Clinical Trials /

Investigating Safety, Tolerability, Efficacy and PK of Olaparib in Paediatric Patients With Solid Tumours

NCT04236414

Description:

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

Related Conditions:
  • Ewing Sarcoma
  • Malignant Solid Tumor
  • Neuroblastoma
  • Osteosarcoma
  • Rhabdomyosarcoma
  • Soft Tissue Sarcoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: 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

Clinical Trial IDs

  • ORG STUDY ID: D0816C00025
  • SECONDARY ID: 2018-003355-38
  • NCT ID: NCT04236414

Conditions

  • Solid Tumours

Interventions

DrugSynonymsArms
OlaparibCohort A: ≥12 to <18 years

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
Cohort A: ≥12 to <18 yearsExperimentalPatients will receive a single dose of olaparib on Day 1, followed by initiation of bd continuous dosing from Day 2 onwards. Olaparib tablets should be taken at the same time each day (morning and evening), approximately 12 hours apart with one glass of water. The tablets should be swallowed whole and not chewed, crushed, dissolved or divided. Olaparib tablets can be taken with or without food, with the exception of Day 8 (a PK sampling day) when patients aged ≥3 years old receiving tablets should take olaparib at least 1 hour after food and should refrain from eating for up to 2 hours afterwards.
  • Olaparib
Cohort B: ≥3 to <12 yearsExperimentalPatients will receive a single dose of olaparib on Day 1, followed by initiation of bd continuous dosing from Day 2 onwards. Olaparib tablets should be taken at the same time each day (morning and evening), approximately 12 hours apart with one glass of water. The tablets should be swallowed whole and not chewed, crushed, dissolved or divided. Olaparib tablets can be taken with or without food, with the exception of Day 8 (a PK sampling day) when patients aged ≥3 years old receiving tablets should take olaparib at least 1 hour after food and should refrain from eating for up to 2 hours afterwards.
  • Olaparib
Cohort C: ≥6 months to <6 yearsExperimentalPatients will receive a single dose of olaparib on Day 1, followed by initiation of bd continuous dosing from Day 2 onwards, using the AAF when available (if required). Olaparib tablets should be taken at the same time each day (morning and evening), approximately 12 hours apart with one glass of water. The tablets should be swallowed whole and not chewed, crushed, dissolved or divided. Olaparib tablets/AAF can be taken with or without food, with the exception of Day 8 (a PK sampling day) when patients aged ≥3 years old receiving tablets should take olaparib at least 1 hour after food and should refrain from eating for up to 2 hours afterwards.
  • Olaparib
Signal identificationExperimentalA secondary analysis of response in patients recruited into the signal identification phase will be conducted. Patients included in this analysis must have documented evidence of a deleterious or suspected deleterious germline or tumour HRR gene mutation. A minimum of 10 patients across age and dose cohorts with deleterious or suspected deleterious HRR mutations will be enrolled.
  • Olaparib

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)
      
Maximum Eligible Age:18 Years
Minimum Eligible Age:6 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Dose limiting toxicity [DLTs]
Time Frame:28 days
Safety Issue:
Description:DLT - Dose limiting toxicity

Secondary Outcome Measures

Measure:Apparent total clearance of the drug from plasma at steady state after oral administration [CLss/F]
Time Frame: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.
Safety Issue:
Description:Olaparib levels in mcg/mL
Measure:Maximum plasma concentration at steady state [Css,max]
Time Frame: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.
Safety Issue:
Description:Olaparib levels in mcg/mL
Measure:Minimum plasma concentration at steady state [Css, min]
Time Frame: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.
Safety Issue:
Description:Olaparib levels in mcg/mL
Measure:Time to maximum plasma concentration at steady state [tss,max]
Time Frame: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.
Safety Issue:
Description:Olaparib levels in mcg/mL
Measure:Area under the curve at steady state [AUCss]
Time Frame: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.
Safety Issue:
Description:Olaparib levels in mcg/mL
Measure:Dose normalised area under the curve at steady state [dose normalised AUCss]
Time Frame: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.
Safety Issue:
Description:Olaparib levels in mcg/mL
Measure:Area under the curve at 0-8 hours [AUC(0-8)]
Time Frame: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.
Safety Issue:
Description:Olaparib levels in mcg/mL
Measure:Area under the curve from zero up to time t [AUC0-t]
Time Frame: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.
Safety Issue:
Description:Olaparib levels in mcg/mL
Measure:Dose normalised maximum plasma concentration at steady state [dose normalised Css,max]
Time Frame: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.
Safety Issue:
Description:Olaparib levels in mcg/mL
Measure:ORR as defined by Investigator-assessed RECIST v1.1, INRC or RANO
Time Frame:Up to 64 months
Safety Issue:
Description:ORR - Objective response rate INRC - International Neuroblastoma Response Criteria RECIST - Response Evaluation Criteria in Solid tumours RANO - Response Assessment in Neuro-oncology
Measure:DCR as defined by Investigator-assessed RECIST v1.1, INRC or RANO
Time Frame:Up to 64 months
Safety Issue:
Description:DCR - Disease control rate INRC - International Neuroblastoma Response Criteria RECIST - Response Evaluation Criteria in Solid tumours RANO - Response Assessment in Neuro-oncology
Measure:DoR as defined by Investigator-assessed RECIST v1.1, INRC or RANO
Time Frame:Up to 64 months
Safety Issue:
Description:DoR - Duration of response INRC - International Neuroblastoma Response Criteria RECIST - Response Evaluation Criteria in Solid tumours RANO - Response Assessment in Neuro-oncology

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:AstraZeneca

Trial Keywords

  • Cancer
  • Malignant cancer
  • Paediatric population
  • Olaparib

Last Updated

July 29, 2020