小児悪性腫瘍に対するデュルバルマブとトレメリムマブ

実験的：Durvalumab / Tremelimumab Combination Therapy

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)

薬：Durvalumab / Tremelimumab Combination Therapy

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.

他の名前：

• デュルバルマブ：インフィンジ、MEDI4736
• トレメリムマブ: CP-675,206

Dose-Finding Phase: Maximum Serum Concentration (Cmax) of Durvalumab

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

Dose-Finding Phase: Minimum Serum Concentration (Cmin) of Durvalumab

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

Dose-Finding Phase: Area Under the Serum Concentration-Time Curve (AUC) From Zero to 14 (AUC 0-14) of Durvalumab

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

Dose-Finding Phase: AUC From Zero to 28 (AUC 0-28) of Durvalumab

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

Dose-Finding Phase: Time to Cmax (Tmax) of Durvalumab

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

Dose-Finding Phase: Apparent Terminal Elimination Half-life Associated With the Terminal Slope of the Semi-logarithmic Concentration Time Curve (t½λz) of Durvalumab

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

Dose-Finding Phase: Dose-Normalized AUC (0-14) (AUC [0-14]/D) of Durvalumab

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

Dose-Finding Phase: Dose-Normalized AUC (0-28) (AUC [0-28]/D) of Durvalumab

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

Dose-Finding Phase: Dose-Normalized Cmax (Cmax/D) of Durvalumab

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

Dose-Finding Phase: Cmax of Tremelimumab

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

Dose-Finding Phase: Cmin of Tremelimumab

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

Dose-Finding Phase: (AUC 0-14) of Tremelimumab

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

Dose-Finding Phase: (AUC 0-28) of Tremelimumab

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

Dose-Finding Phase: Tmax of Tremelimumab

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

Dose-Finding Phase: T½λz of Tremelimumab

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

Dose-Finding Phase: AUC (0-14)/D of Tremelimumab

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

Dose-Finding Phase: AUC (0-28)/D of Tremelimumab

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

Dose-Finding Phase: Cmax/D of Tremelimumab

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

Dose-Finding Phase: Number of Participants With Adverse Events (AE), Serious AE (SAE), AE Leading to Discontinuation of Durvalumab and Tremelimumab, AE of Special Interest (AESI) or AE of Possible Interest (AEPI) Related to Durvalumab and Tremelimumab

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.

Dose-Expansion Phase Only: Objective Response Rate (ORR)

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.

Dose-Expansion Phase Only: Duration of Response (DOR)

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.

Dose-Expansion Phase Only: Best Objective Response (BOR)

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.

Dose-Expansion Phase Only: Disease Control Rate (DCR)

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.

Dose-Expansion Phase Only: PFS

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.

Dose-Expansion Phase Only: Overall Survival (OS)

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).

Dose-Expansion Phase Only: Survival Rate at 12 Months and 24 Months

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

Dose-Expansion Phase: Cmax of Durvalumab

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

Dose-Expansion Phase: Cmin of Durvalumab

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

Dose-Expansion Phase: AUC (0-14) of Durvalumab

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

Dose-Expansion Phase: AUC (0-28) of Durvalumab

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

Dose-Expansion Phase: Tmax of Durvalumab

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

Dose-Expansion Phase: T½λz of Durvalumab

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

Dose-Expansion Phase: AUC (0-14)/D of Durvalumab

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

Dose-Expansion Phase: AUC (0-28)/D of Durvalumab

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

Dose-Expansion Phase: Cmax/D of Durvalumab

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

Dose-Expansion Phase: Cmax of Tremelimumab

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

Dose-Expansion Phase: Cmin of Tremelimumab

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

Dose-Expansion Phase: AUC (0-14) of Tremelimumab

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

Dose-Expansion Phase: AUC (0-28) of Tremelimumab

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

Dose-Expansion Phase: Tmax of Tremelimumab

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

Dose-Expansion Phase: T½λz of Tremelimumab

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

Dose-Expansion Phase: AUC (0-14)/D of Tremelimumab

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

Dose-Expansion Phase: AUC (0-28)/D of Tremelimumab

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

Dose-Expansion Phase: Cmax/D of Tremelimumab

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

Dose-Finding Phase: Percentage of Participants Who Developed Detectable Anti-Drug Antibodies (ADAs)

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.

Dose-Expansion Phase: Percentage of Participants Who Developed Detectable ADAs

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.

Number of Participants With Individual Antibody Titer Measurement

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

Median Percent Change From Baseline of Cluster of Differentiation 4+ (CD4+), CD8+, B Cells, Natural Killer (NK) Cells, and T-cell Activation With Ki67

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.