Anti-Arrhythmia Agents

Vasodilator Agents

Analgesics

All Drugs and Chemicals

Adenosine

Participants received 50 milligrams (mg) M3541 orally once per fraction day (FD) in combination with palliative radiotherapy (RT) administered in fraction of 30 Gray (Gy) given in 10 fractions of 3 Gy/FD on FD 1 to FD 10, for 2 consecutive calendar weeks (ie, Monday through Friday, with the intervening Saturday and Sunday as M3541 / RT holidays).

Participants received 100 mg M3541 orally once per FD in combination with palliative RT administered in fraction of 30 Gray (Gy) given in 10 fractions of 3 Gy/FD on FD 1 to FD 10 for 2 consecutive calendar weeks (ie, Monday through Friday, with the intervening Saturday and Sunday as M3541 / RT holidays).

Participants received 200 mg M3541 orally once per FD in combination with palliative RT administered in fraction of 30 Gray (Gy) given in 10 fractions of 3 Gy/FD on FD 1 to FD 10 for 2 consecutive calendar weeks (ie, Monday through Friday, with the intervening Saturday and Sunday as M3541 / RT holidays).

Participants received 300 mg M3541 orally once per FD in combination with palliative RT administered in fraction of 30 Gray (Gy) given in 10 fractions of 3 Gy/FD on FD 1 to FD 10 for 2 consecutive calendar weeks (ie, Monday through Friday, with the intervening Saturday and Sunday as M3541 / RT holidays).

Participants received M3541 orally once per fraction day (FD) for two consecutive calendar weeks (that is, Monday through Friday, with Saturday and Sunday as M3541 holidays).

M3541

Participants received RT dose of 30 Gray (Gy) given in 10 fractions (3 Gy given per fraction day) administered over two consecutive calendar weeks (that is, Monday through Friday, with Saturday and Sunday as RT holidays).

Palliative Radiotherapy (RT)

Medical Responsible

This dose-escalation study evaluated the safety, tolerability, pharmacokinetic (PK), pharmacodynamic, and explore antitumor activity of M3541 in combination with fractionated palliative radiotherapy (RT) in participants with solid tumors with malignant lesions in the thorax, abdominal cavity, head and neck region, or extremities likely to benefit from palliative RT.

Subsequent cohorts of patients treated at different dose levels.

M3541 in Combination With Radiotherapy in Solid Tumors

A Phase I, Open-label, Uncontrolled, Multicenter, Dose-escalation Study of M3541 in Combination With Palliative Radiotherapy in Subjects With Solid Tumors

DLT is classified per the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 and defined as any of the following events occurring after first dose of study intervention and judged not to be related to underlying disease or any previous or concomitant medication. Grade (Gr) \>=3 non-hematologic toxicity with exception of Nausea, vomiting and diarrhea lasting =\<3 days in once per FD; Worsening of preexisting tumor pain associated with tumor lesions for which participant was irradiated in context of this study; Evidence of treatment-related hepatocellular injury for \>3 days in the once per FD; Any occurrence of Hy's law; Gr 4 neutropenia lasting for \>5 days, Gr 4 thrombocytopenia or Gr 4 anemia that was unexplained by underlying disease; Any toxicity related to study treatment that caused participant to interrupt treatment for not to be able to be treated within 24 hours of the scheduled treatment time.

An AE was defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug. A serious AE was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. TEAEs are events with start date on or after the date of first dose of study treatment and up to and including 30 days after the last dose of study treatment, or events with start date prior to the date of first dose of study treatment, and worsened in severity or become serious during treatment. TEAEs include both Serious TEAEs and non-serious TEAEs.

The laboratory assessment included measurements hematology and biochemistry parameters. It had been graded according to NCI-CTCAE version 4.03 into Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe), Grade 4 (Life-threatening) and Grade 5 = death. Participants with grade 3 or higher were reported.

Vital signs assessment included blood pressure, pulse rate, body temperature, respiratory rate, and body weight. Notably abnormal vital signs were: Blood pressure: systolic blood pressure \>= 140 millimeter of mercury (mmHg) \& diastolic blood pressure \>=90 mmHg on treatment; Pulse rate \>100 beats/min; Body temperature \>= 38 degree Celsius (°C) on treatment; Respiratory rate \>= 20 breaths/min; Weight (kilogram) \> +/-20% from baseline. Number of Participants with abnormalities in vital signs were reported.

Number of participants with any clinically significant abnormalities in physical examination reported as adverse events with National Cancer Institute Common Terminology Criteria (NCI-CTC) Grade \>=3 were presented.

The 12-lead ECG was recorded after the participant was in semi-supine position for at least 5 minutes. The ECG was obtained using a Holter recorder. Number of Participants with abnormal change from baseline in ECG were reported.

BOR was determined according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). 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 or recurrence (taking the smallest measurement recorded since the start of treatment as reference). CR: 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. SD=Neither sufficient increase to qualify for PD nor sufficient shrinkage to qualify for PR. PD is defined as at least a 20 percent (%) increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions.

PFS is defined as the time (in months) from first administration of M3541 until the first date of progressive disease (PD) or death due to any cause. PFS was assessed as per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). PD was defined as at least a 20% increase in the sum of longest diameter (SLD), taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions and unequivocal progression of non-target lesions. Participants with neither disease progression nor death were censored at the last date of the last tumor assessment that confirmed that their disease had not progressed. Participant wise data reported for this outcome measure.

Cmax was obtained directly from the plasma concentration versus time curve.

Dose normalized was calculated as Cmax obtained directly from the concentration versus time curve divided by dose.

Time to reach the maximum plasma concentration (Tmax) was obtained directly from the concentration versus time curve.

Apparent terminal half-life was defined as the time required for the plasma concentration of drug to decrease 50 percent in the final stage of its elimination.

AUC(0-last) is defined as the area under the concentration-time curve from dosing (time 0) to the time of the last measured concentration. AUC(0-last) will be estimated using the Linear Up Log Down calculation method.

The Dose normalized AUC from time zero to the last sampling time (0-last) at which the concentration is at or above the lower limit of quantification. Normalized using the actual dose, using the formula AUC0-last/Dose.

Area under the drug concentration-time curve from 0 to 6 hour post dosing for M3541. AUC0-6 was calculated according to the mixed log-linear trapezoidal rule.

AUC0-inf is the area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time.

Dose normalized was calculated as area under the plasma concentration-time curve from time zero to 8 h postdose divided by dose.

Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. CL/f = Dose /AUC0-inf. Predicted AUC0-inf should be used.

Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed.

The Vz/f was defined as the theoretical volume in which the total amount of required to uniformly distribute to produce the desired plasma concentration. Apparent volume of distribution after oral dose (Vz/F) was influenced by the fraction absorbed. The Vz/f was calculated by dividing the dose with area under the concentration time curve from time zero to infinity multiplied with terminal elimination rate constant Lambda(z). Vz/f=Dose/AUC(0-inf)\* Lambda(z).

Volume of distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Vss/f after oral dose was influenced by the fraction absorbed.

The accumulation ratio to assess the increase in exposure via AUC0-6h. Racc(AUC0-6h)= (AUC0-6h after multiple dose) / (AUC0-6h after single dose).

The accumulation ratio is to assess the increase in maximum concentration with multiple dosing. Racc(Cmax) = (Cmax after multiple dose)/ (Cmax after single dose).

Ctrough is the concentration prior to study drug administration.

Cmin is minimum observed plasma concentration obtained directly from the concentration versus time curve.

Cavg was defined as average plasma concentration.

Merck KGaA, Darmstadt, Germany

EMD Serono Research & Development Institute, Inc.

M3541 50 mg + RT

M3541 100 mg + RT

M3541 200 mg + RT

M3541 300 mg + RT

Total

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

Safety analysis set included all participants who received at least 1 dose of M3541.

The study was terminated early per sponsor decision to halt further development of M3541 due to pharmaceutical and PK/pharmacodynamics properties that precluded further clinical development.

Communication Center

DLT analysis set included participants who received at least 1 dose of M3541and met at least one of the following criteria: Experienced at least 1 DLT during the DLT evaluation period, regardless of the number of doses of M3541 administered or received at least 80% of planned dose of each treatment, that is, 8 fractions of RT and 8 of 10 M3541 administrations during the treatment period

M3541 50 mg + 100 mg + 200 mg + RT: Number of Participants With Dose Limiting Toxicities (DLTs)

Participants with TEAEs

Participants with Grade >=3 AEs

Participants with Serious TEAEs

Participants with Death

Number of Participants With Treatment Emergent Adverse Events (TEAEs), Grade >=3 Adverse Events (AEs), Serious TEAEs and Deaths According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events, Version 4.03 (CTCAE V4.03)

Hematology

Biochemistry

Number of Participants With Grade 3 or Higher Laboratory Abnormalities Based on National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE)

Blood Pressure

Pulse rate

Body temperature

Respiratory rate

Weight

Number of Participants With Abnormalities in Vital Signs

Number of Participants With Abnormalities in Physical Examination Reported as Adverse Events (AEs)

Safety analysis set included all participants who received at least 1 dose of M3541. Here "Number of Participants Analyzed" signifies those participants who were evaluable for this outcome measure with normal ECG at baseline.

Number of Participants With Abnormal Change From Baseline in Electrocardiogram (ECG)

Number of Participants With Best Overall Response (BOR) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1

Participant-1

Participant-2

Participant-3

Participant-4

Participant-5

Participant-6

Participant-7

Participant-8

Participant-9

Participant-10

Participant-11

Participant-12

Participant-13

Participant-14

Participant-15

Safety analysis set included all participants who received at least 1 dose of M3541. The summarized data was not available for this outcome measure, therefore individual data was presented. "Number Analyzed" signifies participants evaluable in respective arm.

Progression-Free Survival (PFS) Using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Investigator

As per changes in planned analysis, the outcome measure related to pharmacokinetic parameters was not assessed.

Spots Global Cancer Trial Database for M3541 in Combination With Radiotherapy in Solid Tumors

Trial Identification

Conditions

Interventions

Study Description

Keywords

Eligibility

Locations

Contact Details

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