Durvalumab and Tremelimumab for Pediatric Malignancies

Phase 2Active Not RecruitingNCT03837899

AstraZeneca50 enrolled

Overview

The purpose of the study is to determine the recommended dose of durvalumab and tremelimumab (immunotherapy drugs) in pediatric patients with advanced solid and hematological cancers and expand in a second phase to test the efficacy of these drugs once this dose is determined.

This is a first time in pediatrics study primarily designed to evaluate the safety and tolerability of durvalumab and durvalumab in combination with tremelimumab at increasing doses in pediatric patients with advanced solid malignancies and hematological malignancies (including lymphomas) and for whom no standard of care treatments exist. Although treatment efficacy is not a primary objective of this study given its early phase nature, the patients screened for this study have no curative options and this study offers the potential of some benefit. The study will also characterize the PK of durvalumab and durvalumab in combination with tremelimumab in children and adolescents and explore potential biological activity and immunogenicity by assessing pharmacodynamics, anti drug antibody (ADA) levels, and anti-tumor activity. The results from this trial will form the basis for decisions for potential future pediatric studies

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Pediatric Cancer Solid Tumor Pediatric Hematological Malignancies

Interventions

Durvalumab / Tremelimumab Combination TherapyDRUG

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.

Eligibility

Sex: ALLMin age: 0 YearsMax age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Max Age =17 years * Solid Tumors (except primary central nervous system malignant tumors): Patients must have a histopathologic confirmation of malignancy. Patients must have progressed or are refractory to standard therapies, and for whom no standard of care treatments exist * Non-Hodgkin's Lymphoma, limited to primary mediastinal B-cell lymphoma and anaplastic large cell lymphoma. Patients must have progressed or are refractory to standard therapies, and for whom no standard of care treatments exist. * Provision of diagnostic tumor sample mandated if available * Evaluable disease * No prior exposure to immune-mediated therapy * Adequate organ and marrow function * Life expectancy of at least 3 months Exclusion Criteria: * History of allogeneic organ transplantation (exceptions may be allowed for NHL after discussion with Sponsor). History of autologous bone marrow transplant may be allowed (after discussion with Sponsor). * Active or prior documented autoimmune or inflammatory disorders (exceptions) * Uncontrolled intercurrent illness * History of primary immunodeficiency * Active infection including tuberculosis, hepatitis B, C or HIV * Any unresolved toxicity NCI CTCAE version 5.0 Grade ≥2 from previous anticancer therapy (exceptions)

Locations (19)

Research Site

Baltimore, Maryland, United States

Research Site

Boston, Massachusetts, United States

Research Site

Outcomes

Primary Outcomes

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.

Time frame: Pre-infusion and post-infusion on Cycle 1 Day 1, Cycle 1 Day 8, Cycle 1 Day 15, pre-infusion and post-infusion on Cycle 2 Day 1, pre-infusion and post-infusion in Cycle 3, 4, 6, 8, 10 and 12

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.

Time frame: Pre-infusion and post-infusion on Cycle 1 Day 1 and Cycle 1 Day 8

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.

Time frame: Pre-infusion and post-infusion on Cycle 1 Day 1, Cycle 1 Day 8, and Cycle 1 Day 15

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.

Data from ClinicalTrials.gov

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New Hyde Park, New York, United States

Research Site

Oklahoma City, Oklahoma, United States

Research Site

Charleston, South Carolina, United States

Research Site

Lille, France

Research Site

Marseille, France

Research Site

Paris, France

Research Site

Cologne, Germany

Research Site

Genova, Italy

...and 9 more locations

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.

Time frame: Pre-infusion and post-infusion on Cycle 1 Day 1 and Cycle 1 Day 8

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.

Time frame: Pre-infusion and post-infusion on Cycle 1 Day 1, Cycle 1 Day 8, and Cycle 1 Day 15

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.

Time frame: Pre-infusion and post-infusion on Cycle 2 Day 1, Cycle 2 Day 8, Cycle 2 Day 15, pre-infusion and post-infusion in Cycle 3, 4, and 5

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.

Time frame: Pre-infusion and post-infusion on Cycle 2 Day 1, Cycle 2 Day 8, Cycle 2 Day 15, pre-infusion and post-infusion in Cycle 3, 4, and 5

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.

Time frame: Pre-infusion and post-infusion on Cycle 2 Day 1, and Cycle 2 Day 8

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.

Time frame: Pre-infusion and post-infusion on Cycle 2 Day 1, Cycle 2 Day 8, and Cycle 2 Day 15

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.

Time frame: Pre-infusion and post-infusion on Cycle 2 Day 1, Cycle 2 Day 8, Cycle 2 Day 15, pre-infusion and post-infusion in Cycle 3, 4, and 5

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.

Time frame: Pre-infusion and post-infusion on Cycle 2 Day 1, Cycle 2 Day 8, Cycle 2 Day 15, pre-infusion and post-infusion in Cycle 3, 4, and 5

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.

Time frame: Pre-infusion and post-infusion on Cycle 2 Day 1 and Cycle 2 Day 8

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.

Time frame: Pre-infusion and post-infusion on Cycle 2 Day 1, Cycle 2 Day 8, and Cycle 2 Day 15

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.

Time frame: Pre-infusion and post-infusion on Cycle 2 Day 1, Cycle 2 Day 8, Cycle 2 Day 15, pre-infusion and post-infusion in Cycle 3, 4, and 5

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.

Time frame: From Day 1 up to 15 months

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.

Time frame: From first dose of study treatment until death or up to approximately 4 years (clinical DCO of 20 Apr 2023)

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.

Time frame: From first dose of study treatment until death or up to approximately 4 years (clinical DCO of 20 Apr 2023)

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.

Time frame: From first dose of study treatment until death or up to approximately 4 years (clinical DCO of 20 Apr 2023)

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.

Time frame: At 16 and 24 Weeks

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.

Time frame: From first dose of study treatment until death or up to approximately 4 years (clinical DCO of 20 Apr 2023)

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).

Time frame: From first dose of study treatment until death or up to approximately 4 years (clinical DCO of 20 Apr 2023)

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.

Time frame: At 12 and 24 Weeks

Secondary Outcomes

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.

Time frame: Pre-infusion and post-infusion on Cycle 1 Day 1, Cycle 1 Day 8, Cycle 1 Day 15, pre-infusion and post-infusion on Cycle 2 Day 1, pre-infusion and post-infusion in Cycle 3, 4, 8, and 12

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.

Time frame: Pre-infusion and post-infusion on Cycle 1 Day 1, Cycle 1 Day 8, Cycle 1 Day 15, pre-infusion and post-infusion on Cycle 2 Day 1, pre-infusion and post-infusion in Cycle 3, 4, 8, and 12

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.

Time frame: Pre-infusion and post-infusion on Cycle 1 Day 1 and Cycle 1 Day 8

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.

Time frame: Pre-infusion and post-infusion on Cycle 1 Day 1, Cycle 1 Day 8, and Cycle 1 Day 15

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.

Time frame: Pre-infusion and post-infusion on Cycle 1 Day 1, Cycle 1 Day 8, Cycle 1 Day 15, pre-infusion and post-infusion on Cycle 2 Day 1, pre-infusion and post-infusion in Cycle 3, 4, 8, and 12

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.

Time frame: Pre-infusion and post-infusion on Cycle 1 Day 1, Cycle 1 Day 8, Cycle 1 Day 15, pre-infusion and post-infusion on Cycle 2 Day 1, pre-infusion and post-infusion in Cycle 3, 4, 8, and 12

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.

Time frame: Pre-infusion and post-infusion on Cycle 1 Day 1 and Cycle 1 Day 8

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.

Time frame: Pre-infusion and post-infusion on Cycle 1 Day 1, Cycle 1 Day 8, and Cycle 1 Day 15

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.

Time frame: Pre-infusion and post-infusion on Cycle 1 Day 1, Cycle 1 Day 8, Cycle 1 Day 15, pre-infusion and post-infusion on Cycle 2 Day 1, pre-infusion and post-infusion in Cycle 3, 4, 8, and 12

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.

Time frame: Pre-infusion and post-infusion on Cycle 1 Day 1, Cycle 1 Day 8, Cycle 1 Day 15, pre-infusion and post-infusion on Cycle 2 Day 1, Cycle 3 Day 1 pre-infusion and post-infusion on Cycle 4

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.

Time frame: Pre-infusion and post-infusion on Cycle 1 Day 1, Cycle 1 Day 8, Cycle 1 Day 15, pre-infusion and post-infusion on Cycle 2 Day 1, Cycle 3 Day 1 pre-infusion and post-infusion on Cycle 4

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.

Time frame: Pre-infusion and post-infusion on Cycle 1 Day 1 and Cycle 1 Day 8

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.

Time frame: Pre-infusion and post-infusion on Cycle 1 Day 1, Cycle 1 Day 8, and Cycle 1 Day 15

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.

Time frame: Pre-infusion and post-infusion on Cycle 1 Day 1, Cycle 1 Day 8, Cycle 1 Day 15, pre-infusion and post-infusion on Cycle 2 Day 1, Cycle 3 Day 1 pre-infusion and post-infusion on Cycle 4

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.

Time frame: Pre-infusion and post-infusion on Cycle 1 Day 1, Cycle 1 Day 8, Cycle 1 Day 15, pre-infusion and post-infusion on Cycle 2 Day 1, Cycle 3 Day 1 pre-infusion and post-infusion on Cycle 4

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.

Time frame: Pre-infusion and post-infusion on Cycle 1 Day 1 and Cycle 1 Day 8

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.

Time frame: Pre-infusion and post-infusion on Cycle 1 Day 1, Cycle 1 Day 8, and Cycle 1 Day 15

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.

Time frame: Pre-infusion and post-infusion on Cycle 1 Day 1, Cycle 1 Day 8, Cycle 1 Day 15, pre-infusion and post-infusion on Cycle 2 Day 1, Cycle 3 Day 1 pre-infusion and post-infusion on Cycle 4

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.

Time frame: Pre-infusion on Cycle 1 Day 1 and Cycle 3 Day 1 (durvalumab and tremelimumab), pre-infusion on Cycle 2 Day 1, Cycle 5 Day 1 and Cycle 8 Day 1 for tremelimumab

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.

Time frame: Pre-infusion on Cycle 1 Day 1 and Cycle 3 Day 1 (durvalumab and tremelimumab) and random sample on Cycle 7 Day 1 for tremelimumab

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.

Time frame: Pre-infusion on Cycle 1 Day 1 and Cycle 4 Day 1 for durvalumab, pre-infusion on Cycle 1 Day 1, pre-infusion on Cycle 3, 4, and 8 Day 1 for tremelimumab (dose-expansion)

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.

Time frame: Pre-dose Cycle 1 Day 8, pre-dose Cycle 2 Day 1, Cycle 2 Day 8, pre-dose Cycle 3 Day 1 (Dose-finding); Pre-dose Cycle 1 Day 1, Cycle 1 Day 8, pre-dose Cycle 2 Day 1 (Dose-expansion)