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Clinical Trials/NCT01943461
NCT01943461CompletedPhase 1

A Phase I Trial to Investigate the Tolerability, Safety, Pharmacokinetics, Biological and Clinical Activity of Avelumab (MSB0010718C) in Japanese Subjects With Metastatic or Locally Advanced Solid Tumors, With Expansion Part in Asian Subjects With Gastric Cancer

Merck KGaA, Darmstadt, Germany1 site in 1 country57 target enrollmentStarted: September 2, 2013Last updated:
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Conditions
Interventions
Drugs

Trial Snapshot

Phase
Phase 1
Status
Completed
Enrollment
57
Locations
1
Primary Endpoint
Dose-escalation Cohorts: Number of Participants With Dose Limiting Toxicities (DLTs)
Study OverviewStudy DesignEligibility CriteriaArms & InterventionsOutcomesInvestigatorsSitesRecords & IdentifiersSimilar Trials

Study Overview

Brief Summary

This was a Phase 1, open-label, dose-escalation trial of avelumab (antibody targeting programmed death ligand 1 [anti PD-L1]) in Japanese participants with metastatic or locally advanced solid tumors, followed by a consecutive expansion part in Asian participants with gastric cancer.

Study Design

Study Type
Interventional
Allocation
Non Randomized
Intervention Model
Sequential
Primary Purpose
Treatment
Masking
None

Eligibility Criteria

Ages
20 Years to — (Adult, Older Adult)
Sex
All
Accepts Healthy Volunteers
No

Inclusion Criteria

  • •Signed written informed consent
  • •Male or female participants aged greater than or equal to (>=) 20 years
  • •For dose escalation part: Histologically or cytologically proven metastatic or locally advanced solid tumors, for which no standard therapy exists or standard therapy has failed
  • •For expansion part:
  • •Availability of fresh and archive tumor in formalin fixed paraffin embedded tissue
  • •With histologically or cytologically confirmed recurrent or refractory unresectable Stage IV gastric or gastro-esophageal junctional adenocarcinoma (according to American Joint Committee on Cancer/Union Internationale Contre le Cancer [UICC] 7th edition) and whose disease progressed after one or two prior chemotherapy regimen(s) involving both fluoropyrimidines and platinum
  • •Presence of at least 1 measurable lesion according to RECIST version 1.1
  • •Participants should not have severe peritoneal metastases. The following criteria were applied:
  • •No clinical ileus or subileus
  • •No moderate-to-severe ascites (participants with ascites restricted to the perihepatic space or pelvic cavity)
  • •Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 at the trial entry and an estimated life expectancy of at least 3 months
  • •Adequate hematological, hepatic and renal function as defined in the protocol
  • •All participants must agree to use effective means of contraception with their partner from entry into the trial through 6 months after the last dose of avelumab

Exclusion Criteria

  • •Concurrent treatment with a non-permitted drug
  • •Prior therapy with any antibody/drug targeting T cell co-regulatory proteins (immune checkpoints)
  • •Concurrent anticancer treatment or concurrent systemic therapy with steroids or other immunosuppressive agents, or use of any investigational drug within 30 days before the start of trial treatment. Short-term administration of steroids (that is, for allergic reactions or the management of immune-related adverse events [irAE]) is allowed
  • •Previous malignant disease within the last 5 years with the exception of adequately treated non-melanoma skin cancer, in situ cancer, or other cancer
  • •Non-oncology vaccine therapies for prevention of infection disease (e.g. seasonal flu vaccine, human papilloma virus vaccine) within 4 weeks of study drug administration. Vaccination while on study is also prohibited except for administration of the inactivated influenza vaccine.
  • •Pregnancy or lactation period
  • •Known alcohol or drug abuse
  • •Clinically significant (that is, active) cardiovascular disease
  • •All other significant diseases (for example, inflammatory bowel disease), which, in the opinion of the investigator, might impair the participant's tolerance of trial treatment
  • •Any psychiatric condition that would prohibit the understanding or rendering of informed consent
  • •Legal incapacity or limited legal capacity
  • •Other protocol defined exclusion criteria could apply

Arms & Interventions

Dose-escalation Cohort: Avelumab 3 mg/kg

Experimental

Intervention: Avelumab 3 mg/kg (Drug)

Dose-escalation Cohort: Avelumab 10 mg/kg

Experimental

Intervention: Avelumab 10 mg/kg (Drug)

Dose-escalation Cohort: Avelumab 20 mg/kg

Experimental

Intervention: Avelumab 20 mg/kg (Drug)

Expansion Cohort: Avelumab 10 mg/kg

Experimental

Intervention: Avelumab 10 mg/kg (Drug)

Outcomes

Primary Outcomes

Dose-escalation Cohorts: Number of Participants With Dose Limiting Toxicities (DLTs)

Time Frame: Baseline up to 3 weeks

DLT: any Grade greater than or equal to (\>=) 3 or Adverse Events (AE) according to National Cancer Institute Common Toxicity Criteria for AE Version 4.03 (NCI-CTCAE v4.03); observed during first 3 weeks of dose-escalation part and as being related to Avelumab by Investigator/Sponsor. Following events were not considered as DLT: Grade 3 infusion-related reaction resolving to (\<=) Grade 1 within 6 hours and controlled with medical management; Transient (\<=6 hours) Grade 3 flulike symptoms/fever controlled with medical management and resolved to \<= Grade 1;Transient (\<=24 hours) Grade 3 fatigue, local reactions, headache, nausea, emesis that resolved to \<=Grade1 with/without medical management, Grade 3 diarrhea, Grade 3 skin toxicity, Grade3 out-of-range laboratory values without any clinical correlate that resolves to \<= Grade 1 or Baseline in \< 7 days after medical management; Tumor flare phenomenon defined as local pain, irritation, rash localized at sites of known or suspected tumor.

Secondary Outcomes

  • Dose-escalation Cohorts: Time to Reach Maximum Observed Serum Concentration (Tmax) of Avelumab(Within 6 hours before the infusion, at end of 1-hour infusion (Day 1), 0.5, 1, 2, 4, 6,12, 24, 36, 48, 168 hours after end of infusion)
  • Dose-escalation Cohorts: Area Under the Serum Concentration-Time Curve From the Time of Dosing to the Time of the Last Observation (AUC0-t) of Avelumab(Within 6 hours before the infusion, at end of 1-hour infusion (Day 1), 0.5, 1, 2, 4, 6,12, 24, 36, 48, 168 hours after end of infusion)
  • Dose-escalation Cohorts: Area Under the Serum Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Avelumab(Within 6 hours before the infusion, at end of 1-hour infusion (Day 1), 0.5, 1, 2, 4, 6,12, 24, 36, 48, 168 hours after end of infusion)
  • Dose-escalation Cohorts: Terminal Half-Life (t1/2) of Avelumab(Within 6 hours before the infusion, at end of 1-hour infusion (Day 1), 0.5, 1, 2, 4, 6,12, 24, 36, 48, 168 hours after end of infusion)
  • Dose-escalation Cohorts: Terminal Elimination Rate Constant (Lambda z) of Avelumab(Within 6 hours before the infusion, at end of 1-hour infusion (Day 1), 0.5, 1, 2, 4, 6,12, 24, 36, 48, 168 hours after end of infusion)
  • Dose-escalation Cohorts: Programmed Death Ligand 1 (PD-L1) Receptor Occupancy(Pre-infusion on Day 1; 4 and 48 hours after infusion on Day 3; Pre-infusion on Days 15, 29, 43, and 85)
  • Expansion Cohort: Number of Participants With Programmed Death Ligand 1 (PD-L1) Tumor Expression(Time from first dose of study treatment up to 1906 days)
  • Dose-escalation Cohorts: Maximum Observed Serum Concentration (Cmax) of Avelumab(Within 6 hours before the infusion, at end of 1-hour infusion (Day 1), 0.5, 1, 2, 4, 6,12, 24, 36, 48, 168 hours after end of infusion)
  • Dose-escalation Cohorts: Log Fold Change From Baseline in Cytokine Levels(Baseline (Day 1 [Pre-infusion]), Day 3 (48 hours after infusion), Day 8 (168 hours after infusion), Day 15 (Pre-infusion), Day 43 (Pre-infusion), Day 45 (48 hours after infusion), Day 50 (168 hours after infusion))
  • Dose-escalation Cohorts: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Death, and TEAEs Leading to Discontinuation(Time from first dose of study treatment up to 2205 days)
  • Expansion Cohort: Area Under the Serum Concentration-Time Curve From the Time of Dosing to the End of Dose Interval (AUC0-336hour [hr]) of Avelumab(Within 6 hours before and the end of the 1-hour infusion (Day 1) and 336 hours after end of infusion)
  • Expansion Cohort: Serum Trough Concentration Levels (Ctrough) of Avelumab(Within 6 hours before the 1-hour infusion on Day 15, Day 29, Day 43, Day 85, Day 127 and Day 169.)
  • Expansion Cohort: Number of Participants With Treatment-Emergent Positive Human Anti-Human Antibody (HAHA)(Day 15 up to Day 1906)
  • Dose-escalation Cohorts: Absolute Value of Cytokine Levels(Day 1 (Pre-infusion), Day 3 (48 hours after infusion), Day 8 (168 hours after infusion), Day 15 (Pre-infusion), Day 43 (Pre-infusion), Day 45 (48 hours after infusion), Day 50 (168 hours after infusion))
  • Expansion Cohort: Absolute Values of Cytokine Levels(Day 1 (Pre-infusion), Day 8 (168 hour after infusion) and Day 43 (Pre-infusion))
  • Expansion Cohort: Log Fold Change From Baseline in Cytokine Levels(Baseline (Day 1 [Pre-infusion]), Day 8 (168 hour after infusion) and Day 43 (Pre-infusion))
  • Expansion Cohort: Number of Participants With Best Overall Response (BOR) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1(Time from first dose of study treatment up to 1906 days)
  • Expansion Cohort: Progression-Free Survival (PFS) Time According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1(Time from first dose of study treatment up to 1906 days)
  • Dose-escalation Cohorts: Number of Participants With Treatment-Emergent Positive Human Anti-Human Antibody (HAHA)(Day 15 up to Day 2205)
  • Expansion Cohort: Number of Participants With Immune-related Best Overall Response (irBOR) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1(Time from first dose of study treatment up to 1906 days)
  • Expansion Cohort: Immune-related Progression-Free Survival (irPFS) Time According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1(Time from first dose of study treatment up to 1906 days)
  • Expansion Cohort: Overall Survival (OS) Time(Time from first dose of study treatment up to 1906 days)
  • Expansion Cohort: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Death, and TEAEs Leading to Discontinuation(Time from first dose of study treatment up to 1906 days)

Investigators

Sponsor Class
Industry
Responsible Party
Sponsor

Study Sites (1)

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