Durvalumab and Tremelimumab for Pediatric Malignancies

NCT03837899 | Active Not Recruiting Phase 1 Results DMC FDA Drug

• 3 other identifiers: D419EC000012023-510424-68-002018-003118-42
• Study Type: interventional
• Target: 50
• Locations: 7 countries
• Sites: 19

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.

Conditions

Pediatric Cancer; Solid Tumor Pediatric; Hematological Malignancies

Keywords

Pediatric, solid tumors, hematological malignancies, durvalumab, tremelimumab, immunotherapy

Outcome Measures

Primary Outcomes (26)

• 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.

  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.

  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: 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.

  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.

  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.

  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: 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.

  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: 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.

  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.

  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.

  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: Cmax of Tremelimumab

  Serum samples were collected from the participants at the defined timepoints. Cmax was determined using standard non-compartmental methods.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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).

  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.

  At 12 and 24 Weeks

Secondary Outcomes (22)

• 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

Study Arms (1)

Durvalumab / Tremelimumab Combination Therapy

EXPERIMENTAL

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)

Drug: Durvalumab / Tremelimumab Combination Therapy

Interventions

Durvalumab / Tremelimumab Combination Therapy DRUG

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.

Also known as: durvalumab: Imfinzi, MEDI4736, tremelimumab: CP-675,206

Durvalumab / Tremelimumab Combination Therapy

Eligibility Criteria

• Age: 0 Years - 18 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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)

Sponsors & Collaborators

• AstraZeneca: lead

Study Sites (19)

Research Site

Baltimore, Maryland, 21231, United States

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Boston, Massachusetts, 02115, United States

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New Hyde Park, New York, 11040, United States

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Oklahoma City, Oklahoma, 73104, United States

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Charleston, South Carolina, 29425, United States

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Lille, 59020, France

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Marseille, 13385, France

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Paris, 75248, France

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Cologne, 50924, Germany

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Genova, 16100, Italy

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Milan, 20133, Italy

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Rome, 00165, Italy

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Torino, 10126, Italy

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Utrecht, 3584 CS, Netherlands

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Barcelona, 08035, Spain

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Madrid, 28009, Spain

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Leeds, LS1 3EX, United Kingdom

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London, WC1N 3JH, United Kingdom

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Sutton, SM2 5PT, United Kingdom

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Related Links

• Study Protocol
• CSR Synopsis Redacted
• SAP Redacted

MeSH Terms

Conditions

Neoplasms; Hematologic Neoplasms

Interventions

durvalumab; tremelimumab

Condition Hierarchy (Ancestors)

Neoplasms by Site; Hematologic Diseases; Hemic and Lymphatic Diseases

Results Point of Contact

• Title: Global Clinical Lead
• Organization: AstraZeneca

information.center@astrazeneca.com

1-877-240-9479

Study Officials

• Ashok Gupta, MD, PhD

  AstraZeneca Global Medicines Development, Academy House

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 24, 2019
• First Posted: February 12, 2019
• Study Start: March 7, 2019
• Primary Completion: February 28, 2023
• Study Completion (Estimated): December 31, 2026
• Last Updated: April 21, 2026
• Results First Posted: March 19, 2024

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP
• Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure
• Access Criteria: When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool . Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure

Locations

IT (4); GB (3); DE (1); FR (3); US (5); NL (1); ES (2)