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.
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 发起方
- AstraZeneca
- 入组人数
- 50
- 试验地点
- 20
- 主要终点
- Dose-Finding Phase: Maximum Serum Concentration (Cmax) of Durvalumab
研究概览
简要总结
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.
详细描述
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
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 0 Years 至 18 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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)
研究组 & 干预措施
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)
干预措施: Durvalumab / Tremelimumab Combination Therapy (Drug)
结局指标
主要结局
Dose-Finding Phase: Maximum Serum Concentration (Cmax) of Durvalumab
时间窗: 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
时间窗: 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
时间窗: 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
时间窗: 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
时间窗: 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
时间窗: 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
时间窗: 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
时间窗: 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
时间窗: 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
时间窗: 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
时间窗: 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
时间窗: 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
时间窗: 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
时间窗: 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
时间窗: 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
时间窗: 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
时间窗: 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
时间窗: 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
时间窗: 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)
时间窗: 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)
时间窗: 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)
时间窗: 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)
时间窗: 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
时间窗: 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)
时间窗: 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
时间窗: At 12 and 24 Weeks
Survival rates were defined as the Kaplan-Meier estimate of OS at 12 and 24 months.
次要结局
- Dose-Expansion Phase: AUC (0-28) of Tremelimumab(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(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 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, 8, and 12)
- Dose-Expansion Phase: 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, 8, and 12)
- Dose-Expansion Phase: AUC (0-14) of Durvalumab(Pre-infusion and post-infusion on Cycle 1 Day 1 and Cycle 1 Day 8)
- Dose-Expansion Phase: AUC (0-28) of Durvalumab(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(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(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(Pre-infusion and post-infusion on Cycle 1 Day 1 and Cycle 1 Day 8)
- Dose-Expansion Phase: 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)
- Dose-Expansion Phase: AUC (0-14) of Tremelimumab(Pre-infusion and post-infusion on Cycle 1 Day 1 and Cycle 1 Day 8)
- Dose-Expansion Phase: Cmin of Tremelimumab(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)
- Number of Participants With Individual Antibody Titer Measurement(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))
- Dose-Expansion Phase: Cmax of Tremelimumab(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)
- Median Percent Change From Baseline of Cluster of Differentiation 4+ (CD4+), CD8+, B Cells, Natural Killer (NK) Cells, and T-cell Activation With Ki67(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))
- Dose-Expansion Phase: Tmax of Tremelimumab(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(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(Pre-infusion and post-infusion on Cycle 1 Day 1 and Cycle 1 Day 8)
- Dose-Expansion Phase: AUC (0-28)/D of Tremelimumab(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(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)(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(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)