Metastatic Solid Tumors
Conditions
Keywords
Metastatic Solid Tumors, Avelumab, MSB0010718C
Brief summary
The purpose of this study was to evaluate the maximum tolerated dose (MTD) and pharmacokinetics (PK) of Avelumab monotherapy in Chinese subjects.
Interventions
DRUGAvelumab 3 mg/kg Q2W
Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 3 milligrams per kilogram (mg/kg) once every 2 weeks (Q2W) until disease progression, significant clinical deterioration, unacceptable toxicity, or any criterion for withdrawal from the study or from Avelumab occurs.
DRUGAvelumab 10 mg/kg Q2W
Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 10 mg/kg Q2W until disease progression, significant clinical deterioration, unacceptable toxicity, or any criterion for withdrawal from the study or from Avelumab occurs.
DRUGAvelumab 20 mg/kg Q2W
Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 20 mg/kg Q2W until disease progression, significant clinical deterioration, unacceptable toxicity, or any criterion for withdrawal from the study or from Avelumab occurs.
DRUGAvelumab 10 mg/kg QW
Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 10 mg/kg every week (QW) for the first 12 weeks followed by once every 2 weeks, started at Week 13 until disease progression, significant clinical deterioration, unacceptable toxicity, or any criterion for withdrawal from the study or from Avelumab occurs.
Sponsors
Merck KGaA, Darmstadt, Germany
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Subsequent cohorts of subjects treated at different dose levels in this study.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Signed written informed consent prior to any study-related procedures are undertaken that are not part of standard patient management * Histologically or cytologically proven locally advanced unresectable or metastatic solid tumors, for which no standard therapy exists or standard therapy has failed * Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at study entry * Availability of a recently obtained formalin-fixed, paraffin-embedded block containing tumor tissue (biopsy from a non-irradiated area within 6 months) or 12 or more unstained tumor slides suitable for biomarker detection * Other protocol defined inclusion criteria could apply
Exclusion criteria
* Prior therapy with any antibody/drug targeting T-cell coregulatory proteins (immune checkpoints) such as programmed death 1 (PD-1), PD-L1, cytotoxic T-lymphocyte antigen-4 (CTLA-4), 4-1BB, Lymphocyte-activation gene 3 (LAG-3), T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) or anti-Cluster of Differentiation (CD)-127 * Persisting toxicity related to prior therapy (Grade greater than equals to \[\>=\] 2 National Cancer Institute- Common Terminology Criteria for Adverse Events \[NCI-CTCAE\] v4.03, except Grade less than \[\<\] 3 neuropathy and alopecia of any grade) * Concurrent anticancer treatment (for example, cytoreductive therapy, radiotherapy \[with the exception of limited palliative bone-directed radiotherapy\], immune therapy, or cytokine therapy except for erthyropoietin). * Concurrent immunosuppressive agents (except for corticosteroids at physiologic replacement dose, equivalent to less than equals to \[\<=\] 10 milligram \[mg\] prednisone daily) * Severe hypersensitivity reactions to monoclonal antibodies (Grade \>= 3 NCI-CTCAE v4.03) * Active brain metastases (except those treated locally, and have not been progressing for at least 2 weeks after the completion of therapy, with no steroid maintenance therapy required, and no ongoing neurological symptoms related to brain localization of the disease) * Any history of anaphylaxis, or uncontrolled asthma (that is, 3 or more features of partially controlled asthma) * Other protocol defined
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dose Normalized Maximum Observed Serum Concentration (Cmax/Dose) of Avelumab | Day 1: within 2 hours prior to and at the end of the 1-hour infusion, and at 0.5, 1, 2, 4, 6, and 12 hours after the end of the infusion | Cmax/Dose was defined as maximum observed serum concentration divided by dose. |
| Dose Normalized Area Under the Serum Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC0-t/Dose) of Avelumab | Day 1: within 2 hours prior to and at the end of the 1-hour infusion, and at 0.5, 1, 2, 4, 6, and 12 hours after the end of the infusion | AUC0-t/Dose was defined as area under the serum concentration versus time curve from time of dosing to the time of the last measurable concentration divided by dose. AUC0-t/Dose was measured in (microgram\*hour per milliliter)/(milligram per kilogram) (mcg\*h/mL)/(mg/kg). |
| Dose Normalized Area Under the Concentration-Time Curve Over the Dosing Interval (AUCtau/Dose) of Avelumab | Day 1: within 2 hours prior to and at the end of the 1-hour infusion, and at 0.5, 1, 2, 4, 6, and 12 hours after the end of the infusion | AUCtau/Dose was calculated by as dose normalized area under the serum concentration-time curve from time zero to the end of the dosing interval (tau). AUCtau was calculated using the mixed log linear trapezoidal rule. |
| Terminal Elimination Rate Constant (Lambda z) of Avelumab | Day 1: within 2 hours prior to and at the end of the 1-hour infusion, and at 0.5, 1, 2, 4, 6, and 12 hours after the end of the infusion | Lambda z was determined from the terminal slope of the log-transformed serum concentration curve using linear regression method. |
| Maximum Observed Serum Concentration (Cmax) of Avelumab | Day 1: within 2 hours prior to and at the end of the 1-hour infusion, and at 0.5, 1, 2, 4, 6, and 12 hours after the end of the infusion | Cmax was obtained directly from the serum concentration versus time curve. |
| Number of Participants With of Dose-limiting Toxicities (DLTs) According to National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI-CTCAE) Version 4.03 | Day 1 to Day 21 | DLT is defined as greater than or equal to \[\>=\] Grade (Gr)3 Adverse drug reaction (ADR) according to NCI-CTCAE v4.03, occurring during DLT observation period of dose escalation cohorts. ADR: any AE suspected to be related to avelumab by Investigator and/Sponsor. Following events were not considered as DLT: Gr3 infusion-related reaction resolving within 6 hours and controlled with medical management. Transient (less than or equal to \[\<=\] 6 hours) Gr3 flu-like symptoms/fever, controlled with medical management. Transient (\<=24 hours) Gr3 fatigue, local reactions, headache, nausea, emesis, resolves to \<= Gr1. Gr3 skin toxicity/Gr3 Liver function test increase that resolves to \<= Grade 1 in \< 7 days after medical management. Gr3 diarrhea, out-of-range laboratory values without any clinical correlate that resolves to \<= Grade 1 within 7 days with adequate medical management; Tumor flare phenomenon defined as local pain, irritation, rash localized at sites of known or suspected tumor. |
| Area Under the Serum Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-t) of Avelumab | Day 1: within 2 hours prior to and at the end of the 1-hour infusion, and at 0.5, 1, 2, 4, 6, and 12 hours after the end of the infusion | 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 (LLOQ). AUC0-t was calculated according to the mixed log linear trapezoidal rule. |
| Area Under the Serum Concentration-Time Curve During a Dosing Interval (AUCtau) of Avelumab | Day 1: within 2 hours prior to and at the end of the 1-hour infusion, and at 0.5, 1, 2, 4, 6, and 12 hours after the end of the infusion | AUCtau was defined as area under the serum concentration-time curve from time zero to the end of the dosing interval (tau). AUCtau was calculated using the mixed log linear trapezoidal rule. |
| Area Under the Serum Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Avelumab | Day 1: within 2 hours prior to and at the end of the 1-hour infusion, and at 0.5, 1, 2, 4, 6, and 12 hours after the end of the infusion | AUC0-inf was calculated by combining AUC0-t and AUCextra. AUCextra represents an extrapolated value obtained by Clast pred/Lambda z, where Clast pred was the calculated serum concentration at the last sampling time point at which the measured serum concentration is at or above the Lower Limit of quantification (LLOQ) and Lambda z was the apparent terminal rate constant determined by log-linear regression analysis of the measured serum concentrations of the terminal log-linear phase. |
| Last Quantifiable Serum Concentration (Clast) of Avelumab | Day 1: within 2 hours prior to and at the end of the 1-hour infusion, and at 0.5, 1, 2, 4, 6, and 12 hours after the end of the infusion | Clast is the last measurable serum concentration of Avelumab. |
| Serum Trough Concentration Levels (Ctrough) of Avelumab | Day 1: within 2 hours prior to 1 hour infusion | Ctrough is defined as the concentration observed immediately before next dosing. |
| Time to Reach Maximum Observed Serum Concentration (Tmax) of Avelumab | Day 1: within 2 hours prior to and at the end of the 1-hour infusion, and at 0.5, 1, 2, 4, 6, and 12 hours after the end of the infusion | The time to reach the maximum observed serum concentration (tmax) was obtained directly from the concentration versus time curve. |
| Apparent Terminal Half Life (t1/2) of Avelumab | Day 1: within 2 hours prior to and at the end of the 1-hour infusion, and at 0.5, 1, 2, 4, 6, and 12 hours after the end of the infusion | Apparent terminal half-life was defined as the time required for the serum concentration of drug to decrease 50 percent in the final stage of its elimination. t1/2 was calculated as log2/ lambda z. Lambda z was determined from the terminal slope of the log-transformed serum concentration curve using linear regression method. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With at Least 1 Positive Anti-Avelumab Antibodies (ADA) | Time from first study treatment up to 139 weeks | Serum samples were analyzed by a validated electrochemiluminescence immunoassay to detect the presence of antidrug antibodies (ADA). Number of participants with ADA positive results for Avelumab were reported. |
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment Related TEAEs According to National Cancer Institute- Common Terminology Criteria for Adverse Events Version 4.03 (NCI-CTCAE v4.03) | Time from first study treatment up to 139 weeks | 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. TEAEs were defined as events that emerge during treatment having been absent pre-treatment, or worsen relative to the pre-treatment state and with onset dates occurring within the first dosing day of study treatment until 30 days after the last dose of study treatment. TEAEs include both Serious TEAEs and non-serious TEAEs. Treatment-related TEAEs: reasonably related to the study intervention. |
Countries
China
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Avelumab 3 mg/kg Q2W Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 3 milligrams per kilogram (mg/kg) once every 2 weeks (Q2W) until disease progression, significant clinical deterioration, unacceptable toxicity, or any criterion for withdrawal from the study or from Avelumab occurs. | 3 |
| Avelumab 10 mg/kg Q2W Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 10 mg/kg once Q2W until disease progression, significant clinical deterioration, unacceptable toxicity, or any criterion for withdrawal from the study or from Avelumab occurs. | 7 |
| Avelumab 20 mg/kg Q2W Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 20 mg/kg once Q2W until disease progression, significant clinical deterioration, unacceptable toxicity, or any criterion for withdrawal from the study or from Avelumab occurs. | 6 |
| Avelumab 10 mg/kg QW Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 10 mg/kg once every week (QW) for the first 12 weeks followed by once every 2 weeks, started at Week 13 until disease progression, significant clinical deterioration, unacceptable toxicity, or any criterion for withdrawal from the study or from Avelumab occurs. | 8 |
| Total | 24 |
Baseline characteristics
| Characteristic | Avelumab 10 mg/kg QW | Total | Avelumab 3 mg/kg Q2W | Avelumab 10 mg/kg Q2W | Avelumab 20 mg/kg Q2W |
|---|---|---|---|---|---|
| Age, Continuous | 61 years STANDARD_DEVIATION 13.1 | 55 years STANDARD_DEVIATION 14.7 | 54 years STANDARD_DEVIATION 17.7 | 52 years STANDARD_DEVIATION 14.3 | 50 years STANDARD_DEVIATION 16.6 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 8 Participants | 24 Participants | 3 Participants | 7 Participants | 6 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 4 Participants | 10 Participants | 0 Participants | 2 Participants | 4 Participants |
| Sex: Female, Male Male | 4 Participants | 14 Participants | 3 Participants | 5 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 3 | 4 / 7 | 6 / 6 | 7 / 8 |
| other Total, other adverse events | 3 / 3 | 7 / 7 | 6 / 6 | 8 / 8 |
| serious Total, serious adverse events | 1 / 3 | 3 / 7 | 2 / 6 | 2 / 8 |
Outcome results
Primary
Apparent Terminal Half Life (t1/2) of Avelumab
Apparent terminal half-life was defined as the time required for the serum concentration of drug to decrease 50 percent in the final stage of its elimination. t1/2 was calculated as log2/ lambda z. Lambda z was determined from the terminal slope of the log-transformed serum concentration curve using linear regression method.
Time frame: Day 1: within 2 hours prior to and at the end of the 1-hour infusion, and at 0.5, 1, 2, 4, 6, and 12 hours after the end of the infusion
Population: PK analysis set included all participants who have completed at least 1 infusion of avelumab, and who have provided valid PK samples. As pre-specified in SAP, data for t1/2 was planned to be reported for Avelumab 3 mg/kg Q2W, Avelumab 10 mg/kg Q2W and Avelumab 20 mg/kg Q2W arms only.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Avelumab 3 mg/kg Q2W | Apparent Terminal Half Life (t1/2) of Avelumab | 96.5 hours | Geometric Coefficient of Variation 18.6 |
| Avelumab 10 mg/kg Q2W | Apparent Terminal Half Life (t1/2) of Avelumab | 90.3 hours | Geometric Coefficient of Variation 21.1 |
| Avelumab 20 mg/kg Q2W | Apparent Terminal Half Life (t1/2) of Avelumab | 85.5 hours | Geometric Coefficient of Variation 9.1 |
Primary
Area Under the Serum Concentration-Time Curve During a Dosing Interval (AUCtau) of Avelumab
AUCtau was defined as area under the serum concentration-time curve from time zero to the end of the dosing interval (tau). AUCtau was calculated using the mixed log linear trapezoidal rule.
Time frame: Day 1: within 2 hours prior to and at the end of the 1-hour infusion, and at 0.5, 1, 2, 4, 6, and 12 hours after the end of the infusion
Population: PK analysis set included all participants who have completed at least 1 infusion of avelumab, and who have provided valid PK samples. As pre-specified in SAP, data for AUCtau was planned to be reported for Avelumab 3 mg/kg Q2W, Avelumab 10 mg/kg Q2W and Avelumab 20 mg/kg Q2W arms only.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Avelumab 3 mg/kg Q2W | Area Under the Serum Concentration-Time Curve During a Dosing Interval (AUCtau) of Avelumab | 7000 mcg*h/mL | Geometric Coefficient of Variation 2.9 |
| Avelumab 10 mg/kg Q2W | Area Under the Serum Concentration-Time Curve During a Dosing Interval (AUCtau) of Avelumab | 20800 mcg*h/mL | Geometric Coefficient of Variation 27.8 |
| Avelumab 20 mg/kg Q2W | Area Under the Serum Concentration-Time Curve During a Dosing Interval (AUCtau) of Avelumab | 35800 mcg*h/mL | Geometric Coefficient of Variation 22.3 |
Primary
Area Under the Serum Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Avelumab
AUC0-inf was calculated by combining AUC0-t and AUCextra. AUCextra represents an extrapolated value obtained by Clast pred/Lambda z, where Clast pred was the calculated serum concentration at the last sampling time point at which the measured serum concentration is at or above the Lower Limit of quantification (LLOQ) and Lambda z was the apparent terminal rate constant determined by log-linear regression analysis of the measured serum concentrations of the terminal log-linear phase.
Time frame: Day 1: within 2 hours prior to and at the end of the 1-hour infusion, and at 0.5, 1, 2, 4, 6, and 12 hours after the end of the infusion
Population: PK analysis set included all participants who have completed at least 1 infusion of avelumab, and who have provided valid PK samples. As pre-specified in SAP, data for AUC0-inf was planned to be reported for Avelumab 3 mg/kg Q2W, Avelumab 10 mg/kg Q2W and Avelumab 20 mg/kg Q2W arms only.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Avelumab 3 mg/kg Q2W | Area Under the Serum Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Avelumab | 7710 mcg*h/mL | Geometric Coefficient of Variation 6.2 |
| Avelumab 10 mg/kg Q2W | Area Under the Serum Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Avelumab | 22600 mcg*h/mL | Geometric Coefficient of Variation 29.7 |
| Avelumab 20 mg/kg Q2W | Area Under the Serum Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Avelumab | 38300 mcg*h/mL | Geometric Coefficient of Variation 23.4 |
Primary
Area Under the Serum Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-t) of Avelumab
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 (LLOQ). AUC0-t was calculated according to the mixed log linear trapezoidal rule.
Time frame: Day 1: within 2 hours prior to and at the end of the 1-hour infusion, and at 0.5, 1, 2, 4, 6, and 12 hours after the end of the infusion
Population: Pharmacokinetics (PK) analysis set included all participants who have completed at least 1 infusion of avelumab, and who have provided valid PK samples. As pre-specified in statistical analysis plan (SAP), data for AUC0-t was planned to be reported for Avelumab 3 mg/kg Q2W, Avelumab 10 mg/kg Q2W and Avelumab 20 mg/kg Q2W arms only.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Avelumab 3 mg/kg Q2W | Area Under the Serum Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-t) of Avelumab | 7000 microgram*hour per milliliter (mcg*h/mL) | Geometric Coefficient of Variation 3 |
| Avelumab 10 mg/kg Q2W | Area Under the Serum Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-t) of Avelumab | 20400 microgram*hour per milliliter (mcg*h/mL) | Geometric Coefficient of Variation 31.3 |
| Avelumab 20 mg/kg Q2W | Area Under the Serum Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-t) of Avelumab | 35600 microgram*hour per milliliter (mcg*h/mL) | Geometric Coefficient of Variation 20.6 |
Primary
Dose Normalized Area Under the Concentration-Time Curve Over the Dosing Interval (AUCtau/Dose) of Avelumab
AUCtau/Dose was calculated by as dose normalized area under the serum concentration-time curve from time zero to the end of the dosing interval (tau). AUCtau was calculated using the mixed log linear trapezoidal rule.
Time frame: Day 1: within 2 hours prior to and at the end of the 1-hour infusion, and at 0.5, 1, 2, 4, 6, and 12 hours after the end of the infusion
Population: PK analysis set included all participants who have completed at least 1 infusion of avelumab, and who have provided valid PK samples. As pre-specified in SAP, data for AUCtau/dose was planned to be reported for Avelumab 3 mg/kg Q2W, Avelumab 10 mg/kg Q2W and Avelumab 20 mg/kg Q2W arms only.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Avelumab 3 mg/kg Q2W | Dose Normalized Area Under the Concentration-Time Curve Over the Dosing Interval (AUCtau/Dose) of Avelumab | 2330 (mcg*h/mL)/(mg/kg) | Geometric Coefficient of Variation 2.9 |
| Avelumab 10 mg/kg Q2W | Dose Normalized Area Under the Concentration-Time Curve Over the Dosing Interval (AUCtau/Dose) of Avelumab | 2080 (mcg*h/mL)/(mg/kg) | Geometric Coefficient of Variation 27.8 |
| Avelumab 20 mg/kg Q2W | Dose Normalized Area Under the Concentration-Time Curve Over the Dosing Interval (AUCtau/Dose) of Avelumab | 1790 (mcg*h/mL)/(mg/kg) | Geometric Coefficient of Variation 22.3 |
Primary
Dose Normalized Area Under the Serum Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC0-t/Dose) of Avelumab
AUC0-t/Dose was defined as area under the serum concentration versus time curve from time of dosing to the time of the last measurable concentration divided by dose. AUC0-t/Dose was measured in (microgram\*hour per milliliter)/(milligram per kilogram) (mcg\*h/mL)/(mg/kg).
Time frame: Day 1: within 2 hours prior to and at the end of the 1-hour infusion, and at 0.5, 1, 2, 4, 6, and 12 hours after the end of the infusion
Population: PK analysis set included all participants who have completed at least 1 infusion of avelumab, and who have provided valid PK samples. As pre-specified in SAP, data for AUC0-t/dose was planned to be reported for Avelumab 3 mg/kg Q2W, Avelumab 10 mg/kg Q2W and Avelumab 20 mg/kg Q2W arms only.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Avelumab 3 mg/kg Q2W | Dose Normalized Area Under the Serum Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC0-t/Dose) of Avelumab | 2330 (mcg*h/mL)/(mg/kg) | Geometric Coefficient of Variation 3 |
| Avelumab 10 mg/kg Q2W | Dose Normalized Area Under the Serum Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC0-t/Dose) of Avelumab | 2040 (mcg*h/mL)/(mg/kg) | Geometric Coefficient of Variation 31.3 |
| Avelumab 20 mg/kg Q2W | Dose Normalized Area Under the Serum Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC0-t/Dose) of Avelumab | 1780 (mcg*h/mL)/(mg/kg) | Geometric Coefficient of Variation 20.6 |
Primary
Dose Normalized Maximum Observed Serum Concentration (Cmax/Dose) of Avelumab
Cmax/Dose was defined as maximum observed serum concentration divided by dose.
Time frame: Day 1: within 2 hours prior to and at the end of the 1-hour infusion, and at 0.5, 1, 2, 4, 6, and 12 hours after the end of the infusion
Population: PK analysis set included all participants who have completed at least 1 infusion of avelumab, and who have provided valid PK samples. As pre-specified in SAP, data for Cmax/dose was planned to be reported for Avelumab 3 mg/kg Q2W, Avelumab 10 mg/kg Q2W and Avelumab 20 mg/kg Q2W arms only.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Avelumab 3 mg/kg Q2W | Dose Normalized Maximum Observed Serum Concentration (Cmax/Dose) of Avelumab | 25.9 (mcg/mL)/(mg/kg) | Geometric Coefficient of Variation 13.9 |
| Avelumab 10 mg/kg Q2W | Dose Normalized Maximum Observed Serum Concentration (Cmax/Dose) of Avelumab | 29.4 (mcg/mL)/(mg/kg) | Geometric Coefficient of Variation 44.7 |
| Avelumab 20 mg/kg Q2W | Dose Normalized Maximum Observed Serum Concentration (Cmax/Dose) of Avelumab | 22.5 (mcg/mL)/(mg/kg) | Geometric Coefficient of Variation 36.5 |
Primary
Last Quantifiable Serum Concentration (Clast) of Avelumab
Clast is the last measurable serum concentration of Avelumab.
Time frame: Day 1: within 2 hours prior to and at the end of the 1-hour infusion, and at 0.5, 1, 2, 4, 6, and 12 hours after the end of the infusion
Population: PK analysis set included all participants who have completed at least 1 infusion of avelumab, and who have provided valid PK samples. As pre-specified in SAP, data for Clast was planned to be reported for Avelumab 3 mg/kg Q2W, Avelumab 10 mg/kg Q2W and Avelumab 20 mg/kg Q2W arms only.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Avelumab 3 mg/kg Q2W | Last Quantifiable Serum Concentration (Clast) of Avelumab | 4.94 mcg/mL | Geometric Coefficient of Variation 33.7 |
| Avelumab 10 mg/kg Q2W | Last Quantifiable Serum Concentration (Clast) of Avelumab | 16.3 mcg/mL | Geometric Coefficient of Variation 51.2 |
| Avelumab 20 mg/kg Q2W | Last Quantifiable Serum Concentration (Clast) of Avelumab | 21.4 mcg/mL | Geometric Coefficient of Variation 50.3 |
Primary
Maximum Observed Serum Concentration (Cmax) of Avelumab
Cmax was obtained directly from the serum concentration versus time curve.
Time frame: Day 1: within 2 hours prior to and at the end of the 1-hour infusion, and at 0.5, 1, 2, 4, 6, and 12 hours after the end of the infusion
Population: PK analysis set included all participants who have completed at least 1 infusion of avelumab, and who have provided valid PK samples. As pre-specified in SAP, data for Cmax was planned to be reported for Avelumab 3 mg/kg Q2W, Avelumab 10 mg/kg Q2W and Avelumab 20 mg/kg Q2W arms only.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Avelumab 3 mg/kg Q2W | Maximum Observed Serum Concentration (Cmax) of Avelumab | 77.6 microgram per milliliter (mcg/mL) | Geometric Coefficient of Variation 13.9 |
| Avelumab 10 mg/kg Q2W | Maximum Observed Serum Concentration (Cmax) of Avelumab | 294 microgram per milliliter (mcg/mL) | Geometric Coefficient of Variation 44.7 |
| Avelumab 20 mg/kg Q2W | Maximum Observed Serum Concentration (Cmax) of Avelumab | 450 microgram per milliliter (mcg/mL) | Geometric Coefficient of Variation 36.5 |
Primary
Number of Participants With of Dose-limiting Toxicities (DLTs) According to National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI-CTCAE) Version 4.03
DLT is defined as greater than or equal to \[\>=\] Grade (Gr)3 Adverse drug reaction (ADR) according to NCI-CTCAE v4.03, occurring during DLT observation period of dose escalation cohorts. ADR: any AE suspected to be related to avelumab by Investigator and/Sponsor. Following events were not considered as DLT: Gr3 infusion-related reaction resolving within 6 hours and controlled with medical management. Transient (less than or equal to \[\<=\] 6 hours) Gr3 flu-like symptoms/fever, controlled with medical management. Transient (\<=24 hours) Gr3 fatigue, local reactions, headache, nausea, emesis, resolves to \<= Gr1. Gr3 skin toxicity/Gr3 Liver function test increase that resolves to \<= Grade 1 in \< 7 days after medical management. Gr3 diarrhea, out-of-range laboratory values without any clinical correlate that resolves to \<= Grade 1 within 7 days with adequate medical management; Tumor flare phenomenon defined as local pain, irritation, rash localized at sites of known or suspected tumor.
Time frame: Day 1 to Day 21
Population: DLT analysis set included all participants with data used for implementing the dose escalation schedule (excluding 6 participants in 10 mg/kg once weekly cohort) and received all Avelumab administrations in the DLT observation period or should have stopped treatment because of DLTs in the DLT observation period.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Avelumab 3 mg/kg Q2W | Number of Participants With of Dose-limiting Toxicities (DLTs) According to National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI-CTCAE) Version 4.03 | 0 Participants |
| Avelumab 10 mg/kg Q2W | Number of Participants With of Dose-limiting Toxicities (DLTs) According to National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI-CTCAE) Version 4.03 | 0 Participants |
| Avelumab 20 mg/kg Q2W | Number of Participants With of Dose-limiting Toxicities (DLTs) According to National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI-CTCAE) Version 4.03 | 0 Participants |
Primary
Serum Trough Concentration Levels (Ctrough) of Avelumab
Ctrough is defined as the concentration observed immediately before next dosing.
Time frame: Day 1: within 2 hours prior to 1 hour infusion
Population: PK analysis set included all participants who have completed at least 1 infusion of avelumab, and who have provided valid PK samples. Here, Overall Number of Participants Analyzed signifies those participants who were evaluable for this outcome measure. As pre-specified in SAP, data for Ctrough was planned to be reported for Avelumab 3 mg/kg Q2W, Avelumab 10 mg/kg Q2W and Avelumab 20 mg/kg Q2W arms only.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Avelumab 3 mg/kg Q2W | Serum Trough Concentration Levels (Ctrough) of Avelumab | 4.94 mcg/mL | Geometric Coefficient of Variation 33.7 |
| Avelumab 10 mg/kg Q2W | Serum Trough Concentration Levels (Ctrough) of Avelumab | 14.8 mcg/mL | Geometric Coefficient of Variation 47.2 |
| Avelumab 20 mg/kg Q2W | Serum Trough Concentration Levels (Ctrough) of Avelumab | 21.4 mcg/mL | Geometric Coefficient of Variation 50.3 |
Primary
Terminal Elimination Rate Constant (Lambda z) of Avelumab
Lambda z was determined from the terminal slope of the log-transformed serum concentration curve using linear regression method.
Time frame: Day 1: within 2 hours prior to and at the end of the 1-hour infusion, and at 0.5, 1, 2, 4, 6, and 12 hours after the end of the infusion
Population: PK analysis set included all participants who have completed at least 1 infusion of avelumab, and who have provided valid PK samples. As pre-specified in SAP, data for Lambda z was planned to be reported for Avelumab 3 mg/kg Q2W, Avelumab 10 mg/kg Q2W and Avelumab 20 mg/kg Q2W arms only.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Avelumab 3 mg/kg Q2W | Terminal Elimination Rate Constant (Lambda z) of Avelumab | 0.00719 1/hour | Geometric Coefficient of Variation 18.6 |
| Avelumab 10 mg/kg Q2W | Terminal Elimination Rate Constant (Lambda z) of Avelumab | 0.00767 1/hour | Geometric Coefficient of Variation 21.1 |
| Avelumab 20 mg/kg Q2W | Terminal Elimination Rate Constant (Lambda z) of Avelumab | 0.00811 1/hour | Geometric Coefficient of Variation 9.1 |
Primary
Time to Reach Maximum Observed Serum Concentration (Tmax) of Avelumab
The time to reach the maximum observed serum concentration (tmax) was obtained directly from the concentration versus time curve.
Time frame: Day 1: within 2 hours prior to and at the end of the 1-hour infusion, and at 0.5, 1, 2, 4, 6, and 12 hours after the end of the infusion
Population: PK analysis set included all participants who have completed at least 1 infusion of avelumab, and who have provided valid PK samples. As pre-specified in SAP, data for tmax was planned to be reported for Avelumab 3 mg/kg Q2W, Avelumab 10 mg/kg Q2W and Avelumab 20 mg/kg Q2W arms only.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Avelumab 3 mg/kg Q2W | Time to Reach Maximum Observed Serum Concentration (Tmax) of Avelumab | 1.55 hours |
| Avelumab 10 mg/kg Q2W | Time to Reach Maximum Observed Serum Concentration (Tmax) of Avelumab | 1.52 hours |
| Avelumab 20 mg/kg Q2W | Time to Reach Maximum Observed Serum Concentration (Tmax) of Avelumab | 1.97 hours |
Secondary
Number of Participants With at Least 1 Positive Anti-Avelumab Antibodies (ADA)
Serum samples were analyzed by a validated electrochemiluminescence immunoassay to detect the presence of antidrug antibodies (ADA). Number of participants with ADA positive results for Avelumab were reported.
Time frame: Time from first study treatment up to 139 weeks
Population: Immunogenicity Analysis Set included all participants who have any dose of avelumab and who have at least one valid ADA result.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Avelumab 3 mg/kg Q2W | Number of Participants With at Least 1 Positive Anti-Avelumab Antibodies (ADA) | 2 Participants |
| Avelumab 10 mg/kg Q2W | Number of Participants With at Least 1 Positive Anti-Avelumab Antibodies (ADA) | 0 Participants |
| Avelumab 20 mg/kg Q2W | Number of Participants With at Least 1 Positive Anti-Avelumab Antibodies (ADA) | 0 Participants |
| Avelumab 10 mg/kg QW | Number of Participants With at Least 1 Positive Anti-Avelumab Antibodies (ADA) | 0 Participants |
Secondary
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment Related TEAEs According to National Cancer Institute- Common Terminology Criteria for Adverse Events Version 4.03 (NCI-CTCAE v4.03)
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. TEAEs were defined as events that emerge during treatment having been absent pre-treatment, or worsen relative to the pre-treatment state and with onset dates occurring within the first dosing day of study treatment until 30 days after the last dose of study treatment. TEAEs include both Serious TEAEs and non-serious TEAEs. Treatment-related TEAEs: reasonably related to the study intervention.
Time frame: Time from first study treatment up to 139 weeks
Population: SAF included all participants who have received at least 1 dose of Avelumab.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Avelumab 3 mg/kg Q2W | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment Related TEAEs According to National Cancer Institute- Common Terminology Criteria for Adverse Events Version 4.03 (NCI-CTCAE v4.03) | Participants with TEAEs | 3 Participants |
| Avelumab 3 mg/kg Q2W | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment Related TEAEs According to National Cancer Institute- Common Terminology Criteria for Adverse Events Version 4.03 (NCI-CTCAE v4.03) | Participants with Treatment Related TEAEs | 3 Participants |
| Avelumab 10 mg/kg Q2W | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment Related TEAEs According to National Cancer Institute- Common Terminology Criteria for Adverse Events Version 4.03 (NCI-CTCAE v4.03) | Participants with Treatment Related TEAEs | 6 Participants |
| Avelumab 10 mg/kg Q2W | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment Related TEAEs According to National Cancer Institute- Common Terminology Criteria for Adverse Events Version 4.03 (NCI-CTCAE v4.03) | Participants with TEAEs | 7 Participants |
| Avelumab 20 mg/kg Q2W | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment Related TEAEs According to National Cancer Institute- Common Terminology Criteria for Adverse Events Version 4.03 (NCI-CTCAE v4.03) | Participants with TEAEs | 6 Participants |
| Avelumab 20 mg/kg Q2W | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment Related TEAEs According to National Cancer Institute- Common Terminology Criteria for Adverse Events Version 4.03 (NCI-CTCAE v4.03) | Participants with Treatment Related TEAEs | 6 Participants |
| Avelumab 10 mg/kg QW | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment Related TEAEs According to National Cancer Institute- Common Terminology Criteria for Adverse Events Version 4.03 (NCI-CTCAE v4.03) | Participants with TEAEs | 8 Participants |
| Avelumab 10 mg/kg QW | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment Related TEAEs According to National Cancer Institute- Common Terminology Criteria for Adverse Events Version 4.03 (NCI-CTCAE v4.03) | Participants with Treatment Related TEAEs | 6 Participants |