A clinical study to evaluate the safety, tolerability and early efficacy of the study drug (Durvalumab) alone and a combination of study drugs (Durvalumab and Tremelimumab) in children with advanced solid tumours and blood cancer

Overview

Sponsor-declared trial summary

Key facts

Sponsor

AstraZeneca AB

Participant type

Pediatric, Patients

Age range

0-17 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

28 May 2019 → ongoing

Decision date (initial)

2024-06-28

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

AstraZeneca AB

External identifiers

EU CT number

2023-510424-68-00

EudraCT number

2018-003118-42

ClinicalTrials.gov

NCT03837899

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacokinetic, Efficacy, Safety, Pharmacodynamic

Dose-finding:
-To determine the adult equivalent exposure/MTD/recommended Phase II pediatric dose of durvalumab in combination with tremelimumab and durvalumab as monotherapy following combination therapy.
-To determine the safety profile of durvalumab in combination with tremelimumab and durvalumab as monotherapy following combination therapy
Dose-expansion:
- To determine the preliminary antitumor activity of durvalumab in combination with tremelimumab and durvalumab as monotherapy following combination therapy at the recommended dose, using cohortspecific response criteria (eg, RECIST 1.1).

Secondary objectives 5

1. To describe the PK of durvalumab and tremelimumab in combination and durvalumab as monotherapy following combination therapy, in children and young adults with solid tumors.
2. To determine the immunogenicity of durvalumab and tremelimumab in combination and durvalumab as monotherapy following combination therapy, in children and young adults with solid tumors
3. To determine the immunogenicity of durvalumab in combination with tremelimumab and durvalumab as monotherapy following combination therapy, in children and young adults with solid tumors
4. To measure effects on immune checkpoint inhibition in response to routine immunizations (dose-expansion phase only).
5. To evaluate immune activation and counts of NK-, B- and T-cells.

Conditions and MedDRA coding

Advanced Solid Tumors

Regulatory references

EMA paediatric investigation plan (PIP)

EMEA-002029-PIP01-16, EMEA-002028-PIP01-16

Plan to share IPD

Yes

IPD plan description

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal Vivli.org. All requests will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure. Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared. AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA PhRMA Data Sharing Principles. When a request has been approved AstraZeneca will provide access to the anonymized individual patient-level data via secure research environment https://vivli.org/. Signed Data Usage Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 5

1. 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.
2. If available, patients must provide a diagnostic tumor sample taken ˂3 years prior to screening for evaluation of PD-L1 status.
3. 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)
4. Patients must have measurable/evaluable disease as defined by methods used in common clinical practice.
5. 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 8

1. History of allogeneic organ transplantation. Patients who have previously received an autologous bone marrow transplant may be eligible
2. 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.
3. 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.
4. History of primary immunodeficiency.
5. 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).
6. 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.
7. 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.
8. 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

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 4

1. Based on PK parameters (including Cmax, Cmin, AUC, and others), identify the adult equivalent exposure/MTD of durvalumab in combination with tremelimumab and durvalumab as monotherapy following combination therapy, among children and young adults from birth to <18 years of age with advanced solid tumors using a q4w dosing schedule.
2. Identify the safety and tolerability of durvalumab in combination with tremelimumab and durvalumab as monotherapy following combination therapy, at the adult equivalent exposure/MTD among children and young adults from birth to <18 years of age with advanced solid tumor using a q4w dosing schedule. Endpoints include AEs, vital signs, physical examinations, ECGs, and laboratory evaluations
3. Objective response rate as determined by the Investigator assessed RECIST 1.1 or alternative pre-specified tumor-specific response rates for different scoring systems. -Assessment of antitumor activity will be specific to tumor cohort, eg, Investigator assessed RECIST 1.1 (other malignancies will be analyzed based on the best response assessed by the Investigator).
4. Additional efficacy endpoints that will be collected include DoR, BoR, DCR, PFS, APF12, and APF18 based on RECIST 1.1 assessed by the Investigator, and OS, OS12, and OS24 as appropriate

Secondary endpoints 4

1. Individual durvalumab and tremelimumab concentrations in serum, and PK parameters including Cmax, Cmin, AUC.
2. Number and percentage of patients who develop detectable ADAs.
3. Individual antibody titer measurements before and after planned routine immunization during treatment and Cycle 4 or follow-up, whichever is earlier.
4. Flow cytometry for CD4, CD8, B and NK cells, including T-cell activation with Ki67

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

AstraZeneca AB

Sponsor organisation

AstraZeneca AB

Address

-

City

Sodertalje

Postcode

151 85

Country

Sweden

Scientific contact point

Organisation

AstraZeneca AB

Contact name

AstraZeneca Clinical Study Information Center

Public contact point

Organisation

AstraZeneca AB

Contact name

AstraZeneca Clinical Study Information Center

Third parties 1

Locations

1 EU/EEA country · 2 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 5 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

3 submissions — initial application plus substantial / non-substantial modifications