The main purpose of this Phase I study was to test MSB0011359C (M7824) at different dose levels to see if it is safe and well tolerated when given once every 2 weeks. Phase I means the study drug has not previously been given to humans or has only been given to a limited number of people, although it has been extensively studied in animals. Based on this information, it is hoped to find out which dose could be best for the treatment of patients. There are two parts of this research study: a dose-escalation part and an expansion part. Dose escalation means that the first people taking part in the study will receive low doses of the study drug, and as more people take part, the additional participants will receive a higher dose. This is done to find the safest dose for the study drug. Expansion means that after the dose-escalation part of the study has looked at the safety and effectiveness of different doses, many more people will be invited to take part in the study and will receive the study drug at the safest dose. Additional purposes of the study are to find out whether the study drug has anti-cancer effects and how the study drug is processed by the body.
This is a Phase I, open-label, dose-escalation trial with consecutive parallel-group expansion in selected solid tumor indications. The current trial wascomposed of a standard dose escalation "3 + 3" cohort design, for which 3 to 6 subjects will be enrolled at each dose level depending on the occurrence of dose limiting toxicities (DLTs), followed by a consecutive parallel-group expansion in selected solid tumor in dications. Cohorts of 3 subjects with metastatic or locally advanced solid tumors, for which no standard effective therapy exists or standard therapy has failed, will receive MSB0011359C (M7824) at escalating dose levels. After determination of the Maximum tolerated dose (MTD), enrollment in several expansion cohorts will be opened to determine the safety, pharmacokinetic (PK) / Pharmacodynamic, and clinical activity of MSB0011359C (M7824). Subjects who have experienced a confirmed complete response (CR) should continue treatment through the end of 12 months, although additional treatment is possible. In the case of progressive disease (PD), subjects should continue treatment through their next tumor assessment. Additional indications will be planned based on emerging data in the field.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
600
Subjects would receive intravenous infusion of MSB0011359C once every 2 weeks in a dose escalation fashion until confirmed progression, unacceptable toxicity, or any criterion for withdrawal from the trial or investigational medicinal product (IMP) occurs.
Arizona Clinical Research Center
Tucson, Arizona, United States
Pacific Oncology Associates
Escondido, California, United States
University of California Davis Health System
Sacramento, California, United States
California Pacific Medical Center
San Francisco, California, United States
Innovative Clinical Research Institute
Whittier, California, United States
Dose-escalation: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs
Adverse event (AE): any unfavourable 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. Serious AE: 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. TEAE: AE with onset after start of treatment or with onset date before the treatment start date but worsening after the treatment start date. TEAEs included both serious and non-serious TEAEs.
Time frame: From start of study drug administration up to 139 weeks
Dose-escalation: Number of Participants With Treatment-Related TEAEs, Treatment-Related Serious TEAEs and Treatment-related TEAEs Leading to Death
Treatment-related TEAEs are any untoward medical occurrence in a participant who received study drug with causal relationship with the investigational product as assessed by the investigator. Related TEAEs were events with relationship missing, unknown or yes. Number of participants With treatment-related TEAEs, treatment-related serious TEAEs and treatment-related TEAE leading to death were reported.
Time frame: From start of study drug administration up to 139 weeks
Number of Participants With TEAEs and Related TEAEs Based on Severity According to National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI-CTCAE) Version 4.03
AEs were graded according to severity using NCI-CTCAE Version 4.03. Severity of TEAEs were graded as Grade 1: mild (not causing any significant problem, dose adjustment not required), Grade 2: moderate (caused problem that does not interfere significantly with usual activities or the clinical status, dose adjustment needed due to adverse event), Grade 3: Severe (caused problem that interferes significantly with usual activities or the clinical status, study drug stopped due to adverse event), Grade 4: Life-threatening, Grade 5: Death. Number of Participants with TEAEs and Related TEAEs Based on Severity having Grade greater than or equal to (\>=) 3 and Grade \>=4 were reported.
Time frame: From start of study drug administration up to 139 weeks
Dose-escalation: Number of Participants With Dose-Limiting Toxicities According to the National Cancer Institute Common Terminology Criteria For Adverse Events(NCI-CTCAE), v4.03
A DLT was defined as any grade \>= 3 Adverse Event (AE) suspected to be related to IMP by the Investigator and / or Sponsor occurring in the DLT evaluation period confirmed by the Safety Monitoring Committee (SMC) to be relevant for the IMP treatment. According to the NCI-CTCAE, v4.03, occurring in the DLT evaluation period and assessed to be related to study treatment by the Investigator and / or Sponsor confirmed by the safety monitoring committee to be relevant for the study treatment.
Time frame: From start of study drug administration up to 21 days
Dose-expansion: Number of Participants With Best Overall Response (BOR) as Assessed by Independent Endpoint Review Committee (IRC)
BOR according to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 and as adjudicated by the Independent Endpoint Review Committee (IRC). BOR is defined as sum of complete response and partial response (CR+PR). For target lesions (TLs), CR was defined as the disappearance of all TLs; PR was defined as at least a 30% decrease in the sum of largest diameter (SLD) of the TLs, taking as a reference the baseline SLD.
Time frame: From date of randomization up to Week 66
Dose-expansion: Disease Control Rate According to Response Assessment in Neuro-Oncology (RANO) as Adjudicated by the IRC for Participants With Glioblastoma
DCR is defined as the percentage of participants with a confirmed CR+PR+SD+ Non-CR/non-PD at any time as per RANO criteria. A responder is a participant with a Complete Response (CR) or Partial Response (PR), and a non-responder is a participant with Stable Disease (SD) or Progressive Disease (PD) assessed by the RANO criteria. CR is no T1 gadolinium enhancing disease, no new lesions, or corticosteroids, and stable or decreasing T2-weighted-Fluid-Attenuated Inversion Recovery (T2/FLAIR). PR is ≥50% decrease in T1 gadolinium enhancing disease, no new lesions, stable or decreasing T2/FLAIR or corticosteroids, and stable or increasing clinical status. SD is \<50% decrease in T1 gadolinium enhancing disease but \< 25% increase, no new lesions, stable or decreasing T2/FLAIR or corticosteroids, and stable or increase in clinical status. PD is ≥25% increase in T1 gadolinium enhancing disease.
Time frame: From date of randomization up to Week 66
Maximum Concentration (Cmax) of M7824 in Plasma
Cmax was obtained directly from the concentration versus time curve.
Time frame: 0 hours (pre-dose), 1, 4, 10, 25, 72, 168, 240, 336 hours post-dose
Area Under the Concentration-Time Curve From Time Zero up to Time Tau (AUCtau) of M7824
Area under the concentration-time curve from time zero up to time Tau, where Tau is the dosing interval (336 hours).
Time frame: 0 hours (pre-dose), 1, 4, 10, 25, 72, 168, 240, 336 hours post-dose post-dose
Apparent Terminal Half Life (t1/2) of M7824
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: Pre-dose, 0, 1, 4, 10, 25, 72, 168, 240, 336 hours post-dose
Trough Plasma Concentration (Ctrough) of M7824
Ctrough is the plasma concentration of a drug prior to administration.
Time frame: 0 hours (Pre-dose), 1, 4, 10, 25, 72, 168, 240, 336 hours post-dose
Apparent Plasma Clearance (CL) of M7824
CL is defined as the time it takes for the study drug to be completely removed from the body's plasma.
Time frame: 0 hours (Pre-dose), 1, 4, 10, 25, 72, 168, 240, 336 hours post-dose
Number of Participants With Positive Anti-Drug Antibody (ADA) of M7824
The detection of antibodies to M7824 was performed using a validated immunoassay method with tiered testing of screening, confirmatory and titration. Number of participants with positive ADA of M7824 were reported.
Time frame: Predose, up to Week 52
Number of Participants With Best Overall Response (BOR) as Assessed by Investigator
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.
Rocky Mountain Cancer Centers, LLP
Denver, Colorado, United States
Eastern Connecticut Hematology/Oncology Assoc.
Norwich, Connecticut, United States
Sylvester Cancer Center
Miami, Florida, United States
Hematology - Oncology Associates of Treasure Coast
Port Saint Lucie, Florida, United States
University Cancer & Blood Center, LLC
Athens, Georgia, United States
...and 108 more locations
BOR according to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 and as adjudicated by the Investigator. BOR is defined as sum of complete response and partial response (CR+PR). For target lesions (TLs), CR was defined as the disappearance of all TLs; PR was defined as at least a 30% decrease in the sum of largest diameter (SLD) of the TLs, taking as a reference the baseline SLD.
Time frame: From date of randomization up to Week 66
Dose Expansion: Number of Participants With TEAEs and Serious TEAEs
An Adverse Event (AE) was defined as any new untoward medical occurrences/worsening of pre-existing medical condition without regard to possibility of causal relationship. TEAEs were defined as events with onset date or worsening during the on-treatment period. 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. Any TEAE included participants with both serious and non-serious AEs.
Time frame: From start of study drug administration up to 200 weeks
Dose Expansion: Number of Participants With Treatment-Related TEAEs, Treatment-Related Serious TEAEs and Treatment-related TEAE Leading to Death
Treatment-related TEAEs are any untoward medical occurrence in a participant who received study drug with causal relationship with the investigational product as assessed by the investigator. Related TEAEs were events with relationship missing, unknown or yes. Number of participants with treatment-related TEAEs, treatment-related serious TEAEs and treatment-related TEAE leading to death were reported.
Time frame: From start of study drug administration up to 200 weeks
Dose Expansion: Number of Participants With TEAEs and Related TEAEs Based on Severity According to NCI-CTCAE Version 4.03
AEs were graded according to severity using NCI-CTCAE Version 4.03. Severity of TEAEs were graded as Grade 1: mild (not causing any significant problem, dose adjustment not required), Grade 2: moderate (caused problem that does not interfere significantly with usual activities or the clinical status, dose adjustment needed due to adverse event), Grade 3: Severe (caused problem that interferes significantly with usual activities or the clinical status, study drug stopped due to adverse event), Grade 4: Life-threatening, Grade 5: Death. Number of Participants with TEAEs and Related TEAEs Based on Severity having Grade \>= 3 and Grade \>=4 TEAEs were reported.
Time frame: From start of study drug administration up to 200 weeks