Back to resultsM8891 First in Human in Solid Tumors (M8891)
Primary Purpose
Advanced Solid Tumors, Metastatic Renal Cell Carcinoma
Status
Terminated
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Part 1: M8891
Sponsored by
About this trial
This is an interventional treatment trial for Advanced Solid Tumors focused on measuring Advanced Solid Tumors, Metastatic Renal Cell Carcinoma, M8891, Methionine Aminopeptidase 2 Inhibitor
Eligibility 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
Sites / Locations
- Smilow Cancer Hospital - Yale
- Indiana University Health Hospital
- Sidney Kimmel Cancer Center - Johns Hopkins
- Henry Ford Health System
- Nebraska Cancer Specialists
- Comprehensive Cancer Centers of Nevada
- Rutgers Cancer Institute of New Jersey
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm 4
Arm 5
Arm 6
Arm Type
Experimental
Experimental
Experimental
Experimental
Experimental
Experimental
Arm Label
M8891 7 mg
M8891 12 mg
M8891 20 mg
M8891 35 mg
M8891 60 mg
M8891 80 mg
Arm 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.
Outcomes
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
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
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
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
Maximum observed plasma concentration (Cmax) was taken directly from the observed concentration-time curve.
Time to Reach Maximum Observed Plasma Concentration (Tmax) of M8891
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
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
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
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
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
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
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
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
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
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
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
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
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)
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
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
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
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
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
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.
Full Information
NCT ID
NCT03138538
First Posted
April 26, 2017
Last Updated
December 21, 2021
Sponsor
EMD Serono Research & Development Institute, Inc.
Collaborators
Merck KGaA, Darmstadt, Germany
1. Study Identification
Unique Protocol Identification Number
NCT03138538
Brief Title
M8891 First in Human in Solid Tumors
Acronym
M8891
Official Title
An Open-label, Phase I Dose Escalation Trial of Methionine Aminopeptidase 2 Inhibitor M8891 in Subjects With Advanced Solid Tumors
Study Type
Interventional
2. Study Status
Record Verification Date
December 2021
Overall Recruitment Status
Terminated
Why Stopped
As part of a portfolio-level management of the company's oncology pipeline, it was decided to stop the next phase of internal development of the MetAP2 (M8891) program to enable realization of other opportunities within the oncology portfolio.
Study Start Date
August 8, 2017 (Actual)
Primary Completion Date
September 16, 2020 (Actual)
Study Completion Date
September 16, 2020 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
EMD Serono Research & Development Institute, Inc.
Collaborators
Merck KGaA, Darmstadt, Germany
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No
5. 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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Advanced Solid Tumors, Metastatic Renal Cell Carcinoma
Keywords
Advanced Solid Tumors, Metastatic Renal Cell Carcinoma, M8891, Methionine Aminopeptidase 2 Inhibitor
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
27 (Actual)
8. Arms, Groups, and Interventions
Arm Title
M8891 7 mg
Arm Type
Experimental
Arm 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.
Arm Title
M8891 12 mg
Arm Type
Experimental
Arm Description
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.
Arm Title
M8891 20 mg
Arm Type
Experimental
Arm Description
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.
Arm Title
M8891 35 mg
Arm Type
Experimental
Arm Description
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.
Arm Title
M8891 60 mg
Arm Type
Experimental
Arm Description
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.
Arm Title
M8891 80 mg
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Part 1: M8891
Intervention Description
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.
Primary Outcome Measure Information:
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)
Secondary Outcome Measure Information:
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
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
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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
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
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
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
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
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
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
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
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Medical Responsible
Organizational Affiliation
EMD Serono Research & Development Institute, Inc., a business of Merck KGaA, Darmstadt, Germany
Official's Role
Study Director
Facility Information:
Facility Name
Smilow Cancer Hospital - Yale
City
New Haven
State/Province
Connecticut
ZIP/Postal Code
06510
Country
United States
Facility Name
Indiana University Health Hospital
City
Indianapolis
State/Province
Indiana
ZIP/Postal Code
46202
Country
United States
Facility Name
Sidney Kimmel Cancer Center - Johns Hopkins
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21205-1911
Country
United States
Facility Name
Henry Ford Health System
City
Detroit
State/Province
Michigan
ZIP/Postal Code
48202
Country
United States
Facility Name
Nebraska Cancer Specialists
City
Omaha
State/Province
Nebraska
ZIP/Postal Code
68130
Country
United States
Facility Name
Comprehensive Cancer Centers of Nevada
City
Las Vegas
State/Province
Nevada
ZIP/Postal Code
89169
Country
United States
Facility Name
Rutgers Cancer Institute of New Jersey
City
New Brunswick
State/Province
New Jersey
ZIP/Postal Code
08901
Country
United States
12. IPD Sharing Statement
Plan to Share IPD
No
IPD Sharing Plan Description
Per company policy, following approval of a new product or a new indication for an approved product in both the EU and the US, EMD Serono will share study protocols, anonymized patient level and study level data and redacted clinical study reports from clinical trials in patients with qualified scientific and medical researchers, upon request, as necessary for conducting legitimate research. Further information on how to request data can be found on our website https://www.emdgroup.com/en/research/our-approach-to-research-and-development/healthcare/clinical-trials/commitment-responsible-data-sharing.html
Links:
URL
https://clinicaltrials.emdgroup.com/en/trial-details/?id=MS100015_0019
Description
Trial Awareness and Transparency website
URL
https://medical.emdserono.com/en_US/home.html
Description
US Medical Information website, Medical Resources
Learn more about this trial
M8891 First in Human in Solid Tumors
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