Dose Escalation and Cohort Expansion Study of Niraparib and Dostarlimab in Paediatric Participants With Solid Tumours

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Glaxosmithkline Research & Development Limited

Participant type

Pediatric, Patients

Age range

0-17 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

10 Feb 2022 → 23 Apr 2025

Decision date (initial)

2024-04-30

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

GlaxoSmithKline Research & Development Limited, United Kingdom

External identifiers

EU CT number

2024-511071-16-00

EudraCT number

2020-002359-39

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Others, Pharmacoeconomic, Therapy, Pharmacokinetic, Safety, Efficacy, Dose response

Part 1A: Establish the RP2D of the combination of niraparib tablet and dostarlimab in paediatric participants
Part 1B: Establish the RP2D of the combination of niraparib tablet for oral suspension (TfOS) and dostarlimab in paediatric participants
Part 2: Please refer to the separate cohort-specific supplements for this information.

Secondary objectives 5

1. Evaluation of additional measures of anticancer activity (including objective response rate [ORR] and duration of response [DOR]) in paediatric participants.
2. Evaluation of the safety and tolerability of the combination of niraparib (tablet or TfOS) and dostarlimab in paediatric participants
3. Characterisation of the PK of the combination of niraparib and dostarlimab in paediatric participants
4. Assessment of the immunogenicity of dostarlimab in pediatric participants
5. CCI

Conditions and MedDRA coding

Solid Tumours

Regulatory references

EMA paediatric investigation plan (PIP)

EMEA-002268-PIP02-18, EMEA-002463-PIP01-18

Plan to share IPD

Yes

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 6

1. Participant is child or adolescent ≥6 months to <18 years old at the time of informed consent/assent. If a participant is enrolled under Protocol Amendment 04, the participant must be ≥6 months to <8 years old at the time of informed consent/assent.
2. Participant with disease other than neuroblastoma has radiologically measurable disease that can be tracked as RECIST v1.1. Participant with neuroblastoma has measurable/evaluable disease by International Neuroblastoma Response Criteria (INRC) at the time of study enrolment. Neuroblastoma participants with recurrent/relapsed bone metastasis that is MIBG-positive (or FDG positive, for MIBG-nonavid tumours) as only site of disease are eligible.
3. Under Protocol Amendment 03 (or earlier), a participant in Part 1A must be able to swallow the "CCI" and have a baseline body weight of ≥20 kg. Participants in Part 1A who are unable to swallow the "CCI" or who have a baseline body weight <20 kg are eligible to receive "CCI" only. As of Protocol Amendment 04, there are no inclusion criteria addressing ability to swallow niraparib tablets.
4. Performance status must be ≥60% on the Karnofsky scale for participants >16 years of age and ≥60% 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: a. absolute neutrophil count (ANC) ≥1000/μL b. platelets ≥100000/μL c. haemoglobin ≥8 g/dL or ≥5.0 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 conditions per protocol.

Exclusion criteria 15

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 or acute myeloid leukaemia.
4. Participant has active autoimmune disease that has required systemic treatment in the past 2 years (i.e., with use of disease-modifying antirheumatic drugs, corticosteroids, or immunosuppressive drugs). Replacement therapy (e.g., 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 and have no evidence of new, enlarging, or progressing brain metastases (using the identical imaging modality for each assessment, either MRI or CT scan) for at least 4 weeks (28 days) prior to the first dose of study treatment. In addition, the participant must not have 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 (second primary) 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), requirement for 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
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 at least 4 months after the last dose of dostarlimab or at least 30 days after the last dose of niraparib, whichever is longer.
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 documented presence of HbsAg and/or HBcAb at Screening or within 3 months prior to first dose of study intervention. Participants with a negative HbsAg and positive HbcAb result are eligible only if HBV DNA is negative.
13. Participant must not have a gastrointestinal condition, such as bowel obstruction, that can impact absorption of oral medications and is identified by clinical symptoms or CT scan, etc.
14. Participant has had any known Grade 3 or 4 anaemia, neutropenia, and/or thrombocytopenia that was related to the most recent prior anticancer treatment and that persisted >4 weeks (28 days).
15. Exclusion criteria for Part 2 of the study are described in each cohort-specific supplement

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. 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 TfOS in Part 1b) and dostarlimab. Part 2: Please refer to the separate cohort-specific supplements for this information.

Secondary endpoints 3

1. • 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).
2. • 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).
3. Part 1: Please refer to main study protocol for further Endpoints Part 2: Please refer to the separate cohort-specific supplements for this information.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 7

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Glaxosmithkline Research & Development Limited

Sponsor organisation

Glaxosmithkline Research & Development Limited

Address

G S K House, 980 Great West Road 980 Great West Road

City

Brentford

Postcode

TW8 9GS

Country

United Kingdom

Scientific contact point

Organisation

Glaxosmithkline Research & Development Limited

Contact name

EU GSK Clinical Trials Call Center

Public contact point

Organisation

Glaxosmithkline Research & Development Limited

Contact name

EU GSK Clinical Trials Call Center

Third parties 14

Locations

5 EU/EEA countries · 21 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Temporary halts 5 · Art. 38 CTR

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 13 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications