Clinical trial NCT04236414: Investigating Safety, Tolerability, Efficacy and PK of Olaparib in Paediatric Patients With Solid Tumours
Official title: A Phase I, Open-label, Parallel Group Study to Investigate Olaparib Safety and Tolerability, Efficacy and Pharmacokinetics in Paediatric Patients With Solid Tumours
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Solid Tumours
Keywords: Cancer
Malignant cancer
Paediatric population
Olaparib
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
First posted: 2020-01-22
Enrollment: 16
Sex: ALL
Minimum age (years): 0
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: A study to find out whether olaparib is safe and well tolerated when administered to children and adolescents with solid tumours.

Detailed description: A Phase I open-label, multicentre study to determine the RP2D of olaparib monotherapy in the paediatric population, and to evaluate the safety, tolerability, PK, PDx and preliminary efficacy of olaparib monotherapy in paediatric patients from ≥6 months to \<18 years of age at enrolment, with relapsed or refractory solid or primary CNS tumours (excluding lymphoid malignancies) for whom there are no standard treatment options. It is anticipated that eligible patients fulfilling all of the inclusion criteria and none of the exclusion criteria, will include but will not be limited to those with osteosarcoma, rhabdomyosarcoma, non-rhabdomyosarcoma soft tissue sarcoma, Ewing Sarcoma, neuroblastoma, medulloblastoma and glioma

Eligibility criteria: Key Inclusion Criteria:

* Provision of Informed Consent
* Male and female patients who are ≥6 months to \<18 years of age at consent
* 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, non rhabdomyosarcoma soft tissue sarcoma, Ewing Sarcoma, neuroblastoma, medulloblastoma and glioma
* For dose finding phase only: recruitment will be open to all patients with HRR deficiency, based on a local test. For the signal identification phase: recruitment will be open only to patients with documented evidence of a deleterious or suspected deleterious germline or tumour HRR gene mutation that meets the AZ HRR rules
* 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 all non-neuroblastoma tumours, patients must have at least 1 radiographical assessable lesion (measurable and/or non-measurable). For neuroblastoma tumours, patients must have radiographical assessable disease with at least 1 lesion (measurable and/or non measurable) OR disease evidenced by uptake of meta-iodobenzylguanidine- (MIBG) or fluorodeoxyglucose positron emission tomography (FDG-PET) scans
* Adequate performance status, organ, and marrow function and adequate weight to obtain blood samples for both safety laboratory assessments and PK analysis.
* Ability to swallow tablets

Key Exclusion Criteria:

* Patients with MDS/AML or with features suggestive of MDS/AML
* Patients unable to swallow orally administered medication
* Unresolved toxicity from previous anticancer therapy
* Unstable or untreated CNS disease (i.e., symptomatic uncontrolled brain metastases or untreated spinal cord compression)
* Previous treatment with a PARP inhibitor, including olaparib
* Receipt of any radiotherapy for cancer treatment (except for palliative reasons) within 30 days prior to first dose of study treatment or receipt of last dose of an approved (marketed) anticancer therapy (chemotherapy, targeted therapy, biologic therapy, monoclonal antibodies, etc) within 21 days prior to the first dose of study treatment
* Concomitant use of known strong or moderate CYP3A inhibitors or concomitant use of known strong or moderate CYP3A inducers
* Whole blood transfusions in the last 120 days prior to screening (packed red blood cells and platelet transfusions are acceptable)

Primary outcomes:
measure: Dose limiting toxicity [DLTs]
timeFrame: 28 days
measure: Safety profile
timeFrame: Until 30 days after last dose
Secondary outcomes:
measure: Apparent total clearance of the drug from plasma at steady state after oral administration [CLss/F]
timeFrame: The pre-dose sample should be collected within 12±0.5 hours of the Day 7 evening dose of olaparib, prior to the Day 8 morning dose and within 12±1 hours of the Day 28 evening olaparib dose, prior to the Day 29 morning dose.
measure: Maximum plasma concentration at steady state [Css,max]
timeFrame: The pre-dose sample should be collected within 12±0.5 hours of the Day 7 evening dose of olaparib, prior to the Day 8 morning dose and within 12±1 hours of the Day 28 evening olaparib dose, prior to the Day 29 morning dose.
measure: Minimum plasma concentration at steady state [Css, min]
timeFrame: The pre-dose sample should be collected within 12±0.5 hours of the Day 7 evening dose of olaparib, prior to the Day 8 morning dose and within 12±1 hours of the Day 28 evening olaparib dose, prior to the Day 29 morning dose.
measure: Time to maximum plasma concentration at steady state [tss,max]
timeFrame: The pre-dose sample should be collected within 12±0.5 hours of the Day 7 evening dose of olaparib, prior to the Day 8 morning dose and within 12±1 hours of the Day 28 evening olaparib dose, prior to the Day 29 morning dose.
measure: Area under the curve at steady state [AUCss]
timeFrame: The pre-dose sample should be collected within 12±0.5 hours of the Day 7 evening dose of olaparib, prior to the Day 8 morning dose and within 12±1 hours of the Day 28 evening olaparib dose, prior to the Day 29 morning dose.
measure: Dose normalised area under the curve at steady state [dose normalised AUCss]
timeFrame: The pre-dose sample should be collected within 12±0.5 hours of the Day 7 evening dose of olaparib, prior to the Day 8 morning dose and within 12±1 hours of the Day 28 evening olaparib dose, prior to the Day 29 morning dose.
measure: Area under the curve at 0-8 hours [AUC(0-8)]
timeFrame: The pre-dose sample should be collected within 12±0.5 hours of the Day 7 evening dose of olaparib, prior to the Day 8 morning dose and within 12±1 hours of the Day 28 evening olaparib dose, prior to the Day 29 morning dose.
measure: Area under the curve from zero up to time t [AUC0-t]
timeFrame: The pre-dose sample should be collected within 12±0.5 hours of the Day 7 evening dose of olaparib, prior to the Day 8 morning dose and within 12±1 hours of the Day 28 evening olaparib dose, prior to the Day 29 morning dose.
measure: Dose normalised maximum plasma concentration at steady state [dose normalised Css,max]
timeFrame: The pre-dose sample should be collected within 12±0.5 hours of the Day 7 evening dose of olaparib, prior to the Day 8 morning dose and within 12±1 hours of the Day 28 evening olaparib dose, prior to the Day 29 morning dose.
measure: ORR as defined by Investigator-assessed RECIST v1.1, INRC or RANO
timeFrame: Up to 64 months
measure: DCR as defined by Investigator-assessed RECIST v1.1, INRC or RANO
timeFrame: Up to 64 months
measure: DoR as defined by Investigator-assessed RECIST v1.1, INRC or RANO
timeFrame: Up to 64 months
Other outcomes:
Locations:
city: København Ø
country: Denmark
facility: Research Site
city: Lille
country: France
facility: Research Site
city: Toulouse
country: France
facility: Research Site
city: Villejuif Cedex
country: France
facility: Research Site
city: Heidelberg
country: Germany
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Madrid
country: Spain
facility: Research Site
city: Glasgow
country: United Kingdom
facility: Research Site
city: Sutton
country: United Kingdom
facility: Research Site
Study officials:
affiliation: AstraZeneca
name: Milenkova Tsveta
role: STUDY_DIRECTOR
References: