Clinical trial NCT03837899: Durvalumab and Tremelimumab for Pediatric Malignancies
Official title: Phase I/II, Open-Label Study to Evaluate the Safety, Tolerability, and Preliminary Efficacy of Durvalumab Monotherapy or in Combination With Tremelimumab in Pediatric Patients With Advanced Solid Tumors and Hematological Malignancies.
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
PHASE2
Conditions: Pediatric Cancer
Solid Tumor Pediatric
Hematological Malignancies
Keywords: Pediatric, solid tumors, hematological malignancies, durvalumab, tremelimumab, immunotherapy
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
First posted: 2019-02-12
Enrollment: 50
Sex: ALL
Minimum age (years): 0
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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

Eligibility criteria: 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)

Primary outcomes:
measure: Dose-Finding Phase: Maximum Serum Concentration (Cmax) of Durvalumab
timeFrame: 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
measure: Dose-Finding Phase: Minimum Serum Concentration (Cmin) of Durvalumab
timeFrame: 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
measure: Dose-Finding Phase: Area Under the Serum Concentration-Time Curve (AUC) From Zero to 14 (AUC 0-14) of Durvalumab
timeFrame: Pre-infusion and post-infusion on Cycle 1 Day 1 and Cycle 1 Day 8
measure: Dose-Finding Phase: AUC From Zero to 28 (AUC 0-28) of Durvalumab
timeFrame: Pre-infusion and post-infusion on Cycle 1 Day 1, Cycle 1 Day 8, and Cycle 1 Day 15
measure: Dose-Finding Phase: Time to Cmax (Tmax) of Durvalumab
timeFrame: 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
measure: Dose-Finding Phase: Apparent Terminal Elimination Half-life Associated With the Terminal Slope of the Semi-logarithmic Concentration Time Curve (t½λz) of Durvalumab
timeFrame: 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
measure: Dose-Finding Phase: Dose-Normalized AUC (0-14) (AUC [0-14]/D) of Durvalumab
timeFrame: Pre-infusion and post-infusion on Cycle 1 Day 1 and Cycle 1 Day 8
measure: Dose-Finding Phase: Dose-Normalized AUC (0-28) (AUC [0-28]/D) of Durvalumab
timeFrame: Pre-infusion and post-infusion on Cycle 1 Day 1, Cycle 1 Day 8, and Cycle 1 Day 15
measure: Dose-Finding Phase: Dose-Normalized Cmax (Cmax/D) of Durvalumab
timeFrame: 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
measure: Dose-Finding Phase: Cmax of Tremelimumab
timeFrame: 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
measure: Dose-Finding Phase: Cmin of Tremelimumab
timeFrame: 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
measure: Dose-Finding Phase: (AUC 0-14) of Tremelimumab
timeFrame: Pre-infusion and post-infusion on Cycle 2 Day 1, and Cycle 2 Day 8
measure: Dose-Finding Phase: (AUC 0-28) of Tremelimumab
timeFrame: Pre-infusion and post-infusion on Cycle 2 Day 1, Cycle 2 Day 8, and Cycle 2 Day 15
measure: Dose-Finding Phase: Tmax of Tremelimumab
timeFrame: 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
measure: Dose-Finding Phase: T½λz of Tremelimumab
timeFrame: 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
measure: Dose-Finding Phase: AUC (0-14)/D of Tremelimumab
timeFrame: Pre-infusion and post-infusion on Cycle 2 Day 1 and Cycle 2 Day 8
measure: Dose-Finding Phase: AUC (0-28)/D of Tremelimumab
timeFrame: Pre-infusion and post-infusion on Cycle 2 Day 1, Cycle 2 Day 8, and Cycle 2 Day 15
measure: Dose-Finding Phase: Cmax/D of Tremelimumab
timeFrame: 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
measure: 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
timeFrame: From Day 1 up to 15 months
measure: Dose-Expansion Phase Only: Objective Response Rate (ORR)
timeFrame: From first dose of study treatment until death or up to approximately 4 years (clinical DCO of 20 Apr 2023)
measure: Dose-Expansion Phase Only: Duration of Response (DOR)
timeFrame: From first dose of study treatment until death or up to approximately 4 years (clinical DCO of 20 Apr 2023)
measure: Dose-Expansion Phase Only: Best Objective Response (BOR)
timeFrame: From first dose of study treatment until death or up to approximately 4 years (clinical DCO of 20 Apr 2023)
measure: Dose-Expansion Phase Only: Disease Control Rate (DCR)
timeFrame: At 16 and 24 Weeks
measure: Dose-Expansion Phase Only: PFS
timeFrame: From first dose of study treatment until death or up to approximately 4 years (clinical DCO of 20 Apr 2023)
measure: Dose-Expansion Phase Only: Overall Survival (OS)
timeFrame: From first dose of study treatment until death or up to approximately 4 years (clinical DCO of 20 Apr 2023)
measure: Dose-Expansion Phase Only: Survival Rate at 12 Months and 24 Months
timeFrame: At 12 and 24 Weeks
Secondary outcomes:
measure: Dose-Expansion Phase: Cmax of Durvalumab
timeFrame: 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
measure: Dose-Expansion Phase: Cmin of Durvalumab
timeFrame: 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
measure: Dose-Expansion Phase: AUC (0-14) of Durvalumab
timeFrame: Pre-infusion and post-infusion on Cycle 1 Day 1 and Cycle 1 Day 8
measure: Dose-Expansion Phase: AUC (0-28) of Durvalumab
timeFrame: Pre-infusion and post-infusion on Cycle 1 Day 1, Cycle 1 Day 8, and Cycle 1 Day 15
measure: Dose-Expansion Phase: Tmax of Durvalumab
timeFrame: 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
measure: Dose-Expansion Phase: T½λz of Durvalumab
timeFrame: 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
measure: Dose-Expansion Phase: AUC (0-14)/D of Durvalumab
timeFrame: Pre-infusion and post-infusion on Cycle 1 Day 1 and Cycle 1 Day 8
measure: Dose-Expansion Phase: AUC (0-28)/D of Durvalumab
timeFrame: Pre-infusion and post-infusion on Cycle 1 Day 1, Cycle 1 Day 8, and Cycle 1 Day 15
measure: Dose-Expansion Phase: Cmax/D of Durvalumab
timeFrame: 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
measure: Dose-Expansion Phase: Cmax of Tremelimumab
timeFrame: 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
measure: Dose-Expansion Phase: Cmin of Tremelimumab
timeFrame: 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
measure: Dose-Expansion Phase: AUC (0-14) of Tremelimumab
timeFrame: Pre-infusion and post-infusion on Cycle 1 Day 1 and Cycle 1 Day 8
measure: Dose-Expansion Phase: AUC (0-28) of Tremelimumab
timeFrame: Pre-infusion and post-infusion on Cycle 1 Day 1, Cycle 1 Day 8, and Cycle 1 Day 15
measure: Dose-Expansion Phase: Tmax of Tremelimumab
timeFrame: 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
measure: Dose-Expansion Phase: T½λz of Tremelimumab
timeFrame: 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
measure: Dose-Expansion Phase: AUC (0-14)/D of Tremelimumab
timeFrame: Pre-infusion and post-infusion on Cycle 1 Day 1 and Cycle 1 Day 8
measure: Dose-Expansion Phase: AUC (0-28)/D of Tremelimumab
timeFrame: Pre-infusion and post-infusion on Cycle 1 Day 1, Cycle 1 Day 8, and Cycle 1 Day 15
measure: Dose-Expansion Phase: Cmax/D of Tremelimumab
timeFrame: 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
measure: Dose-Finding Phase: Percentage of Participants Who Developed Detectable Anti-Drug Antibodies (ADAs)
timeFrame: 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
measure: Dose-Expansion Phase: Percentage of Participants Who Developed Detectable ADAs
timeFrame: 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
measure: Number of Participants With Individual Antibody Titer Measurement
timeFrame: 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)
measure: Median Percent Change From Baseline of Cluster of Differentiation 4+ (CD4+), CD8+, B Cells, Natural Killer (NK) Cells, and T-cell Activation With Ki67
timeFrame: 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)
Other outcomes:
Locations:
city: Baltimore
country: United States
facility: Research Site
state: Maryland
city: Boston
country: United States
facility: Research Site
state: Massachusetts
city: New Hyde Park
country: United States
facility: Research Site
state: New York
city: Oklahoma City
country: United States
facility: Research Site
state: Oklahoma
city: Charleston
country: United States
facility: Research Site
state: South Carolina
city: Lille Cedex
country: France
facility: Research Site
city: Marseille
country: France
facility: Research Site
city: Paris Cedex 05
country: France
facility: Research Site
city: Köln
country: Germany
facility: Research Site
city: Genova
country: Italy
facility: Research Site
city: Milano
country: Italy
facility: Research Site
city: Rome
country: Italy
facility: Research Site
city: Torino
country: Italy
facility: Research Site
city: Utrecht
country: Netherlands
facility: Research Site
city: Barcelona
country: Spain
facility: Research Site
city: Madrid
country: Spain
facility: Research Site
city: Leeds
country: United Kingdom
facility: Research Site
city: London
country: United Kingdom
facility: Research Site
city: Sutton
country: United Kingdom
facility: Research Site
Study officials:
affiliation: AstraZeneca Global Medicines Development, Academy House
name: Ashok Gupta, MD, PhD
role: STUDY_DIRECTOR
References: