Phase I/Ib Multiple Ascending Dose Study in China

NCT03523390 | Completed Phase 1 Results DMC

• 1 other identifier: MS100070_0035
• Study Type: interventional
• Target: 24
• Locations: 1 country
• Sites: 3

Brief Summary

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

Conditions

Metastatic Solid Tumors

Keywords

Metastatic Solid Tumors; Avelumab; MSB0010718C

Outcome Measures

Primary Outcomes (13)

• 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.

  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.

  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.

  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

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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).

  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.

  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.

  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 (2)

• 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

• Number of Participants With at Least 1 Positive Anti-Avelumab Antibodies (ADA)

  Time from first study treatment up to 139 weeks

Study Arms (4)

Avelumab 3 mg/kg Q2W

EXPERIMENTAL

Drug: Avelumab 3 mg/kg Q2W

Avelumab 10 mg/kg Q2W

EXPERIMENTAL

Drug: Avelumab 10 mg/kg Q2W

Avelumab 20 mg/kg Q2W

EXPERIMENTAL

Drug: Avelumab 20 mg/kg Q2W

Avelumab 10 mg/kg QW

EXPERIMENTAL

Drug: Avelumab 10 mg/kg QW

Interventions

Avelumab 3 mg/kg Q2W DRUG

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.

Also known as: MSB0010718C

Avelumab 3 mg/kg Q2W

Avelumab 10 mg/kg Q2W DRUG

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 10 mg/kg Q2W

Avelumab 20 mg/kg Q2W DRUG

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.

Avelumab 20 mg/kg Q2W

Avelumab 10 mg/kg QW DRUG

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.

Avelumab 10 mg/kg QW

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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)

Sponsors & Collaborators

• Merck KGaA, Darmstadt, Germany: lead

Study Sites (3)

Research site

Guangzhou, Guangzhou, China

Location

Research site

Changchun, Jilin, China

Location

Research site

Hangzhou, Zhejiang, China

Location

Related Publications (1)

• Wu YL, Cheng Y, Chen H, Tu H, Xu C, Wang Z, Liu Y, Xin Y, Lou H, Wang W, Chin K, Li D, Zhao D, Gao Y, Xu W, Pan H. Phase I/Ib dose-escalation study of avelumab in Chinese patients with advanced solid tumors. Future Oncol. 2022 Jun;18(17):2053-2062. doi: 10.2217/fon-2021-1342. Epub 2022 Mar 31.

  PMID: 35354274 RESULT

Related Links

• Trial Awareness and Transparency website
• Medical Information Location Map - Med Info Contacts

MeSH Terms

Interventions

avelumab

Results Point of Contact

• Title: Communication Center
• Organization: Merck KGaA, Darmstadt, Germany

service@emdgroup.com

+49-6151-72-5200

Study Officials

• Medical Responsible

  Merck KGaA, Darmstadt, Germany

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Subsequent cohorts of subjects treated at different dose levels in this study.

Study Record Dates

• First Submitted: May 1, 2018
• First Posted: May 14, 2018
• Study Start: April 24, 2018
• Primary Completion: July 29, 2019
• Study Completion: February 8, 2021
• Last Updated: February 23, 2024
• Results First Posted: February 23, 2024

Record last verified: 2023-07

Locations

CN (3)