History of Changes for Study: NCT04236414

Version	Submitted Date	Changes
1	January 21, 2020	None (earliest Version on record)
2	March 5, 2020	Study Status and Contacts/Locations
3	May 28, 2020	Study Status and IPDSharing
4	July 29, 2020	Eligibility, Outcome Measures, Study Status, Contacts/Locations and Study Description
5	August 25, 2020	Study Status and Study Design
6	October 2, 2020	Study Status, Contacts/Locations and Eligibility
7	November 12, 2020	Oversight and Study Status
8	December 16, 2020	Study Status and Contacts/Locations
9	January 18, 2021	Study Status and Contacts/Locations
10	February 25, 2021	Study Status and Contacts/Locations
11	March 25, 2021	Study Status
12	May 26, 2021	Study Status and Contacts/Locations
13	June 21, 2021	Study Status
14	July 20, 2021	Study Status and Study Description
15	August 26, 2021	Contacts/Locations and Study Status
16	September 21, 2021	Study Status
17	October 22, 2021	Study Status
18	November 25, 2021	Study Status and Study Description
19	December 23, 2021	Study Status
20	January 28, 2022	Contacts/Locations and Study Status
21	February 28, 2022	Study Status
22	April 21, 2022	Arms and Interventions, Study Status and Contacts/Locations
23	May 23, 2022	Study Status and Study Description
24	July 26, 2022	Study Status
25	September 1, 2022	Contacts/Locations and Study Status
26	September 30, 2022	Study Status
27	November 7, 2022	Contacts/Locations and Study Status
28	December 2, 2022	Study Status and Contacts/Locations
29	February 8, 2023	Study Status and Contacts/Locations
30	March 17, 2023	Study Status and Contacts/Locations
31	June 30, 2023	Contacts/Locations and Study Status
32	November 24, 2023	Contacts/Locations and Study Status
33	January 5, 2024	Study Status and Contacts/Locations
34	February 7, 2024	Study Status

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 non-CNS solid tumours 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 and neuroblastoma.

Arms and Interventions

Arms	Assigned Interventions
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.	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 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. 25 and 100 mg tablet strengths available for ages ≥3 to <18 years. Feasibility for an AAF for ≥0.5 to <6 years planned.
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.	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 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. 25 and 100 mg tablet strengths available for ages ≥3 to <18 years. Feasibility for an AAF for ≥0.5 to <6 years planned.
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, 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.	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 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. 25 and 100 mg tablet strengths available for ages ≥3 to <18 years. Feasibility for an AAF for ≥0.5 to <6 years planned.
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.	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 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. 25 and 100 mg tablet strengths available for ages ≥3 to <18 years. Feasibility for an AAF for ≥0.5 to <6 years planned.

Primary Outcome Measures:

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

Secondary Outcome Measures:

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

10.

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

11.

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

12.

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

13.

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

Minimum Age:

6 Months

Maximum Age:

17 Years

Sex:

All

Gender Based:

Accepts Healthy Volunteers:

Criteria:

Key Inclusion Criteria:

Provision of Informed Consent
Male and female patients who are ≥6 months to <18 years of age at the screening visit.
Pathologically confirmed relapsed or refractory non-CNS solid tumours (excluding lymphoid malignancies), with a HRR deficiency, 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 and neuroblastoma.
For dose finding phase only: recruitment will be open to all patients with HRR deficiency, either based on a local test or by using a central germline 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 olaparib HRR classification rules
An FFPE tumour sample from the primary cancer (all patients) and blood sample (patients ≥2 years old) suitable for central HRR 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).

Central Contact Person:

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

Study Officials:

Milenkova Tsveta
Study Director
AstraZeneca

Locations:

Denmark

Research Site
[Not yet recruiting]
København Ø, Denmark, 2100

France

Research Site
[Not yet recruiting]
Lille, France, 59000

Research Site
[Not yet recruiting]
Marseille, France, 13005

Research Site
[Not yet recruiting]
Paris, France, 75005

Research Site
[Not yet recruiting]
Toulouse, France, 31300

Research Site
[Not yet recruiting]
Villejuif, France, 94800

Germany

Research Site
[Not yet recruiting]
Heidelberg, Germany, 69120

Research Site
[Not yet recruiting]
Mainz A. Rhein, Germany, 55131

Israel

Research Site
[Not yet recruiting]
Haifa, Israel, 31096

Research Site
[Not yet recruiting]
Petah Tikva, Israel, 4920235

Korea, Republic of

Research Site
[Recruiting]
Seoul, Korea, Republic of, 03080

Research Site
[Not yet recruiting]
Seoul, Korea, Republic of, 06351

Research Site
[Not yet recruiting]
Songpa-gu, Korea, Republic of, 05505

Spain

Research Site
[Not yet recruiting]
Barcelona, Spain, 08035

Research Site
[Not yet recruiting]
Esplugues De Llobregat (Barc), Spain, 08950

Research Site
[Not yet recruiting]
Madrid, Spain, 28009

Research Site
[Not yet recruiting]
Madrid, Spain, 28046

Research Site
[Not yet recruiting]
Valencia, Spain, 46026

United Kingdom

Research Site
[Not yet recruiting]
Birmingham, United Kingdom, B4 6NH

Research Site
[Not yet recruiting]
Glasgow, United Kingdom, G51 4TF

Research Site
[Not yet recruiting]
Leeds, United Kingdom, LS1 3EX

Research Site
[Not yet recruiting]
Sutton, United Kingdom, SM2 5PT