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

Phase 1

• Conditions: Recurrent or refractory solid tumour; MedDRA version: 21.1Level: LLTClassification code 10065147Term: Malignant solid tumorSystem Organ Class: 100000004864; MedDRA version: 21.1Level: LLTClassification code 10065252Term: Solid tumorSystem Organ Class: 100000004864; Therapeutic area: Diseases [C] - Cancer [C04]

• Registration Number: EUCTR2020-002359-39-GB
• Lead Sponsor: GlaxoSmithKline Research & Development Limited

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2020-09-11
• Last Update Posted: 5 January 2021

Recruitment & Eligibility

• Status: A
• Sex: All
• Target Recruitment: 116

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 aft

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 receivi

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified