Open-label, Phase I/II Study to Evaluate Pharmacokinetics, Pharmacodynamics, Safety, and Anticancer Activity of Avelumab in Pediatric Subjects From Birth to Less Than 18 Years of Age With Refractory or Relapsed Solid Tumors and Lymphoma
Overview
- Phase
- Phase 1
- Intervention
- Avelumab
- Conditions
- Refractory or Relapsed Solid Tumors
- Sponsor
- EMD Serono Research & Development Institute, Inc.
- Enrollment
- 21
- Locations
- 11
- Primary Endpoint
- Number of Participants With Treatment-Emergent Adverse Events (TEAEs) as Per Severity With Grade 3 or Higher According to National Cancer Institute-Common Terminology Criteria for Adverse Events Version 4.03 (NCI-CTCAE v4.03)
- Status
- Terminated
- Last Updated
- last year
Overview
Brief Summary
This is a multi-center, open-label, international study to evaluate the dose, safety and tolerability, antitumor activity, pharmacokinetic and pharmacodynamics of avelumab in pediatric subjects 0 to less than 18 years of age with refractory or relapsed malignant solid tumors (including central nervous system tumors) and lymphoma for which no standard therapy is available or for which the subject is not eligible for the existing therapy.
The study was planned to be conducted in 2 parts: the dose-finding part (Phase I) and the tumor-specified expansion part (Phase II). However, Phase II was cancelled due to limited clinical benefit of PD-L1 monotherapy in pediatric participants.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Male or female subjects 0 to less than 18 years of age at the time of first treatment dose with histologically or cytologically confirmed solid malignant tumors (including CNS tumors) or lymphoma for which no standard therapy is available
- •Confirmed progression on or refractory to standard therapy or no standard therapy available.
- •Availability of archival formalin-fixed, paraffin-embedded block containing tumor tissue, or slides, or a fresh/recent tumor biopsy prior to avelumab treatment for subjects in Phase 2
- •Adequate bone marrow, kidney, and liver function
- •Other protocol defined inclusion criteria could apply
Exclusion Criteria
- •Prior therapy with any antibody or drug targeting T-cell coregulatory proteins
- •Concurrent anticancer treatment or immunosuppressive agents
- •Prior organ transplantation
- •Significant acute or chronic infections
- •Other significant diseases or conditions that might impair the subject's tolerance of trial treatment
- •Other protocol defined exclusion criteria could apply
Arms & Interventions
Avelumab: 10 miligram per kilogram (mg/kg)
Intervention: Avelumab
Avelumab 20mg/kg
Intervention: Avelumab
Outcomes
Primary Outcomes
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) as Per Severity With Grade 3 or Higher According to National Cancer Institute-Common Terminology Criteria for Adverse Events Version 4.03 (NCI-CTCAE v4.03)
Time Frame: Baseline up to 1182 days
Adverse event (AE) was defined as any untoward medical occurrence in a participant, which does not necessarily have causal relationship with treatment. A serious AE was defined as an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged in participant hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. TEAEs were those events with onset dates occurring during the on-treatment period for the first time, or if the worsening of an event was during the on-treatment period. TEAEs included both serious TEAEs and non-serious TEAEs. Severity of grade 3 or higher TEAEs were graded using NCI-CTCAE v4.03 toxicity grades, as follows: Grade 1 = Mild, Grade 2= Moderate, Grade 3 = Severe; Grade 4 = Life-threatening and Grade 5 = Death. Number of participants with TEAEs as per severity with Grade 3 and higher were reported.
Number of Participants Who Experienced Dose-Limiting Toxicities (DLTs)
Time Frame: Baseline up to 28 days
For the purpose of dose finding, any of the following AEs occurring during the primary DLT observation period. Hematologic: Grade 4 neutropenia for more than 7 days in duration; Grade greater than or equal to (\>=) 3 neutropenic infection; Grade \>= 3 thrombocytopenia with bleeding; Grade 4 thrombocytopenia \> 7 days and Grade 4 anemia. Nonhematologic: Any Grade \>= 3 toxicity, except for any of the following: Transient (less than or equal to (\<=) 72 hours; Grade 3 flu-like symptoms or fever, which was controlled with medical management; Transient (\<= 72 hours) Grade 3 fatigue, local reactions, headache, nausea, or emesis that resolved to Grade \<= 1 or to Baseline. Grade 3 diarrhea or Grade 3 skin toxicity that resolved to Grade \<= 1 in less than 7 days after medical management (immunosuppressant treatment) had been initiated. Grade \>= 3 amylase or lipase abnormality that was not associated with clinical manifestations of pancreatitis.
Secondary Outcomes
- Duration of Response (DOR) as Per Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1) and as Adjudicated by the Investigator(Time from first documentation of objective response up to 1182 days)
- Number of Participants With Confirmed Best Overall Response (BOR) as Per Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1) and as Adjudicated by the Investigator(Baseline up to 1182 days)
- Area Under the Serum Concentration-Time Curve From Time Zero to the 336 Hours Post-Dose (AUC 0-336 Hours) of Avelumab(Pre-dose, end of infusion (1 hour), 3 hours to 336 hours post-dose)
- Number of Participants With Substantial, Sustained, or Significant Changes From Baseline for B-cell and Natural Killer Cell (NK-Cell) in Blood(Baseline up to end of treatment visit (27.5 weeks))
- Number of Participants With Treatment-Emergent Adverse Events, Adverse Events of Special Interest (AESI) and Treatment-related Adverse Events According to NCI-CTCAE v4.03(Baseline up to 1182 days)
- Number of Participants With Substantial, Sustained, or Significant Changes From Baseline for Vaccination-Related Antibody Concentrations(Baseline up to end of treatment visit (27.5 weeks))
- Number of Participants With TEAEs Related to Vital Signs That Resulted in Treatment Discontinuation(Baseline up to 1182 days)
- Time to Response According to Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1) and as Adjudicated by the Investigator(Time from start of study treatment up to 1182 days)
- Progression-Free Survival According to Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1) and as Adjudicated by the Investigator(Time from first administration of study drug until the first documentation of PD or death, assessed up to 1182 days)
- Minimum Serum Post-dose Trough (Ctrough) Concentration of Avelumab(Pre-dose at Day 15)
- Number of Participants With Positive Tumor Programmed Death Ligand 1 (PD-L1) Expression(Baseline up to end of treatment visit (27.5 weeks))
- Overall Survival (OS)(Time from first administration of study drug up to 1182 days)
- Number of Participants With Grade 3 or Higher Laboratory Abnormalities According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 4.03(Baseline up to 1182 days)
- Maximum Observed Serum Concentration (Cmax) of Avelumab(Pre-dose, end of infusion (1 hour), 3 hours post-dose on Day 1, cycle 1 (each cycle is for 14 days))
- Number of Participants With Positive Treatment Emergent Anti-drug Antibodies (ADA) and Neutralizing Antibodies (Nabs)(Baseline up to 1182 days)
- Apparent Terminal Half Life (t1/2) of Avelumab(Pre-dose, end of infusion (1 hour), 3 hours post-dose on Day 1, cycle 1 (each cycle is for 14 days))
- Number of Participants With Substantial, Sustained, or Significant Changes From Baseline for Tumor-Infiltrating T-cell Levels(Baseline up to end of treatment visit (27.5 weeks))
- Number of Participants With Substantial, Sustained, or Significant Changes From Baseline for T-cell Population in Blood(Baseline up to end of treatment visit (27.5 weeks))