| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To describe the safety and tolerability of olaparib monotherapy and identify the RP2D of olaparib in the paediatric population. |
|
| E.2.2 | Secondary objectives of the trial |
- 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. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
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, non-rhabdomyosarcoma 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 by case 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.
Please refer to the protocol for full inclusion criteria. |
|
| E.4 | Principal exclusion criteria |
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 active infection, 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.
Please refer to the protocol for full exclusion criteria. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| DLTs, RP2D, AEs/SAEs/deaths, discontinuation rate of olaparib treatment due to AEs throughout the study, clinical chemistry/haematology parameters, vital signs. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Please refer to the Schedule of Assessments of the protocol. |
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| E.5.2 | Secondary end point(s) |
- 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 |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Please refer to the Schedule of Assessments of the protocol. |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| Determination of the recommended Phase II dose (RP2D) in paediatric patients |
|
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Different dose of olaparib |
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| E.8.2.4 | Number of treatment arms in the trial | 15 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 25 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Israel |
| Korea, Republic of |
| Denmark |
| France |
| Germany |
| United Kingdom |
| Spain |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | 17 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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