A study to find out whether olaparib is safe and well tolerated when administered to children and adolescents

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

27 Jan 2020 → 5 Feb 2025

Decision date (initial)

2024-10-08

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

AstraZeneca AB, Sweden

External identifiers

EU CT number

2023-507904-30-00

EudraCT number

2018-003355-38

ClinicalTrials.gov

NCT04236414

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Pharmacodynamic, Pharmacokinetic, Safety

To describe the safety and tolerability of olaparib monotherapy and identify the RP2D of olaparib in the paediatric population

Secondary objectives 1

1. To describe the paediatric PK profile and to identify the adult equivalent (300 mg bd tablet) dose based upon PK modelling. To describe anti-tumour activity based upon RECIST v1.1 criteria, INRC, or RANO in paediatric patients with measurable or non-measurable assessable disease including in the subset of the minimum of 10 patients with deleterious or suspected deleterious HRR gene mutations

Conditions and MedDRA coding

solid tumors

Regulatory references

EMA paediatric investigation plan (PIP)

EMEA-002269-PIP01-17

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 1

1. 1 Paediatric patients with pathologically confirmed relapsed or refractory solid or primary CNS tumours (excluding lymphoid malignancies), with a HRR deficiency/gene mutation, and for whom there are no standard treatment options. Eligible patients may include but not be limited to those with osteosarcoma, rhabdomyosarcoma, nonrhabdomyosarcoma soft tissue sarcoma, Ewing Sarcoma, neuroblastoma, medulloblastoma and glioma. (a) Any number of prior treatment regimens allowed. (b) A select group of first-line patients may be considered on a case bycase basis to be eligible for screening and enrolment. These patients will be enrolled based on Investigator assessment after discussion with the sponsor as patients for whom no curative standard of care treatment options exist or such therapies are not tolerable. 2 A formalin fixed, paraffin embedded (FFPE) tumour sample from the primary cancer (all patients) suitable for central HRR testing and a blood sample (patients ≥2 years old) for central germline BRCA testing must be provided for each patient for central laboratory assessment. Patients with a known HRR deficiency/gene mutation (based on local testing) are not required to wait for the results of the central test to proceed with the main part of the study, assuming all other eligibility criteria are met. The blood sample (from patients with a known HRR deficiency/gene mutation) and tumour sample should be shipped to the central laboratory following consent; patients with unknown HRR deficiency status will have their blood samples sent for central evaluation prior to enrolment. (a) A FFPE tumour tissue block is required, but if not available, tissue sections are accepted. The tumour specimen submitted should be of sufficient quantity (b) Patients who don't have an archival tumour sample may be allowed to provide a newly biopsied FFPE tumour tissue sample provided the sample is taken as part of routine clinical practice. The most recent sample available should be provided. Tumour lesions used for newly acquired biopsies should not be the same lesions used as RECIST v1.1, INRC or RANO target lesions, unless there are no other lesions suitable for biopsy (re-assessment after biopsy may be required). 3 Lansky scale ≥50 for patients ≤16 years of age; or Karnofsky score ≥ 50 for patients >16 years of age (see Appendix F). 4 For all non-neuroblastoma tumours, patients must have at least 1 lesion (measurable and/or non-measurable), not previously irradiated, that can be accurately assessed at baseline and is suitable for repeated assessment using RECIST v1.1 or RANO. 5 For neuroblastoma tumours, patients must have: (a) Radiographical assessable disease with at least 1 lesion (measurable and/or non-measurable) that can be accurately assessed at baseline and is suitable for repeated assessment using INRC; OR, (b) Disease evidenced by uptake of meta-iodobenzylguanidine- (MIBG) or fluorodeoxyglucose positron emission tomography (FDG-PET) scans. 6 Patients must have normal organ and bone marrow function measured within 28 days prior to administration of study treatment as defined in the protocol.

Exclusion criteria 1

1. 1 Patients with MDS/AML or with features suggestive of MDS/AML. 2 Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the study drug. 3 Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with the exception of alopecia, vitiligo, lymphopenia, and the laboratory values defined in the inclusion criterion. Patients with a toxicity not reasonably expected to be exacerbated by study treatment (eg, hearing loss, gastrostomy tube) may be included after consultation with the Study Physician. 4 Patients considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection. Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 3 months) myocardial infarction, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, extensive interstitial bilateral lung disease on High Resolution Computed Tomography scan, ongoing or activeinfection, symptomatic congestive heart failure, cardiac arrhythmia, interstitial lung disease, or any psychiatric illness or social situations that would limit compliance with study requirements, substantially increase the risk of incurring AEs from IP, or compromise the ability of the patient to give written informed assent. 5 History of other primary malignancy unless curatively treated with no evidence of disease for ≥5 years. Non-invasive malignancies such as adequately treated non-melanoma skin cancer or in situ carcinomas that have been adequately treated may be permitted after detailed discussion with the Study Physician. 6 Patients with primary or metastatic CNS disease meeting the following criteria: (a) Symptomatic uncontrolled brain metastases at baseline. A scan to confirm the absence of brain metastases is not required. (b) Patients with brain metastases or primary brain tumours who require corticosteroids for management of symptoms or progression. (c) Patients with spinal cord compression unless considered to have received definitive treatment for this and evidence of clinically stable disease for 28 days. 7 History of active primary immunodeficiency or immunocompromised patients, eg, patients who are known to be serologically positive for human immunodeficiency virus (HIV). 8 Patients with known active hepatitis (ie, Hepatitis B or C). (a) Active hepatitis B virus (HBV) is defined by a known positive HBV surface antigen (HBsAg) result. Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody and absence of HBsAg) are eligible. (b) Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV ribonucleic acid. 9 Resting ECG indicating uncontrolled, potentially reversible cardiac conditions, as judged by the Investigator (eg, unstable ischemia, uncontrolled symptomatic arrhythmia, congestive heart failure, corrected QT interval (QTc) prolongation >500 ms, electrolyte disturbances, etc.), or patients with congenital long QT syndrome. 10 Any condition that, in the opinion of the Investigator, would interfere with evaluation of the study treatment or interpretation of patient safety or study results.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. DLTs, RP2D, AEs/SAEs/deaths, discontinuation rate of olaparib treatment due to AEs throughout the study, clinical chemistry/haematology parameters, vital signs

Secondary endpoints 1

1. PK parameters: CLss/F, Css,max, Css, min, tss,max, AUCss, dose normalised AUCss, AUC(0-8), AUC0-t, and dose normalised Css,max ORR, DCR and DoR as defined by Investigator-assessed RECIST v1.1, INRC, or RANO

Investigational products

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

Test 4

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

AstraZeneca AB

Sponsor organisation

AstraZeneca AB

Address

Astraallen Gartuna, Karlebyhus Byggnad 674 Karlebyhus Byggnad 674

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 10

Locations

5 EU/EEA countries · 12 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

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 7 files

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

Application history

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