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.
Study 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.
Eligibility
Sex
ALL
Min age
0 Years
Max age
18 Years
Healthy volunteers
No
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 outcome measure(s)
Dose-Finding Phase: Maximum Serum Concentration (Cmax) of Durvalumab — 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 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 — 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 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 — Pre-infusion and post-infusion on Cycle 1 Day 1 and Cycle 1 Day 8 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 — Pre-infusion and post-infusion on Cycle 1 Day 1, Cycle 1 Day 8, and Cycle 1 Day 15 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 — 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 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 — 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 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 — Pre-infusion and post-infusion on Cycle 1 Day 1 and Cycle 1 Day 8 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 — Pre-infusion and post-infusion on Cycle 1 Day 1, Cycle 1 Day 8, and Cycle 1 Day 15 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 — 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 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 — 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 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 — 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 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 — Pre-infusion and post-infusion on Cycle 2 Day 1, and Cycle 2 Day 8 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 — Pre-infusion and post-infusion on Cycle 2 Day 1, Cycle 2 Day 8, and Cycle 2 Day 15 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 — 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 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 — 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 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 — Pre-infusion and post-infusion on Cycle 2 Day 1 and Cycle 2 Day 8 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 — Pre-infusion and post-infusion on Cycle 2 Day 1, Cycle 2 Day 8, and Cycle 2 Day 15 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 — 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 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 — From Day 1 up to 15 months 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) — From first dose of study treatment until death or up to approximately 4 years (clinical DCO of 20 Apr 2023) 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) — From first dose of study treatment until death or up to approximately 4 years (clinical DCO of 20 Apr 2023) 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) — From first dose of study treatment until death or up to approximately 4 years (clinical DCO of 20 Apr 2023) 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) — At 16 and 24 Weeks 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 — From first dose of study treatment until death or up to approximately 4 years (clinical DCO of 20 Apr 2023) 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) — From first dose of study treatment until death or up to approximately 4 years (clinical DCO of 20 Apr 2023) 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 — At 12 and 24 Weeks Survival rates were defined as the Kaplan-Meier estimate of OS at 12 and 24 months.
This page summarises publicly available registry data for informational purposes — not medical advice. Eligibility is determined by each study team; patients should discuss participation with their clinician.
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