Phase I/Ib Multiple Ascending Dose Study in China

Merck KGaA, Darmstadt, Germany24 enrolled

Overview

The purpose of this study was to evaluate the maximum tolerated dose (MTD) and pharmacokinetics (PK) of Avelumab monotherapy in Chinese subjects.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Metastatic Solid Tumors

Interventions

Avelumab 3 mg/kg Q2WDRUG

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.

Avelumab 10 mg/kg Q2WDRUG

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.

Avelumab 20 mg/kg Q2WDRUG

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.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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 exclusion criteria could apply

Locations (3)

Research site

Guangzhou, Guangzhou, China

Research site

Changchun, Jilin, China

Research site

Hangzhou, Zhejiang, China

Outcomes

Primary Outcomes

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

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

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

Area Under the Serum Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Avelumab

Data from ClinicalTrials.gov

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Avelumab 10 mg/kg QWDRUG

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.

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

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

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

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

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

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

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

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

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

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

Secondary Outcomes

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

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