Evaluation of Durvalumab and Tremelimumab in Pediatric Patients with Advanced Solid Tumors and Hematological Malignancies: A Phase I/II Open-Label Study
- Trial ID
- 2023-510424-68-00
- Protocol
- D419EC00001
- Sponsor
- AstraZeneca AB
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to determine the adult equivalent exposure, maximum tolerated dose (MTD), and recommended Phase II pediatric dose of **durvalumab** in combination with **tremelimumab**, as well as **durvalumab** as monotherapy following combination therapy, in pediatric patients with advanced solid tumors and hematological malignancies. Additionally, the study aims to assess the safety profile of these treatments. In the dose-expansion phase, the study seeks to evaluate the preliminary antitumor activity of the treatments at the recommended dose using cohort-specific response criteria, such as RECIST 1.1. These objectives are clinically relevant as they aim to establish safe and effective dosing regimens for pediatric patients, potentially improving therapeutic outcomes in this population.
Secondary objectives include:
- Describing the pharmacokinetics (PK) of **durvalumab** and **tremelimumab** in combination and as monotherapy following combination therapy in children and young adults with solid tumors.
- Determining the immunogenicity of these treatments in the same patient population.
- Measuring effects on immune checkpoint inhibition in response to routine immunizations during the dose-expansion phase.
- Evaluating immune activation and counts of NK-, B-, and T-cells.
Participants
The clinical trial involves participants diagnosed with **advanced solid tumors**. The study population includes both male and female subjects, with an age range starting from 1 year and above. Participants are required to have a histopathologic confirmation of malignancy and must have progressed or be refractory to standard therapies, with no existing standard of care treatments available. The trial includes a vulnerable population, indicating that special considerations are in place for the protection of these participants. The sponsor has not provided the total number of participants involved in the study. Participants must have measurable or evaluable disease and should not have prior exposure to immune checkpoint inhibitors or genetically engineered cellular therapies, although exposure to other investigational agents may be permitted after discussion with the sponsor. The trial population was selected based on specific inclusion criteria, including performance status scores and the availability of a diagnostic tumor sample for evaluation of PD-L1 status, if available. Lifestyle considerations such as diet and physical activity are not specified in the provided data.
Plans and Procedures
The clinical trial is a **Phase I/II, open-label, multicenter study** designed to evaluate the safety, tolerability, and preliminary efficacy of **durvalumab** monotherapy or durvalumab in combination with **tremelimumab** in pediatric patients with advanced solid tumors and hematological malignancies. The trial employs a dose-finding and dose-expansion approach to determine the adult equivalent exposure, maximum tolerated dose (MTD), and recommended Phase II pediatric dose. The study aims to assess the safety profile and preliminary antitumor activity of the investigational drugs using cohort-specific response criteria, such as RECIST 1.1.
The trial is expected to run from January 31, 2019, to December 31, 2025. Participants will be involved in the study for the duration necessary to complete the dosing and follow-up assessments, with the possibility of early termination if they experience unacceptable toxicity, disease progression, or withdrawal of consent. The study includes an initial screening visit to confirm eligibility, followed by regular follow-up visits to monitor safety and efficacy, and concludes with an end-of-study visit to assess overall outcomes.
Inclusion criteria require participants to have a histopathologic confirmation of malignancy, progression or refractoriness to standard therapies, and measurable or evaluable disease. Exclusion criteria include prior exposure to immune checkpoint inhibitors or genetically engineered cellular therapies. The primary endpoints focus on pharmacokinetic parameters, safety, and objective response rate, while secondary endpoints include individual drug concentrations, development of detectable anti-drug antibodies, and immune cell profiling through flow cytometry.
Treatment
The clinical trial involves the administration of **IMJUDO**, a concentrate for solution for infusion containing the active substance **tremelimumab**. This pharmaceutical form is a sterile concentrate, with a concentration of 20 mg/mL. The medication is administered via **intravenous use**. The dosing schedule and frequency of administration are determined based on the study protocol, aiming to achieve the adult equivalent exposure, maximum tolerated dose (MTD), or recommended Phase II pediatric dose. Participant compliance is monitored throughout the trial to ensure adherence to the dosing regimen.
Additionally, the trial includes the administration of **IMFINZI**, another concentrate for solution for infusion, which contains the active substance **durvalumab**. This medication is also provided in a sterile concentrate form with a concentration of 50 mg/mL. Similar to IMJUDO, IMFINZI is administered intravenously. The trial evaluates the safety and tolerability of durvalumab both as a monotherapy and in combination with tremelimumab. The dosing schedule is designed to determine the preliminary antitumor activity at the recommended dose, using cohort-specific response criteria such as RECIST 1.1.
Both medications are produced by AstraZeneca AB and are not formulated specifically for pediatric use. The trial does not include any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatment. The study is structured to assess the safety profile and preliminary efficacy of these investigational drugs in pediatric patients with advanced solid tumors and hematological malignancies.
Efficacy
Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoints include pharmacokinetic (PK) parameters such as Cmax, Cmin, and AUC to identify the adult equivalent exposure/maximum tolerated dose (MTD) of **durvalumab** in combination with **tremelimumab** and as monotherapy. Safety and tolerability will also be evaluated at the adult equivalent exposure/MTD, with endpoints including adverse events (AEs), vital signs, physical examinations, ECGs, and laboratory evaluations. The objective response rate will be determined by the Investigator using RECIST 1.1 or alternative tumor-specific response criteria, with antitumor activity assessed specific to each tumor cohort.
Additional efficacy endpoints include duration of response (DoR), best overall response (BoR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS), with specific timepoints such as OS12 and OS24. Secondary endpoints involve measuring individual concentrations of durvalumab and tremelimumab in serum, PK parameters, and the number and percentage of patients developing detectable anti-drug antibodies (ADAs). Flow cytometry will be used to analyze CD4, CD8, B, and NK cells, including T-cell activation with Ki67. These assessments will be conducted at specified intervals throughout the trial to ensure comprehensive evaluation of the treatment's efficacy.
Inclusion and Exclusion Criteria
Inclusion Criteria
- 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.
- If available, patients must provide a diagnostic tumor sample taken ˂3 years prior to screening for evaluation of PD-L1 status.
- Lansky play performance scale ≥50 for patients ≥1 and <16 years of age and Karnofsky performance status score ≥50 for patients ≥16 years of age (patients <1 year of age are exempt from this criterion)
- Patients must have measurable/evaluable disease as defined by methods used in common clinical practice.
- No prior exposure to immune checkpoint inhibitors or genetically engineered cellular therapies including, but not limited to, other anti-CTLA-4, anti-PD-1, anti-PD-L1, anti-PD-L2 antibodies and CAR-T or other cell therapies, excluding therapeutic anticancer vaccines. Exposure to other investigational agents may be permitted after discussion with the Sponsor or designee.
Exclusion Criteria
- History of allogeneic organ transplantation. Patients who have previously received an autologous bone marrow transplant may be eligible
- Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease, diverticulitis, celiac disease or other serious GI chronic conditions associated with diarrhea, systemic lupus erythematosus, Wegener syndrome; myasthenia gravis, Graves’ disease, rheumatoid arthritis, hypophysitis, uveitis, etc.), autoimmune myocarditis, and autoimmune pneumonitis. The following are exceptions to this criterion: − Patients with vitiligo or alopecia − Patients with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement − Psoriasis that does not require systemic therapy − Patients with celiac disease controlled by diet alone.
- Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, cardiac arrhythmia, ILD, or psychiatric illness or social situations that would limit compliance with study requirements, substantially increase risk of incurring AEs from IP, or compromise the ability of the patient to give written informed consent.
- History of primary immunodeficiency.
- Active infection including tuberculosis, hepatitis B, hepatitis C, or HIV. Patients with a past or resolved HBV infection are eligible. Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV ribonucleic acid (RNA).
- Any unresolved toxicity NCI CTCAE version 5.0 Grade ≥2 from previous anticancer therapy with the exception of alopecia, vitiligo, lymphopenia and the laboratory values defined in the inclusion criteria − Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis and may be included after consultation with the Study Physician. − Persistent toxicities (CTCAE Grade ≥2) caused by previous anticancer therapy, excluding alopecia. Patients with toxicity not reasonably expected to be exacerbated by treatment with durvalumab or tremelimumab in the opinion of the Investigator (eg, hearing loss, gastrostomy tube), may be included.
- Patients with clinically active brain metastases (known or suspected), spinal cord compression, and choloromas are excluded, unless these conditions have been previously treated and are considered stable.
- History of leptomeningeal carcinomatosis, or involvement of any other anatomic area that, in the opinion of the Investigator, may cause significant symptoms if an inflammatory reaction occurs
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Spain | Recruiting | 31 Jan 2019 | 11 |
Sites & Investigators
Research sites
Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
IMFINZI 50 mg/mL concentrate for solution for infusion. | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS USE | — | — | PRD6651398 |
IMJUDO 20 mg/ml concentrate for solution for infusion. | Test | CONCENTRATE FOR SOLUTION FOR INFUSION (STERILE CONCENTRATE). | INTRAVENOUS USE | — | — | PRD10239823 |