| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Recurrent or refractory solid tumour |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10065147 |
| E.1.2 | Term | Malignant solid tumor |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10065252 |
| E.1.2 | Term | Solid tumor |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 |
• Part 1A: to establish the recommended Phase 2 dose (RP2D) of the combination of niraparib tablet and dostarlimab in paediatric participants
• Part 1B: to establish the RP2D of the combination of niraparib age-appropriate oral liquid formulation (AAOLF) and dostarlimab in paediatric participants |
|
| E.2.2 | Secondary objectives of the trial |
Secondary objectives for Part 1 of this study:
• to evaluate additional measures of anticancer activity including objective response rate (ORR) and duration of response (DOR)
• to evaluate the safety and tolerability of the combination of niraparib (tablet or AAOLF) and dostarlimab in paediatric participants
• to characterise the pharmacokinetics (PK) of the combination of niraparib and dostarlimab in paediatric participants
• to assess the acceptability and palatability of niraparib tablets and AAOLF in paediatric participants |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
• Supplement A: Expansion cohort of participants with osteosarcoma (the “OS cohort”) to assess the antitumour activity of the combination of niraparib and dostarlimab, assessed primarily by the progression-free survival rate at 6 months using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria.
The primary objective of this cohort is as follows:
- to assess the antitumour activity of the combination of niraparib and dostarlimab, assessed primarily by the progression-free survival rate at 6 months (PFS6) (using Response Evaluation Criteria in Solid Tumours [RECIST] v1.1 criteria)
The secondary objectives of this cohort are as follows:
- to evaluate additional measures of anticancer activity, including objective response rate (ORR), duration of response (DOR), disease control rate (DCR), and progression-free survival (PFS)
- to evaluate the safety of the combination of niraparib (tablet or age-appropriate oral liquid formulation [AAOLF]) and dostarlimab in paediatric participants
- to characterise the pharmacokinetics (PK) of the combination of niraparib and dostarlimab in paediatric participants
- to assess the acceptability and palatability of niraparib tablets and AAOLF in paediatric participants
The exploratory objective of this cohort is as follows:
- to assess the correlation between clinical outcome and biomarkers related to poly(adenosine diphosphate-ribose) polymerase (PARP) inhibition and/or anti-programmed cell death protein 1 (anti-PD-1) therapy
• Supplement B: Expansion cohort of participants with neuroblastoma (the “NB cohort”) to assess the antitumour activity of the combination of niraparib and dostarlimab, assessed primarily by ORR using International Neuroblastoma Response Criteria (INRC).
The primary objective of this cohort is as follows:
- to assess the antitumour activity of the combination of niraparib and dostarlimab, assessed primarily by objective response rate (ORR) (using International Neuroblastoma Response Criteria [INRC])
Secondary:
The secondary objectives of this cohort are as follows:
- to evaluate additional measures of anticancer activity, including duration of response (DOR), disease control rate (DCR), and progression-free survival (PFS)
- to evaluate the safety of the combination of niraparib (tablet or age-appropriate oral liquid formulation [AAOLF]) and dostarlimab in paediatric participants
- to characterise the pharmacokinetics (PK) of the combination of niraparib and dostarlimab in paediatric participants
- to assess the acceptability and palatability of niraparib tablets and AAOLF in paediatric participants
The exploratory objective of this cohort is as follows:
- to assess the correlation between clinical outcome and biomarkers related to poly(adenosine diphosphate-ribose) polymerase (PARP) inhibition and/or anti-programmed cell death protein 1 (anti-PD-1) therapy |
|
| E.3 | Principal inclusion criteria |
1. Participant has recurrent or refractory osteosarcoma, neuroblastoma, adrenocortical carcinoma, Ewing sarcoma, rhabdomyosarcoma, or any other solid tumour (excluding tumours of the CNS) previously documented to have BRCAness mutational signature (mutational signature 3) on DNA sequencing of tumour obtained in the relapsed/recurrent disease setting, within 6 (preferably 3) months prior to enrolment and must not be eligible for local curative treatment. For participants with documented BRCAness mutational signature: Existing information on molecular profiling of the participant’s tumour tissue must be through a molecular profiling platform such as Individualized Therapy for Relapsed Malignancies in Childhood (INFORM). Molecular profile information must contain information from whole exome sequencing or whole genome sequencing, including the mutation status of breast cancer susceptibility gene (BRCA) 1 and BRCA2 and other homologous recombination DNA repair pathway genes, mutational signatures including signature 3, and tumour mutational burden.
2. Participant is child or adolescent ≥6 months to <18 years old at the time of informed consent/assent.
3. In order to be eligible to receive the niraparib tablet formulation, participant must be able to swallow the 100 mg niraparib tablet and have a baseline body weight of ≥20 kg. Participants who are unable to swallow the 100 mg niraparib tablet or who have a baseline body weight <20 kg are eligible to receive the niraparib AAOLF only.
4. Performance status must be ≥70% on the Karnofsky scale for participants >16 years of age and ≥50% on the Lansky scale for participants ≤16 years of age. Note: Neurologic deficits in participants with brain metastases must have been stable for at least 7 days prior to study enrolment. Participants who are unable to walk because of paralysis, but who are upright in a wheelchair, will be considered ambulatory for the purpose of assessing the performance status.
5. Participant has adequate organ function, defined as follows: Note: CBC should be obtained without transfusion or receipt of colony-stimulating factors in the 2 weeks before obtaining sample.
a. absolute neutrophil count (ANC) ≥1,500/μL
b. platelets ≥100,000/μL
c. haemoglobin ≥9 g/dL or ≥5.6 mmol/L
d. serum creatinine ≤1.5 × upper limit of normal (ULN) for age or calculated creatinine clearance or radioisotope glomerular filtration rate ≥60 mL/min/1.73 m2
e. total bilirubin ≤1.5 × ULN or direct bilirubin ≤1 × ULN
f. aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 × ULN unless liver metastases are present, in which case AST and ALT must be ≤5 × ULN
g. international normalised ratio or prothrombin time (PT) ≤1.5 × ULN unless the participant is receiving anticoagulant therapy as long as PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants
h. activated PTT ≤1.5 × ULN unless the participant is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants
6. A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies:
a. Is not a woman of childbearing potential (WOCBP). or
b. Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of <1% per year), preferably with low user dependency, as described in Appendix 3, from the Screening Visit through at least 180 days after the last dose of study treatment and agrees not to donate eggs (ova, oocytes) for the purpose of reproduction during this period. The Investigator should evaluate the effectiveness of the contraceptive method in relationship to the first dose of study treatment.
- A WOCBP must have a negative highly sensitive pregnancy test (urine or serum, as required by local regulations) within 72 hours prior to the first dose of study treatment.
Please review study protocol for further Part 1 inclusion criteria.
Inclusion criteria for Part 2 of the study are described in each cohort-specific supplement. |
|
| E.4 | Principal exclusion criteria |
1. Participation presents unacceptable risk to the prospective participant based on the Investigator’s judgment.
2. Participant has known hypersensitivity to dostarlimab or niraparib, their components, or their excipients.
3. Participant has a known history of myelodysplastic syndrome (MDS) or AML.
4. Participant has active autoimmune disease that has required systemic treatment in the past 2 years (ie, with use of disease-modifying antirheumatic drugs, corticosteroids, or immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment.
5. Participant has known active CNS metastases, carcinomatous meningitis, or both. Note: Participants with previously treated brain metastases may participate provided they are clinically stable (without evidence of progression by imaging [using the identical imaging
modality for each assessment, either MRI or CT scan] for at least 4 weeks prior to the first dose of study treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and have not been using steroids for at
least 7 days prior to the first dose of study treatment. Carcinomatous meningitis precludes a participant from study participation regardless of clinical stability.
6. Participant had a known additional malignancy that progressed or required active treatment within the last 2 years.
7. Participant is considered a poor medical risk due to a serious, uncontrolled medical disorder, nonmalignant systemic disease, or active infection that requires systemic therapy. Specific examples include, but are not limited to, history of (noninfectious) pneumonitis that required steroids or current pneumonitis, uncontrolled ventricular arrhythmia, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, or any psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study (including obtaining assent/consent).
8. Participant has a condition (such as transfusion-dependent anaemia or thrombocytopenia), therapy, or laboratory abnormality that might confound the study results or interfere with the participant’s participation for the full duration of the study treatment including the following:
a. Participants who received a transfusion (platelets or red blood cells) within 6 weeks of the first dose of study drug are not eligible.
b. Participants who received colony-stimulating factors (eg, granulocyte-colony stimulating factor [G-CSF], granulocyte-macrophage colony-stimulating factor, or recombinant erythropoietin) within 4 weeks prior to the first dose of study treatment are not eligible.
9. Participant is pregnant, breastfeeding, or expecting to conceive within the projected duration of the study, starting with the Screening Visit through 180 days after the last dose of study treatment. No data are available regarding the presence of dostarlimab or niraparib or its metabolites in human milk, or on its effects on the breastfed infant or milk production. Because of the potential for serious adverse reactions in breastfed infants from dostarlimab and/or niraparib, female participants should not breastfeed during treatment with dostarlimab and/or niraparib and for 1 month after receiving the final dose.
10. Participant has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study treatment.
11. Participant has a known history of HIV (type 1 or 2 antibodies).
12. Participant has known active hepatitis B (eg, hepatitis B surface antigen reactive) or hepatitis C (eg, hepatitis C virus ribonucleic acid [qualitative] is detected).
13. Participant is currently participating and receiving study treatment or has participated in a study of an investigational agent and received study treatment or used an investigational device within 4 weeks of the first dose of study treatment.
14. Participant has had any known Grade 3 or 4 anaemia, neutropenia, or thrombocytopenia due to prior chemotherapy that persisted >4 weeks related to the most recent prior treatment.
Please review study protocol for further Part 1 exclusion criteria.
Exclusion criteria for Part 2 of the study are described in each cohort-specific supplement.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Part 1A and 1B: Assess the incidence of DLTs by study part and cohort for the DLT-evaluable population to establish the RP2D of the combination of niraparib (both tablet in Part 1a and age-appropriate oral formulation AAOF in Part 1b) and dostarlimab.
Part 2: Please refer to the separate cohort-specific supplements for this information. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The DLT observation period is 42 days following the initiation of study treatment (ie, the first 2 treatment cycles) in Part 1 |
|
| E.5.2 | Secondary end point(s) |
• ORR based on Investigator assessment is defined as the proportion of participants with a BOR of confirmed CR or PR as
determined by the Investigator using RECIST v1.1 or INRC (for participants with neuroblastoma only).
• DOR is defined as the time from first documentation of response (CR or PR) until the time of first documented PD by RECIST v1.1 or INRC (for participants with neuroblastoma only) based on Investigator assessment or death (whichever occurs first).
Part 1: Please refers to main study protocol for further Endpoints
Part 2: Please refer to the separate cohort-specific supplements for this information.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Timepoint is included in each Endpoint |
|
| 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 | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Toxicity - Tolerability - Acceptability and Palatability - Immunogenecity and Exploratory Biomarkers - ORR - ADA |
|
| 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 |
| dose escalation and cohort expansion study |
|
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| 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 | No |
| 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 | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 17 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| 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
|
| The end of the study is defined as the date of the last scheduled procedure for the last participant in any part of the study. A participant is considered to have completed the study if he/she has completed all study assessments, including the last scheduled procedure shown in Table 1 for Part 1 and in the SoAs specific to the cohorts provided in the supplements |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 8 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 9 |
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