Durvalumab og Tremelimumab for pediatriske maligniteter

Part 1 (dose finding) Durvalumab + tremelimumab Combination Treatment. Durvalumab and tremelimumab are initially administered at dose level 1 and dose escalated based on results from PK modeling and tolerance to determine the RP2D. Both drugs are administered every 4 weeks as intravenous infusions. Tremelimumab is only administered with durvavalumab for 4 doses, from cycles 2-5. (sarcoma, NB and NHL)

Part 2 (dose expansion phase) Durvalumab + tremelimumab Combination Treatment. Durvalumab and tremelimumab are administered at the RP2D, every 4 weeks as intravenous infusions. Tremelimumab is only administered with durvalumab for 4 doses, from cycles 1-4. Tremelimumab may be added for 4 doses at time of progressive disease. Cohorts: solid tumors, sarcomas, NHL restricted to PMBCL and ALCL subtypes)

Starting dose:

durvalumab: 20mg/kg tremelimumab: 1mg/kg at cycles 2 to 5 only co-administered with durvalumab. The Recommended Phase 2 dose will be used for the dose expansion phase.

• durvalumab: Imfinzi, MEDI4736
• tremelimumab: CP-675,206

Serum samples were collected from the participants at the defined timepoints. Cmax was determined using standard non-compartmental methods.

Serum samples were collected from the participants at the defined timepoints. Cmin was determined using standard non-compartmental methods.

Serum samples were collected from the participants at the defined timepoints. AUC (0-14) was determined using standard non-compartmental methods.

Serum samples were collected from the participants at the defined timepoints. AUC (0-28) was determined using standard non-compartmental methods.

Serum samples were collected from the participants at the defined timepoints. Tmax was determined using standard non-compartmental methods.

Serum samples were collected from the participants at the defined timepoints. T½λz was determined using standard non-compartmental methods.

Serum samples were collected from the participants at the defined timepoints. AUC(0-14)/D was determined using standard non-compartmental methods.

Serum samples were collected from the participants at the defined timepoints. AUC(0-28)/D was determined using standard non-compartmental methods.

Serum samples were collected from the participants at the defined timepoints. Cmax/D was determined using standard non-compartmental methods.

Serum samples were collected from the participants at the defined timepoints. Cmax was determined using standard non-compartmental methods.

Serum samples were collected from the participants at the defined timepoints. Cmin was determined using standard non-compartmental methods.

Serum samples were collected from the participants at the defined timepoints. AUC (0-14) was determined using standard non-compartmental methods.

Serum samples were collected from the participants at the defined timepoints. AUC (0-28) was determined using standard non-compartmental methods.

Serum samples were collected from the participants at the defined timepoints. Tmax was determined using standard non-compartmental methods.

Serum samples were collected from the participants at the defined timepoints. T½λz was determined using standard non-compartmental methods.

Serum samples were collected from the participants at the defined timepoints. AUC(0-14)/D was determined using standard non-compartmental methods.

Serum samples were collected from the participants at the defined timepoints. AUC(0-28)/D was determined using standard non-compartmental methods.

Serum samples were collected from the participants at the defined timepoints. Cmax/D was determined using standard non-compartmental methods.

An AE was defined as any untoward medical occurrence in a participant temporally associated with the use of study treatment, whether or not considered related to the study treatment. SAEs were any untoward medical occurrence that at any dose: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, was a medically important event. Some AEs and higher-level terms were considered AESI or AEPIs and this list of categories were provided by the patient safety team.

ORR as per RECIST 1.1 was defined as the percentage of participants with at least 1 investigator-assessed visit response of complete response (CR) or partial response (PR) that was subsequently confirmed on another scan not less than 4 weeks after visit observed response. CR was defined as disappearance of all target lesions (TLs), any pathological lymph nodes selected as TLs with reduction in short axis to < 10 millimeter (mm). PR was defined as at least a 30% decrease in the sum of diameters of TLs, with reference to baseline sum of diameters as long as criteria for PD are not met.

Duration of response was the time from the first documentation of CR/PR (which was subsequently confirmed) until the date of documented progression, or death which coincides with the progression free survival (PFS) endpoint. For participants who did not progress following a response, the DOR was censored during the PFS censoring time. It was calculated using Kaplan-Meier technique.

BOR was calculated based on the overall visit responses from each RECIST 1.1 assessment. Categorization of BOR for solid tumors were based on RECIST 1.1 using the following response categories: CR, PR, stable disease (SD), progression of disease (PD), and not evaluable (NE). CR: disappearance of all TLs. Any pathological lymph nodes selected as TLs had a reduction in short axis to <10 mm. PR: 30% decrease in the sum of diameters of TLs. SD: Neither sufficient decrease in sum of diameters to qualify for PR nor sufficient increased to qualify for PD. PD: >= 20 % increase in the sum of diameters to TLs and an increase of >= 5 mm. NE: Only relevant if any of the TLs were not assessed or NE or had a lesion intervention at visit. Non-CR/Non-PD: Persistence of 1+ non-target lesion (s). Non-CR/non-PD was relevant to participants who did not have measurable disease at baseline.

DCR was defined as the percentage of participants who achieved a BOR of unconfirmed CR or PR, respectively, or who had SD. CR was defined as disappearance of all TLs, any pathological lymph nodes selected as TLs with reduction in short axis to < 10 mm. PR was defined as at least a 30% decrease in the sum of diameters of TLs, with reference to baseline sum of diameters as long as criteria for PD are not met. SD: Neither sufficient decrease in sum of diameters to qualify for PR nor sufficient increased to qualify for PD.

PFS as per RECIST 1.1 was defined as the time from the date of first dose of study treatment until the date of objective disease progression or death by any cause in the absence of progression, regardless of whether the participant withdrew from study therapy or received another anti-cancer therapy prior to progression (date of PFS event or censoring - date of first dose + 1). Confidence interval was calculated using Kaplan-Meier technique.

OS was defined as the time from the date of first dose of study treatment until death due to any cause regardless of whether the patient withdraws from study treatment or received another anti-cancer therapy (i.e date of death or censoring - date of first dose + 1).

Survival rates were defined as the Kaplan-Meier estimate of OS at 12 and 24 months.

Serum samples were collected from the participants at the defined timepoints. Cmax was determined using standard non-compartmental methods.

Serum samples were collected from the participants at the defined timepoints. Cmin was determined using standard non-compartmental methods.

Serum samples were collected from the participants at the defined timepoints. AUC (0-14) was determined using standard non-compartmental methods.

Serum samples were collected from the participants at the defined timepoints. AUC (0-28) was determined using standard non-compartmental methods.

Serum samples were collected from the participants at the defined timepoints. Tmax was determined using standard non-compartmental methods.

Serum samples were collected from the participants at the defined timepoints. T½λz was determined using standard non-compartmental methods.

Serum samples were collected from the participants at the defined timepoints. AUC (0-14)/D was determined using standard non-compartmental methods.

Serum samples were collected from the participants at the defined timepoints. AUC (0-28)/D was determined using standard non-compartmental methods.

Serum samples were collected from the participants at the defined timepoints. Cmax/D was determined using standard non-compartmental methods.

Serum samples were collected from the participants at the defined timepoints. Cmax was determined using standard non-compartmental methods.

Serum samples were collected from the participants at the defined timepoints. Cmin was determined using standard non-compartmental methods.

Serum samples were collected from the participants at the defined timepoints. AUC (0-14) was determined using standard non-compartmental methods.

Serum samples were collected from the participants at the defined timepoints. AUC (0-28) was determined using standard non-compartmental methods.

Serum samples were collected from the participants at the defined timepoints. Tmax was determined using standard non-compartmental methods.

Serum samples were collected from the participants at the defined timepoints. T½λz was determined using standard non-compartmental methods.

Serum samples were collected from the participants at the defined timepoints. AUC (0-14)/D was determined using standard non-compartmental methods.

Serum samples were collected from the participants at the defined timepoints. AUC (0-28)/D was determined using standard non-compartmental methods.

Serum samples were collected from the participants at the defined timepoints. Cmax/D was determined using standard non-compartmental methods.

ADA prevalence was defined as the percentage of participants with positive ADA result at any time, baseline or post-baseline. Persistently positive was defined as having at least 2 post-baseline ADA positive measurements with at least 16 weeks (112 days) between the first and last positive measurements, or an ADA positive result at the last available assessment. Transiently positive was defined as having at least 1 post-baseline ADA positive measurement and not fulfilling the conditions for persistently positive.

ADA prevalence was defined as the percentage of participants with positive ADA result at any time, baseline or post-baseline. Persistently positive was defined as having at least 2 post-baseline ADA positive measurements with at least 16 weeks (112 days) between the first and last positive measurements, or an ADA positive result at the last available assessment. The category includes participants meeting these criteria who are ADA positive at baseline. Transiently positive was defined as having at least 1 post-baseline ADA positive measurement and not fulfilling the conditions for persistently positive. The category includes participants meeting these criteria who are ADA positive at baseline.

Blood samples were planned to be collected for vaccine antibody titer measurements before and after planned routine immunization.

Blood samples were collected at indicated timepoints for flow cytometry assessment. Cycle (C) and Day (D). Data collected for the flow cytometry analysis from the participants enrolled in both the dose finding and dose expansion phase were analyzed in the context of the dosing regimen received, to determine any potential differences in the immune response based on the durvalumab dose.