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Female Urogenital Diseases and Pregnancy Complications

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Methionine

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.

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.

Part 1: M8891

Medical Responsible

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.

M8891 First in Human in Solid Tumors

An Open-label, Phase I Dose Escalation Trial of Methionine Aminopeptidase 2 Inhibitor M8891 in Subjects With Advanced Solid Tumors

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

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.

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.

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) was taken directly from the observed concentration-time curve.

The time to reach the maximum observed plasma concentration (tmax) was obtained directly from the concentration versus time curve.

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).

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.

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).

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.

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 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.

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 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.

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 was calculated as Cmax, after dosing on Day 15 divided by Cmax, after dosing on Day 1 of Cycle 1.

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.

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) 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.

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.

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.

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.

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.

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.

Merck KGaA, Darmstadt, Germany

EMD Serono Research & Development Institute, Inc.

M8891 7 mg

M8891 12 mg

M8891 20 mg

M8891 35 mg

M8891 60 mg

M8891 80 mg

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.

Total

Age, Categorical

Sex: Female, Male

Race (NIH/OMB)

Safety analysis set included all participants who received at least 1 dose of study drug.

Communication Center

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.

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

TEAEs

TEAEs leading to death

Number of Participants With Treatment-Emergent Adverse Events (TEAE) and TEAEs Leading to Death

Grade >=3

Grade >=4

Grade 5

Number of Participants With Treatment-Emergent Adverse Events (TEAE) by Severity

Day 1

Day 15

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.

Maximum Observed Plasma Concentration (Cmax) of M8891

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.

Time to Reach Maximum Observed Plasma Concentration (Tmax) of M8891

Area Under the Plasma Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-t) of M8891

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.

Area Under the Concentration-time Curve From Zero Extrapolated to Infinity (AUC0-inf) of M8891

Area Under the Plasma Concentration Versus Time Curve Within One Dosing Interval (AUC0-tau) of M8891

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.

Apparent Terminal Half Life (t1/2) of M8891

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.

Terminal Elimination Rate Constant (Lambda z) of M8891

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.

Apparent Total Body Clearance (CL/f) of M8891

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.

Apparent Body Clearance of Drug Following Extravascular Administration At Steady State (CLss/f) of M8891

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.

Apparent Volume of Distribution During Terminal Phase (VZ/f) of M8891

Accumulation Ratios of AUC (Racc AUC) of M8891

Accumulation Ratio of Cmax (Racc Cmax) of M8891

Complete Response

Partial Response

Stable Disease

Progressive Disease

Not Evaluable

Number of Participants With Best Overall Response Assessment According to Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST v1.1) Criteria

Number of Participants With Clinical Benefit

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.

Less Than or Equal to (<=) 20 mg M8891

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.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
M8891 First in Human in Solid Tumors	NCT03138538	Advanced Solid ... Metastatic Rena...	Part 1: M8891	18 Years -	EMD Serono
M8891 First in Human in Solid Tumors	NCT03138538	Advanced Solid ... Metastatic Rena...	Part 1: M8891	18 Years -	EMD Serono

Spots Global Cancer Trial Database for methionine aminopeptidase 2 inhibitor