An Open-label, Dose Escalation, Pharmacodynamic, Pharmaco... | NCT01773421 | Trialant
NCT01773421
Sponsor
Eisai Inc.
Status
Completed
Last Update Posted
Jun 22, 2023Actual
Enrollment
45Actual
Phase
Phase 1
Conditions
Advanced Solid Tumors
Interventions
E7820
E7820
Countries
Netherlands
United Kingdom
Protocol Section
Identification Module
NCT ID
NCT01773421
Obsolete or Duplicate NCT IDs
Not provided
Organization Study
E7820-E044-110
Secondary IDs
ID
Type
Description
Link
2010-023655-28
EudraCT Number
Brief Title
An Open-label, Dose Escalation, Pharmacodynamic, Pharmacokinetic, and Effect of Food Phase 1 Study of E7820 to Determine the Maximum Tolerated Dose Following Twice Daily Oral Administration in Subjects With Unresectable Solid Tumors
Official Title
An Open-label, Dose Escalation, Pharmacodynamic, Pharmacokinetic, and Effect of Food Phase 1 Study of E7820, to Determine the Maximum Tolerated Dose Following Twice Daily Oral Administration in Subjects With Unresectable Solid Tumors
Acronym
Not provided
Organization
Eisai Inc.INDUSTRY
Status Module
Record Verification Date
Feb 2018
Overall Recruitment Status or Expanded Access Status
Completed
Last Known Status
Not provided
Delayed Posting
Not provided
Why Stopped
Not provided
Expanded Access Info
No
Start Date
Jun 30, 2011Actual
Primary Completion Date
Apr 30, 2014Actual
Completion Date
Nov 12, 2017Actual
First Submitted Date
Jan 17, 2013
First Submission Date that Met QC Criteria
Jan 18, 2013
First Posted Date
Jan 23, 2013Estimated
Results Waived
Not provided
Results First Submitted Date
Oct 4, 2019
Results First Submitted that Met QC Criteria
Jan 3, 2020
Results First Posted Date
Jan 18, 2020Actual
Certification/Extension (aka Delayed Results) First Submitted Date
Not provided
Certification/Extension First Submitted that Passed QC Review
Not provided
Certification/Extension First Posted Date
Not provided
Last Update Submitted Date
Jun 16, 2023
Last Update Posted Date
Jun 22, 2023Actual
Sponsor/Collaborators Module
Responsible Party, by Official Title
Sponsor
Lead Sponsor
Eisai Inc.INDUSTRY
Collaborators
Not provided
Oversight Module
Has Data Monitoring Committee (DMC)
No
Is FDA Regulated Drug
No
Is FDA Regulated Device
No
Is Unapproved Device
Not provided
Pediatric Postmarket Surveillance of a Device Product
Not provided
Product Exported from US
No
FDAAA801 Violation
Not provided
Description Module
Brief Summary
This study consists of two Parts. Part A (Food Effect Study) and Part B (Determination of Maximum Tolerated Dose [MTD] for twice daily [BID] Dosing).Part A will be initiated first, and Part B will be initiated after the PK results of Part A have been evaluated.
Detailed Description
Not provided
Conditions Module
Conditions
Advanced Solid Tumors
Keywords
Not provided
Design Module
Study Type
Interventional
Number of References to an Expanded Access Study
Not provided
Expanded Access Types
Not provided
Patient Registry
Not provided
Target Follow-Up Duration
Not provided
Phases
Phase 1
Interventional Study Design
Allocation
Biospecimen
No data available
No data is available for this block.
Enrollment
45Actual
Arms/Interventions Module
Arm Groups
Label
Type
Description
Intervention Names
Part A
Experimental
Drug: E7820
Part B
Experimental
Drug: E7820
Interventions
Name
Type
Description
Arm Group Labels
Other Names
E7820
Drug
FOOD EFFECT STUDY:
Each subject (a minimum of 12 subjects) will be assigned according to a randomization code to receive a single 50 mg dose of E7820 on Day 1, either after fasting for 10 hours, or immediately after consuming a high fat breakfast. Following a 7-day washout period, the subjects will crossover and a second 50 mg dose of E7820 will be administered on Day 8.
Outcomes Module
Primary Outcomes
Measure
Description
Time Frame
Treatment Phase Part A: AUC(0-inf): Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for E7820
Day 1 or 8: 0.5-48 hours
Treatment Phase Part A: AUC(0-t): Area Under the Plasma Concentration- Time Curve From Time 0 to t for E7820
Day 1 or 8: 0.5-48 hours
Treatment Phase Part A: Cmax: Maximum Observed Plasma Concentration for E7820
Day 1 or 8: 0.5-48 hours
Treatment Phase Part B: Maximum Tolerated Dose (MTD) of E7820 BID Dosing Schedule
MTD defined as the highest dose level at which no more than 1 of 6 participants experienced a dose-limiting toxicity(DLT), with the next higher dose having at least 2 of 3 or 2 of 6 participants experiencing DLTs. DLTs were defined using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events(CTCAE) Version 4.03 as: Neutropenia less than(<) 0.5*10^9/liter(L) for greater than(>) 5 days; neutropenia <1*10^9/L with fever; thrombocytopenia <25*10^9/L accompanied by bleeding or thrombocytopenia <10*10^9/L; any Grade 3 or 4 nonhematological toxicity for which the study drug could not be excluded as a cause (other than nausea, vomiting or diarrhea in the absence of appropriate prophylaxis) with the following clarification: Grade 3 or 4 nonhematological laboratory abnormalities for which there was no expected clinical correlation would not be considered DLTs; treatment delay of >14 days required to recover from E7820-related toxicities.
Up to Cycle 6 (Cycle length =28 days)
Secondary Outcomes
Measure
Description
Time Frame
Extension Phase Part A, and Treatment and Extension Phase Part B: Number of Participants With Best Overall Response (BOR)
BOR based on RECIST 1.1 for target and non-target lesions is complete response (CR) or partial response (PR) for >4 weeks or stable disease (SD) for >5 weeks from first dose. CR: disappearance of target and non-target lesions, normalization of tumor marker level, all lymph nodes must be non- pathological in size (<10 millimeter [mm] short axis). PR: at least 30% decrease in sum of diameters (SOD) of target lesions, taking as reference the baseline SOD persistence of one or more non- target lesions and/or maintenance of tumor marker level above the normal limits. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest SOD. PD: at least 20% increase (including an absolute increase of at least 5 mm) in the SOD of target lesions, taking as reference the smallest sum and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions.
Other Outcomes
Not provided
Eligibility Module
Eligibility Criteria
Inclusion Criteria:
Age 18 years or older.
Histological or cytological evidence of an unresectable or refractory solid tumor.
Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2
Subjects with known brain metastases will be eligible under the following conditions A. Have undergone complete surgical excision and are more then 1 month post surgery with no radiographic evidence of brain disease recurrence or B. Have undergone stereotactic radio surgery (gamma knife procedure) and are more then 1 month post procedure and with no radiographic evidence of brain disease progression and C. Are asymptomatic and D. Discontinued corticosteroid treatment at least 30 days prior to Cycle 1, Day 1
Adequate liver function as evidenced by bilirubin less than or equal to 1.5 times the upper limits of normal (ULN) and alkaline phosphatase, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) less than or equal to 3 x ULN (in the case of liver metastases less than or equal to 5 x ULN) In case alkaline phosphatase is greater than 3 x ULN (in absence of liver metastases) or greater than 5 x ULN (in presence of liver metastases) AND subject also is known to have bone metastases, the liver specific alkaline phosphatase must be separated from the total and used to assess the liver function instead of the total alkaline phosphatase.
Adequate renal function as evidenced by serum creatinine less than or equal to 2.0 mg/dL (177 micro-mol/L) or calculated creatinine clearance greater than or equal to 40 mL/min per the Cockcroft and Gault formula
Provide written informed consent.
Are willing and able to comply with all aspects of the protocol.
Adequate bone marrow function as evidenced by absolute neutrophil count (ANC) greater than or equal to 1.5 x 109/L, hemoglobin greater than or equal to 9 g/dL (5.5 mmol/L) and platelet count greater than or equal to 100 x 109/L.
Females must not be lactating or pregnant at Screening or Baseline (as documented by a negative beta-human chorionic gonadotropin [beta-hCG] test with a minimum sensitivity of 25 IU/L or equivalent units of beta-hCG). A separate baseline assessment is required if a negative screening pregnancy test was obtained more than 72 hours before the first dose of study drug.
All females will be considered to be of childbearing potential unless they are postmenopausal (amenorrheic for at least 12 consecutive months, in the appropriate age group, and without other known or suspected cause) or have been sterilized surgically (i.e., bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, all with surgery at least 1 month before dosing).
Females of childbearing potential must not have had unprotected sexual intercourse within 30 days prior to study entry and must agree to use a highly effective method of contraception (e.g., total abstinence, an intrauterine device, a double-barrier method [such as condom plus diaphragm with spermicide], a contraceptive implant, an oral contraceptive or have a vasectomized partner with confirmed azoospermia) throughout the entire study period and for 30 days after study drug discontinuation. If currently abstinent, the subject must agree to use a double-barrier method as described above if she becomes sexually active during the study period or for 30 days after study drug discontinuation. Females who are using hormonal contraceptives must have been on a stable dose of the same hormonal contraceptive product for at least 4 weeks prior to dosing and must continue to use the same contraceptive during the study and for 30 days after study drug discontinuation.
Male subjects must have had a successful vasectomy (confirmed azoospermia) or they and their female partners must meet the criteria above (i.e., not of childbearing potential or practicing highly effective contraception throughout the study period and for 30 days after study drug discontinuation). No sperm donation is allowed during the study period and for 30 days after study drug discontinuation.
Exclusion Criteria:
Leptomeningeal metastases or brain metastases (except as for inclusion criteria #4).
Active hemoptysis (at least 2.5 mL [0.5 teaspoon] bright red blood) within 3 weeks prior to the first dose of study drug.
Hypersensitivity to sulfonamide derivatives.
Subjects who have had radiation to greater than or equal to 30% of their bone marrow.
Subjects who require therapeutic anti-coagulant therapy with warfarin or related vitamin K antagonists. Prophylactic doses of heparin or low molecular weight heparin or thrombin inhibitors may be used in place of warfarin.
Left ventricular ejection fraction less than 50% on echocardiography or MUGA scanning.
Anticancer therapies that have not been completed at least 28 days (42 days in the case of mitomycin C or nitrosoureas) prior to treatment with E7820 (other than surgery or treatment with a protein kinase inhibitor which must have been completed no less than one week prior to treatment with E7820).
Incomplete recovery from previous radiotherapy, chemotherapy, or surgery other than residual cutaneous effects or stable less than Grade 2 gastrointestinal toxicity.
History of an ischemic cardiac event, myocardial infarction or unstable cardiac disease within 3 months before study entry.
A clinically significant electrocardiogram (ECG) abnormality, including a marked baseline prolongation of QTc interval greater than 480 msec.
Evidence of clinically significant disease (e.g., cardiac, respiratory, gastrointestinal, renal disease) that in the opinion of the investigator(s) could affect the subject's safety or study conduct.
Concurrent treatment with CYP3A4 inhibitors such as verapamil, cyclosporin, quinidine, erythromycin, mibefradil, clarithramycin and azoles.
Concurrent treatment with drugs known to be extensively metabolized by CYP2C9 and/or CYP2C19.
Chronic treatment with known inducers of CYP3A4 within four weeks of receiving treatment with E7820 other than corticosteroids (Appendix 6).
Subjects who have a positive test result for human immunodeficiency virus (HIV), hepatitis A, hepatitis B or hepatitis C.
Psychotic disorder(s) or unstable recurrent affective disorder(s) evident by use of antipsychotics or prior suicide attempt(s) within approximately the last 2 years.
History of drug or alcohol dependency or abuse within approximately the last 2 years.
Presence of a progressive central nervous system (CNS) disease, including degenerative CNS diseases and progressive tumors.
Pulmonary lymphangitic involvement that results in pulmonary dysfunction requiring active treatment, including the use of oxygen.
Use of illegal recreational drugs.
Any medical or other condition that, in the opinion of the investigator, would preclude the subject's participation in a study.
Accepts Healthy Volunteers
No
Sex
All
Sex/Gender Based
Not provided
Sex/Gender Description
Not provided
Minimum Age
18 Years
Maximum Age
Not provided
Standard Ages
AdultOlder Adult
Study Population
Not provided
Sampling Method
Not provided
Contacts/Locations Module
Central Contacts
Not provided
Overall Officials
Not provided
Locations
Facility
Status
City
State
ZIP
Country
Contacts
Netherlands Cancer Institute
Amsterdam
Netherlands
University Medical Centre Utrecht
References Module
No data available
No data is available for this block.
IPD Sharing Statement Module
No data available
No data is available for this block.
Results Section
Participant Flow Module
Pre-assignment Details
In Part A, a total of 18 participants were enrolled, out of which 15 participants were randomized and treated. In Part B, a total of 27 participants were enrolled, out of which 26 participants were treated.
Recruitment Details
Participants took part in the study at 6 investigative sites in the Netherlands and United Kingdom from 30 June 2011 to 12 November 2017.
Participants received E7820 50 milligram (mg), tablet, orally, under fed condition on Day 1, followed by E7820 50 mg, tablet, orally, under fasted condition on Day 8. A washout period of 7 days was maintained between the doses.
FG001
Periods
Title
Milestones
Reasons Not Completed
Treatment Phase
Type
Comment
Milestone Data
STARTED
Baseline Characteristics Module
Baseline Analysis Population Description
Not provided
Outcome Measures Module
Outcome Measures
Adverse Events Module
Frequency Threshold
0
More Info Module
Limitations and Caveats
Not provided
Annotation Section
No data available
No data is available for this block.
Document Section
No data available
No data is available for this block.
Derived Section
Miscellaneous Info Module
Version Holder
Jul 10, 2026
Removed Countries
Not provided
Submission Tracking
No data available
No data is available for this block.
Condition Browse Module
No data available
No data is available for this block.
Intervention Browse Module
MeSH Terms
Randomized
Intervention Model
Crossover Assignment
Intervention Model Description
Not provided
Primary Purpose
Treatment
Observational Model
Not provided
Time Perspective
Not provided
Masking Info
Masking
None (Open Label)
Masking Description
Not provided
Who Masked
Not provided
Part A
E7820
Drug
MTD DETERMINATION FOR BID DOSING SCHEDULE
The initial dose of E7820 will be 50 mg BID. If allowed by the rules for dose escalation, the dose escalations will be to 60 mg BID, 80 mg BID, and 100 mg BID.
Part B
From first dose of study drug (Baseline) up to approximately 6.6 years
Extension Phase Part A, and Treatment and Extension Phase Part B: Duration of Response
Duration of response based on RECIST 1.1 for target and non-target lesions is the time from the date of first documented confirmed CR/PR until the first documentation of confirmed progressive disease (PD) or death, whichever came first. CR: disappearance of target and non-target lesions,normalization of tumor marker level,all lymph nodes must be non-pathological in size(<10 mm short axis). PR: at least 30% decrease in SOD of target lesions,taking as reference the baseline SOD persistence of one or more non- target lesions and/or maintenance of tumor marker level above the normal limits. PD:at least 20% increase (including an absolute increase of at least 5 mm) in the SOD of target lesions,taking as reference the smallest sum and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions.
From date of first documented confirmed CR/PR until date of first documentation of PD or death (approximately up to 6.6 years)
Extension Phase Part A, and Treatment and Extension Phase Part B: Number of Participants With Death and Progressive Disease (PD)
PD: at least 20% increase (including an absolute increase of at least 5 mm) in the SOD of target lesions. For PD: participants with best response of PD have been reported. For Death: participants with death known to have died at any point have been reported.
From first dose date to the date of the first documentation of confirmed PD or death (approximately up to 6.6 years)
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
Safety assessments consisted of monitoring and recording all AEs and SAEs; regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, ECG, and multiple-gated acquisition (MUGA) scans or echocardiograms.
From the first dose of study drug up to 30 days after the last dose of study drug (approximately up to 6.6 years)
Participants received E7820 50 mg, tablet, orally, under fasted condition on Day 1, followed by E7820 50 mg, tablet, orally, under fed condition on Day 8. A washout period of 7 days was maintained between the doses.
FG002
Treatment Phase Part B: E7820 50 mg
Participants received E7820 50 mg, BID, tablet, orally, during each 28-day cycle for up to 6 cycles or early discontinuation.
FG003
Treatment Phase Part B: E7820 60 mg
Participants received E7820 60 mg, BID, tablet, orally, during each 28-day cycle for up to 6 cycles or early discontinuation.
FG004
Extension Phase Part A: E7820 100 mg
Participants at the end of treatment phase (who received study drug at the time of data cutoff for the primary analysis) moved on to extension phase and received E7820 100 mg, once daily, tablet, orally, under fasted condition, during 28-day cycle until disease progression, development of unacceptable toxicity, withdrawal of consent, or sponsor discontinuation of E7820 development.
FG005
Extension Phase Part B: E7820 50 mg
Participants at the end of treatment phase (who received study drug at the time of data cutoff for the primary analysis) moved on to extension phase and received E7820 50 mg, BID, tablet, orally, during each 28-day cycle for up to 6 cycles until disease progression, development of unacceptable toxicity, withdrawal of consent, or sponsor discontinuation of E7820 development.
FG006
Extension Phase Part B: E7820 60 mg
Participants at the end of treatment phase (who received study drug at the time of data cutoff for the primary analysis) moved on to extension phase and received E7820 60 mg, BID, tablet, orally, during each 28-day cycle for up to 6 cycles until disease progression, development of unacceptable toxicity, withdrawal of consent, or sponsor discontinuation of E7820 development. No participants from the treatment phase Part B: E7820 60 mg entered the extension phase.
Participants received E7820 50 mg, tablet, orally, under fed condition on Day 1, followed by E7820 50 mg, tablet, orally, under fasted condition on Day 8. A washout period of 7 days was maintained between the doses.
Participants received E7820 50 mg, tablet, orally, under fasted condition on Day 1, followed by E7820 50 mg, tablet, orally, under fed condition on Day 8. A washout period of 7 days was maintained between the doses.
BG002
Treatment Phase Part B: E7820 50 mg
Participants received E7820 50 mg, BID, tablet, orally, during each 28-day cycle for up to 6 cycles or early discontinuation.
BG003
Treatment Phase Part B: E7820 60 mg
Participants received E7820 60 mg, BID, tablet, orally, during each 28-day cycle for up to 6 cycles or early discontinuation.
BG004
Total
Total of all reporting groups
Denominators
Units
Counts
Participants
BG0007
BG0018
BG00219
BG0037
BG00441
Baseline Measures
Title
Description
Population Description
Parameter Type
Dispersion Type
Unit of Measure
Calculate Percentage
Denominator Units Selected
Denominators
Classes
Age, Customized
Count of Participants
Participants
Title
Denominators
Categories
Between 18 and 44 years
Title
Measurements
BG0000
BG0012
BG0021
BG003
Sex: Female, Male
Count of Participants
Participants
Title
Denominators
Categories
Title
Measurements
Female
BG0004
BG0013
BG002
Ethnicity (NIH/OMB)
Count of Participants
Participants
Title
Denominators
Categories
Title
Measurements
Hispanic or Latino
BG0000
BG0010
BG002
Race/Ethnicity, Customized
Count of Participants
Participants
Title
Denominators
Categories
White
Title
Measurements
BG0006
BG0018
BG002
ECOG Score
ECOG performance status was measured on 6 point scale to assess participant's performance status, where: 0 (fully active, able to carry on all pre-disease activities without restriction); 1(restricted in physically strenuous activity, but ambulatory and able to carry out light or sedentary work);2(ambulatory for >50 percent of waking hours),capable of all self-care, unable to carry out any work activities);3(capable of only limited self-care, confined to bed or chair for >50 percent of waking hours); 4(completely disabled,cannot carry on any self-care,totally confined to bed or chair);5(dead).
Count of Participants
Participants
Title
Denominators
Categories
Title
Measurements
0
BG0001
BG001
Type
Title
Description
Population Description
Reporting Status
Anticipated Posting Date
Parameter Type
Dispersion Type
Unit of Measure
Calculate Percentage
Time Frame
Units Analyzed
Denominator Units Selected
Arm/Group Information
Denominators
Classes
Analyses
Primary
Treatment Phase Part A: AUC(0-inf): Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for E7820
The pharmacokinetic (PK) analysis set included all participants who had sufficient PK data to derive at least 1 PK parameter. Participants who were evaluable at a particular time point for this endpoint were included in the assessment.
Posted
Mean
Standard Deviation
nanogram*hour per milliliter (ng*hr/mL)
Day 1 or 8: 0.5-48 hours
ID
Title
Description
OG000
Treatment Phase Part A: E7820 50 mg Fed
Participants received E7820 50 mg, tablet, orally, under fed condition, once on Day 1 or Day 8 in treatment phase.
OG001
Treatment Phase Part A: E7820 50 mg Fasted
Participants received E7820 50 mg, tablet, orally, under fasted condition, once on Day 1 or Day 8 in treatment phase.
Units
Counts
Participants
OG00012
OG00114
Title
Denominators
Categories
Title
Measurements
OG00012500± 3510
OG00111500± 3490
Group IDs
Group Description
Statistical Method
Statistical Comment
P-Value
P-Value Comment
Parameter Type
Parameter Value
Dispersion Type
Dispersion Value
Confidence Interval Sides
Confidence Interval %
CI Lower Limit
CI Upper Limit
CI Lower Limit Comment
CI Upper Limit Comment
Estimate Comment
Tested Non-Inferiority
Non-Inferiority Type
Non-Inferiority Comment
Other Analysis Description
OG000
OG001
Geometric Least Square (LS) Mean Ratio
1.06
2-Sided
90
0.97
1.15
Equivalence
Log-transformed pharmacokinetic parameters were fit using a mixed effects model with sequence, treatment, period and sequence as fixed effects and participant as a random effect. Geometric LS means and geometric LS mean ratio were back-transformed to obtain the treatment estimates.
Primary
Treatment Phase Part A: AUC(0-t): Area Under the Plasma Concentration- Time Curve From Time 0 to t for E7820
The PK analysis set included all participants who had sufficient PK data to derive at least 1 PK parameter.
Posted
Mean
Standard Deviation
ng*hr/mL
Day 1 or 8: 0.5-48 hours
ID
Title
Description
OG000
Treatment Phase Part A: E7820 50 mg Fed
Participants received E7820 50 mg, tablet, orally, under fed condition, once on Day 1 or Day 8 in treatment phase.
OG001
Treatment Phase Part A: E7820 50 mg Fasted
Participants received E7820 50 mg, tablet, orally, under fasted condition, once on Day 1 or Day 8 in treatment phase.
Units
Counts
Participants
OG000
Primary
Treatment Phase Part A: Cmax: Maximum Observed Plasma Concentration for E7820
The PK analysis set included all participants who had sufficient PK data to derive at least 1 PK parameter.
Posted
Mean
Standard Deviation
nanogram per milliliter (ng/mL)
Day 1 or 8: 0.5-48 hours
ID
Title
Description
OG000
Treatment Phase Part A: E7820 50 mg Fed
Participants received E7820 50 mg, tablet, orally, under fed condition, once on Day 1 or Day 8 in treatment phase.
OG001
Treatment Phase Part A: E7820 50 mg Fasted
Participants received E7820 50 mg, tablet, orally, under fasted condition, once on Day 1 or Day 8 in treatment phase.
Units
Counts
Participants
OG000
Primary
Treatment Phase Part B: Maximum Tolerated Dose (MTD) of E7820 BID Dosing Schedule
MTD defined as the highest dose level at which no more than 1 of 6 participants experienced a dose-limiting toxicity(DLT), with the next higher dose having at least 2 of 3 or 2 of 6 participants experiencing DLTs. DLTs were defined using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events(CTCAE) Version 4.03 as: Neutropenia less than(<) 0.5*10^9/liter(L) for greater than(>) 5 days; neutropenia <1*10^9/L with fever; thrombocytopenia <25*10^9/L accompanied by bleeding or thrombocytopenia <10*10^9/L; any Grade 3 or 4 nonhematological toxicity for which the study drug could not be excluded as a cause (other than nausea, vomiting or diarrhea in the absence of appropriate prophylaxis) with the following clarification: Grade 3 or 4 nonhematological laboratory abnormalities for which there was no expected clinical correlation would not be considered DLTs; treatment delay of >14 days required to recover from E7820-related toxicities.
MTD was assessed in safety analysis set. The safety analysis set included all participants who received at least 1 dose of study drug.
Posted
Number
mg
Up to Cycle 6 (Cycle length =28 days)
ID
Title
Description
OG000
Treatment Phase Part B: All Participants
Participants received E7820 50 mg or 60 mg, BID, tablet, orally, during each 28-day cycle for up to 6 cycles or early discontinuation.
Units
Secondary
Extension Phase Part A, and Treatment and Extension Phase Part B: Number of Participants With Best Overall Response (BOR)
BOR based on RECIST 1.1 for target and non-target lesions is complete response (CR) or partial response (PR) for >4 weeks or stable disease (SD) for >5 weeks from first dose. CR: disappearance of target and non-target lesions, normalization of tumor marker level, all lymph nodes must be non- pathological in size (<10 millimeter [mm] short axis). PR: at least 30% decrease in sum of diameters (SOD) of target lesions, taking as reference the baseline SOD persistence of one or more non- target lesions and/or maintenance of tumor marker level above the normal limits. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest SOD. PD: at least 20% increase (including an absolute increase of at least 5 mm) in the SOD of target lesions, taking as reference the smallest sum and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions.
The efficacy evaluable analysis set: all participants with a completed tumor assessment at Baseline (Chest, Abdomen and Pelvis scans) and at least 1 complete posttreatment tumor assessment (as per Response Evaluation Criteria in Solid Tumors [RECIST] 1.1). Overall number of participants analyzed signifies participants evaluable for this measure.
Posted
Count of Participants
Participants
From first dose of study drug (Baseline) up to approximately 6.6 years
ID
Title
Description
OG000
Extension Phase Part A: E7820 100 mg
Participants at the end of treatment phase (who received study drug at the time of data cutoff for the primary analysis) moved on to extension phase and received E7820 100 mg, once daily, tablet, orally, under fasted condition, during 28-day cycle until disease progression, development of unacceptable toxicity, withdrawal of consent, or sponsor discontinuation of E7820 development.
Secondary
Extension Phase Part A, and Treatment and Extension Phase Part B: Duration of Response
Duration of response based on RECIST 1.1 for target and non-target lesions is the time from the date of first documented confirmed CR/PR until the first documentation of confirmed progressive disease (PD) or death, whichever came first. CR: disappearance of target and non-target lesions,normalization of tumor marker level,all lymph nodes must be non-pathological in size(<10 mm short axis). PR: at least 30% decrease in SOD of target lesions,taking as reference the baseline SOD persistence of one or more non- target lesions and/or maintenance of tumor marker level above the normal limits. PD:at least 20% increase (including an absolute increase of at least 5 mm) in the SOD of target lesions,taking as reference the smallest sum and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions.
Duration of response was not analyzed since no participants had best overall response of CR or PR in the study.
Posted
From date of first documented confirmed CR/PR until date of first documentation of PD or death (approximately up to 6.6 years)
ID
Title
Description
OG000
Extension Phase Part A: E7820 100 mg
Participants at the end of treatment phase (who received study drug at the time of data cutoff for the primary analysis) moved on to extension phase and received E7820 100 mg, once daily, tablet, orally, under fasted condition, during 28-day cycle until disease progression, development of unacceptable toxicity, withdrawal of consent, or sponsor discontinuation of E7820 development.
OG001
Secondary
Extension Phase Part A, and Treatment and Extension Phase Part B: Number of Participants With Death and Progressive Disease (PD)
PD: at least 20% increase (including an absolute increase of at least 5 mm) in the SOD of target lesions. For PD: participants with best response of PD have been reported. For Death: participants with death known to have died at any point have been reported.
The efficacy evaluable set. Due to lack of available summarized data, data has been presented only descriptively in terms of number of participants who were known to have died and number of who had PD.
Posted
Count of Participants
Participants
From first dose date to the date of the first documentation of confirmed PD or death (approximately up to 6.6 years)
ID
Title
Description
OG000
Extension Phase Part A: E7820 100 mg
Participants at the end of treatment phase (who received study drug at the time of data cutoff for the primary analysis) moved on to extension phase and received E7820 100 mg, once daily, tablet, orally, under fasted condition, during 28-day cycle until disease progression, development of unacceptable toxicity, withdrawal of consent, or sponsor discontinuation of E7820 development.
OG001
Treatment and Extension Phase Part B: E7820 50 mg
Participants received E7820 50 mg, BID, tablet, orally, during each 28-day cycle for up to 6 cycles or early discontinuation. Participants at the end of treatment phase (who received study drug at the time of data cutoff for the primary analysis) moved on to extension phase and received E7820 50 mg, BID, tablet, orally, during each 28-day cycle for up to 6 cycles until disease progression, development of unacceptable toxicity, withdrawal of consent, or sponsor discontinuation of E7820 development.
Secondary
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
Safety assessments consisted of monitoring and recording all AEs and SAEs; regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, ECG, and multiple-gated acquisition (MUGA) scans or echocardiograms.
The safety analysis set included all participants who received at least 1 dose of study drug.
Posted
Count of Participants
Participants
From the first dose of study drug up to 30 days after the last dose of study drug (approximately up to 6.6 years)
ID
Title
Description
OG000
Treatment Phase Part A: E7820 50 mg Fed
Participants received E7820 50 mg, tablet, orally, under fed condition, once on Day 1 or Day 8 in treatment phase.
OG001
Treatment Phase Part A: E7820 50 mg Fasted
Participants received E7820 50 mg, tablet, orally, under fasted condition, once on Day 1 or Day 8 in treatment phase.
OG002
Extension Phase Part A: E7820 100 mg
Participants at the end of treatment phase (who received study drug at the time of data cutoff for the primary analysis) moved on to extension phase and received E7820 100 mg, once daily, tablet, orally, under fasted condition, during 28-day cycle until disease progression, development of unacceptable toxicity, withdrawal of consent, or sponsor discontinuation of E7820 development.
Time Frame
From the first dose of study drug up to 30 days after the last dose of study drug (approximately up to 6.6 years)
Description
Not provided
All-Cause Mortality Comment
Not provided
Arm/Groups
ID
Title
Description
Deaths (Affected)
Deaths (At Risk)
Serious Events (Affected)
Serious Events (At Risk)
Other Events (Affected)
Other Events (At Risk)
EG000
Treatment Phase Part A: E7820 50 mg Fed
Participants received E7820 50 mg, tablet, orally, under fed condition, once on Day 1 or Day 8 in treatment phase.
11
15
0
15
7
15
EG001
Treatment Phase Part A: E7820 50 mg Fasted
Participants received E7820 50 mg, tablet, orally, under fasted condition, once on Day 1 or Day 8 in treatment phase.
11
15
1
15
6
15
EG002
Extension Phase Part A: E7820 100 mg
Participants at the end of treatment phase (who received study drug at the time of data cutoff for the primary analysis) moved on to extension phase and received E7820 100 mg, once daily, tablet, orally, under fasted condition, during 28-day cycle until disease progression, development of unacceptable toxicity, withdrawal of consent, or sponsor discontinuation of E7820 development.
11
15
5
15
14
15
EG003
Treatment and Extension Phase Part B: E7820 50 mg
Participants received E7820 50 mg, BID, tablet, orally, during each 28-day cycle for up to 6 cycles or early discontinuation. Participants at the end of treatment phase (who received study drug at the time of data cutoff for the primary analysis) moved on to extension phase and received E7820 50 mg, BID, tablet, orally, during each 28-day cycle for up to 6 cycles until disease progression, development of unacceptable toxicity, withdrawal of consent, or sponsor discontinuation of E7820 development.
14
19
10
19
19
19
EG004
Treatment and Extension Phase Part B: E7820 60 mg
Participants received E7820 60 mg, BID, tablet, orally, during each 28-day cycle for up to 6 cycles or early discontinuation. Participants at the end of treatment phase (who received study drug at the time of data cutoff for the primary analysis) moved on to extension phase and received E7820 60 mg, BID, tablet, orally, during each 28-day cycle for up to 6 cycles until disease progression, development of unacceptable toxicity, withdrawal of consent, or sponsor discontinuation of E7820 development.
5
7
6
7
7
7
Serious Adverse Events
Term
Organ System
Source Vocabulary
Assessment Type
Notes
Statistical Information
Leukopenia
Blood and lymphatic system disorders
MedDRA 16.1
Systematic Assessment
EG0000 events0 affected15 at risk
EG0010 events0 affected15 at risk
EG0020 events0 affected15 at risk
EG0030 events0 affected19 at risk
EG0041 events1 affected7 at risk
Neutropenia
Blood and lymphatic system disorders
MedDRA 16.1
Systematic Assessment
EG0000 events0 affected15 at risk
EG0010 events0 affected15 at risk
EG0021 events1 affected15 at risk
EG003
Thrombocytopenia
Blood and lymphatic system disorders
MedDRA 16.1
Systematic Assessment
EG0000 events0 affected15 at risk
EG0010 events0 affected15 at risk
EG0021 events1 affected15 at risk
EG003
Pericardial effusion
Cardiac disorders
MedDRA 16.1
Systematic Assessment
EG0000 events0 affected15 at risk
EG0010 events0 affected15 at risk
EG0020 events0 affected15 at risk
EG003
Inappropriate antidiuretic hormone secretion
Endocrine disorders
MedDRA 16.1
Systematic Assessment
EG0000 events0 affected15 at risk
EG0010 events0 affected15 at risk
EG0020 events0 affected15 at risk
EG003
Abdominal pain
Gastrointestinal disorders
MedDRA 16.1
Systematic Assessment
EG0000 events0 affected15 at risk
EG0010 events0 affected15 at risk
EG0021 events1 affected15 at risk
EG003
Constipation
Gastrointestinal disorders
MedDRA 16.1
Systematic Assessment
EG0000 events0 affected15 at risk
EG0010 events0 affected15 at risk
EG0020 events0 affected15 at risk
EG003
Duodenal ulcer haemorrhage
Gastrointestinal disorders
MedDRA 16.1
Systematic Assessment
EG0000 events0 affected15 at risk
EG0010 events0 affected15 at risk
EG0020 events0 affected15 at risk
EG003
Dysphagia
Gastrointestinal disorders
MedDRA 16.1
Systematic Assessment
EG0000 events0 affected15 at risk
EG0010 events0 affected15 at risk
EG0020 events0 affected15 at risk
EG003
Nausea
Gastrointestinal disorders
MedDRA 16.1
Systematic Assessment
EG0000 events0 affected15 at risk
EG0010 events0 affected15 at risk
EG0021 events1 affected15 at risk
EG003
Oesophageal ulcer
Gastrointestinal disorders
MedDRA 16.1
Systematic Assessment
EG0000 events0 affected15 at risk
EG0010 events0 affected15 at risk
EG0020 events0 affected15 at risk
EG003
Pancreatic enzyme abnormality
Gastrointestinal disorders
MedDRA 16.1
Systematic Assessment
EG0000 events0 affected15 at risk
EG0010 events0 affected15 at risk
EG0020 events0 affected15 at risk
EG003
Small intestinal obstruction
Gastrointestinal disorders
MedDRA 16.1
Systematic Assessment
EG0000 events0 affected15 at risk
EG0010 events0 affected15 at risk
EG0020 events0 affected15 at risk
EG003
Upper gastrointestinal haemorrhage
Gastrointestinal disorders
MedDRA 16.1
Systematic Assessment
EG0000 events0 affected15 at risk
EG0010 events0 affected15 at risk
EG0020 events0 affected15 at risk
EG003
Vomiting
Gastrointestinal disorders
MedDRA 16.1
Systematic Assessment
EG0000 events0 affected15 at risk
EG0010 events0 affected15 at risk
EG0021 events1 affected15 at risk
EG003
Malaise
General disorders
MedDRA 16.1
Systematic Assessment
EG0000 events0 affected15 at risk
EG0010 events0 affected15 at risk
EG0021 events1 affected15 at risk
EG003
Pyrexia
General disorders
MedDRA 16.1
Systematic Assessment
EG0000 events0 affected15 at risk
EG0010 events0 affected15 at risk
EG0021 events1 affected15 at risk
EG003
Food allergy
Immune system disorders
MedDRA 16.1
Systematic Assessment
EG0000 events0 affected15 at risk
EG0010 events0 affected15 at risk
EG0021 events1 affected15 at risk
EG003
Bronchitis
Infections and infestations
MedDRA 16.1
Systematic Assessment
EG0000 events0 affected15 at risk
EG0010 events0 affected15 at risk
EG0021 events1 affected15 at risk
EG003
Clostridium difficile infection
Infections and infestations
MedDRA 16.1
Systematic Assessment
EG0000 events0 affected15 at risk
EG0010 events0 affected15 at risk
EG0020 events0 affected15 at risk
EG003
Neutropenic sepsis
Infections and infestations
MedDRA 16.1
Systematic Assessment
EG0000 events0 affected15 at risk
EG0010 events0 affected15 at risk
EG0020 events0 affected15 at risk
EG003
Urosepsis
Infections and infestations
MedDRA 16.1
Systematic Assessment
EG0000 events0 affected15 at risk
EG0010 events0 affected15 at risk
EG0020 events0 affected15 at risk
EG003
Hepatic enzyme abnormal
Investigations
MedDRA 16.1
Systematic Assessment
EG0000 events0 affected15 at risk
EG0010 events0 affected15 at risk
EG0020 events0 affected15 at risk
EG003
Tumour haemorrhage
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Log-transformed pharmacokinetic parameters were fit using a mixed effects model with sequence, treatment, period and sequence as fixed effects and participant as a random effect. Geometric LS means and geometric LS mean ratio were back-transformed to obtain the treatment estimates.
14
OG00115
Title
Denominators
Categories
Title
Measurements
OG0001030± 311
OG001901± 242
Group IDs
Group Description
Statistical Method
Statistical Comment
P-Value
P-Value Comment
Parameter Type
Parameter Value
Dispersion Type
Dispersion Value
Confidence Interval Sides
Confidence Interval %
CI Lower Limit
CI Upper Limit
CI Lower Limit Comment
CI Upper Limit Comment
Estimate Comment
Tested Non-Inferiority
Non-Inferiority Type
Non-Inferiority Comment
Other Analysis Description
OG000
OG001
Geometric LS Mean Ratio
1.13
2-Sided
90
1
1.27
Equivalence
Log-transformed pharmacokinetic parameters were fit using a mixed effects model with sequence, treatment, period and sequence as fixed effects and participant as a random effect. Geometric LS means and geometric LS mean ratio were back-transformed to obtain the treatment estimates.
Counts
Participants
OG00026
Title
Denominators
Categories
Title
Measurements
OG00050
OG001
Treatment and Extension Phase Part B: E7820 50 mg
Participants received E7820 50 mg, BID, tablet, orally, during each 28-day cycle for up to 6 cycles or early discontinuation. Participants at the end of treatment phase (who received study drug at the time of data cutoff for the primary analysis) moved on to extension phase and received E7820 50 mg, BID, tablet, orally, during each 28-day cycle for up to 6 cycles until disease progression, development of unacceptable toxicity, withdrawal of consent, or sponsor discontinuation of E7820 development.
OG002
Treatment and Extension Phase Part B: E7820 60 mg
Participants received E7820 60 mg, BID, tablet, orally, during each 28-day cycle for up to 6 cycles or early discontinuation. Participants at the end of treatment phase (who received study drug at the time of data cutoff for the primary analysis) moved on to extension phase and received E7820 60 mg, BID, tablet, orally, during each 28-day cycle for up to 6 cycles until disease progression, development of unacceptable toxicity, withdrawal of consent, or sponsor discontinuation of E7820 development.
Units
Counts
Participants
OG00013
OG00118
OG0025
Title
Denominators
Categories
Complete response
Title
Measurements
OG0000
OG0010
OG0020
Partial response
Title
Measurements
OG0000
OG0010
OG0020
Stable disease
Title
Measurements
OG0003
OG00112
OG0022
Treatment and Extension Phase Part B: E7820 50 mg
Participants received E7820 50 mg, BID, tablet, orally, during each 28-day cycle for up to 6 cycles or early discontinuation. Participants at the end of treatment phase (who received study drug at the time of data cutoff for the primary analysis) moved on to extension phase and received E7820 50 mg, BID, tablet, orally, during each 28-day cycle for up to 6 cycles until disease progression, development of unacceptable toxicity, withdrawal of consent, or sponsor discontinuation of E7820 development.
OG002
Treatment and Extension Phase Part B: E7820 60 mg
Participants received E7820 60 mg, BID, tablet, orally, during each 28-day cycle for up to 6 cycles or early discontinuation. Participants at the end of treatment phase (who received study drug at the time of data cutoff for the primary analysis) moved on to extension phase and received E7820 60 mg, BID, tablet, orally, during each 28-day cycle for up to 6 cycles until disease progression, development of unacceptable toxicity, withdrawal of consent, or sponsor discontinuation of E7820 development.
Units
Counts
Participants
OG0000
OG0010
OG0020
OG002
Treatment and Extension Phase Part B: E7820 60 mg
Participants received E7820 60 mg, BID, tablet, orally, during each 28-day cycle for up to 6 cycles or early discontinuation. Participants at the end of treatment phase (who received study drug at the time of data cutoff for the primary analysis) moved on to extension phase and received E7820 60 mg, BID, tablet, orally, during each 28-day cycle for up to 6 cycles until disease progression, development of unacceptable toxicity, withdrawal of consent, or sponsor discontinuation of E7820 development.
Units
Counts
Participants
OG00013
OG00118
OG0027
Title
Denominators
Categories
Death
Title
Measurements
OG00011
OG00114
OG0025
PD
Title
Measurements
OG0009
OG0016
OG0022
OG003
Treatment and Extension Phase Part B: E7820 50 mg
Participants received E7820 50 mg, BID, tablet, orally, during each 28-day cycle for up to 6 cycles or early discontinuation. Participants at the end of treatment phase (who received study drug at the time of data cutoff for the primary analysis) moved on to extension phase and received E7820 50 mg, BID, tablet, orally, during each 28-day cycle for up to 6 cycles until disease progression, development of unacceptable toxicity, withdrawal of consent, or sponsor discontinuation of E7820 development.
OG004
Treatment and Extension Phase Part B: E7820 60 mg
Participants received E7820 60 mg, BID, tablet, orally, during each 28-day cycle for up to 6 cycles or early discontinuation. Participants at the end of treatment phase (who received study drug at the time of data cutoff for the primary analysis) moved on to extension phase and received E7820 60 mg, BID, tablet, orally, during each 28-day cycle for up to 6 cycles until disease progression, development of unacceptable toxicity, withdrawal of consent, or sponsor discontinuation of E7820 development.