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

• ClinicalTrials.gov Identifier: NCT04236414
• Recruitment Status: Recruiting
• First Posted: January 22, 2020
• Last Update Posted: February 8, 2024
• Sponsor: AstraZeneca
• Information provided by (Responsible Party): AstraZeneca

Tracking Information

• First Submitted Date: November 13, 2019
• First Posted Date: January 22, 2020
• Last Update Posted Date: February 8, 2024
• Actual Study Start Date: January 14, 2020
• Estimated Primary Completion Date: December 30, 2025 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 21, 2020)

• Dose limiting toxicity [DLTs] [ Time Frame: 28 days ]
  DLT - Dose limiting toxicity
• Safety profile [ Time Frame: Until 30 days after last dose ]
  Number of patients with adverse events

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: July 29, 2020)

• 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. ]
  Olaparib levels in mcg/mL
• 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. ]
  Olaparib levels in mcg/mL
• 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. ]
  Olaparib levels in mcg/mL
• 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. ]
  Olaparib levels in mcg/mL
• 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. ]
  Olaparib levels in mcg/mL
• 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. ]
  Olaparib levels in mcg/mL
• 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. ]
  Olaparib levels in mcg/mL
• 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. ]
  Olaparib levels in mcg/mL
• 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. ]
  Olaparib levels in mcg/mL
• ORR as defined by Investigator-assessed RECIST v1.1, INRC or RANO [ Time Frame: Up to 64 months ]
  ORR - Objective response rate INRC - International Neuroblastoma Response Criteria RECIST - Response Evaluation Criteria in Solid tumours RANO - Response Assessment in Neuro-oncology
• DCR as defined by Investigator-assessed RECIST v1.1, INRC or RANO [ Time Frame: Up to 64 months ]
  DCR - Disease control rate INRC - International Neuroblastoma Response Criteria RECIST - Response Evaluation Criteria in Solid tumours RANO - Response Assessment in Neuro-oncology
• DoR as defined by Investigator-assessed RECIST v1.1, INRC or RANO [ Time Frame: Up to 64 months ]
  DoR - Duration of response INRC - International Neuroblastoma Response Criteria RECIST - Response Evaluation Criteria in Solid tumours RANO - Response Assessment in Neuro-oncology

Original Secondary Outcome Measures (submitted: January 21, 2020)

• 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. ]
  Olaparib levels in mcg/mL
• 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. ]
  Olaparib levels in mcg/mL
• 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. ]
  Olaparib levels in mcg/mL
• 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. ]
  Olaparib levels in mcg/mL
• 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. ]
  Olaparib levels in mcg/mL
• 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. ]
  Olaparib levels in mcg/mL
• 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. ]
  Olaparib levels in mcg/mL
• 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. ]
  Olaparib levels in mcg/mL
• 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. ]
  Olaparib levels in mcg/mL
• Mean % inhibition of PARP-1 from baseline in PBMC samples [ Time Frame: 28 days ]
  PARP - Polyadenosine 5'diphosphoribose [poly (ADP ribose)] polymerase PDMC - Peripheral blood mononuclear cells
• ORR as defined by Investigator-assessed RECIST v1.1 or INRC [ Time Frame: Up to 64 months ]
  ORR - Objective response rate INRC - International Neuroblastoma Response Criteria RECIST - Response Evaluation Criteria in Solid tumours
• DCR as defined by Investigator-assessed RECIST v1.1 or INRC [ Time Frame: Up to 64 months ]
  DCR - Disease control rate INRC - International Neuroblastoma Response Criteria RECIST - Response Evaluation Criteria in Solid tumours
• DoR as defined by Investigator-assessed RECIST v1.1 or INRC [ Time Frame: Up to 64 months ]
  DoR - Duration of response INRC - International Neuroblastoma Response Criteria RECIST - Response Evaluation Criteria in Solid tumours

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• 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
• 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
• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Solid Tumours

Intervention

Drug: Olaparib

Patients will receive a single dose of olaparib on Day 1, followed by initiation of bd continuous dosing from Day 2 onwards. Olaparib 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. 25 and 100 mg tablet strengths available for ages ≥3 to <18 years. AAF available for ≥0.5 to <6 years; The AAF is a sprinkle capsule formulation, available in dose strengths of 15 mg and 19.5 mg. The sprinkle capsules contain 1.5 mg granules which are to be dispersed onto a food vehicle prior to dosing.

Study Arms

• Experimental: Cohort A: ≥12 to <18 years
  Patients 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.
  Intervention: Drug: Olaparib
• Experimental: Cohort B: ≥3 to <12 years
  Patients 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.
  Intervention: Drug: Olaparib
• Experimental: Cohort C: ≥6 months to <6 years
  Patients will receive a single dose of olaparib on Day 1, followed by initiation of bd continuous dosing from Day 2 onwards. Olaparib should be taken at the same time each day (morning and evening), approximately 12 hours apart. Patients in Cohort C will receive a predetermined number of each sprinkle capsule strength (15 and 19.5 mg,) to make up the required dose. Olaparib sprinkle capsules will be administered to the child by the parent/caregiver. Patients in Cohort C are not required to fast including PK sampling days. The dispensed granules should be swallowed whole and not chewed, crushed, dissolved or divided, and should be consumed within 30 minutes of preparation.
  Intervention: Drug: Olaparib
• Experimental: Signal identification
  A 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.
  Intervention: Drug: Olaparib

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: August 25, 2020): 30
• Original Estimated Enrollment (submitted: January 21, 2020): 48
• Estimated Study Completion Date: December 30, 2025
• Estimated Primary Completion Date: December 30, 2025 (Final data collection date for primary outcome measure)

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)

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 0 Years to 18 Years (Child, Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: AstraZeneca Clinical Study Information Center; 1-877-240-9479; information.center@astrazeneca.com

• Listed Location Countries: Australia, Austria, Brazil, Canada, Denmark, France, Germany, Hungary, Israel, Italy, Korea, Republic of, Poland, Russian Federation, Spain, Ukraine, United Kingdom, United States

Administrative Information

• NCT Number: NCT04236414
• Other Study ID Numbers: D0816C00025; 2018-003355-38 ( EudraCT Number )
• Has Data Monitoring Committee: Not Provided

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• 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. All request will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure
• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (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 refer 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 assessors) 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
• URL: https://astrazenecagroup-dt.pharmacm.com/DT/Home

• Current Responsible Party: AstraZeneca
• Original Responsible Party: Same as current
• Current Study Sponsor: AstraZeneca
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Milenkova Tsveta; AstraZeneca

• PRS Account: AstraZeneca
• Verification Date: February 2024