First in Human Study of M6223

EMD Serono Research & Development Institute, Inc.58 enrolled

Overview

The main purpose of this study was to determine the safety, tolerability, pharmacokinetics (PK), immunogenicity and (if observed) the maximum tolerated dose (MTD) of M6223 as a single agent (Part 1A) for both the every 2 weeks (Q2W) regimen and the every 3 weeks (Q3W) regimen and of M6223 combined with bintrafusp alfa (Part 1B) for Q2W regimen in participants with metastatic or locally advanced solid unresectable tumors.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Metastatic Solid Tumors

Interventions

M6223DRUG

Participants received an intravenous (IV) infusion of M6223 at escalated doses every 2 weeks (Q2W) or every 3 weeks (Q3W) on Day 1 of each Cycle (Each cycle is of 14 days) according to the recommendation of the SMC(Safety Monitoring Committee) until the maximum tolerated dose(MTD) has been reached or confirmed disease progression.

Bintrafusp alfaDRUG

Participants received an IV infusion of bintrafusp alfa Q2W on Day 1 of each Cycle (Cycle is 14 days) until confirmed disease progression.

M6223DRUG

Participants received an IV infusion of M6223 at escalated doses Q2W on Day 1 of each Cycle (Each cycle is of 21 days) according to the recommendation of the SMC until the MTD has been reached or confirmed disease progression.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Participants have histologically or cytologically proven locally advanced or advanced solid malignancies who are refractory to or have progressed under standard treatment and have no other treatment options known to confer clinical benefit * Participants with Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 to 1 at Screening * Participant has a formalin-fixed paraffin-embedded block containing tumor tissue or a minimum of 15 (preferably 25) unstained tumor slides suitable for immunohistochemistry-based staining of protein expression * Participants with life expectancy of at least 12 weeks * Participants with measurable disease according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) * Adequate hematological, hepatic and renal function as defined in the protocol * Other protocol defined inclusion criteria may apply Exclusion Criteria: * Participants with persisting toxicity related to prior therapy Grade greater than (\>) 1 National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0, however, alopecia, sensory neuropathy Grade less than or equal to (\<=) 2, or other non-immune-related Grade \<= 2 not constituting a safety risk * Participants with prior organ transplantation including allogeneic stem cell transplantation * Participants with prior toxicity related to an immune checkpoint inhibitor Grade greater than equal to (\>=) 3 NCI-CTCAE Version 5.0 unless resolved to Grade \<= 1 prior to study inclusion * Participants with current significant cardiac conduction abnormalities, including corrected QT interval (QTcF, corrected with Fridericia formula) prolongation of \> 450 milli seconds (ms) on triplicate 12-lead ECG or impaired cardiovascular function, ventricular tachycardia, hypokalemia or a history of paroxysmal atrial fibrillation, serious cardiac arrhythmia and family history of sudden death or long QT syndrome * A history of vascular, cardiovascular or cerebrovascular disease like, cerebral vascular accident/stroke (less than \[\<\] 6 months prior to enrollment), myocardial infarction (\< 6 months prior to enrollment), unstable angina, congestive heart failure (New York Heart Association Classification Class \>= II), deep vein thrombosis (\< 3 months prior to enrollment) or pulmonary thrombosis/embolism (\< 3 months prior to enrollment) * Other protocol defined exclusion criteria may apply

Locations (4)

Sarah Cannon Research Institute

Nashville, Tennessee, United States

MD Anderson Cancer Center

Houston, Texas, United States

Next Oncology

San Antonio, Texas, United States

Princess Margaret Cancer Centre

Toronto, Canada

Outcomes

Primary Outcomes

Part 1A and 1B: Number of Participants Who Experienced Dose Limiting Toxicities (DLTs) Assessed Using National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE) Version 5.0

A DLT is defined as any Grade ≥ 3 non-hematologic AE or any Grade ≥ 4 hematologic AE according to the NCI-CTCAE, occurring during the DLT observation period (28 days from first administration of study intervention) that is not clearly related to the underlying disease or any previous or concomitant medication, concomitant disease or unrelated illness. A DLT must be confirmed by the Safety Monitoring Committee. DLT is considered if the following related AEs occur: • Grade ≥ 3 neutropenia with clinical signs/symptoms (e.g., febrile neutropenia). • Grade ≥ 3 thrombocytopenia with medically concerning bleeding. • A study intervention-related treatment-emergent AE that in the opinion of the SMC is of potential clinical significance such that further dose escalation would expose participants to unacceptable risk. • Grade ≥ 3 hematological AE with symptoms that require growth factor support or transfusion to prevent further damage to the participant.

Time frame: Day 1 to Day 28

Part 1A and 1B: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Related TEAEs

An adverse event (AE) is defined as any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of study intervention, whether considered related to the study intervention or not. 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 were defined as events that started or worsened after first dose of study intervention until 30 days after last dose. TEAEs included both serious and non-serious TEAEs. Treatment-related TEAEs is defined as reasonably related to the study intervention.

Time frame: Approximately 2 years 11 months

Part 1A and 1B: Number of Participants With TEAES With Severity of Grade Greater or Equal to 3 and TEAEs Leading to Deaths

An adverse event (AE) is any untoward medical occurrence in a participant temporally associated with the use of the study intervention, regardless of causality. A serious AE results in death, is life-threatening, requires/prolongs hospitalization, causes disability/incapacity, leads to a congenital anomaly/birth defect, or is otherwise medically significant. Treatment-emergent adverse events (TEAEs) are those that begin or worsen after the first dose through 30 days post-treatment, and include both serious and non-serious events. Treatment-related TEAEs are those reasonably related to the study intervention. Severity is graded per CTCAE v24.1: Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe/medically significant), Grade 4 (life-threatening/disabling), Grade 5 (death related to AE).

Data from ClinicalTrials.gov

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Secondary Outcomes

Part 1A and Part 1B: Area Under the Serum Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC 0-t) of M6223

Area under the serum concentration-time curve from time zero to the last sampling time at which the concentration is at or above lower limit of quantification (LLQ). AUC0-t was calculated according to the mixed log linear trapezoidal rule. The full form of unit of measure h\*mcg/mL is hours · micrograms per milliliter.

Time frame: Pre-dose up to 14 days (in Q2W regimen) or 21 days (in Q3W regimen) post-dose of Cycles 1, 2, and 4 (Each cycle is of 14 days in Q2W regimen and each Cycle is of 21 days in Q3W regimen)

Part 1A and Part 1B: Area Under the Serum Concentration-Time Curve From Time Zero to Infinity (AUC 0-inf) of M6223

Area under the serum concentration time curve from time zero to infinity, calculated as AUC0 t + AUCextra. AUCextra represents an extrapolated value obtained by Clast/λz, where Clast is the calculated serum concentration at the last sampling time point at which the measured serum concentration is at or above LLQ and λz is elimination rate constant.

Time frame: Pre-dose up to 14 days (in Q2W regimen) or 21 days (in Q3W regimen) post-dose of Cycles 1, 2, and 4 (Each cycle is of 14 days in Q2W regimen and each Cycle is of 21 days in Q3W regimen)

Part 1A and Part 1B: Area Under Serum Concentration-Time Curve Over a Dosing Interval From Time Zero to Tau (AUC-tau) of M6223

Area under the concentration-time curve from time zero up to time Tau, where Tau is the dosing interval.

Time frame: Pre-dose up to 14 days (in Q2W regimen) or 21 days (in Q3W regimen) post-dose of Cycle 1 (Cycle is of 21 days in Q3W regimen)

Part 1A and Part 1B: Maximum Observed Serum Concentration (Cmax) of M6223

Maximum measured serum concentration, calculated from the serum concentration vs. time profile of the individual participants.

Time frame: Pre-dose up to 14 days (in Q2W regimen) or 21 days (in Q3W regimen) post-dose of Cycles 1, 2, and 4 (Each cycle is of 14 days in Q2W regimen and each Cycle is of 21 days in Q3W regimen)

Part 1A and Part 1B: Serum Concentration Observed Immediately Before Next Dosing (Ctrough) of M6223

Ctrough is the concentration prior to study drug administration.

Time frame: Pre-dose up to 14 days (in Q2W regimen) or 21 days (in Q3W regimen) post-dose of Cycles 1, 2, and 4 (Each cycle is of 14 days in Q2W regimen and each Cycle is of 21 days in Q3W regimen)

Part 1A and Part 1B: Time to Reach Maximum Serum Concentration (Tmax) of M6223

Time taken to reach maximum concentration of M66223 after admistration is reported.

Time frame: Cycle 1 and 2: Day 1 (-2h, EOI, 4-6h), Day 2 (25-31h), Day 5 (±1h), Day 8 (±1h); Cycle 3 to end of treatment: Day 1 (-2h pre-dose only)

Part 1A and Part 1B: Apparent Terminal Half-Life (t1/2) of M6223

Terminal half-life is the time measured for the concentration to decrease by one half. Terminal half-life is calculated by dividing the natural logarithm to the base e (Log e) multiplied by (\*) 2/ λz, where 'λz' is the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve.

Time frame: Cycle 1 and 2: Day 1 (-2h, EOI, 4-6h), Day 2 (25-31h), Day 5 (±1h), Day 8 (±1h); Cycle 3 to end of treatment: Day 1 (-2h pre-dose only)

Part 1A and Part 1B: Elimination Rate Constant (Lambda z) of M6223

Elimination rate constant was obtained from linear regression of the terminal phase of the log transformed concentration-time data.

Time frame: Pre-dose up to 14 days (in Q2W regimen) or 21 days (in Q3W regimen) post-dose of Cycles 1, 2, and 4 (Each cycle is of 14 days in Q2W regimen and each Cycle is of 21 days in Q3W regimen)

Part 1B: Maximum Observed Serum Concentration (Cmax) of Bintrafusp Alfa

Maximum measured serum concentration, calculated from the serum concentration vs. time profile of the individual participants.

Time frame: Day 1 of Treatment of Cycles 1 and 4 from time zero to 14 days postdose

Part 1B: Serum Concentration Observed Immediately Before Next Dosing (Ctrough) of Bintrafusp Alfa

Ctrough is the concentration prior to study drug administration.

Time frame: Day 1 of Treatment of Cycles 1 and 4 from time zero to 14 days postdose

Part IA and 1B: Number of Participants With Positive Antidrug Antibody (ADA) Assays

Serum samples were analyzed by a validated assay method to detect the presence of antidrug antibodies (ADA). Number of participants with positive ADA were reported.

Time frame: Pre-dose of Day 1 Cycle 1 (Each Cycle is of 14 days in Q2W regimen and 21 days in Q3W regimen) up to end of safety follow-up visit ( approximately 2 years 11 months)

Part 1A and IB: Best Overall Response According to Response Criteria in Solid Tumors Version 1.1 (RECIST 1.1) Assessed as Per Investigator

The ORR is defined as the number of participants with a documented BOR (complete response (CR) or partial response (PR)) by the investigator during treatment with avelumab plus axitinib as firstline therapy. The BOR is defined as the best tumor response recorded during the observation period. The definitions of tumor responses are as follows: Complete or PR as the best adjudication result (CR \> PR \> stable disease \[SD\] \> progressive disease \[PD\], not Evaluable \[NE\]) complies with the RECIST tumor assessment guidelines as closely as possible in clinical practice.

Time frame: From first study drug administration until documented disease progression or death due to any cause whichever occurs first (approximately 2 years 11 months)

Part 1A and 1B: Duration of Response (DOR) According to Response Criteria in Solid Tumors Version 1.1 (RECIST 1.1) Assessed as Per Investigator

DOR was defined for participants with a confirmed objective response as the time from first documentation of a confirmed objective response (CR or PR) according to RECIST 1.1 to the date of first documentation of objective PD or death due to any cause, whichever occurs first. CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30 percent (%) reduction from baseline in sum of longest diameter (SLD) of all lesions. PD: 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. DOR was determined according to RECIST v1.1 and assessed by IRC.

Time frame: From first study drug administration until documented disease progression or death due to any cause whichever occurs first( approximately 2 years 11 months)

Part 1A and 1B: Time to Tumor Response (TTR) According to Response Criteria in Solid Tumors Version 1.1 (RECIST 1.1) Assessed as Per Investigator

TTR was defined for participants who achieved objective response as time from first study drug administration to first documentation of objective tumor response (CR or PR) that was subsequently confirmed. CR was defined as a score of 1 (no uptake above background), 2 (uptake \<= mediastinum), or 3 (uptake \<mediastinum but \<=liver) with or without a residual mass on PET 5-PS, for lymph nodes and extralymphatic sites; no new lesions; no evidence of FDG-avid disease in bone marrow. PR was defined as \>=50% decrease in SPD of up to six of the largest dominant lymph nodes, no increase in size of other nodes, liver, or spleen volume, a \>=50% decrease in SPD of hepatic and splenic nodules, absence of other organ involvement, and no new sites of disease.

Time frame: From first study drug administration until documented disease progression or death due to any cause whichever occurs first (approximately 2 years 11 months))

Part 1A and 1B: Disease Control According to Response Criteria in Solid Tumors Version 1.1 (RECIST 1.1) Assessed as Per Investigator

Disease control rate was defined as percentage of participants with disease control. Disease Control (DC) was defined as the best overall response of CR, PR, or stable disease (SD). CR: score of 1 (no uptake above background), 2 (uptake \<= mediastinum), or 3 (uptake less than \<mediastinum but \<=liver) with or without a residual mass on Positron Emission Tomography 5-Point Scale, for lymph nodes and extra lymphatic sites; no new lesions; no evidence of fluorodeoxyglucose -avid disease in bone marrow. PR: \>=50% decrease in SPD of up to six of the largest dominant lymph nodes, no increase in size of other nodes, liver, or spleen volume, a \>=50% decrease in Sum of the Products of Diameters of hepatic and splenic nodules, absence of other organ involvement, and no new sites of disease. SD: \<50% decrease in SDP of up to 6 dominant, measurable nodes and extranodal sites; no criteria for progressive disease met.

Time frame: From first study drug administration until documented disease progression or death due to any cause whichever occurs first (approximately 2 years 11 months))

Part 1A and 1B: Progression-free Survival Time According to Response Criteria in Solid Tumors Version 1.1 (RECIST 1.1) Assessed as Per Investigator

Progression Free Survival (PFS) time is defined as the time from start date of treatment to the date of the first documentation of objective progression of disease (PD) or death due to any cause, whichever occurs first. The tumor response will be determined according to RECIST 1.1 and assessed by the investigator.

Time frame: From first study drug administration until documented disease progression or death due to any cause whichever occurs first (approximately 2 years 11 months)

Part 1A and 1B: Overall Survival

Overall survival was defined as the time (in months) from first study drug administration to the date of death due to any cause. Participants last known to be alive were censored at date of last contact. Analysis was performed using Kaplan-Meier method.

Time frame: From first study drug administration to the date of death due to any cause (approximately 2 years 11 months)