up to maximum 3.8 years]
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).
Secondary Outcome Measures
- Phase 2: Progression Free Survival (PFS) Time Based on Tumor Assessment by the Independent Review Committee (IRC) [Up to 2.8 years]
Progression-free survival (PFS) time was defined as the time in months from randomization to either first observation of disease progression (based on RECIST v1.1) or occurrence of death due to any cause within 84 days of either randomization or the last tumor assessment. PD is defined as at least a 20 percent (%) increase in the sum of diameters of target lesions, taking as reference the smallest sum on study; and/or unequivocal progression of existing non-target lesions and/or the presence of new lesions. The sum must also demonstrate an absolute increase of at least 5 millimeter(mm). PFS was measured using Kaplan-Meier (KM) estimates.
- Phase 2: Overall Survival (OS) [Time from randomization to the date of death or up to 6.9 years]
Overall survival time was measured as time in months between the date of randomization and the date of death.
- 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]
TTP was defined as the time in months from randomization to date of the observation of radiological PD (based on RECIST v1.1) assessed by the investigator. PD is defined as at least a 20 percent (%) increase in the sum of diameters of target lesions, taking as reference the smallest sum on study; and/or unequivocal progression of existing non-target lesions and/or the presence of new lesions. The sum must also demonstrate an absolute increase of at least 5 mm.
- 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)]
The AUC(0-inf) was estimated by determining the total area under the curve of the concentration versus time curve extrapolated to infinity.
- 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)]
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 (LLLQ). AUC(0-t) was calculated according to the mixed log-linear trapezoidal rule.
- Phase 1b: Area Under the Plasma Concentration-Time Curve Within 1 Dosing Interval (AUC 0-tau) 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)]
AUC (0-tau) is the area under the plasma concentration time curve within 1 dosing interval.
- Phase 1b: Maximum Observed Plasma Concentration (Cmax) 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)]
Cmax is the maximum observed plasma concentration obtained directly from the concentration versus time curve.
- Phase 1b: Minimum Observed Plasma Concentration (Cmin) of Tepotinib [Predose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours postdose; Day 15 of Cycle 1 (each Cycle is 21 days)]
Cmin is minimum observed plasma concentration obtained directly from the concentration versus time curve.
- Phase 1b: Average Observed Plasma Concentration (Cav) of Tepotinib [Predose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours postdose; Day 15 of Cycle 1 (each Cycle is 21 days)]
Cavg is the average plasma concentration within 1 dosing interval obtained directly from the concentration versus time curve.
- Phase 1b: Time to Reach Maximum Plasma Concentration (Tmax) 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)]
Tmax is time to reach maximum observed plasma concentration obtained directly from the concentration versus time curve.
- Phase 1b: Apparent Volume of Distribution During the Terminal Phase (Vz/f) 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)]
The Vz/f was defined as the theoretical volume in which the total amount of required to uniformly distribute to produce the desired plasma concentration. Apparent volume of distribution after oral dose (Vz/F) was influenced by the fraction absorbed. The Vz/f was calculated by dividing the dose with area under the concentration time curve from time zero to infinity multiplied with terminal elimination rate constant Lambda(z). Vz/f=Dose/AUC(0-inf)* Lambda(z).
- Phase 1b: Apparent Total Body Clearance From Plasma (CL/f) 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)]
The CL/f is a measure of the rate at which it was metabolized or eliminated by normal biological processes. Clearance obtained after oral dose was influenced by the fraction of the dose absorbed. The CL/F from plasma was calculated using the formula: Dose divided by area under the concentration time curve from time zero to infinity (AUC0-inf).
- Phase 1b: Apparent Volume of Distribution During the Steady State (Vss/f) 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)]
Volume of distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Vss/f after oral dose was influenced by the fraction absorbed.
- Phase 1b: Apparent Terminal Elimination Rate Constant Lambda(z) 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)]
Lambda(z) was determined from the terminal slope of the log-transformed plasma concentration curve using linear regression method.
- Phase 1b: Apparent Terminal Half-life (t1/2) 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)]
Apparent terminal half-life was defined as the time required for the plasma concentration of drug to decrease 50 percent in the final stage of its elimination.
- Phase 2: Time-to-Symptomatic Progression (TTSP) [Up to 6.9 years]
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.
- Phase 2: Objective Response Rate (ORR) Based on Tumor Assessment by the IRC [Time from randomization until the first occurrence of PD assessed up to 6.9 years]
The objective response rate (ORR) was defined as the percentage of participants who had achieved complete response (CR) or partial response (PR) as the best overall response according to radiological assessments as adjudicated by the IRC from randomization until the first occurrence of PD. CR: 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. PD 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.
- Phase 2: Percentage of Participants With Disease Control Based on Tumor Assessment by IRC According to Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST v1.1) Criteria [Time from randomization until the first occurrence of PD assessed up to 6.9 years]
Disease control was defined as CR, PR, or stable disease (SD) as the best overall response according to radiological assessments as adjudicated by the IRC from randomization until the first occurrence of PD. 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. Percentage of participants with disease control were reported.
- Phase 2: Progression-free Survival (PFS) Based on Tumor Assessment by the Investigator [Time from randomization to disease progression or occurrence of death due to any cause within 84 days of either randomization or the last tumor assessment, assessed up to 6.9 years]
Progression-free survival (assessed by the Investigator) time was defined as the time in months from randomization to either first observation of radiologically confirmed progression disease by the investigator or occurrence of death due to any cause within 84 days of either randomization or the last tumor assessment. PD is defined as at least a 20 percent (%) increase in the sum of diameters of target lesions, taking as reference the smallest sum on study; and/or unequivocal progression of existing non-target lesions and/or the presence of new lesions. The sum must also demonstrate an absolute increase of at least 5 mm. PFS was measured using Kaplan-Meier (KM) estimates.
- Phase 2: Objective Response Rate (ORR) Based on Tumor Assessment by the Investigator [Time from randomization until the first occurrence of PD assessed up to 6.9 years]
The objective response rate was defined as the percentage of participants who had achieved CR or PR as the best overall response according to radiological assessments as adjudicated by the investigator from randomization until the first occurrence of PD. 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.
- Phase 2: Percentage of Participants With Disease Control Based on Tumor Assessment by Investigator According to Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST v1.1) Criteria [Approximately up to 6.9 years]
Disease control was defined as CR, PR, or stable disease (SD) as the best overall response according to radiological assessments as adjudicated by the IRC from randomization until the first occurrence of PD. 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. Percentage of participants with disease control were reported.
Eligibility Criteria
Criteria
Ages Eligible for Study:
18 Years
and Older
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
Inclusion Criteria:
-
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
Exclusion Criteria:
-
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)
-
Known or suspected drug hypersensitivity to any ingredients of sorafenib (Phase 2 only) and MSC2156119J
-
Female participants who were pregnant or lactating, or males and females of reproductive potential not willing or not able to employ a highly effective method of birth control/contraception to prevent pregnancy from 2 weeks before receiving study drug until 3 months after receiving the last dose of study drug
-
Concurrent treatment with a non-permitted drug
-
Substance abuse, other acute or chronic medical or psychiatric condition, or laboratory abnormalities that may increase the risk associated with trial participation in the opinion of the investigator
-
Participation in another clinical trial within the past 28 days
-
Previous anticancer treatment-related toxicities not recovered to baseline or Grade 0-1 (except alopecia and peripheral neuropathy)
-
Participants with any concurrent medical condition or disease that will potentially compromise the conduct of the study at the discretion of the investigators
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | 307 Hosptial of PLA | Beijing | Beijing | China | 100071 |
| 2 | Peking University Cancer Hospital | Beijing | Beijing | China | 100142 |
| 3 | Fuzhou General Hospital of Nanjing Military Area Command of Chinese PLA | Fuzhou | Fujian | China | 350025 |
| 4 | Sun Yat-sen University, Cancer Center | Guangzhou | Guangdong | China | 510060 |
| 5 | Nanfang Hospital | Guangzhou | Guangdong | China | 510515 |
| 6 | Harbin Medical University Cancer Hospital | Harbin | Heilongjiang | China | 150081 |
| 7 | The Third Xiangya Hospital of Central South University | Changsha | Hunan | China | 410013 |
| 8 | Nanjing Bayi Hospital | Nanjing | Jiangsu | China | 210002 |
| 9 | Nanjing First Hospital Affiliated to Nanjing Medical University | Nanjing | Jiangsu | China | 210029 |
| 10 | Jilin Cancer Hospital | Changchun | Jilin | China | 130012 |
| 11 | Shanghai Cancer Hospital, Fudan University | Shanghai | Shanghai | China | 200032 |
| 12 | Zhongshan Hospital Fudan University | Shanghai | Shanghai | China | 200032 |
| 13 | Cancer Hospital, Tianjin Medical University | Tianjin | Zhejiang | China | 300060 |
| 14 | Sir Run Run Shaw Hospital, Zhejiang University, School of Medicine | Zhejiang | Zhejiang | China | 310016 |
| 15 | Beijing Friendship Hospital, Capital Medical University | Beijing | China | 100050 | |
| 16 | Dong-A University Hospital | Busan | Korea, Republic of | 602-715 | |
| 17 | Pusan National University Hospital | Busan | Korea, Republic of | 602-739 | |
| 18 | Keimyung University Dongsan Hospital | Daegu | Korea, Republic of | 41931 | |
| 19 | Kyungpook National University Hospital | Daegu | Korea, Republic of | 700-721 | |
| 20 | National Cancer Center | Goyang-si | Korea, Republic of | 10408 | |
| 21 | CHA Bundang Medical Center, CHA University | Seongnam-si, | Korea, Republic of | 13496 | |
| 22 | Seoul National University Bundang Hospital | Seongnam-si | Korea, Republic of | 13620 | |
| 23 | Kyung Hee University Hospital | Seoul | Korea, Republic of | 02447 | |
| 24 | Korea University Anam Hospital | Seoul | Korea, Republic of | 02841 | |
| 25 | Severance Hospital, Yonsei University | Seoul | Korea, Republic of | 03722 | |
| 26 | Asan Medical Center | Seoul | Korea, Republic of | 05505 | |
| 27 | Gangnam Severance Hospital, Yonsei University Health System | Seoul | Korea, Republic of | 06273 | |
| 28 | Samsung Medical Center | Seoul | Korea, Republic of | 06351 | |
| 29 | The Catholic University of Korea, Seoul St. Mary's Hospital | Seoul | Korea, Republic of | 06591 | |
| 30 | Korea University Guro Hospital | Seoul | Korea, Republic of | 08308 | |
| 31 | Seoul National University Hospital | Seoul | Korea, Republic of | 110744 | |
| 32 | Ajou University Hospital | Suwon-si | Korea, Republic of | 443-380 | |
| 33 | Pusan National University Yangsan Hospital | Yangsan | Korea, Republic of | 626-770 | |
| 34 | Changhua Christian Hospital | Changhua | Taiwan | 50004 | |
| 35 | Kaohsiung Medical University Chung-Ho Memorial Hospital | Kaohsiung | Taiwan | 807 | |
| 36 | Kaohsiung Chang Gung Memorial Hospital | Kaohsiung | Taiwan | 83301 | |
| 37 | Taichung Veterans General Hospital | Taichung | Taiwan | 40705 | |
| 38 | National Cheng Kung University Hospital | Tainan | Taiwan | 704 | |
| 39 | Chi Mei Medical Center, Liou Ying | Tainan | Taiwan | 736 | |
| 40 | National Taiwan University Hospital | Taipei | Taiwan | 100 | |
| 41 | Mackay Memorial Hospital | Taipei | Taiwan | 10449 | |
| 42 | Taipei Veterans General Hospital | Taipei | Taiwan | 11217 | |
| 43 | Chang Gung Memorial Hospital, Linkou | Taoyuan | Taiwan | 333 |
Sponsors and Collaborators
- Merck KGaA, Darmstadt, Germany
Investigators
- Study Director: Medical Responsible, Merck KGaA, Darmstadt, Germany
Study Documents (Full-Text)
More Information
Additional Information:
Publications
None provided.Responsible Party:
Merck KGaA, Darmstadt, Germany
ClinicalTrials.gov Identifier:
NCT01988493
Other Study ID Numbers:
- 200095-004
First Posted:
Nov 20, 2013
Last Update Posted:
Mar 7, 2022
Last Verified:
Dec 1, 2021
Studies a U.S. FDA-regulated Drug Product:
No
Studies a U.S. FDA-regulated Device Product:
No
Keywords provided by Merck KGaA, Darmstadt, Germany
Additional relevant MeSH terms:
Study Results
Participant Flow
| Recruitment Details | First participant enrolled 06 Jan 2014. Last participant last visit: 03 Dec 2020. |
|---|---|
| Pre-assignment Detail | A total of 27 participants were enrolled in Phase 1b part of the study and a total of 90 participants were enrolled in phase 2 part of the study. Participants enrolled in phase 1b were not eligible for randomization in phase 2. |
| Arm/Group Title | Phase 1b: Tepotinib 300 mg | Phase 1b: Tepotinib 500 mg | Phase 1b: Tepotinib 1000 mg | Phase 2: Tepotinib | Phase 2 Sorafenib |
|---|---|---|---|---|---|
| Arm/Group Description | Participants received Tepotinib 300 milligram (mg) orally once daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal. | Participants received Tepotinib 500 mg orally once daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal. | Participants received Tepotinib 1000 mg orally once daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal. | 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. | Participants randomized to receive Sorafenib 400 mg orally twice daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal. |
| Period Title: Overall Study | |||||
| STARTED | 7 | 14 | 6 | 45 | 45 |
| Treated | 7 | 14 | 6 | 45 | 44 |
| Safety Population | 7 | 14 | 6 | 45 | 44 |
| COMPLETED | 7 | 14 | 6 | 45 | 44 |
| NOT COMPLETED | 0 | 0 | 0 | 0 | 1 |
Baseline Characteristics
| Arm/Group Title | Phase 1b: Tepotinib 300 mg | Phase 1b: Tepotinib 500 mg | Phase 1b: Tepotinib 1000 mg | Phase 2: Tepotinib | Phase 2 Sorafenib | Total |
|---|---|---|---|---|---|---|
| Arm/Group Description | Participants received Tepotinib 300 milligram (mg) orally once daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal. | Participants received Tepotinib 500 mg orally once daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal. | Participants received Tepotinib 1000 mg orally once daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal. | 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. | Participants randomized to receive Sorafenib 400 mg orally twice daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal. | Total of all reporting groups |
| Overall Participants | 7 | 14 | 6 | 45 | 44 | 116 |
| Age (Count of Participants) | ||||||
| <=18 years |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Between 18 and 65 years |
6
85.7%
|
11
78.6%
|
5
83.3%
|
34
75.6%
|
37
84.1%
|
93
80.2%
|
| >=65 years |
1
14.3%
|
3
21.4%
|
1
16.7%
|
11
24.4%
|
7
15.9%
|
23
19.8%
|
| Sex: Female, Male (Count of Participants) | ||||||
| Female |
1
14.3%
|
2
14.3%
|
1
16.7%
|
4
8.9%
|
3
6.8%
|
11
9.5%
|
| Male |
6
85.7%
|
12
85.7%
|
5
83.3%
|
41
91.1%
|
41
93.2%
|
105
90.5%
|
| Ethnicity (NIH/OMB) (Count of Participants) | ||||||
| Hispanic or Latino |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Not Hispanic or Latino |
7
100%
|
14
100%
|
6
100%
|
45
100%
|
44
100%
|
116
100%
|
| Unknown or Not Reported |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Race (NIH/OMB) (Count of Participants) | ||||||
| American Indian or Alaska Native |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Asian |
7
100%
|
14
100%
|
6
100%
|
45
100%
|
44
100%
|
116
100%
|
| Native Hawaiian or Other Pacific Islander |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Black or African American |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| White |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| More than one race |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Unknown or Not Reported |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
Outcome Measures
| Title | Phase 1b: Number of Participants Experiencing Dose Limiting Toxicity |
|---|---|
| Description | 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. |
| Time Frame | Day 1 to Day 21 of Cycle 1 (each cycle is 21 days) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Dose Limiting Toxicity (DLT) set included all participants who experienced a DLT during Cycle 1, or received at least 80 percent of all planned doses of treatment during Cycle. |
| Arm/Group Title | Phase 1b: Tepotinib 300 mg | Phase 1b: Tepotinib 500 mg | Phase 1b: Tepotinib 1000 mg |
|---|---|---|---|
| Arm/Group Description | Participants received Tepotinib 300 milligram (mg) orally once daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal. | Participants received Tepotinib 500 mg orally once daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal. | Participants received Tepotinib 1000 mg orally once daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal. |
| Measure Participants | 6 | 12 | 5 |
| Count of Participants [Participants] |
0
0%
|
0
0%
|
0
0%
|
| Title | Phase 1b: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs |
|---|---|
| Description | 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. |
| Time Frame | Baseline up to Day 30 after the last dose of study treatment, assessed up to 94 weeks |
Outcome Measure Data
| Analysis Population Description |
|---|
| The safety analysis set included all participants who had received any dose of the study medication. |
| Arm/Group Title | Phase 1b: Tepotinib 300 mg | Phase 1b: Tepotinib 500 mg | Phase 1b: Tepotinib 1000 mg |
|---|---|---|---|
| Arm/Group Description | Participants received Tepotinib 300 milligram (mg) orally once daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal. | Participants received Tepotinib 500 mg orally once daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal. | Participants received Tepotinib 1000 mg orally once daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal. |
| Measure Participants | 7 | 14 | 6 |
| Any TEAE |
7
100%
|
14
100%
|
6
100%
|
| Any Serious TEAE |
2
28.6%
|
9
64.3%
|
4
66.7%
|
| Title | Phase 2: Time to Progression (TTP) Based on Tumor Assessment by an Independent Review Committee (IRC) |
|---|---|
| Description | 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). |
| Time Frame | From randomization to date of the observation of radiological progressive disease, assessed up to maximum 3.8 years |
Outcome Measure Data
| Analysis Population Description |
|---|
| The modified intent-to treat (mITT) analysis set in the Phase 2 part of this study included all participants with Mesenchymal-epithelial transition (MET)+ hepatocelluar carcinoma (HCC) who were randomized to study treatment. |
| Arm/Group Title | Phase 2: Tepotinib | Phase 2 Sorafenib |
|---|---|---|
| Arm/Group Description | 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. | Participants randomized to receive Sorafenib 400 mg orally twice daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal. |
| Measure Participants | 38 | 37 |
| Median (90% Confidence Interval) [Months] |
2.9
|
1.4
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Phase 1b: Tepotinib 300 mg, Phase 1b: Tepotinib 500 mg |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Equivalence | |
| Comments | Sample size required 100 TTP events to ensure 80% power with a two-sided significance level of 10% for rejecting the null hypothesis of equal treatment effect between treatment arms. | |
| Statistical Test of Hypothesis | p-Value | 0.0087 |
| Comments | ||
| Method | Log Rank | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.46 | |
| Confidence Interval |
(2-Sided) 90% 0.28 to 0.76 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Phase 2: Progression Free Survival (PFS) Time Based on Tumor Assessment by the Independent Review Committee (IRC) |
|---|---|
| Description | Progression-free survival (PFS) time was defined as the time in months from randomization to either first observation of disease progression (based on RECIST v1.1) or occurrence of death due to any cause within 84 days of either randomization or the last tumor assessment. PD is defined as at least a 20 percent (%) increase in the sum of diameters of target lesions, taking as reference the smallest sum on study; and/or unequivocal progression of existing non-target lesions and/or the presence of new lesions. The sum must also demonstrate an absolute increase of at least 5 millimeter(mm). PFS was measured using Kaplan-Meier (KM) estimates. |
| Time Frame | Up to 2.8 years |
Outcome Measure Data
| Analysis Population Description |
|---|
| The mITT analysis set in the Phase 2 part of this study included all participants with MET+ HCC who were randomized to study treatment. |
| Arm/Group Title | Phase 2: Tepotinib | Phase 2 Sorafenib |
|---|---|---|
| Arm/Group Description | 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. | Participants randomized to receive Sorafenib 400 mg orally twice daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal. |
| Measure Participants | 38 | 37 |
| Median (90% Confidence Interval) [Months] |
2.8
|
1.4
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Phase 1b: Tepotinib 300 mg, Phase 1b: Tepotinib 500 mg |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Equivalence | |
| Comments | Sample size required 100 TTP events to ensure 80% power with a two-sided significance level of 10% for rejecting the null hypothesis of equal treatment effect between treatment arms. | |
| Statistical Test of Hypothesis | p-Value | 0.0229 |
| Comments | ||
| Method | Log Rank | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.53 | |
| Confidence Interval |
() 90% 0.33 to 0.84 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Phase 2: Overall Survival (OS) |
|---|---|
| Description | Overall survival time was measured as time in months between the date of randomization and the date of death. |
| Time Frame | Time from randomization to the date of death or up to 6.9 years |
Outcome Measure Data
| Analysis Population Description |
|---|
| The mITT analysis set in the Phase 2 part of this study included all participants with MET+ HCC who were randomized to study treatment. |
| Arm/Group Title | Phase 2: Tepotinib | Phase 2 Sorafenib |
|---|---|---|
| Arm/Group Description | 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. | Participants randomized to receive Sorafenib 400 mg orally twice daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal. |
| Measure Participants | 38 | 37 |
| Median (90% Confidence Interval) [Months] |
9.3
|
8.6
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Phase 1b: Tepotinib 300 mg, Phase 1b: Tepotinib 500 mg |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Equivalence | |
| Comments | Sample size required 100 TTP events to ensure 80% power with a two-sided significance level of 10% for rejecting the null hypothesis of equal treatment effect between treatment arms. | |
| Statistical Test of Hypothesis | p-Value | 0.2333 |
| Comments | ||
| Method | Log Rank | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.71 | |
| Confidence Interval |
() 90% 0.45 to 1.14 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Phase 2: Time to Progression (TTP) Based on Tumor Assessment by Investigator |
|---|---|
| Description | TTP was defined as the time in months from randomization to date of the observation of radiological PD (based on RECIST v1.1) assessed by the investigator. PD is defined as at least a 20 percent (%) increase in the sum of diameters of target lesions, taking as reference the smallest sum on study; and/or unequivocal progression of existing non-target lesions and/or the presence of new lesions. The sum must also demonstrate an absolute increase of at least 5 mm. |
| Time Frame | From randomization to date of the observation of radiological progressive disease, assessed up to maximum 2.8 years |
Outcome Measure Data
| Analysis Population Description |
|---|
| The mITT analysis set in the Phase 2 part of this study included all participants with MET+ HCC who were randomized to study treatment. |
| Arm/Group Title | Phase 2: Tepotinib | Phase 2 Sorafenib |
|---|---|---|
| Arm/Group Description | 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. | Participants randomized to receive Sorafenib 400 mg orally twice daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal. |
| Measure Participants | 38 | 37 |
| Median (90% Confidence Interval) [Months] |
5.6
|
2.8
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Phase 1b: Tepotinib 300 mg, Phase 1b: Tepotinib 500 mg |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Equivalence | |
| Comments | Sample size required 100 TTP events to ensure 80% power with a two-sided significance level of 10% for rejecting the null hypothesis of equal treatment effect between treatment arms. | |
| Statistical Test of Hypothesis | p-Value | 0.0059 |
| Comments | ||
| Method | Log Rank | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.45 | |
| Confidence Interval |
() 90% 0.28 to 0.73 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Phase 1b: Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC0-infinity) of Tepotinib |
|---|---|
| Description | The AUC(0-inf) was estimated by determining the total area under the curve of the concentration versus time curve extrapolated to infinity. |
| Time Frame | 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| The Pharmacokinetic (PK) analysis included all participants who had received at least 1 dose of Tepotinib and who had provided at least 1 plasma concentration measurement of Tepotinib after the first dose. |
| Arm/Group Title | Phase 1b: Tepotinib 300 mg | Phase 1b: Tepotinib 500 mg | Phase 1b: Tepotinib 1000 mg |
|---|---|---|---|
| Arm/Group Description | Participants received Tepotinib 300 milligram (mg) orally once daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal. | Participants received Tepotinib 500 mg orally once daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal. | Participants received Tepotinib 1000 mg orally once daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal. |
| Measure Participants | 7 | 14 | 6 |
| Day 1 |
NA
(NA)
|
NA
(NA)
|
NA
(NA)
|
| Day 15 |
NA
(NA)
|
NA
(NA)
|
NA
(NA)
|
| Title | Phase 1b: Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC 0-t) of Tepotinib |
|---|---|
| Description | 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 (LLLQ). AUC(0-t) was calculated according to the mixed log-linear trapezoidal rule. |
| Time Frame | 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| The PK analysis set was used. Here, "Overall number of participants analyzed" signifies those participants who were evaluable for this outcome measure and "Number Analyzed" signifies those participants who were evaluable at each specified time point. |
| Arm/Group Title | Phase 1b: Tepotinib 300 mg | Phase 1b: Tepotinib 500 mg | Phase 1b: Tepotinib 1000 mg |
|---|---|---|---|
| Arm/Group Description | Participants received Tepotinib 300 milligram (mg) orally once daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal. | Participants received Tepotinib 500 mg orally once daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal. | Participants received Tepotinib 1000 mg orally once daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal. |
| Measure Participants | 5 | 14 | 6 |
| Day 1 of Cycle 1 |
4700
(12.1)
|
6760
(28.0)
|
11900
(40.3)
|
| Day 15 of Cycle 1 |
11800
(35.7)
|
16700
(29.7)
|
28600
(38.8)
|
| Title | Phase 1b: Area Under the Plasma Concentration-Time Curve Within 1 Dosing Interval (AUC 0-tau) of Tepotinib |
|---|---|
| Description | AUC (0-tau) is the area under the plasma concentration time curve within 1 dosing interval. |
| Time Frame | 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| The PK analysis set was used. Here, "Overall number of participants analyzed" signifies those participants who were evaluable for this outcome measure and "Number Analyzed" signifies those participants who were evaluable at each specified time point. |
| Arm/Group Title | Phase 1b: Tepotinib 300 mg | Phase 1b: Tepotinib 500 mg | Phase 1b: Tepotinib 1000 mg |
|---|---|---|---|
| Arm/Group Description | Participants received Tepotinib 300 milligram (mg) orally once daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal. | Participants received Tepotinib 500 mg orally once daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal. | Participants received Tepotinib 1000 mg orally once daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal. |
| Measure Participants | 5 | 14 | 6 |
| Day 1 of Cycle 1 |
4700
(12.1)
|
6760
(28.0)
|
11900
(40.3)
|
| Day 15 of Cycle 1 |
11800
(35.7)
|
16700
(29.7)
|
28600
(38.8)
|
| Title | Phase 1b: Maximum Observed Plasma Concentration (Cmax) of Tepotinib |
|---|---|
| Description | Cmax is the maximum observed plasma concentration obtained directly from the concentration versus time curve. |
| Time Frame | 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| The PK analysis set was used. Here "Number Analyzed" signifies those participants who were evaluable for specified time point. |
| Arm/Group Title | Phase 1b: Tepotinib 300 mg | Phase 1b: Tepotinib 500 mg | Phase 1b: Tepotinib 1000 mg |
|---|---|---|---|
| Arm/Group Description | Participants received Tepotinib 300 milligram (mg) orally once daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal. | Participants received Tepotinib 500 mg orally once daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal. | Participants received Tepotinib 1000 mg orally once daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal. |
| Measure Participants | 7 | 14 | 6 |
| Day 1 of Cycle 1 |
266
(24.7)
|
394
(30.4)
|
680
(44.0)
|
| Day 15 of Cycle 1 |
585
(30.8)
|
815
(31.6)
|
1370
(36.3)
|
| Title | Phase 1b: Minimum Observed Plasma Concentration (Cmin) of Tepotinib |
|---|---|
| Description | Cmin is minimum observed plasma concentration obtained directly from the concentration versus time curve. |
| Time Frame | Predose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours postdose; Day 15 of Cycle 1 (each Cycle is 21 days) |
Outcome Measure Data
| Analysis Population Description |
|---|
| The PK analysis set was used. Here, "Number of participants analyzed" signifies those participants who were evaluable for this outcome measure. |
| Arm/Group Title | Phase 1b: Tepotinib 300 mg | Phase 1b: Tepotinib 500 mg | Phase 1b: Tepotinib 1000 mg |
|---|---|---|---|
| Arm/Group Description | Participants received Tepotinib 300 milligram (mg) orally once daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal. | Participants received Tepotinib 500 mg orally once daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal. | Participants received Tepotinib 1000 mg orally once daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal. |
| Measure Participants | 5 | 11 | 6 |
| Geometric Mean (Geometric Coefficient of Variation) [ng/mL] |
398
(39.0)
|
529
(43.6)
|
1010
(38.8)
|
| Title | Phase 1b: Average Observed Plasma Concentration (Cav) of Tepotinib |
|---|---|
| Description | Cavg is the average plasma concentration within 1 dosing interval obtained directly from the concentration versus time curve. |
| Time Frame | Predose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours postdose; Day 15 of Cycle 1 (each Cycle is 21 days) |
Outcome Measure Data
| Analysis Population Description |
|---|
| The PK analysis set was used. Here, "Number of participants analyzed" signifies those participants who were evaluable for this outcome measure. |
| Arm/Group Title | Phase 1b: Tepotinib 300 mg | Phase 1b: Tepotinib 500 mg | Phase 1b: Tepotinib 1000 mg |
|---|---|---|---|
| Arm/Group Description | Participants received Tepotinib 300 milligram (mg) orally once daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal. | Participants received Tepotinib 500 mg orally once daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal. | Participants received Tepotinib 1000 mg orally once daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal. |
| Measure Participants | 5 | 11 | 6 |
| Geometric Mean (Geometric Coefficient of Variation) [ng/mL] |
494
(35.7)
|
696
(29.7)
|
1190
(38.8)
|
| Title | Phase 1b: Time to Reach Maximum Plasma Concentration (Tmax) of Tepotinib |
|---|---|
| Description | Tmax is time to reach maximum observed plasma concentration obtained directly from the concentration versus time curve. |
| Time Frame | 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| The PK analysis set was used. Here "Number Analyzed" signifies those participants who were evaluable for specified time point. |
| Arm/Group Title | Phase 1b: Tepotinib 300 mg | Phase 1b: Tepotinib 500 mg | Phase 1b: Tepotinib 1000 mg |
|---|---|---|---|
| Arm/Group Description | Participants received Tepotinib 300 milligram (mg) orally once daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal. | Participants received Tepotinib 500 mg orally once daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal. | Participants received Tepotinib 1000 mg orally once daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal. |
| Measure Participants | 7 | 14 | 6 |
| Day 1 of Cycle 1 |
8.00
|
8.00
|
10.00
|
| Day 15 of Cycle 1 |
6.00
|
8.00
|
8.00
|
| Title | Phase 1b: Apparent Volume of Distribution During the Terminal Phase (Vz/f) of Tepotinib |
|---|---|
| Description | The Vz/f was defined as the theoretical volume in which the total amount of required to uniformly distribute to produce the desired plasma concentration. Apparent volume of distribution after oral dose (Vz/F) was influenced by the fraction absorbed. The Vz/f was calculated by dividing the dose with area under the concentration time curve from time zero to infinity multiplied with terminal elimination rate constant Lambda(z). Vz/f=Dose/AUC(0-inf)* Lambda(z). |
| Time Frame | 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| The PK analysis included all participants who had received at least 1 dose of Tepotinib and who had provided at least 1 plasma concentration measurement of Tepotinib after the first dose. |
| Arm/Group Title | Phase 1b: Tepotinib 300 mg | Phase 1b: Tepotinib 500 mg | Phase 1b: Tepotinib 1000 mg |
|---|---|---|---|
| Arm/Group Description | Participants received Tepotinib 300 milligram (mg) orally once daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal. | Participants received Tepotinib 500 mg orally once daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal. | Participants received Tepotinib 1000 mg orally once daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal. |
| Measure Participants | 7 | 14 | 6 |
| Day 1 |
NA
(NA)
|
NA
(NA)
|
NA
(NA)
|
| Day 15 |
NA
(NA)
|
NA
(NA)
|
NA
(NA)
|
| Title | Phase 1b: Apparent Total Body Clearance From Plasma (CL/f) of Tepotinib |
|---|---|
| Description | The CL/f is a measure of the rate at which it was metabolized or eliminated by normal biological processes. Clearance obtained after oral dose was influenced by the fraction of the dose absorbed. The CL/F from plasma was calculated using the formula: Dose divided by area under the concentration time curve from time zero to infinity (AUC0-inf). |
| Time Frame | 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| The PK analysis included all participants who had received at least 1 dose of Tepotinib and who had provided at least 1 plasma concentration measurement of Tepotinib after the first dose. |
| Arm/Group Title | Phase 1b: Tepotinib 300 mg | Phase 1b: Tepotinib 500 mg | Phase 1b: Tepotinib 1000 mg |
|---|---|---|---|
| Arm/Group Description | Participants received Tepotinib 300 milligram (mg) orally once daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal. | Participants received Tepotinib 500 mg orally once daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal. | Participants received Tepotinib 1000 mg orally once daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal. |
| Measure Participants | 7 | 14 | 6 |
| Day 1 |
NA
(NA)
|
NA
(NA)
|
NA
(NA)
|
| Day 15 |
NA
(NA)
|
NA
(NA)
|
NA
(NA)
|
| Title | Phase 1b: Apparent Volume of Distribution During the Steady State (Vss/f) of Tepotinib |
|---|---|
| Description | Volume of distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Vss/f after oral dose was influenced by the fraction absorbed. |
| Time Frame | 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| The PK analysis included all participants who had received at least 1 dose of Tepotinib and who had provided at least 1 plasma concentration measurement of Tepotinib after the first dose. |
| Arm/Group Title | Phase 1b: Tepotinib 300 mg | Phase 1b: Tepotinib 500 mg | Phase 1b: Tepotinib 1000 mg |
|---|---|---|---|
| Arm/Group Description | Participants received Tepotinib 300 milligram (mg) orally once daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal. | Participants received Tepotinib 500 mg orally once daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal. | Participants received Tepotinib 1000 mg orally once daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal. |
| Measure Participants | 7 | 14 | 6 |
| Day 1 |
NA
(NA)
|
NA
(NA)
|
NA
(NA)
|
| Day 15 |
NA
(NA)
|
NA
(NA)
|
NA
(NA)
|
| Title | Phase 1b: Apparent Terminal Elimination Rate Constant Lambda(z) of Tepotinib |
|---|---|
| Description | Lambda(z) was determined from the terminal slope of the log-transformed plasma concentration curve using linear regression method. |
| Time Frame | 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| The PK analysis included all participants who had received at least 1 dose of Tepotinib and who had provided at least 1 plasma concentration measurement of Tepotinib after the first dose. |
| Arm/Group Title | Phase 1b: Tepotinib 300 mg | Phase 1b: Tepotinib 500 mg | Phase 1b: Tepotinib 1000 mg |
|---|---|---|---|
| Arm/Group Description | Participants received Tepotinib 300 milligram (mg) orally once daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal. | Participants received Tepotinib 500 mg orally once daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal. | Participants received Tepotinib 1000 mg orally once daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal. |
| Measure Participants | 7 | 14 | 6 |
| Day 1 |
NA
(NA)
|
NA
(NA)
|
NA
(NA)
|
| Day 15 |
NA
(NA)
|
NA
(NA)
|
NA
(NA)
|
| Title | Phase 1b: Apparent Terminal Half-life (t1/2) of Tepotinib |
|---|---|
| Description | Apparent terminal half-life was defined as the time required for the plasma concentration of drug to decrease 50 percent in the final stage of its elimination. |
| Time Frame | 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| The PK analysis included all participants who had received at least 1 dose of Tepotinib and who had provided at least 1 plasma concentration measurement of Tepotinib after the first dose. |
| Arm/Group Title | Phase 1b: Tepotinib 300 mg | Phase 1b: Tepotinib 500 mg | Phase 1b: Tepotinib 1000 mg |
|---|---|---|---|
| Arm/Group Description | Participants received Tepotinib 300 milligram (mg) orally once daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal. | Participants received Tepotinib 500 mg orally once daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal. | Participants received Tepotinib 1000 mg orally once daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal. |
| Measure Participants | 7 | 14 | 6 |
| Day 1 |
NA
|
NA
|
NA
|
| Day 15 |
NA
|
NA
|
NA
|
| Title | Phase 2: Time-to-Symptomatic Progression (TTSP) |
|---|---|
| Description | 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. |
| Time Frame | Up to 6.9 years |
Outcome Measure Data
| Analysis Population Description |
|---|
| The mITT analysis set in the Phase 2 part of this study included all participants with MET+ HCC who were randomized to study treatment. As per planned analysis, data for this outcome was analyzed only for phase 2 based on combined analysis of both FHSI-8 and ECOG. |
| Arm/Group Title | Phase 2: Tepotinib | Phase 2 Sorafenib |
|---|---|---|
| Arm/Group Description | 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. | Participants randomized to receive Sorafenib 400 mg orally twice daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal. |
| Measure Participants | 38 | 37 |
| Median (90% Confidence Interval) [Months] |
2.2
|
2.7
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Phase 1b: Tepotinib 300 mg, Phase 1b: Tepotinib 500 mg |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Equivalence | |
| Comments | Sample size required 100 TTP events to ensure 80% power with a two-sided significance level of 10% for rejecting the null hypothesis of equal treatment effect between treatment arms. | |
| Statistical Test of Hypothesis | p-Value | 0.8915 |
| Comments | ||
| Method | Log Rank | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 1.04 | |
| Confidence Interval |
() 90% 0.62 to 1.77 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Phase 2: Objective Response Rate (ORR) Based on Tumor Assessment by the IRC |
|---|---|
| Description | The objective response rate (ORR) was defined as the percentage of participants who had achieved complete response (CR) or partial response (PR) as the best overall response according to radiological assessments as adjudicated by the IRC from randomization until the first occurrence of PD. CR: 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. PD 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. |
| Time Frame | Time from randomization until the first occurrence of PD assessed up to 6.9 years |
Outcome Measure Data
| Analysis Population Description |
|---|
| The mITT analysis set in the Phase 2 part of this study included all participants with MET+ HCC who were randomized to study treatment. |
| Arm/Group Title | Phase 2: Tepotinib | Phase 2 Sorafenib |
|---|---|---|
| Arm/Group Description | 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. | Participants randomized to receive Sorafenib 400 mg orally twice daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal. |
| Measure Participants | 38 | 37 |
| Number (90% Confidence Interval) [Percentage of participants] |
10.5
150%
|
0
0%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Phase 1b: Tepotinib 300 mg, Phase 1b: Tepotinib 500 mg |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Equivalence | |
| Comments | Sample size required 100 TTP events to ensure 80% power with a two-sided significance level of 10% for rejecting the null hypothesis of equal treatment effect between treatment arms. | |
| Statistical Test of Hypothesis | p-Value | 0.0438 |
| Comments | ||
| Method | Cochran-Mantel-Haenszel | |
| Comments | ||
| Title | Phase 2: Percentage of Participants With Disease Control Based on Tumor Assessment by IRC According to Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST v1.1) Criteria |
|---|---|
| Description | Disease control was defined as CR, PR, or stable disease (SD) as the best overall response according to radiological assessments as adjudicated by the IRC from randomization until the first occurrence of PD. 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. Percentage of participants with disease control were reported. |
| Time Frame | Time from randomization until the first occurrence of PD assessed up to 6.9 years |
Outcome Measure Data
| Analysis Population Description |
|---|
| The mITT analysis set in the Phase 2 part of this study included all participants with MET+ HCC who were randomized to study treatment. |
| Arm/Group Title | Phase 2: Tepotinib | Phase 2 Sorafenib |
|---|---|---|
| Arm/Group Description | 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. | Participants randomized to receive Sorafenib 400 mg orally twice daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal. |
| Measure Participants | 38 | 37 |
| Number (90% Confidence Interval) [Percentage of participants] |
50
714.3%
|
21.6
154.3%
|
| Title | Phase 2: Progression-free Survival (PFS) Based on Tumor Assessment by the Investigator |
|---|---|
| Description | Progression-free survival (assessed by the Investigator) time was defined as the time in months from randomization to either first observation of radiologically confirmed progression disease by the investigator or occurrence of death due to any cause within 84 days of either randomization or the last tumor assessment. PD is defined as at least a 20 percent (%) increase in the sum of diameters of target lesions, taking as reference the smallest sum on study; and/or unequivocal progression of existing non-target lesions and/or the presence of new lesions. The sum must also demonstrate an absolute increase of at least 5 mm. PFS was measured using Kaplan-Meier (KM) estimates. |
| Time Frame | Time from randomization to disease progression or occurrence of death due to any cause within 84 days of either randomization or the last tumor assessment, assessed up to 6.9 years |
Outcome Measure Data
| Analysis Population Description |
|---|
| The mITT analysis set in the Phase 2 part of this study included all participants with MET+ HCC who were randomized to study treatment. |
| Arm/Group Title | Phase 2: Tepotinib | Phase 2 Sorafenib |
|---|---|---|
| Arm/Group Description | 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. | Participants randomized to receive Sorafenib 400 mg orally twice daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal. |
| Measure Participants | 38 | 37 |
| Median (90% Confidence Interval) [Months] |
3.2
|
2.8
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Phase 1b: Tepotinib 300 mg, Phase 1b: Tepotinib 500 mg |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Equivalence | |
| Comments | Sample size required 100 TTP events to ensure 80% power with a two-sided significance level of 10% for rejecting the null hypothesis of equal treatment effect between treatment arms. | |
| Statistical Test of Hypothesis | p-Value | 0.0496 |
| Comments | ||
| Method | Log Rank | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.59 | |
| Confidence Interval |
(2-Sided) 90% 0.38 to 0.92 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Phase 2: Objective Response Rate (ORR) Based on Tumor Assessment by the Investigator |
|---|---|
| Description | The objective response rate was defined as the percentage of participants who had achieved CR or PR as the best overall response according to radiological assessments as adjudicated by the investigator from randomization until the first occurrence of PD. 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. |
| Time Frame | Time from randomization until the first occurrence of PD assessed up to 6.9 years |
Outcome Measure Data
| Analysis Population Description |
|---|
| The mITT analysis set in the Phase 2 part of this study included all participants with MET+ HCC who were randomized to study treatment. |
| Arm/Group Title | Phase 2: Tepotinib | Phase 2 Sorafenib |
|---|---|---|
| Arm/Group Description | 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. | Participants randomized to receive Sorafenib 400 mg orally twice daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal. |
| Measure Participants | 38 | 37 |
| Number (90% Confidence Interval) [Percentage of participants] |
15.8
225.7%
|
2.7
19.3%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Phase 1b: Tepotinib 300 mg, Phase 1b: Tepotinib 500 mg |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Equivalence | |
| Comments | Sample size required 100 TTP events to ensure 80% power with a two-sided significance level of 10% for rejecting the null hypothesis of equal treatment effect between treatment arms. | |
| Statistical Test of Hypothesis | p-Value | 0.0527 |
| Comments | ||
| Method | Cochran-Mantel-Haenszel | |
| Comments | ||
| Title | Phase 2: Percentage of Participants With Disease Control Based on Tumor Assessment by Investigator According to Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST v1.1) Criteria |
|---|---|
| Description | Disease control was defined as CR, PR, or stable disease (SD) as the best overall response according to radiological assessments as adjudicated by the IRC from randomization until the first occurrence of PD. 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. Percentage of participants with disease control were reported. |
| Time Frame | Approximately up to 6.9 years |
Outcome Measure Data
| Analysis Population Description |
|---|
| The mITT analysis set in the Phase 2 part of this study included all participants with MET+ HCC who were randomized to study treatment. |
| Arm/Group Title | Phase 2: Tepotinib | Phase 2 Sorafenib |
|---|---|---|
| Arm/Group Description | 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. | Participants randomized to receive Sorafenib 400 mg orally twice daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal. |
| Measure Participants | 38 | 37 |
| Number (90% Confidence Interval) [Percentage of Participants] |
60.5
864.3%
|
45.9
327.9%
|
Adverse Events
| Time Frame | Baseline up to Day 30 after the last dose of study treatment, assessed up to 94 weeks (Phase 1b) and 6.9 years (Phase 2). | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Adverse Event Reporting Description | The safety analysis set included all participants who had received any dose of the study medication. | |||||||||
| Arm/Group Title | Phase 1b: Tepotinib 300 mg | Phase 1b: Tepotinib 500 mg | Phase 1b: Tepotinib 1000 mg | Phase 2: Tepotinib | Phase 2 Sorafenib | |||||
| Arm/Group Description | Participants received Tepotinib 300 milligram (mg) orally once daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal. | Participants received Tepotinib 500 mg orally once daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal. | Participants received Tepotinib 1000 mg orally once daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal. | 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. | Participants randomized to receive Sorafenib 400 mg orally twice daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal. | |||||
All Cause Mortality |
||||||||||
| Phase 1b: Tepotinib 300 mg | Phase 1b: Tepotinib 500 mg | Phase 1b: Tepotinib 1000 mg | Phase 2: Tepotinib | Phase 2 Sorafenib | ||||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 7/7 (100%) | 11/14 (78.6%) | 3/6 (50%) | 24/45 (53.3%) | 30/44 (68.2%) | |||||
Serious Adverse Events |
||||||||||
| Phase 1b: Tepotinib 300 mg | Phase 1b: Tepotinib 500 mg | Phase 1b: Tepotinib 1000 mg | Phase 2: Tepotinib | Phase 2 Sorafenib | ||||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 2/7 (28.6%) | 9/14 (64.3%) | 4/6 (66.7%) | 23/45 (51.1%) | 12/44 (27.3%) | |||||
| Blood and lymphatic system disorders | ||||||||||
| Thrombocytopenia | 0/7 (0%) | 0/14 (0%) | 0/6 (0%) | 1/45 (2.2%) | 0/44 (0%) | |||||
| Cardiac disorders | ||||||||||
| Supraventricular tachycardia | 0/7 (0%) | 0/14 (0%) | 0/6 (0%) | 1/45 (2.2%) | 0/44 (0%) | |||||
| Gastrointestinal disorders | ||||||||||
| Abdominal pain | 0/7 (0%) | 1/14 (7.1%) | 1/6 (16.7%) | 2/45 (4.4%) | 2/44 (4.5%) | |||||
| Ascites | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | 2/45 (4.4%) | 0/44 (0%) | |||||
| Diarrhoea | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | 1/45 (2.2%) | 1/44 (2.3%) | |||||
| Duodenal ulcer | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | 0/45 (0%) | 0/44 (0%) | |||||
| Encapsulating peritoneal sclerosis | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | 0/45 (0%) | 0/44 (0%) | |||||
| Ileus | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | 1/45 (2.2%) | 0/44 (0%) | |||||
| Melaena | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | 0/45 (0%) | 0/44 (0%) | |||||
| Upper gastrointestinal haemorrhage | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | 1/45 (2.2%) | 1/44 (2.3%) | |||||
| Duodenal ulcer haemorrhage | 0/7 (0%) | 0/14 (0%) | 0/6 (0%) | 1/45 (2.2%) | 0/44 (0%) | |||||
| Peritoneal haemorrhage | 0/7 (0%) | 0/14 (0%) | 0/6 (0%) | 1/45 (2.2%) | 0/44 (0%) | |||||
| General disorders | ||||||||||
| Disease progression | 1/7 (14.3%) | 0/14 (0%) | 0/6 (0%) | 7/45 (15.6%) | 2/44 (4.5%) | |||||
| Asthenia | 0/7 (0%) | 0/14 (0%) | 0/6 (0%) | 0/45 (0%) | 1/44 (2.3%) | |||||
| Hernia | 0/7 (0%) | 0/14 (0%) | 0/6 (0%) | 1/45 (2.2%) | 0/44 (0%) | |||||
| Oedema peripheral | 0/7 (0%) | 0/14 (0%) | 0/6 (0%) | 2/45 (4.4%) | 0/44 (0%) | |||||
| Hepatobiliary disorders | ||||||||||
| Cholecystitis acute | 0/7 (0%) | 0/14 (0%) | 0/6 (0%) | 0/45 (0%) | 1/44 (2.3%) | |||||
| Hepatic failure | 0/7 (0%) | 0/14 (0%) | 0/6 (0%) | 1/45 (2.2%) | 1/44 (2.3%) | |||||
| Hepatic function abnormal | 0/7 (0%) | 0/14 (0%) | 0/6 (0%) | 1/45 (2.2%) | 0/44 (0%) | |||||
| Infections and infestations | ||||||||||
| Candida infection | 0/7 (0%) | 0/14 (0%) | 1/6 (16.7%) | 0/45 (0%) | 0/44 (0%) | |||||
| Cellulitis | 0/7 (0%) | 0/14 (0%) | 0/6 (0%) | 1/45 (2.2%) | 0/44 (0%) | |||||
| Enteritis infectious | 0/7 (0%) | 0/14 (0%) | 0/6 (0%) | 1/45 (2.2%) | 0/44 (0%) | |||||
| Pneumonia | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | 0/45 (0%) | 0/44 (0%) | |||||
| Investigations | ||||||||||
| Alanine aminotransferase increased | 1/7 (14.3%) | 0/14 (0%) | 0/6 (0%) | 0/45 (0%) | 0/44 (0%) | |||||
| Aspartate aminotransferase increased | 1/7 (14.3%) | 0/14 (0%) | 0/6 (0%) | 0/45 (0%) | 0/44 (0%) | |||||
| Blood bilirubin increased | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | 0/45 (0%) | 1/44 (2.3%) | |||||
| Lipase increased | 0/7 (0%) | 0/14 (0%) | 0/6 (0%) | 0/45 (0%) | 1/44 (2.3%) | |||||
| Metabolism and nutrition disorders | ||||||||||
| Decreased appetite | 0/7 (0%) | 0/14 (0%) | 1/6 (16.7%) | 1/45 (2.2%) | 0/44 (0%) | |||||
| Hyperglycaemia | 0/7 (0%) | 0/14 (0%) | 0/6 (0%) | 1/45 (2.2%) | 0/44 (0%) | |||||
| Musculoskeletal and connective tissue disorders | ||||||||||
| Muscular weakness | 0/7 (0%) | 0/14 (0%) | 1/6 (16.7%) | 0/45 (0%) | 0/44 (0%) | |||||
| Musculoskeletal pain | 0/7 (0%) | 0/14 (0%) | 0/6 (0%) | 1/45 (2.2%) | 0/44 (0%) | |||||
| Gouty arthritis | 0/7 (0%) | 0/14 (0%) | 0/6 (0%) | 1/45 (2.2%) | 0/44 (0%) | |||||
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||||||||
| Metastases to central nervous system | 0/7 (0%) | 0/14 (0%) | 0/6 (0%) | 0/45 (0%) | 1/44 (2.3%) | |||||
| Bladder cancer | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | 0/45 (0%) | 0/44 (0%) | |||||
| Nervous system disorders | ||||||||||
| Cerebrovascular accident | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | 0/45 (0%) | 0/44 (0%) | |||||
| Haemorrhage intracranial | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | 0/45 (0%) | 1/44 (2.3%) | |||||
| Hepatic encephalopathy | 0/7 (0%) | 0/14 (0%) | 0/6 (0%) | 2/45 (4.4%) | 1/44 (2.3%) | |||||
| Paraesthesia | 0/7 (0%) | 0/14 (0%) | 0/6 (0%) | 2/45 (4.4%) | 0/44 (0%) | |||||
| Seizure | 0/7 (0%) | 0/14 (0%) | 1/6 (16.7%) | 0/45 (0%) | 0/44 (0%) | |||||
| Respiratory, thoracic and mediastinal disorders | ||||||||||
| Dyspnoea exertional | 1/7 (14.3%) | 0/14 (0%) | 0/6 (0%) | 0/45 (0%) | 0/44 (0%) | |||||
| Haemoptysis | 1/7 (14.3%) | 0/14 (0%) | 0/6 (0%) | 0/45 (0%) | 0/44 (0%) | |||||
| Pleural effusion | 1/7 (14.3%) | 0/14 (0%) | 0/6 (0%) | 0/45 (0%) | 0/44 (0%) | |||||
| Skin and subcutaneous tissue disorders | ||||||||||
| Rash maculo-papular | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | 0/45 (0%) | 0/44 (0%) | |||||
| Vascular disorders | ||||||||||
| Deep vein thrombosis | 0/7 (0%) | 0/14 (0%) | 0/6 (0%) | 0/45 (0%) | 1/44 (2.3%) | |||||
| Hypertension | 1/7 (14.3%) | 0/14 (0%) | 0/6 (0%) | 0/45 (0%) | 0/44 (0%) | |||||
| Lymphoedema | 0/7 (0%) | 0/14 (0%) | 0/6 (0%) | 1/45 (2.2%) | 0/44 (0%) | |||||
Other (Not Including Serious) Adverse Events |
||||||||||
| Phase 1b: Tepotinib 300 mg | Phase 1b: Tepotinib 500 mg | Phase 1b: Tepotinib 1000 mg | Phase 2: Tepotinib | Phase 2 Sorafenib | ||||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 7/7 (100%) | 14/14 (100%) | 6/6 (100%) | 43/45 (95.6%) | 43/44 (97.7%) | |||||
| Blood and lymphatic system disorders | ||||||||||
| Anaemia | 0/7 (0%) | 2/14 (14.3%) | 1/6 (16.7%) | 4/45 (8.9%) | 2/44 (4.5%) | |||||
| Thrombocytopenia | 0/7 (0%) | 0/14 (0%) | 0/6 (0%) | 3/45 (6.7%) | 2/44 (4.5%) | |||||
| Eye disorders | ||||||||||
| Dry eye | 0/7 (0%) | 0/14 (0%) | 1/6 (16.7%) | 0/45 (0%) | 0/44 (0%) | |||||
| Gastrointestinal disorders | ||||||||||
| Abdominal discomfort | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | 0/45 (0%) | 0/44 (0%) | |||||
| Abdominal distension | 4/7 (57.1%) | 4/14 (28.6%) | 0/6 (0%) | 9/45 (20%) | 5/44 (11.4%) | |||||
| Abdominal mass | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | 0/45 (0%) | 0/44 (0%) | |||||
| Abdominal pain | 2/7 (28.6%) | 6/14 (42.9%) | 1/6 (16.7%) | 11/45 (24.4%) | 9/44 (20.5%) | |||||
| Abdominal pain upper | 1/7 (14.3%) | 2/14 (14.3%) | 1/6 (16.7%) | 2/45 (4.4%) | 7/44 (15.9%) | |||||
| Anorectal discomfort | 0/7 (0%) | 0/14 (0%) | 1/6 (16.7%) | 0/45 (0%) | 0/44 (0%) | |||||
| Ascites | 0/7 (0%) | 3/14 (21.4%) | 3/6 (50%) | 11/45 (24.4%) | 4/44 (9.1%) | |||||
| Constipation | 1/7 (14.3%) | 4/14 (28.6%) | 4/6 (66.7%) | 6/45 (13.3%) | 8/44 (18.2%) | |||||
| Diarrhoea | 2/7 (28.6%) | 6/14 (42.9%) | 4/6 (66.7%) | 16/45 (35.6%) | 17/44 (38.6%) | |||||
| Dyspepsia | 0/7 (0%) | 3/14 (21.4%) | 1/6 (16.7%) | 4/45 (8.9%) | 6/44 (13.6%) | |||||
| Gastric ulcer | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | 0/45 (0%) | 0/44 (0%) | |||||
| Gingival bleeding | 0/7 (0%) | 0/14 (0%) | 0/6 (0%) | 0/45 (0%) | 4/44 (9.1%) | |||||
| Gastritis | 0/7 (0%) | 1/14 (7.1%) | 1/6 (16.7%) | 0/45 (0%) | 0/44 (0%) | |||||
| Nausea | 3/7 (42.9%) | 3/14 (21.4%) | 2/6 (33.3%) | 4/45 (8.9%) | 7/44 (15.9%) | |||||
| Stomatitis | 1/7 (14.3%) | 1/14 (7.1%) | 0/6 (0%) | 1/45 (2.2%) | 3/44 (6.8%) | |||||
| Vomiting | 1/7 (14.3%) | 3/14 (21.4%) | 1/6 (16.7%) | 3/45 (6.7%) | 6/44 (13.6%) | |||||
| General disorders | ||||||||||
| Asthenia | 0/7 (0%) | 0/14 (0%) | 0/6 (0%) | 0/45 (0%) | 5/44 (11.4%) | |||||
| Chest pain | 0/7 (0%) | 0/14 (0%) | 0/6 (0%) | 3/45 (6.7%) | 2/44 (4.5%) | |||||
| Fatigue | 1/7 (14.3%) | 3/14 (21.4%) | 2/6 (33.3%) | 12/45 (26.7%) | 13/44 (29.5%) | |||||
| Disease progression | 0/7 (0%) | 0/14 (0%) | 0/6 (0%) | 3/45 (6.7%) | 1/44 (2.3%) | |||||
| Influenza like illness | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | 0/45 (0%) | 0/44 (0%) | |||||
| Localised oedema | 1/7 (14.3%) | 1/14 (7.1%) | 1/6 (16.7%) | 0/45 (0%) | 0/44 (0%) | |||||
| Malaise | 1/7 (14.3%) | 1/14 (7.1%) | 0/6 (0%) | 0/45 (0%) | 0/44 (0%) | |||||
| Non-cardiac chest pain | 1/7 (14.3%) | 0/14 (0%) | 0/6 (0%) | 0/45 (0%) | 0/44 (0%) | |||||
| Oedema | 0/7 (0%) | 0/14 (0%) | 0/6 (0%) | 3/45 (6.7%) | 1/44 (2.3%) | |||||
| Oedema peripheral | 2/7 (28.6%) | 4/14 (28.6%) | 1/6 (16.7%) | 20/45 (44.4%) | 1/44 (2.3%) | |||||
| Pain | 0/7 (0%) | 0/14 (0%) | 1/6 (16.7%) | 0/45 (0%) | 0/44 (0%) | |||||
| Pyrexia | 0/7 (0%) | 4/14 (28.6%) | 2/6 (33.3%) | 7/45 (15.6%) | 7/44 (15.9%) | |||||
| Hepatobiliary disorders | ||||||||||
| Hepatorenal syndrome | 0/7 (0%) | 0/14 (0%) | 1/6 (16.7%) | 0/45 (0%) | 0/44 (0%) | |||||
| Immune system disorders | ||||||||||
| Anaphylactic reaction | 0/7 (0%) | 0/14 (0%) | 1/6 (16.7%) | 0/45 (0%) | 0/44 (0%) | |||||
| Infections and infestations | ||||||||||
| Rash pustular | 0/7 (0%) | 0/14 (0%) | 0/6 (0%) | 0/45 (0%) | 3/44 (6.8%) | |||||
| Upper respiratory tract infection | 0/7 (0%) | 2/14 (14.3%) | 0/6 (0%) | 3/45 (6.7%) | 3/44 (6.8%) | |||||
| Bacteraemia | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | 0/45 (0%) | 0/44 (0%) | |||||
| Cellulitis | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | 0/45 (0%) | 0/44 (0%) | |||||
| Infection | 1/7 (14.3%) | 0/14 (0%) | 0/6 (0%) | 0/45 (0%) | 0/44 (0%) | |||||
| Investigations | ||||||||||
| Alanine aminotransferase increased | 2/7 (28.6%) | 1/14 (7.1%) | 3/6 (50%) | 7/45 (15.6%) | 9/44 (20.5%) | |||||
| Amylase increased | 0/7 (0%) | 2/14 (14.3%) | 1/6 (16.7%) | 4/45 (8.9%) | 7/44 (15.9%) | |||||
| Aspartate aminotransferase increased | 3/7 (42.9%) | 3/14 (21.4%) | 4/6 (66.7%) | 10/45 (22.2%) | 16/44 (36.4%) | |||||
| Blood alkaline phosphatase increased | 0/7 (0%) | 0/14 (0%) | 3/6 (50%) | 5/45 (11.1%) | 3/44 (6.8%) | |||||
| Blood bilirubin increased | 0/7 (0%) | 1/14 (7.1%) | 1/6 (16.7%) | 4/45 (8.9%) | 11/44 (25%) | |||||
| Blood creatinine increased | 1/7 (14.3%) | 0/14 (0%) | 3/6 (50%) | 7/45 (15.6%) | 1/44 (2.3%) | |||||
| Creatinine renal clearance decreased | 0/7 (0%) | 0/14 (0%) | 1/6 (16.7%) | 0/45 (0%) | 0/44 (0%) | |||||
| Creatinine renal clearance increased | 0/7 (0%) | 0/14 (0%) | 1/6 (16.7%) | 0/45 (0%) | 0/44 (0%) | |||||
| Electrocardiogram QT prolonged | 0/7 (0%) | 0/14 (0%) | 0/6 (0%) | 3/45 (6.7%) | 1/44 (2.3%) | |||||
| Gamma-glutamyltransferase increased | 0/7 (0%) | 0/14 (0%) | 1/6 (16.7%) | 3/45 (6.7%) | 8/44 (18.2%) | |||||
| Lipase increased | 0/7 (0%) | 3/14 (21.4%) | 1/6 (16.7%) | 2/45 (4.4%) | 8/44 (18.2%) | |||||
| Lymphocyte count decreased | 0/7 (0%) | 0/14 (0%) | 1/6 (16.7%) | 0/45 (0%) | 0/44 (0%) | |||||
| Neutrophil count decreased | 0/7 (0%) | 0/14 (0%) | 1/6 (16.7%) | 2/45 (4.4%) | 4/44 (9.1%) | |||||
| Platelet count decreased | 0/7 (0%) | 0/14 (0%) | 1/6 (16.7%) | 7/45 (15.6%) | 7/44 (15.9%) | |||||
| White blood cell count decreased | 0/7 (0%) | 0/14 (0%) | 1/6 (16.7%) | 0/45 (0%) | 3/44 (6.8%) | |||||
| White blood cell count increased | 0/7 (0%) | 0/14 (0%) | 1/6 (16.7%) | 0/45 (0%) | 0/44 (0%) | |||||
| Weight decreased | 0/7 (0%) | 0/14 (0%) | 0/6 (0%) | 2/45 (4.4%) | 9/44 (20.5%) | |||||
| Metabolism and nutrition disorders | ||||||||||
| Decreased appetite | 1/7 (14.3%) | 3/14 (21.4%) | 2/6 (33.3%) | 16/45 (35.6%) | 18/44 (40.9%) | |||||
| Hyperglycaemia | 0/7 (0%) | 0/14 (0%) | 1/6 (16.7%) | 0/45 (0%) | 0/44 (0%) | |||||
| Hyperkalaemia | 0/7 (0%) | 2/14 (14.3%) | 0/6 (0%) | 4/45 (8.9%) | 2/44 (4.5%) | |||||
| Hyperuricaemia | 1/7 (14.3%) | 0/14 (0%) | 0/6 (0%) | 0/45 (0%) | 0/44 (0%) | |||||
| Hypocalcaemia | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | 1/45 (2.2%) | 0/44 (0%) | |||||
| Hypoglycaemia | 0/7 (0%) | 0/14 (0%) | 1/6 (16.7%) | 0/45 (0%) | 0/44 (0%) | |||||
| Hyponatraemia | 1/7 (14.3%) | 0/14 (0%) | 0/6 (0%) | 5/45 (11.1%) | 2/44 (4.5%) | |||||
| Hypophosphataemia | 0/7 (0%) | 0/14 (0%) | 0/6 (0%) | 0/45 (0%) | 3/44 (6.8%) | |||||
| Hypoalbuminaemia | 1/7 (14.3%) | 1/14 (7.1%) | 4/6 (66.7%) | 12/45 (26.7%) | 4/44 (9.1%) | |||||
| Hypokalaemia | 0/7 (0%) | 1/14 (7.1%) | 1/6 (16.7%) | 0/45 (0%) | 0/44 (0%) | |||||
| Musculoskeletal and connective tissue disorders | ||||||||||
| Back pain | 0/7 (0%) | 0/14 (0%) | 0/6 (0%) | 2/45 (4.4%) | 3/44 (6.8%) | |||||
| Musculoskeletal pain | 1/7 (14.3%) | 1/14 (7.1%) | 0/6 (0%) | 1/45 (2.2%) | 3/44 (6.8%) | |||||
| Pain in extremity | 0/7 (0%) | 0/14 (0%) | 0/6 (0%) | 4/45 (8.9%) | 5/44 (11.4%) | |||||
| Arthralgia | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | 0/45 (0%) | 0/44 (0%) | |||||
| Muscle spasms | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | 0/45 (0%) | 0/44 (0%) | |||||
| Muscular weakness | 0/7 (0%) | 0/14 (0%) | 1/6 (16.7%) | 0/45 (0%) | 0/44 (0%) | |||||
| Musculoskeletal chest pain | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | 0/45 (0%) | 0/44 (0%) | |||||
| Myalgia | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | 0/45 (0%) | 0/44 (0%) | |||||
| Nervous system disorders | ||||||||||
| Brain injury | 0/7 (0%) | 0/14 (0%) | 1/6 (16.7%) | 0/45 (0%) | 0/44 (0%) | |||||
| Dizziness | 0/7 (0%) | 2/14 (14.3%) | 1/6 (16.7%) | 0/45 (0%) | 0/44 (0%) | |||||
| Generalised tonic-clonic seizure | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | 0/45 (0%) | 0/44 (0%) | |||||
| Headache | 0/7 (0%) | 3/14 (21.4%) | 1/6 (16.7%) | 2/45 (4.4%) | 5/44 (11.4%) | |||||
| Metabolic encephalopathy | 0/7 (0%) | 0/14 (0%) | 1/6 (16.7%) | 0/45 (0%) | 0/44 (0%) | |||||
| Posterior reversible encephalopathy syndrome | 0/7 (0%) | 0/14 (0%) | 1/6 (16.7%) | 0/45 (0%) | 0/44 (0%) | |||||
| Tremor | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | 0/45 (0%) | 0/44 (0%) | |||||
| Psychiatric disorders | ||||||||||
| Insomnia | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | 1/45 (2.2%) | 3/44 (6.8%) | |||||
| Mental status changes | 0/7 (0%) | 0/14 (0%) | 1/6 (16.7%) | 0/45 (0%) | 0/44 (0%) | |||||
| Renal and urinary disorders | ||||||||||
| Acute kidney injury | 0/7 (0%) | 0/14 (0%) | 1/6 (16.7%) | 0/45 (0%) | 0/44 (0%) | |||||
| Dysuria | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | 0/45 (0%) | 0/44 (0%) | |||||
| Pollakiuria | 0/7 (0%) | 0/14 (0%) | 1/6 (16.7%) | 0/45 (0%) | 0/44 (0%) | |||||
| Proteinuria | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | 0/45 (0%) | 0/44 (0%) | |||||
| Reproductive system and breast disorders | ||||||||||
| Penile swelling | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | 0/45 (0%) | 0/44 (0%) | |||||
| Scrotal swelling | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | 0/45 (0%) | 0/44 (0%) | |||||
| Respiratory, thoracic and mediastinal disorders | ||||||||||
| Cough | 0/7 (0%) | 0/14 (0%) | 0/6 (0%) | 1/45 (2.2%) | 3/44 (6.8%) | |||||
| Dysphonia | 1/7 (14.3%) | 0/14 (0%) | 0/6 (0%) | 2/45 (4.4%) | 4/44 (9.1%) | |||||
| Dyspnoea | 1/7 (14.3%) | 1/14 (7.1%) | 1/6 (16.7%) | 0/45 (0%) | 0/44 (0%) | |||||
| Dyspnoea exertional | 1/7 (14.3%) | 0/14 (0%) | 0/6 (0%) | 0/45 (0%) | 0/44 (0%) | |||||
| Hiccups | 1/7 (14.3%) | 0/14 (0%) | 0/6 (0%) | 0/45 (0%) | 0/44 (0%) | |||||
| Oropharyngeal pain | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | 0/45 (0%) | 0/44 (0%) | |||||
| Pleural effusion | 0/7 (0%) | 1/14 (7.1%) | 2/6 (33.3%) | 0/45 (0%) | 0/44 (0%) | |||||
| Pulmonary oedema | 0/7 (0%) | 0/14 (0%) | 1/6 (16.7%) | 0/45 (0%) | 0/44 (0%) | |||||
| Tachypnoea | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | 0/45 (0%) | 0/44 (0%) | |||||
| Skin and subcutaneous tissue disorders | ||||||||||
| Alopecia | 0/7 (0%) | 0/14 (0%) | 0/6 (0%) | 1/45 (2.2%) | 11/44 (25%) | |||||
| Dermatitis acneiform | 0/7 (0%) | 0/14 (0%) | 0/6 (0%) | 0/45 (0%) | 5/44 (11.4%) | |||||
| Nail disorder | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | 0/45 (0%) | 0/44 (0%) | |||||
| Palmar-plantar erythrodysaesthesia syndrome | 0/7 (0%) | 0/14 (0%) | 1/6 (16.7%) | 11/45 (24.4%) | 27/44 (61.4%) | |||||
| Pruritus | 1/7 (14.3%) | 3/14 (21.4%) | 2/6 (33.3%) | 0/45 (0%) | 0/44 (0%) | |||||
| Rash | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | 4/45 (8.9%) | 4/44 (9.1%) | |||||
| Rash generalised | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | 0/45 (0%) | 0/44 (0%) | |||||
| Rash maculo-papular | 0/7 (0%) | 2/14 (14.3%) | 1/6 (16.7%) | 0/45 (0%) | 0/44 (0%) | |||||
| Skin exfoliation | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | 0/45 (0%) | 0/44 (0%) | |||||
| Pain of skin | 0/7 (0%) | 0/14 (0%) | 0/6 (0%) | 0/45 (0%) | 3/44 (6.8%) | |||||
| Vascular disorders | ||||||||||
| Hypertension | 0/7 (0%) | 0/14 (0%) | 1/6 (16.7%) | 0/45 (0%) | 12/44 (27.3%) | |||||
| Hypotension | 0/7 (0%) | 1/14 (7.1%) | 1/6 (16.7%) | 1/45 (2.2%) | 0/44 (0%) | |||||
| Phlebitis | 0/7 (0%) | 0/14 (0%) | 1/6 (16.7%) | 0/45 (0%) | 0/44 (0%) | |||||
Limitations/Caveats
[Not Specified]
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
Results Point of Contact
| Name/Title | Communication Center |
|---|---|
| Organization | Merck KGaA Darmstadt, Germany |
| Phone | +49-6151-72-5200 |
| service@emdgroup.com |
Responsible Party:
Merck KGaA, Darmstadt, Germany
ClinicalTrials.gov Identifier:
NCT01988493
Other Study ID Numbers:
- 200095-004
First Posted:
Nov 20, 2013
Last Update Posted:
Mar 7, 2022
Last Verified:
Dec 1, 2021