M8891 First in Human in Solid Tumors
Study Details
Study Description
Brief Summary
The purpose of this study was to determine the maximum tolerated dose (MTD), safety, tolerability, Pharmacokinetic (PK), pharmacodynamic and clinical activity of M8891 as single agent in participants with advanced solid tumors in Part 1.
Condition or Disease | Intervention/Treatment | Phase |
---|---|---|
|
Phase 1 |
Study Design
Arms and Interventions
Arm | Intervention/Treatment |
---|---|
Experimental: M8891 7 mg Participant received M8891 at dose of 7 milligrams (mg) orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. |
Drug: Part 1: M8891
Participants receives M8891 orally once daily at escalated dose levels under fasting condition for consecutive 21-day cycles of continuous treatment until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study.
|
Experimental: M8891 12 mg Participant received M8891 at dose of 12 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. |
Drug: Part 1: M8891
Participants receives M8891 orally once daily at escalated dose levels under fasting condition for consecutive 21-day cycles of continuous treatment until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study.
|
Experimental: M8891 20 mg Participant received M8891 at dose of 20 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. |
Drug: Part 1: M8891
Participants receives M8891 orally once daily at escalated dose levels under fasting condition for consecutive 21-day cycles of continuous treatment until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study.
|
Experimental: M8891 35 mg Participant received M8891 at dose of 35 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. |
Drug: Part 1: M8891
Participants receives M8891 orally once daily at escalated dose levels under fasting condition for consecutive 21-day cycles of continuous treatment until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study.
|
Experimental: M8891 60 mg Participant received M8891 at dose of 60 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. |
Drug: Part 1: M8891
Participants receives M8891 orally once daily at escalated dose levels under fasting condition for consecutive 21-day cycles of continuous treatment until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study.
|
Experimental: M8891 80 mg Participant received M8891 at dose of 80 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. |
Drug: Part 1: M8891
Participants receives M8891 orally once daily at escalated dose levels under fasting condition for consecutive 21-day cycles of continuous treatment until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study.
|
Outcome Measures
Primary Outcome Measures
- Number of Participants Who Experienced Dose Limiting Toxicities (DLTs) Assessed Using National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE) Version 4.03 [At the end of Cycle 1 (each Cycle is of 21 days)]
A DLT was defined as the occurrence of any of following events that were judged by the study investigator, to be related to the study medication: Grade 4 liver enzyme elevation; Grade 4 neutropenia lasting >5 days or Grade >= 3 neutropenia with fever; Grade 4 thrombocytopenia lasting >5 days or Grade >=3 thrombocytopenia with clinically significant bleeding; Any treatment interruption >7 days or >30% of total dose in Cycle 1 due to AEs not related to the underlying disease or concomitant medication; Grade >=3 non-hematologic toxicity excluding Grade 3 nausea or vomiting lasting <48 hours, and resolves to <= Grade 1 either spontaneously or with medication, Grade 3 fatigue <= 3 days, Grade 3 hypertension in the absence of maximal medical therapy, Grade 3 rash <= 3 days, Grade 3 electrolyte abnormality that lasts <72 hours, is not clinically complicated, and resolves spontaneously or responds to conventional medication and Grade >=3 single lab value increase without clinical correlate.
Secondary Outcome Measures
- Number of Participants With Treatment-Emergent Adverse Events (TEAE) and TEAEs Leading to Death [Up to 1136 Days]
An Adverse event (AE) was defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease associated with the use of study drug, whether or not considered related to the study drug or worsening of pre-existing medical condition, whether or not related to study drug. A serious adverse event (SAE) 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. The term TEAE is defined as AEs starting or worsening after the first intake of the study drug. TEAEs include both Serious TEAEs and non-serious TEAEs.
- Number of Participants With Treatment-Emergent Adverse Events (TEAE) by Severity [Up to 1136 Days]
Severity of adverse events (AE) were assessed by the investigator according to National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE) version 4.03 as Grade 1 to Grade 5. Grade 1= Mild, Grade 2=Moderate, Grade 3=Severe, Grade 4= Life-threatening and Grade 5= Death. The number of participants that experienced at least one solicited local TEAE were summarized by grade. The term TEAE is defined as AEs starting or worsening after the first intake of the study drug. TEAEs include both Serious TEAEs and non-serious TEAEs. Number of participants with Grade >=3, >=4 and 5 were reported.
- Maximum Observed Plasma Concentration (Cmax) of M8891 [Cycle 1 Pre-dose, 1, 2, 3, 4, 5, 6, 8, 12, 24 hours post-dose on Day 1 and 15 (Each cycle is of 21 days)]
Maximum observed plasma concentration (Cmax) was taken directly from the observed concentration-time curve.
- Time to Reach Maximum Observed Plasma Concentration (Tmax) of M8891 [Cycle 1 Pre-dose, 1, 2, 3, 4, 5, 6, 8, 12, 24 hours post-dose on Day 1 and 15 (Each cycle is of 21 days)]
The time to reach the maximum observed plasma concentration (tmax) was obtained directly from the concentration versus time curve.
- Area Under the Plasma Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-t) of M8891 [Cycle 1 Pre-dose, 1, 2, 3, 4, 5, 6, 8, 12, 24 hours post-dose on Day 1 and 15 (Each cycle is of 21 days)]
The AUC from time zero (= dosing time) to the last sampling time (tlast) at which the concentration is at or above the lower limit of quantification (LLOQ), calculated using the mixed log-linear trapezoidal rule (linear up, log down).
- Area Under the Concentration-time Curve From Zero Extrapolated to Infinity (AUC0-inf) of M8891 [Cycle 1 Pre-dose, 1, 2, 3, 4, 5, 6, 8, 12, 24 hours post-dose on Day 1 and 15 (Each cycle is of 21 days)]
The AUC from time zero (dosing time) extrapolated to infinity, based on the predicted value for the concentration at tlast, as estimated using the linear regression from the determination of the terminal first order (elimination) rate constant (lambda z). AUC0-inf = AUC0-t plus Clast pred/lambda z. Lambda Z was terminal elimination rate constant determined from the terminal slope of the log-transformed plasma concentration curve using linear regression on terminal data points of the curve. Clastpred was the last predicted quantifiable concentration.
- Area Under the Plasma Concentration Versus Time Curve Within One Dosing Interval (AUC0-tau) of M8891 [Cycle 1 Pre-dose, 1, 2, 3, 4, 5, 6, 8, 12, 24 hours post-dose on Day 1 and 15 (Each cycle is of 21 days)]
AUC (0-tau) is the area under the plasma concentration time curve within 1 dosing interval. Calculated using the mixed log linear trapezoidal rule (linear up, log down).
- Apparent Terminal Half Life (t1/2) of M8891 [Cycle 1 Pre-dose, 1, 2, 3, 4, 5, 6, 8, 12, 24 hours post-dose on Day 1 and 15 (Each cycle is of 21 days)]
Terminal half-life of M8891 in Plasma was calculated as log2/ lambda z. Lambda z was determined from the terminal slope of the log-transformed concentration curve using linear regression on terminal data points of the curve.
- Terminal Elimination Rate Constant (Lambda z) of M8891 [Cycle 1 Pre-dose, 1, 2, 3, 4, 5, 6, 8, 12, 24 hours post-dose on Day 1 and 15 (Each cycle is of 21 days)]
Lambda z was determined from the terminal slope of the log-transformed concentration curve using linear regression on terminal data points of the curve.
- Apparent Total Body Clearance (CL/f) of M8891 [Cycle 1 Pre-dose, 1, 2, 3, 4, 5, 6, 8, 12, 24 hours post-dose on Day 1 and 15 (Each cycle is of 21 days)]
Apparent total body clearance of drug from plasma following extravascular administration, calculated as dose/AUC0-infinity for M8891. Area under the plasma concentration-time curve from time zero (dosing time) extrapolated to infinity of unchanged drug calculated as AUC0-t + AUCextra. AUCextra represents the extrapolated part of AUC0-infinity calculated by Clastpred/lambda z, where Clastpred is the predicted plasma concentration at the last sampling time point, calculated from the log linear regression line for lambda z determination at which the measured plasma concentration is at or above lower limit of quantification.
- Apparent Body Clearance of Drug Following Extravascular Administration At Steady State (CLss/f) of M8891 [Cycle 1 Pre-dose, 1, 2, 3, 4, 5, 6, 8, 12, 24 hours post-dose on Day 1 and 15 (Each cycle is of 21 days)]
The apparent total body clearance of drug at steady state following extravascular administration, taking into account the fraction of dose absorbed. It is calculated as dose/AUCtau for M8891.
- Apparent Volume of Distribution During Terminal Phase (VZ/f) of M8891 [Cycle 1 Pre-dose, 1, 2, 3, 4, 5, 6, 8, 12, 24 hours post-dose on Day 1 and 15 (Each cycle is of 21 days)]
Apparent volume of distribution during the terminal phase following extravascular administration for M8891 was calculated. Vz/f = Dose/(AUC0-infinity multiply by Lambda z) following single dose. The AUC from time zero (dosing time) extrapolated to infinity, based on the predicted value for the concentration at tlast, as estimated using the linear regression from lambda z determination. AUC(0- inf)=AUC0-t plus Clastpred/lambda z where Clastpred was last predicted concentration. Lambda Z was terminal elimination rate constant determined from the terminal slope of the log-transformed plasma concentration curve using linear regression on terminal data points of the curve.
- Accumulation Ratios of AUC (Racc AUC) of M8891 [Pre-dose and at 1, 2, 3, 4, 5, 6, 8, 12, 24 hours post-dose on Day 1 and 15 of Cycle 1 (each cycle is 21 days)]
Racc (AUC) is defined as the accumulation factor to assess the increase in exposure until steady state is reached. Accumulation ratio for AUC was calculated as AUC, after dosing on Day 15 divided by AUC, after dosing on Day 1 of Cycle 1.
- Accumulation Ratio of Cmax (Racc Cmax) of M8891 [Pre-dose and at 1, 2, 3, 4, 5, 6, 8, 12, 24 hours post-dose on Day 1 and 15 of Cycle 1 (each cycle is 21 days)]
Accumulation ratio of Cmax was calculated as Cmax, after dosing on Day 15 divided by Cmax, after dosing on Day 1 of Cycle 1.
- Number of Participants With Best Overall Response Assessment According to Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST v1.1) Criteria [Up to 1136 Days]
BOR was determined according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) as assessed by investigators. BOR is defined as the best response of any of the complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD) recorded from the date of randomization until disease progression. CR: Disappearance of all evidence of target and non-target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 millimeter (mm). PR: At least 30% reduction from baseline in the sum of the longest diameter (SLD) of all lesions. Stable disease (SD) defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest SLD while on study. PD is defined as at least a 20 percent (%) increase in the SLD of target lesion, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions.
- Number of Participants With Clinical Benefit [Up to 1136 Days]
Clinical benefit defined as Complete Response (CR), Partial Response (PR) or Stable Disease (SD) for >= 12 weeks. Clinical benefit was assessed according to RECIST Version 1.1. CR: defined as disappearance of all target and all non-target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 millimeter (mm). PR: At least 30% reduction from baseline in the sum of the longest diameter (SLD) of all lesions. SD: defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest SLD while on study. PD is defined as at least a 20 percent (%) increase in the SLD of target lesion, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions.
- Progression-Free Survival (PFS) [Up to 1136 Days]
Progression-free survival (PFS) defined as the time from first study drug administration to either first observation of progressive disease (PD) (as assessed by Investigators according to RECIST v1.1) or occurrence of death due to any cause, whichever occurs first. Progressive disease (PD) defined as at least a 20% increase in sum of longest diameter (SLD) of target lesions, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. PFS was measured using Kaplan-Meier (KM) estimates. Here the 20 mg dose level was selected for stratification as the highest dose level equal to or smaller than the median of all dose levels administered to at least 1 participant.
- Number of Participants With Change From Baseline in Laboratory Test Abnormalities to Grade 3 or Higher Severity Based on NCI-CTCAE Version 4.03 [Up to 1136 Days]
The laboratory measurements included hematology, biochemistry, and urinalysis values were graded with National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.03 toxicity grades (where Grade 1 = mild, Grade 2 = moderate, Grade 3 = severe, Grade 4 = life threatening and Grade 5 = death). Number of participants with change from baseline to grade 3 or higher values for the hematology, biochemistry and urinalysis parameters were reported.
- Number of Participants With Clinically Meaningful Changes From Baseline in Vital Signs [Up to 1136 Days]
Vital sign assessments included assessments of heart rate, diastolic blood pressure, systolic blood pressure, weight, respiratory rate and temperature. Clinical relevance was assessed by the investigator. Number of participants who had any clinically meaningful change from baseline in vital signs were reported.
- Number of Participants With Clinically Meaningful Changes From Baseline in Electrocardiogram (ECG) Values [Up to 1136 Days]
ECG parameters included rhythm, heart rate (as measured by RR interval), PR interval, QRS duration, QT intervals, and corrected QT(QTc) intervals. Clinical significance was determined by the investigator. Number of participants with clinically meaningful change from baseline in 12-lead ECG were reported.
- Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status (PF) Score of 2 or Higher Than 2 [Up to 1136 Days]
ECOG PS score is widely used by doctors and researchers to assess how a participants' disease is progressing, and is used to assess how the disease affects the daily living abilities of the participant, and determine appropriate treatment and prognosis. The score ranges from Grade 0 to Grade 5, where Grade 0 = Fully active, able to carry on all pre-disease performance without restriction, Grade 1 = Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature (like light house work, office work), Grade 2 = Ambulatory and capable of all self-care but unable to carry out any work activities, Grade 3 = Capable of only limited self-care, confined to bed or chair more than 50% of waking hours and Grade 4 = Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair, Grade 5 = Death. Number of participants with ECOG performance status score of 2 or higher than 2 were reported.
- Percentage of Participants With Objective Response [Up to 1136 Days]
Objective response is defined as the percentage of participants with complete response (CR) and partial response (PR). CR is defined as disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in the sum of the longest diameter (SLD) of all lesions.
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Participants must be refractory to or intolerant of existing cancer therapy(ies) known to provide clinical benefit.
-
Histologically confirmed advanced solid tumors with no clear curative treatment options available after at least 1 prior systemic anticancer therapy.
-
Tumor accessible for biopsies and agreement to conduct pre-dose and post-dose fresh tumor biopsies.
-
Male or female subjects at least 18 years of age
-
Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 to 1 at Screening
-
Histologic or cytologic evidence/proven of metastatic renal cell carcinoma (mRCC) with clear cell component
-
Part 2A: Participants should have progressed to 1 or more previous lines of systemic anticancer therapy, excluding treatment with cabozantinib
-
Part 2B: Participants should have progressed to 1 or 2 previous lines of systemic anticancer therapy, excluding treatment with cabozantinib. Participants should have failed to only 1 previous TKI for metastatic disease. Adjuvant therapy with sunitinib will be considered as 1 line of therapy for metastatic disease in the case that disease progression occurs during or within 3 months of the completion of the treatment.
-
Other protocol defined inclusion criteria could apply
Exclusion Criteria:
-
ECOG PS >= 2
-
Extensive prior radiotherapy on more than 30% of bone marrow reserves, or prior bone marrow/stem cell transplantation within 5 years of study start.
-
Severe bone marrow, renal or liver impairment.
-
Tumor in contact with, invading or encasing major blood vessels or radiographic evidence of significant cavitary pulmonary lesions
-
Uncontrolled hypertension defined as sustained Blood Pressure (BP) > 150 millimeters of mercury (mm Hg) systolic or > 100 mm Hg diastolic despite optimal antihypertensive treatment
-
Participant is pregnant or breastfeeding
-
Part 2A and 2B: Previous use of cabozantinib or a MetAP2 inhibitor, tumor in contact with invading or encasing major blood vessels or radiographic evidence of significant cavitary pulmonary lesions
-
Other protocol defined exclusion criteria could apply
Contacts and Locations
Locations
Site | City | State | Country | Postal Code | |
---|---|---|---|---|---|
1 | Smilow Cancer Hospital - Yale | New Haven | Connecticut | United States | 06510 |
2 | Indiana University Health Hospital | Indianapolis | Indiana | United States | 46202 |
3 | Sidney Kimmel Cancer Center - Johns Hopkins | Baltimore | Maryland | United States | 21205-1911 |
4 | Henry Ford Health System | Detroit | Michigan | United States | 48202 |
5 | Nebraska Cancer Specialists | Omaha | Nebraska | United States | 68130 |
6 | Comprehensive Cancer Centers of Nevada | Las Vegas | Nevada | United States | 89169 |
7 | Rutgers Cancer Institute of New Jersey | New Brunswick | New Jersey | United States | 08901 |
Sponsors and Collaborators
- EMD Serono Research & Development Institute, Inc.
- Merck KGaA, Darmstadt, Germany
Investigators
- Study Director: Medical Responsible, EMD Serono Research & Development Institute, Inc., a business of Merck KGaA, Darmstadt, Germany
Study Documents (Full-Text)
More Information
Additional Information:
Publications
None provided.- MS100015_0019
Study Results
Participant Flow
Recruitment Details | First/last participant (informed consent): 08 August 2017. Last participant completed: 16 September 2020. |
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Pre-assignment Detail | This study was to be conducted in 2 parts; Part 1 was the dose escalation phase and Part 2 was the expansion phase. However, due to early termination of the study, the sponsor decided not to conduct the expansion phase (Part 2). |
Arm/Group Title | M8891 7 mg | M8891 12 mg | M8891 20 mg | M8891 35 mg | M8891 60 mg | M8891 80 mg |
---|---|---|---|---|---|---|
Arm/Group Description | Participant received M8891 at dose of 7 milligrams (mg) orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 12 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 20 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 35 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 60 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 80 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. |
Period Title: Overall Study | ||||||
STARTED | 3 | 3 | 3 | 8 | 7 | 3 |
COMPLETED | 3 | 3 | 3 | 8 | 7 | 3 |
NOT COMPLETED | 0 | 0 | 0 | 0 | 0 | 0 |
Baseline Characteristics
Arm/Group Title | M8891 7 mg | M8891 12 mg | M8891 20 mg | M8891 35 mg | M8891 60 mg | M8891 80 mg | Total |
---|---|---|---|---|---|---|---|
Arm/Group Description | Participant received M8891 at dose of 7 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 12 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 20 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 35 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 60 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 80 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Total of all reporting groups |
Overall Participants | 3 | 3 | 3 | 8 | 7 | 3 | 27 |
Age (Count of Participants) | |||||||
<=18 years |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
Between 18 and 65 years |
2
66.7%
|
3
100%
|
2
66.7%
|
4
50%
|
3
42.9%
|
0
0%
|
14
51.9%
|
>=65 years |
1
33.3%
|
0
0%
|
1
33.3%
|
4
50%
|
4
57.1%
|
3
100%
|
13
48.1%
|
Sex: Female, Male (Count of Participants) | |||||||
Female |
3
100%
|
1
33.3%
|
1
33.3%
|
3
37.5%
|
3
42.9%
|
2
66.7%
|
13
48.1%
|
Male |
0
0%
|
2
66.7%
|
2
66.7%
|
5
62.5%
|
4
57.1%
|
1
33.3%
|
14
51.9%
|
Race (NIH/OMB) (Count of Participants) | |||||||
American Indian or Alaska Native |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
Asian |
1
33.3%
|
0
0%
|
0
0%
|
2
25%
|
0
0%
|
0
0%
|
3
11.1%
|
Native Hawaiian or Other Pacific Islander |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
Black or African American |
0
0%
|
0
0%
|
0
0%
|
2
25%
|
0
0%
|
0
0%
|
2
7.4%
|
White |
2
66.7%
|
3
100%
|
3
100%
|
4
50%
|
6
85.7%
|
3
100%
|
21
77.8%
|
More than one race |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
Unknown or Not Reported |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
1
14.3%
|
0
0%
|
1
3.7%
|
Outcome Measures
Title | Number of Participants Who Experienced Dose Limiting Toxicities (DLTs) Assessed Using National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE) Version 4.03 |
---|---|
Description | A DLT was defined as the occurrence of any of following events that were judged by the study investigator, to be related to the study medication: Grade 4 liver enzyme elevation; Grade 4 neutropenia lasting >5 days or Grade >= 3 neutropenia with fever; Grade 4 thrombocytopenia lasting >5 days or Grade >=3 thrombocytopenia with clinically significant bleeding; Any treatment interruption >7 days or >30% of total dose in Cycle 1 due to AEs not related to the underlying disease or concomitant medication; Grade >=3 non-hematologic toxicity excluding Grade 3 nausea or vomiting lasting <48 hours, and resolves to <= Grade 1 either spontaneously or with medication, Grade 3 fatigue <= 3 days, Grade 3 hypertension in the absence of maximal medical therapy, Grade 3 rash <= 3 days, Grade 3 electrolyte abnormality that lasts <72 hours, is not clinically complicated, and resolves spontaneously or responds to conventional medication and Grade >=3 single lab value increase without clinical correlate. |
Time Frame | At the end of Cycle 1 (each Cycle is of 21 days) |
Outcome Measure Data
Analysis Population Description |
---|
Dose escalation set included all participants treated in dose-escalation cohorts who did not miss > 4 cumulative days planned doses of M8891 in the first cycle of the dose-escalation part for other than safety reasons. |
Arm/Group Title | M8891 7 mg | M8891 12 mg | M8891 20 mg | M8891 35 mg | M8891 60 mg | M8891 80 mg |
---|---|---|---|---|---|---|
Arm/Group Description | Participant received M8891 at dose of 7 milligrams (mg) orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 12 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 20 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 35 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 60 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 80 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. |
Measure Participants | 3 | 3 | 2 | 5 | 5 | 2 |
Count of Participants [Participants] |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
1
14.3%
|
1
33.3%
|
Title | Number of Participants With Treatment-Emergent Adverse Events (TEAE) and TEAEs Leading to Death |
---|---|
Description | An Adverse event (AE) was defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease associated with the use of study drug, whether or not considered related to the study drug or worsening of pre-existing medical condition, whether or not related to study drug. A serious adverse event (SAE) 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. The term TEAE is defined as AEs starting or worsening after the first intake of the study drug. TEAEs include both Serious TEAEs and non-serious TEAEs. |
Time Frame | Up to 1136 Days |
Outcome Measure Data
Analysis Population Description |
---|
Safety analysis set included all participants who received at least 1 dose of study drug. |
Arm/Group Title | M8891 7 mg | M8891 12 mg | M8891 20 mg | M8891 35 mg | M8891 60 mg | M8891 80 mg |
---|---|---|---|---|---|---|
Arm/Group Description | Participant received M8891 at dose of 7 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 12 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 20 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 35 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 60 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 12 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. |
Measure Participants | 3 | 3 | 3 | 8 | 7 | 3 |
TEAEs |
3
100%
|
2
66.7%
|
3
100%
|
8
100%
|
7
100%
|
3
100%
|
TEAEs leading to death |
0
0%
|
1
33.3%
|
2
66.7%
|
2
25%
|
0
0%
|
0
0%
|
Title | Number of Participants With Treatment-Emergent Adverse Events (TEAE) by Severity |
---|---|
Description | Severity of adverse events (AE) were assessed by the investigator according to National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE) version 4.03 as Grade 1 to Grade 5. Grade 1= Mild, Grade 2=Moderate, Grade 3=Severe, Grade 4= Life-threatening and Grade 5= Death. The number of participants that experienced at least one solicited local TEAE were summarized by grade. The term TEAE is defined as AEs starting or worsening after the first intake of the study drug. TEAEs include both Serious TEAEs and non-serious TEAEs. Number of participants with Grade >=3, >=4 and 5 were reported. |
Time Frame | Up to 1136 Days |
Outcome Measure Data
Analysis Population Description |
---|
Safety analysis set included all participants who received at least 1 dose of study drug. |
Arm/Group Title | M8891 7 mg | M8891 12 mg | M8891 20 mg | M8891 35 mg | M8891 60 mg | M8891 80 mg |
---|---|---|---|---|---|---|
Arm/Group Description | Participant received M8891 at dose of 7 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 12 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 20 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 35 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 60 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 80 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. |
Measure Participants | 3 | 3 | 3 | 8 | 7 | 3 |
Grade >=3 |
0
0%
|
1
33.3%
|
3
100%
|
8
100%
|
4
57.1%
|
2
66.7%
|
Grade >=4 |
0
0%
|
1
33.3%
|
2
66.7%
|
2
25%
|
1
14.3%
|
1
33.3%
|
Grade 5 |
0
0%
|
1
33.3%
|
2
66.7%
|
2
25%
|
0
0%
|
0
0%
|
Title | Maximum Observed Plasma Concentration (Cmax) of M8891 |
---|---|
Description | Maximum observed plasma concentration (Cmax) was taken directly from the observed concentration-time curve. |
Time Frame | Cycle 1 Pre-dose, 1, 2, 3, 4, 5, 6, 8, 12, 24 hours post-dose on Day 1 and 15 (Each cycle is of 21 days) |
Outcome Measure Data
Analysis Population Description |
---|
Pharmacokinetic (PK) analysis set included all participants from the safety analysis set without major protocol deviations/violations or events that would affect PK. Here "Number Analyzed"=number of participants evaluable at specified time points. |
Arm/Group Title | M8891 7 mg | M8891 12 mg | M8891 20 mg | M8891 35 mg | M8891 60 mg | M8891 80 mg |
---|---|---|---|---|---|---|
Arm/Group Description | Participant received M8891 at dose of 7 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 12 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 20 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 35 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 60 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 80 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. |
Measure Participants | 3 | 3 | 3 | 8 | 7 | 3 |
Day 1 |
514
(16.6)
|
934
(12.4)
|
1780
(48.9)
|
2960
(17.0)
|
3630
(31.2)
|
4760
(15.6)
|
Day 15 |
1260
(39.2)
|
2210
(21.1)
|
NA
(NA)
|
6840
(16.9)
|
6600
(20.2)
|
NA
(NA)
|
Title | Time to Reach Maximum Observed Plasma Concentration (Tmax) of M8891 |
---|---|
Description | The time to reach the maximum observed plasma concentration (tmax) was obtained directly from the concentration versus time curve. |
Time Frame | Cycle 1 Pre-dose, 1, 2, 3, 4, 5, 6, 8, 12, 24 hours post-dose on Day 1 and 15 (Each cycle is of 21 days) |
Outcome Measure Data
Analysis Population Description |
---|
PK analysis set included all participants from the safety analysis set without major protocol deviations/violations or events that would affect PK. Here "Number Analyzed"=number of participants evaluable at specified time points. |
Arm/Group Title | M8891 7 mg | M8891 12 mg | M8891 20 mg | M8891 35 mg | M8891 60 mg | M8891 80 mg |
---|---|---|---|---|---|---|
Arm/Group Description | Participant received M8891 at dose of 7 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 12 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 20 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 35 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 60 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 80 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. |
Measure Participants | 3 | 3 | 3 | 8 | 7 | 3 |
Day 1 |
3.17
|
4.00
|
6.00
|
4.04
|
7.13
|
3.38
|
Day 15 |
4.00
|
2.00
|
NA
|
4.07
|
3.11
|
NA
|
Title | Area Under the Plasma Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-t) of M8891 |
---|---|
Description | The AUC from time zero (= dosing time) to the last sampling time (tlast) at which the concentration is at or above the lower limit of quantification (LLOQ), calculated using the mixed log-linear trapezoidal rule (linear up, log down). |
Time Frame | Cycle 1 Pre-dose, 1, 2, 3, 4, 5, 6, 8, 12, 24 hours post-dose on Day 1 and 15 (Each cycle is of 21 days) |
Outcome Measure Data
Analysis Population Description |
---|
PK analysis set included all participants from the safety analysis set without major protocol deviations/violations or events that would affect PK. Here "Number Analyzed"=number of participants evaluable at specified time points. |
Arm/Group Title | M8891 7 mg | M8891 12 mg | M8891 20 mg | M8891 35 mg | M8891 60 mg | M8891 80 mg |
---|---|---|---|---|---|---|
Arm/Group Description | Participant received M8891 at dose of 7 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 12 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 20 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 35 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 60 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 80 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. |
Measure Participants | 3 | 3 | 3 | 8 | 7 | 3 |
Day 1 |
9080
(21.3)
|
16300
(9.6)
|
34200
(41.0)
|
59400
(22.7)
|
71700
(26.3)
|
86900
(22.5)
|
Day 15 |
25400
(50.3)
|
38600
(17.6)
|
NA
(NA)
|
141000
(13.9)
|
134000
(18.4)
|
NA
(NA)
|
Title | Area Under the Concentration-time Curve From Zero Extrapolated to Infinity (AUC0-inf) of M8891 |
---|---|
Description | The AUC from time zero (dosing time) extrapolated to infinity, based on the predicted value for the concentration at tlast, as estimated using the linear regression from the determination of the terminal first order (elimination) rate constant (lambda z). AUC0-inf = AUC0-t plus Clast pred/lambda z. Lambda Z was terminal elimination rate constant determined from the terminal slope of the log-transformed plasma concentration curve using linear regression on terminal data points of the curve. Clastpred was the last predicted quantifiable concentration. |
Time Frame | Cycle 1 Pre-dose, 1, 2, 3, 4, 5, 6, 8, 12, 24 hours post-dose on Day 1 and 15 (Each cycle is of 21 days) |
Outcome Measure Data
Analysis Population Description |
---|
PK analysis set included all participants from the safety analysis set without major protocol deviations/violations or events that would affect PK. As R2 was <0.80, %AUCextra was >20% and elimination phase was not characterized, AUC0-inf derived from lambda z was regarded as implausible and not calculated. |
Arm/Group Title | M8891 7 mg | M8891 12 mg | M8891 20 mg | M8891 35 mg | M8891 60 mg | M8891 80 mg |
---|---|---|---|---|---|---|
Arm/Group Description | Participant received M8891 at dose of 7 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 12 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 20 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 35 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 60 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 80 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. |
Measure Participants | 0 | 0 | 0 | 0 | 0 | 0 |
Title | Area Under the Plasma Concentration Versus Time Curve Within One Dosing Interval (AUC0-tau) of M8891 |
---|---|
Description | AUC (0-tau) is the area under the plasma concentration time curve within 1 dosing interval. Calculated using the mixed log linear trapezoidal rule (linear up, log down). |
Time Frame | Cycle 1 Pre-dose, 1, 2, 3, 4, 5, 6, 8, 12, 24 hours post-dose on Day 1 and 15 (Each cycle is of 21 days) |
Outcome Measure Data
Analysis Population Description |
---|
PK analysis set included all participants from the safety analysis set without major protocol deviations/violations or events that would affect PK. Here "Number Analyzed"=number of participants evaluable at specified time points. |
Arm/Group Title | M8891 7 mg | M8891 12 mg | M8891 20 mg | M8891 35 mg | M8891 60 mg | M8891 80 mg |
---|---|---|---|---|---|---|
Arm/Group Description | Participant received M8891 at dose of 7 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 12 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 20 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 35 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 60 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 80 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. |
Measure Participants | 3 | 3 | 3 | 8 | 7 | 3 |
Day 1 |
9100
(21.2)
|
16300
(9.6)
|
32400
(35.7)
|
59100
(20.3)
|
71400
(26.8)
|
84500
(20.6)
|
Day 15 |
25700
(48.4)
|
38500
(18.7)
|
NA
(NA)
|
137000
(15.6)
|
133000
(17.4)
|
NA
(NA)
|
Title | Apparent Terminal Half Life (t1/2) of M8891 |
---|---|
Description | Terminal half-life of M8891 in Plasma was calculated as log2/ lambda z. Lambda z was determined from the terminal slope of the log-transformed concentration curve using linear regression on terminal data points of the curve. |
Time Frame | Cycle 1 Pre-dose, 1, 2, 3, 4, 5, 6, 8, 12, 24 hours post-dose on Day 1 and 15 (Each cycle is of 21 days) |
Outcome Measure Data
Analysis Population Description |
---|
PK analysis set included all participants from the safety analysis set without major protocol deviations/violations or events that would affect PK. As coefficient of correlation (R2) was <0.80, %AUCextra was >20% and elimination phase was not characterized, t1/2 derived from lambda z was regarded as implausible and not calculated. |
Arm/Group Title | M8891 7 mg | M8891 12 mg | M8891 20 mg | M8891 35 mg | M8891 60 mg | M8891 80 mg |
---|---|---|---|---|---|---|
Arm/Group Description | Participant received M8891 at dose of 7 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 12 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 20 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 35 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 60 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 80 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. |
Measure Participants | 0 | 0 | 0 | 0 | 0 | 0 |
Title | Terminal Elimination Rate Constant (Lambda z) of M8891 |
---|---|
Description | Lambda z was determined from the terminal slope of the log-transformed concentration curve using linear regression on terminal data points of the curve. |
Time Frame | Cycle 1 Pre-dose, 1, 2, 3, 4, 5, 6, 8, 12, 24 hours post-dose on Day 1 and 15 (Each cycle is of 21 days) |
Outcome Measure Data
Analysis Population Description |
---|
PK analysis set included all participants from the safety analysis set without major protocol deviations/violations or events that would affect PK. As R2 was <0.80, %AUCextra was >20% and elimination phase was not characterized, lambda z was regarded as implausible and not calculated. |
Arm/Group Title | M8891 7 mg | M8891 12 mg | M8891 20 mg | M8891 35 mg | M8891 60 mg | M8891 80 mg |
---|---|---|---|---|---|---|
Arm/Group Description | Participant received M8891 at dose of 7 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 12 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 20 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 35 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 60 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 80 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. |
Measure Participants | 0 | 0 | 0 | 0 | 0 | 0 |
Title | Apparent Total Body Clearance (CL/f) of M8891 |
---|---|
Description | Apparent total body clearance of drug from plasma following extravascular administration, calculated as dose/AUC0-infinity for M8891. Area under the plasma concentration-time curve from time zero (dosing time) extrapolated to infinity of unchanged drug calculated as AUC0-t + AUCextra. AUCextra represents the extrapolated part of AUC0-infinity calculated by Clastpred/lambda z, where Clastpred is the predicted plasma concentration at the last sampling time point, calculated from the log linear regression line for lambda z determination at which the measured plasma concentration is at or above lower limit of quantification. |
Time Frame | Cycle 1 Pre-dose, 1, 2, 3, 4, 5, 6, 8, 12, 24 hours post-dose on Day 1 and 15 (Each cycle is of 21 days) |
Outcome Measure Data
Analysis Population Description |
---|
PK analysis set included all participants from the safety analysis set without major protocol deviations/violations or events that would affect PK. As R2 was <0.80, %AUCextra was >20% and elimination phase was not characterized, CL/f derived from lambda z was regarded as implausible and not calculated. |
Arm/Group Title | M8891 7 mg | M8891 12 mg | M8891 20 mg | M8891 35 mg | M8891 60 mg | M8891 80 mg |
---|---|---|---|---|---|---|
Arm/Group Description | Participant received M8891 at dose of 7 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 12 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 20 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 35 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 60 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 80 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. |
Measure Participants | 0 | 0 | 0 | 0 | 0 | 0 |
Title | Apparent Body Clearance of Drug Following Extravascular Administration At Steady State (CLss/f) of M8891 |
---|---|
Description | The apparent total body clearance of drug at steady state following extravascular administration, taking into account the fraction of dose absorbed. It is calculated as dose/AUCtau for M8891. |
Time Frame | Cycle 1 Pre-dose, 1, 2, 3, 4, 5, 6, 8, 12, 24 hours post-dose on Day 1 and 15 (Each cycle is of 21 days) |
Outcome Measure Data
Analysis Population Description |
---|
PK analysis set included all participants from the safety analysis set without major protocol deviations/violations or events that would affect PK. As R2 was <0.80, %AUCextra was >20% and elimination phase was not characterized, CLss/f derived from lambda z was regarded as implausible and not calculated. |
Arm/Group Title | M8891 7 mg | M8891 12 mg | M8891 20 mg | M8891 35 mg | M8891 60 mg | M8891 80 mg |
---|---|---|---|---|---|---|
Arm/Group Description | Participant received M8891 at dose of 7 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 12 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 20 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 35 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 60 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 80 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. |
Measure Participants | 0 | 0 | 0 | 0 | 0 | 0 |
Title | Apparent Volume of Distribution During Terminal Phase (VZ/f) of M8891 |
---|---|
Description | Apparent volume of distribution during the terminal phase following extravascular administration for M8891 was calculated. Vz/f = Dose/(AUC0-infinity multiply by Lambda z) following single dose. The AUC from time zero (dosing time) extrapolated to infinity, based on the predicted value for the concentration at tlast, as estimated using the linear regression from lambda z determination. AUC(0- inf)=AUC0-t plus Clastpred/lambda z where Clastpred was last predicted concentration. Lambda Z was terminal elimination rate constant determined from the terminal slope of the log-transformed plasma concentration curve using linear regression on terminal data points of the curve. |
Time Frame | Cycle 1 Pre-dose, 1, 2, 3, 4, 5, 6, 8, 12, 24 hours post-dose on Day 1 and 15 (Each cycle is of 21 days) |
Outcome Measure Data
Analysis Population Description |
---|
PK analysis set included all participants from the safety analysis set without major protocol deviations/violations or events that would affect PK. As R2 was <0.80, %AUCextra was >20% and elimination phase was not characterized, VZ/f derived from lambda z was regarded as implausible and not calculated. |
Arm/Group Title | M8891 7 mg | M8891 12 mg | M8891 20 mg | M8891 35 mg | M8891 60 mg | M8891 80 mg |
---|---|---|---|---|---|---|
Arm/Group Description | Participant received M8891 at dose of 7 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 12 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 20 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 35 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 60 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 80 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. |
Measure Participants | 0 | 0 | 0 | 0 | 0 | 0 |
Title | Accumulation Ratios of AUC (Racc AUC) of M8891 |
---|---|
Description | Racc (AUC) is defined as the accumulation factor to assess the increase in exposure until steady state is reached. Accumulation ratio for AUC was calculated as AUC, after dosing on Day 15 divided by AUC, after dosing on Day 1 of Cycle 1. |
Time Frame | Pre-dose and at 1, 2, 3, 4, 5, 6, 8, 12, 24 hours post-dose on Day 1 and 15 of Cycle 1 (each cycle is 21 days) |
Outcome Measure Data
Analysis Population Description |
---|
PK analysis set included all participants from the safety analysis set without major protocol deviations/violations or events that would affect PK. Here "Number Analyzed"=number of participants evaluable at specified time points. |
Arm/Group Title | M8891 7 mg | M8891 12 mg | M8891 20 mg | M8891 35 mg | M8891 60 mg | M8891 80 mg |
---|---|---|---|---|---|---|
Arm/Group Description | Participant received M8891 at dose of 7 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 12 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 20 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 35 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 60 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 80 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. |
Measure Participants | 3 | 3 | 2 | 5 | 4 | 2 |
Geometric Mean (Geometric Coefficient of Variation) [Ratio] |
2.82
(29.3)
|
2.36
(27.4)
|
NA
(NA)
|
2.38
(27.8)
|
1.90
(37.2)
|
NA
(NA)
|
Title | Accumulation Ratio of Cmax (Racc Cmax) of M8891 |
---|---|
Description | Accumulation ratio of Cmax was calculated as Cmax, after dosing on Day 15 divided by Cmax, after dosing on Day 1 of Cycle 1. |
Time Frame | Pre-dose and at 1, 2, 3, 4, 5, 6, 8, 12, 24 hours post-dose on Day 1 and 15 of Cycle 1 (each cycle is 21 days) |
Outcome Measure Data
Analysis Population Description |
---|
PK analysis set included all participants from the safety analysis set without major protocol deviations/violations or events that would affect PK. Here "Number Analyzed"=number of participants evaluable at specified time points. |
Arm/Group Title | M8891 7 mg | M8891 12 mg | M8891 20 mg | M8891 35 mg | M8891 60 mg | M8891 80 mg |
---|---|---|---|---|---|---|
Arm/Group Description | Participant received M8891 at dose of 7 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 12 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 20 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 35 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 60 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 80 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. |
Measure Participants | 3 | 3 | 2 | 5 | 4 | 2 |
Geometric Mean (Geometric Coefficient of Variation) [Ratio] |
2.46
(27.5)
|
2.36
(33.5)
|
NA
(NA)
|
2.32
(27.4)
|
1.97
(37.8)
|
NA
(NA)
|
Title | Number of Participants With Best Overall Response Assessment According to Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST v1.1) Criteria |
---|---|
Description | BOR was determined according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) as assessed by investigators. BOR is defined as the best response of any of the complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD) recorded from the date of randomization until disease progression. CR: Disappearance of all evidence of target and non-target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 millimeter (mm). PR: At least 30% reduction from baseline in the sum of the longest diameter (SLD) of all lesions. Stable disease (SD) defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest SLD while on study. PD is defined as at least a 20 percent (%) increase in the SLD of target lesion, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. |
Time Frame | Up to 1136 Days |
Outcome Measure Data
Analysis Population Description |
---|
Safety analysis set included all participants who received at least 1 dose of study drug. |
Arm/Group Title | M8891 7 mg | M8891 12 mg | M8891 20 mg | M8891 35 mg | M8891 60 mg | M8891 80 mg |
---|---|---|---|---|---|---|
Arm/Group Description | Participant received M8891 at dose of 7 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 12 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 20 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 35 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 60 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 80 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. |
Measure Participants | 3 | 3 | 3 | 8 | 7 | 3 |
Complete Response |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
Partial Response |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
Stable Disease |
2
66.7%
|
2
66.7%
|
1
33.3%
|
0
0%
|
2
28.6%
|
0
0%
|
Progressive Disease |
1
33.3%
|
0
0%
|
0
0%
|
3
37.5%
|
1
14.3%
|
1
33.3%
|
Not Evaluable |
0
0%
|
1
33.3%
|
2
66.7%
|
5
62.5%
|
4
57.1%
|
2
66.7%
|
Title | Number of Participants With Clinical Benefit |
---|---|
Description | Clinical benefit defined as Complete Response (CR), Partial Response (PR) or Stable Disease (SD) for >= 12 weeks. Clinical benefit was assessed according to RECIST Version 1.1. CR: defined as disappearance of all target and all non-target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 millimeter (mm). PR: At least 30% reduction from baseline in the sum of the longest diameter (SLD) of all lesions. SD: defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest SLD while on study. PD is defined as at least a 20 percent (%) increase in the SLD of target lesion, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. |
Time Frame | Up to 1136 Days |
Outcome Measure Data
Analysis Population Description |
---|
Safety analysis set included all participants who received at least 1 dose of study drug. |
Arm/Group Title | M8891 7 mg | M8891 12 mg | M8891 20 mg | M8891 35 mg | M8891 60 mg | M8891 80 mg |
---|---|---|---|---|---|---|
Arm/Group Description | Participant received M8891 at dose of 7 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 12 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 20 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 35 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 60 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 80 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. |
Measure Participants | 3 | 3 | 3 | 8 | 7 | 3 |
Complete Response |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
Partial Response |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
Stable Disease |
2
66.7%
|
0
0%
|
0
0%
|
0
0%
|
1
14.3%
|
0
0%
|
Title | Progression-Free Survival (PFS) |
---|---|
Description | Progression-free survival (PFS) defined as the time from first study drug administration to either first observation of progressive disease (PD) (as assessed by Investigators according to RECIST v1.1) or occurrence of death due to any cause, whichever occurs first. Progressive disease (PD) defined as at least a 20% increase in sum of longest diameter (SLD) of target lesions, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. PFS was measured using Kaplan-Meier (KM) estimates. Here the 20 mg dose level was selected for stratification as the highest dose level equal to or smaller than the median of all dose levels administered to at least 1 participant. |
Time Frame | Up to 1136 Days |
Outcome Measure Data
Analysis Population Description |
---|
Safety analysis set included all participants who received at least 1 dose of study drug. |
Arm/Group Title | Less Than or Equal to (<=) 20 mg M8891 | Greater Than (>) 20 mg M8891 |
---|---|---|
Arm/Group Description | All participants who received oral capsule of M8891 at dose <= 20 mg first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | All participants who received oral capsule of M8891 at dose of > 20mg first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. |
Measure Participants | 9 | 18 |
Median (95% Confidence Interval) [Months] |
2.7598
|
1.3799
|
Title | Number of Participants With Change From Baseline in Laboratory Test Abnormalities to Grade 3 or Higher Severity Based on NCI-CTCAE Version 4.03 |
---|---|
Description | The laboratory measurements included hematology, biochemistry, and urinalysis values were graded with National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.03 toxicity grades (where Grade 1 = mild, Grade 2 = moderate, Grade 3 = severe, Grade 4 = life threatening and Grade 5 = death). Number of participants with change from baseline to grade 3 or higher values for the hematology, biochemistry and urinalysis parameters were reported. |
Time Frame | Up to 1136 Days |
Outcome Measure Data
Analysis Population Description |
---|
Safety analysis set included all participants who received at least 1 dose of study drug. |
Arm/Group Title | M8891 7 mg | M8891 12 mg qd | M8891 20 mg | M8891 35 mg | M8891 60 mg | M8891 80 mg |
---|---|---|---|---|---|---|
Arm/Group Description | Participant received M8891 at dose of 7 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 12 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 20 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 35 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 60 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 80 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. |
Measure Participants | 3 | 3 | 3 | 8 | 7 | 3 |
Grade >= 3 biochemistry |
0
0%
|
0
0%
|
2
66.7%
|
2
25%
|
3
42.9%
|
0
0%
|
Grade >= 3 hematology |
0
0%
|
0
0%
|
1
33.3%
|
2
25%
|
4
57.1%
|
1
33.3%
|
Grade >= 3 urinalysis |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
Title | Number of Participants With Clinically Meaningful Changes From Baseline in Vital Signs |
---|---|
Description | Vital sign assessments included assessments of heart rate, diastolic blood pressure, systolic blood pressure, weight, respiratory rate and temperature. Clinical relevance was assessed by the investigator. Number of participants who had any clinically meaningful change from baseline in vital signs were reported. |
Time Frame | Up to 1136 Days |
Outcome Measure Data
Analysis Population Description |
---|
Safety analysis set included all participants who received at least 1 dose of study drug. |
Arm/Group Title | M8891 7 mg | M8891 12 mg | M8891 20 mg | M8891 35 mg | M8891 60 mg | M8891 80 mg |
---|---|---|---|---|---|---|
Arm/Group Description | Participant received M8891 at dose of 7 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 12 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 20 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 35 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 60 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 80 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. |
Measure Participants | 3 | 3 | 3 | 8 | 7 | 3 |
Count of Participants [Participants] |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
Title | Number of Participants With Clinically Meaningful Changes From Baseline in Electrocardiogram (ECG) Values |
---|---|
Description | ECG parameters included rhythm, heart rate (as measured by RR interval), PR interval, QRS duration, QT intervals, and corrected QT(QTc) intervals. Clinical significance was determined by the investigator. Number of participants with clinically meaningful change from baseline in 12-lead ECG were reported. |
Time Frame | Up to 1136 Days |
Outcome Measure Data
Analysis Population Description |
---|
Safety analysis set included all participants who received at least 1 dose of study drug. |
Arm/Group Title | M8891 7 mg | M8891 12 mg | M8891 20 mg | M8891 35 mg | M8891 60 mg | M8891 80 mg |
---|---|---|---|---|---|---|
Arm/Group Description | Participant received M8891 at dose of 7 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 12 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 20 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 35 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 60 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 80 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. |
Measure Participants | 3 | 3 | 3 | 8 | 7 | 3 |
Count of Participants [Participants] |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
Title | Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status (PF) Score of 2 or Higher Than 2 |
---|---|
Description | ECOG PS score is widely used by doctors and researchers to assess how a participants' disease is progressing, and is used to assess how the disease affects the daily living abilities of the participant, and determine appropriate treatment and prognosis. The score ranges from Grade 0 to Grade 5, where Grade 0 = Fully active, able to carry on all pre-disease performance without restriction, Grade 1 = Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature (like light house work, office work), Grade 2 = Ambulatory and capable of all self-care but unable to carry out any work activities, Grade 3 = Capable of only limited self-care, confined to bed or chair more than 50% of waking hours and Grade 4 = Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair, Grade 5 = Death. Number of participants with ECOG performance status score of 2 or higher than 2 were reported. |
Time Frame | Up to 1136 Days |
Outcome Measure Data
Analysis Population Description |
---|
Safety analysis set included all participants who received at least 1 dose of study drug. |
Arm/Group Title | M8891 7 mg | M8891 12 mg | M8891 20 mg | M8891 35 mg | M8891 60 mg | M8891 80 mg |
---|---|---|---|---|---|---|
Arm/Group Description | Participant received M8891 at dose of 7 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 12 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 20 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 35 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 60 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 80 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. |
Measure Participants | 3 | 3 | 3 | 8 | 7 | 3 |
Count of Participants [Participants] |
0
0%
|
1
33.3%
|
1
33.3%
|
1
12.5%
|
0
0%
|
0
0%
|
Title | Percentage of Participants With Objective Response |
---|---|
Description | Objective response is defined as the percentage of participants with complete response (CR) and partial response (PR). CR is defined as disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in the sum of the longest diameter (SLD) of all lesions. |
Time Frame | Up to 1136 Days |
Outcome Measure Data
Analysis Population Description |
---|
Safety analysis set included all participants who received at least 1 dose of study drug. |
Arm/Group Title | M8891 7 mg | M8891 12 mg | M8891 20 mg | M8891 35 mg | M8891 60 mg | M8891 80 mg |
---|---|---|---|---|---|---|
Arm/Group Description | Participant received M8891 at dose of 7 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 12 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 20 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 35 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 60 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 80 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. |
Measure Participants | 3 | 3 | 3 | 8 | 7 | 3 |
Number (95% Confidence Interval) [Percentage of participants] |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
Adverse Events
Time Frame | Up to 1136 Days | |||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
Adverse Event Reporting Description | ||||||||||||
Arm/Group Title | M8891 7 mg | M8891 12 mg | M8891 20 mg | M8891 35 mg | M8891 60 mg | M8891 80 mg | ||||||
Arm/Group Description | Participant received M8891 at dose of 7 milligrams (mg) orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 12 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 20 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 35 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 60 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | Participant received M8891 at dose of 80 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study. | ||||||
All Cause Mortality |
||||||||||||
M8891 7 mg | M8891 12 mg | M8891 20 mg | M8891 35 mg | M8891 60 mg | M8891 80 mg | |||||||
Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
Total | 0/3 (0%) | 1/3 (33.3%) | 2/3 (66.7%) | 2/8 (25%) | 0/7 (0%) | 0/3 (0%) | ||||||
Serious Adverse Events |
||||||||||||
M8891 7 mg | M8891 12 mg | M8891 20 mg | M8891 35 mg | M8891 60 mg | M8891 80 mg | |||||||
Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
Total | 0/3 (0%) | 1/3 (33.3%) | 3/3 (100%) | 3/8 (37.5%) | 1/7 (14.3%) | 0/3 (0%) | ||||||
Endocrine disorders | ||||||||||||
Adrenal insufficiency | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 1/7 (14.3%) | 0/3 (0%) | ||||||
Gastrointestinal disorders | ||||||||||||
Small intestinal obstruction | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/8 (12.5%) | 0/7 (0%) | 0/3 (0%) | ||||||
General disorders | ||||||||||||
Disease progression | 0/3 (0%) | 1/3 (33.3%) | 2/3 (66.7%) | 2/8 (25%) | 0/7 (0%) | 0/3 (0%) | ||||||
Infections and infestations | ||||||||||||
Sepsis | 0/3 (0%) | 0/3 (0%) | 1/3 (33.3%) | 0/8 (0%) | 0/7 (0%) | 0/3 (0%) | ||||||
Investigations | ||||||||||||
Platelet count decreased | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 1/7 (14.3%) | 0/3 (0%) | ||||||
Respiratory, thoracic and mediastinal disorders | ||||||||||||
Dyspnoea | 0/3 (0%) | 0/3 (0%) | 1/3 (33.3%) | 0/8 (0%) | 1/7 (14.3%) | 0/3 (0%) | ||||||
Pleural effusion | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/8 (12.5%) | 0/7 (0%) | 0/3 (0%) | ||||||
Other (Not Including Serious) Adverse Events |
||||||||||||
M8891 7 mg | M8891 12 mg | M8891 20 mg | M8891 35 mg | M8891 60 mg | M8891 80 mg | |||||||
Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
Total | 3/3 (100%) | 2/3 (66.7%) | 3/3 (100%) | 8/8 (100%) | 7/7 (100%) | 3/3 (100%) | ||||||
Blood and lymphatic system disorders | ||||||||||||
Anaemia | 1/3 (33.3%) | 1/3 (33.3%) | 2/3 (66.7%) | 3/8 (37.5%) | 1/7 (14.3%) | 0/3 (0%) | ||||||
Thrombocytopenia | 0/3 (0%) | 0/3 (0%) | 1/3 (33.3%) | 0/8 (0%) | 1/7 (14.3%) | 0/3 (0%) | ||||||
Cardiac disorders | ||||||||||||
Palpitations | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/7 (0%) | 1/3 (33.3%) | ||||||
Ear and labyrinth disorders | ||||||||||||
Ear pain | 0/3 (0%) | 1/3 (33.3%) | 0/3 (0%) | 0/8 (0%) | 1/7 (14.3%) | 0/3 (0%) | ||||||
Endocrine disorders | ||||||||||||
Adrenal insufficiency | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 1/7 (14.3%) | 0/3 (0%) | ||||||
Eye disorders | ||||||||||||
Eye pruritus | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/7 (0%) | 1/3 (33.3%) | ||||||
Lacrimation increased | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/7 (0%) | 1/3 (33.3%) | ||||||
Vision blurred | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 1/7 (14.3%) | 1/3 (33.3%) | ||||||
Gastrointestinal disorders | ||||||||||||
Abdominal distension | 0/3 (0%) | 0/3 (0%) | 1/3 (33.3%) | 0/8 (0%) | 0/7 (0%) | 0/3 (0%) | ||||||
Abdominal pain | 1/3 (33.3%) | 1/3 (33.3%) | 1/3 (33.3%) | 1/8 (12.5%) | 0/7 (0%) | 1/3 (33.3%) | ||||||
Abdominal pain upper | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 1/7 (14.3%) | 0/3 (0%) | ||||||
Ascites | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/8 (12.5%) | 0/7 (0%) | 0/3 (0%) | ||||||
Constipation | 0/3 (0%) | 1/3 (33.3%) | 1/3 (33.3%) | 2/8 (25%) | 0/7 (0%) | 1/3 (33.3%) | ||||||
Diarrhoea | 0/3 (0%) | 0/3 (0%) | 1/3 (33.3%) | 1/8 (12.5%) | 1/7 (14.3%) | 0/3 (0%) | ||||||
Dry mouth | 1/3 (33.3%) | 0/3 (0%) | 0/3 (0%) | 1/8 (12.5%) | 0/7 (0%) | 0/3 (0%) | ||||||
Flatulence | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/7 (0%) | 1/3 (33.3%) | ||||||
Haematochezia | 1/3 (33.3%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/7 (0%) | 0/3 (0%) | ||||||
Nausea | 1/3 (33.3%) | 1/3 (33.3%) | 0/3 (0%) | 3/8 (37.5%) | 3/7 (42.9%) | 0/3 (0%) | ||||||
Periodontal disease | 1/3 (33.3%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/7 (0%) | 0/3 (0%) | ||||||
Rectal haemorrhage | 1/3 (33.3%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/7 (0%) | 0/3 (0%) | ||||||
Stomatitis | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 1/7 (14.3%) | 0/3 (0%) | ||||||
Vomiting | 1/3 (33.3%) | 1/3 (33.3%) | 0/3 (0%) | 2/8 (25%) | 0/7 (0%) | 0/3 (0%) | ||||||
General disorders | ||||||||||||
Catheter site rash | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 1/7 (14.3%) | 0/3 (0%) | ||||||
Chest pain | 1/3 (33.3%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/7 (0%) | 0/3 (0%) | ||||||
Chills | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/8 (12.5%) | 0/7 (0%) | 0/3 (0%) | ||||||
Fatigue | 0/3 (0%) | 1/3 (33.3%) | 2/3 (66.7%) | 2/8 (25%) | 1/7 (14.3%) | 1/3 (33.3%) | ||||||
Non-cardiac chest pain | 0/3 (0%) | 0/3 (0%) | 1/3 (33.3%) | 0/8 (0%) | 0/7 (0%) | 0/3 (0%) | ||||||
Oedema peripheral | 0/3 (0%) | 0/3 (0%) | 2/3 (66.7%) | 1/8 (12.5%) | 0/7 (0%) | 0/3 (0%) | ||||||
Hepatobiliary disorders | ||||||||||||
Cholelithiasis | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/8 (12.5%) | 0/7 (0%) | 0/3 (0%) | ||||||
Infections and infestations | ||||||||||||
Conjunctivitis | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/7 (0%) | 1/3 (33.3%) | ||||||
Diverticulitis | 1/3 (33.3%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/7 (0%) | 0/3 (0%) | ||||||
Nasopharyngitis | 1/3 (33.3%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/7 (0%) | 0/3 (0%) | ||||||
Pneumonia | 0/3 (0%) | 0/3 (0%) | 1/3 (33.3%) | 0/8 (0%) | 0/7 (0%) | 0/3 (0%) | ||||||
Tinea pedis | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 1/7 (14.3%) | 0/3 (0%) | ||||||
Urinary tract infection | 1/3 (33.3%) | 0/3 (0%) | 0/3 (0%) | 1/8 (12.5%) | 0/7 (0%) | 0/3 (0%) | ||||||
Injury, poisoning and procedural complications | ||||||||||||
Fall | 0/3 (0%) | 0/3 (0%) | 1/3 (33.3%) | 0/8 (0%) | 0/7 (0%) | 0/3 (0%) | ||||||
Wound complication | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/8 (12.5%) | 0/7 (0%) | 0/3 (0%) | ||||||
Investigations | ||||||||||||
Alanine aminotransferase increased | 0/3 (0%) | 1/3 (33.3%) | 0/3 (0%) | 2/8 (25%) | 3/7 (42.9%) | 0/3 (0%) | ||||||
Amylase increased | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/8 (12.5%) | 1/7 (14.3%) | 0/3 (0%) | ||||||
Aspartate aminotransferase increased | 0/3 (0%) | 1/3 (33.3%) | 1/3 (33.3%) | 4/8 (50%) | 2/7 (28.6%) | 0/3 (0%) | ||||||
Bilirubin conjugated increased | 0/3 (0%) | 0/3 (0%) | 1/3 (33.3%) | 0/8 (0%) | 0/7 (0%) | 0/3 (0%) | ||||||
Blood alkaline phosphatase increased | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 2/7 (28.6%) | 0/3 (0%) | ||||||
Blood bilirubin increased | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 1/7 (14.3%) | 0/3 (0%) | ||||||
Fibrin D dimer increased | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 1/7 (14.3%) | 0/3 (0%) | ||||||
Gamma-glutamyltransferase increased | 0/3 (0%) | 1/3 (33.3%) | 0/3 (0%) | 1/8 (12.5%) | 0/7 (0%) | 0/3 (0%) | ||||||
Lipase increased | 1/3 (33.3%) | 0/3 (0%) | 0/3 (0%) | 1/8 (12.5%) | 2/7 (28.6%) | 0/3 (0%) | ||||||
Lymphocyte count decreased | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 1/7 (14.3%) | 0/3 (0%) | ||||||
Platelet count decreased | 0/3 (0%) | 1/3 (33.3%) | 1/3 (33.3%) | 2/8 (25%) | 5/7 (71.4%) | 2/3 (66.7%) | ||||||
Weight decreased | 0/3 (0%) | 0/3 (0%) | 2/3 (66.7%) | 2/8 (25%) | 1/7 (14.3%) | 0/3 (0%) | ||||||
Weight increased | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/8 (12.5%) | 0/7 (0%) | 0/3 (0%) | ||||||
Glomerular filtration rate decreased | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/8 (12.5%) | 0/7 (0%) | 0/3 (0%) | ||||||
Metabolism and nutrition disorders | ||||||||||||
Decreased appetite | 1/3 (33.3%) | 1/3 (33.3%) | 1/3 (33.3%) | 3/8 (37.5%) | 1/7 (14.3%) | 2/3 (66.7%) | ||||||
Dehydration | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 2/7 (28.6%) | 0/3 (0%) | ||||||
Hyperamylasaemia | 0/3 (0%) | 0/3 (0%) | 1/3 (33.3%) | 2/8 (25%) | 0/7 (0%) | 0/3 (0%) | ||||||
Hyperkalaemia | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 1/7 (14.3%) | 0/3 (0%) | ||||||
Hyperlipasaemia | 0/3 (0%) | 0/3 (0%) | 1/3 (33.3%) | 3/8 (37.5%) | 0/7 (0%) | 0/3 (0%) | ||||||
Hyperuricaemia | 0/3 (0%) | 0/3 (0%) | 1/3 (33.3%) | 0/8 (0%) | 0/7 (0%) | 0/3 (0%) | ||||||
Hypoalbuminaemia | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/8 (12.5%) | 0/7 (0%) | 0/3 (0%) | ||||||
Hypokalaemia | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 2/8 (25%) | 0/7 (0%) | 0/3 (0%) | ||||||
Musculoskeletal and connective tissue disorders | ||||||||||||
Arthralgia | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/8 (12.5%) | 1/7 (14.3%) | 0/3 (0%) | ||||||
Back pain | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 2/7 (28.6%) | 0/3 (0%) | ||||||
Muscle spasms | 0/3 (0%) | 0/3 (0%) | 1/3 (33.3%) | 1/8 (12.5%) | 0/7 (0%) | 0/3 (0%) | ||||||
Musculoskeletal pain | 0/3 (0%) | 0/3 (0%) | 1/3 (33.3%) | 0/8 (0%) | 0/7 (0%) | 0/3 (0%) | ||||||
Myalgia | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 1/7 (14.3%) | 0/3 (0%) | ||||||
Neck pain | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 1/7 (14.3%) | 0/3 (0%) | ||||||
Pain in extremity | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 1/7 (14.3%) | 0/3 (0%) | ||||||
Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||||||||||
Cancer pain | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 1/7 (14.3%) | 0/3 (0%) | ||||||
Nervous system disorders | ||||||||||||
Dizziness | 1/3 (33.3%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 2/7 (28.6%) | 2/3 (66.7%) | ||||||
Dysarthria | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 1/7 (14.3%) | 0/3 (0%) | ||||||
Dysgeusia | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/8 (12.5%) | 1/7 (14.3%) | 0/3 (0%) | ||||||
Headache | 0/3 (0%) | 0/3 (0%) | 1/3 (33.3%) | 2/8 (25%) | 1/7 (14.3%) | 2/3 (66.7%) | ||||||
Paraesthesia | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 1/7 (14.3%) | 0/3 (0%) | ||||||
Psychiatric disorders | ||||||||||||
Anxiety | 0/3 (0%) | 0/3 (0%) | 1/3 (33.3%) | 0/8 (0%) | 1/7 (14.3%) | 0/3 (0%) | ||||||
Confusional state | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 1/7 (14.3%) | 0/3 (0%) | ||||||
Depression | 0/3 (0%) | 0/3 (0%) | 1/3 (33.3%) | 1/8 (12.5%) | 1/7 (14.3%) | 0/3 (0%) | ||||||
Hallucination | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/8 (12.5%) | 0/7 (0%) | 0/3 (0%) | ||||||
Insomnia | 0/3 (0%) | 2/3 (66.7%) | 0/3 (0%) | 0/8 (0%) | 0/7 (0%) | 1/3 (33.3%) | ||||||
Reproductive system and breast disorders | ||||||||||||
Vaginal haemorrhage | 1/3 (33.3%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/7 (0%) | 0/3 (0%) | ||||||
Respiratory, thoracic and mediastinal disorders | ||||||||||||
Cough | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/8 (12.5%) | 0/7 (0%) | 0/3 (0%) | ||||||
Dysphonia | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/8 (12.5%) | 0/7 (0%) | 0/3 (0%) | ||||||
Dyspnoea | 0/3 (0%) | 0/3 (0%) | 2/3 (66.7%) | 0/8 (0%) | 0/7 (0%) | 1/3 (33.3%) | ||||||
Hydrothorax | 0/3 (0%) | 0/3 (0%) | 1/3 (33.3%) | 0/8 (0%) | 0/7 (0%) | 0/3 (0%) | ||||||
Nasal ulcer | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 1/7 (14.3%) | 0/3 (0%) | ||||||
Pleural effusion | 0/3 (0%) | 0/3 (0%) | 1/3 (33.3%) | 1/8 (12.5%) | 0/7 (0%) | 0/3 (0%) | ||||||
Productive cough | 0/3 (0%) | 0/3 (0%) | 1/3 (33.3%) | 0/8 (0%) | 0/7 (0%) | 0/3 (0%) | ||||||
Pulmonary embolism | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/7 (0%) | 1/3 (33.3%) | ||||||
Rhinorrhoea | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 1/7 (14.3%) | 0/3 (0%) | ||||||
Upper-airway cough syndrome | 0/3 (0%) | 1/3 (33.3%) | 0/3 (0%) | 0/8 (0%) | 0/7 (0%) | 0/3 (0%) | ||||||
Skin and subcutaneous tissue disorders | ||||||||||||
Alopecia | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/7 (0%) | 1/3 (33.3%) | ||||||
Dry skin | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/8 (12.5%) | 0/7 (0%) | 0/3 (0%) | ||||||
Night sweats | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/7 (0%) | 1/3 (33.3%) | ||||||
Pain of skin | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 1/7 (14.3%) | 0/3 (0%) | ||||||
Pruritus | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 1/7 (14.3%) | 0/3 (0%) | ||||||
Rash | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 2/7 (28.6%) | 1/3 (33.3%) | ||||||
Rash maculo-papular | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/7 (0%) | 1/3 (33.3%) | ||||||
Vascular disorders | ||||||||||||
Deep vein thrombosis | 0/3 (0%) | 0/3 (0%) | 1/3 (33.3%) | 1/8 (12.5%) | 1/7 (14.3%) | 1/3 (33.3%) | ||||||
Thrombophlebitis superficial | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/7 (0%) | 1/3 (33.3%) |
Limitations/Caveats
More Information
Certain Agreements
All Principal Investigators ARE 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 |
- MS100015_0019