Trial Outcomes & Findings for Phase I/II Study of Avelumab in Pediatric Cancer Participants (NCT NCT03451825)

A total of 26 participants were screened for participation in the Phase I part of the study, out of which 21 participants were eligible and received the study treatment.

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 Programmed death ligand 1 (PD-L1) monotherapy in pediatric participants.

Phase I/II Study of Avelumab in Pediatric Cancer Participants

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.

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.

Confirmed BOR was evaluated based on RECIST v1.1 and Investigator's assessments and defined as best response of any of confirmed complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD) recorded from date of study treatment until disease progression. CR: Disappearance of all evidence of target/non-target lesions. PR: At least 30 percent (%) reduction from baseline in sum of longest diameter (SLD) of all lesions. SD: Neither sufficient increase to qualify for PD nor sufficient shrinkage to qualify for PR. PD: at least a 20% increase in SLD, taking as reference smallest SLD recorded from baseline/appearance of 1or more new lesions and unequivocal progression of non-target lesions.

Duration of response was defined for participants with confirmed objective response (OR), as the time from first documentation of objective response (Complete Response or Partial Response) to the date of first documentation of objective PD or death due to any cause, whichever occurred first. CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in the SLD of all lesions. PD: At least a 20 % increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. DOR was determined according to RECIST v1.1 and assessed by Investigator.

Time to response (TTR) was defined, for participants with an objective response, as the time from the start date of study treatment to the first documentation of OR (CR or PR) which was subsequently confirmed.

Progression-Free survival was defined as the time from first administration of study treatment until the first documentation of disease progression (PD) or death due to any cause, whichever occurred first. PD: At least a 20 % increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. PFS was measured using Kaplan-Meier (KM) estimates.

Overall Survival was defined as the time from date of first dose of study drug to the date of death due to any cause. For participants who were still alive at the time of data analysis or who were lost to follow-up, OS time was censored at the date of last contact. OS was measured using Kaplan-Meier (KM) estimates.

Adverse Event (AE) was defined any untoward medical occurrence in a participant administered with a study drug, which does not necessarily had a causal relationship with this treatment. Serious AE was defined AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial/prolonged inpatient hospitalization; congenital anomaly/birth defect. TEAEs: TEAEs was defined as events with onset date or worsening during the on-treatment period. TEAEs included serious AEs and non-serious AEs. Treatment-related TEAEs: reasonably related to the study intervention. AESIs included Infusion-related reactions (IRRs) and Immune-related AE (irAEs).

The total number of participants with laboratory test abnormalities were assessed. Clinical laboratory tests included hematology and biochemistry abnormalities. The hematology and biochemistry abnormalities (by worst on-treatment NCI-CTCAE Grade 3 and Grade 4) were reported. Laboratory abnormalities 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.

Cmax is the maximum observed serum concentration obtained directly from the concentration versus time curve.

Area under the serum concentration-time curve from time zero to the 336 Hours Post-Dose (AUC 0-336 hours) of Avelumab were calculated. Calculated using the mixed loglinear trapezoidal rule (linear up, log down).

Apparent terminal half-life was defined as the time required for the plasma concentration of drug to decrease 50 percent in the final stage of its elimination. Apparent terminal half-life. t1/2 = log (ln) 2/lambdaz (λz).

The concentration observed immediately before next dosing (corresponding to predose or trough concentration for multiple dosing) was calculated.

Serum samples were analyzed by a validated electrochemiluminesce immunoassay to detect the presence of anti-drug antibodies and neutralizing antibodies. Samples that screened positive were subsequently tested in a confirmatory assay. Those confirmed positive were tittered for a quasi-quantitative result. Number of participants with positive treatment emergent anti-drug antibodies and neutralizing antibodies were reported. Participants not positive prior to treatment with avelumab and with at least one positive result in the human-Antihuman Antibodies assay were characterized as treatment-emergent.

Number of participants with positive tumor programmed death ligand 1 (PDL-1) with cut off \>=1%, \>= 5%, \>=25%, \>=50% and \>=80% expression were reported.

Number of participants with substantial, sustained, or significant changes from baseline for Tumor-Infiltrating T-cell Levels were reported. Significant clinical deterioration (clinical progression), defined as new symptoms that are deemed by the Investigator to be clinically significant or significant worsening of existing symptoms.

Number of participants with substantial, sustained, or significant changes from baseline for T-cell population in blood were reported. Significant clinical deterioration (clinical progression), defined as new symptoms that are deemed by the Investigator to be clinically significant or significant worsening of existing symptoms.

Number of participants with substantial, sustained, or significant changes from baseline for B-cell and NK-cell in blood were reported. Significant clinical deterioration (clinical progression), defined as new symptoms that are deemed by the Investigator to be clinically significant or significant worsening of existing symptoms.

Samples for the testing of vaccination-related antibody concentrations for diphtheria, tetanus, and pneumococcal conjugate (PCV-7) were collected. Significant clinical deterioration (clinical progression), defined as new symptoms that are deemed by the Investigator to be clinically significant or significant worsening of existing symptoms.

Vital signs included: Body temperature, Heart Rate, Blood pressure and respiratory rate. Vital signs were measured in semi-supine position after 5 minutes rest for the participants.