Neoplasms
Conditions
Keywords
Dose escalation, Dose expansion, Dostarlimab, Niraparib, Osteosarcoma, Neuroblastoma
Brief summary
This study will evaluate the combination of a poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitor, niraparib, with the programmed cell death protein 1 (PD-1) inhibitor, dostarlimab in the paediatric population. This study will be conducted to determine the recommended Phase 2 dose (RP2D) and evaluate the pharmacokinetics (PK), safety, and efficacy of niraparib in combination with dostarlimab in paediatric participants with recurrent or refractory solid tumors.
Interventions
DRUGNiraparib (Tablet for oral suspension)
Niraparib will be administered as TfOS (Tablet for oral suspension)
DRUGDostarlimab
Dostarlimab will be administered as IV infusion
Niraparib will be administered as tablet
Sponsors
GlaxoSmithKline
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Masking description
This will be an open-label study.
Eligibility
Sex/Gender
ALL
Age
6 Months to 17 Years
Healthy volunteers
No
Inclusion criteria
For Part 1 and Part 2: * Participant is a child or an adolescent greater than or equal to (\>=) 6 months to less than (\<) 18 years old at the time of informed consent/assent. * Participant with disease other than neuroblastoma has radiologically measurable disease at screening that can be tracked as RECIST v1.1 target lesion(s). * Participant with neuroblastoma has measurable/evaluable target and/or non-target disease by INRC at screening. Neuroblastoma participants with recurrent/relapsed bone metastasis that is metaiodobenzylguanidine (MIBG)-positive (or FDG-PET positive, for MIBG-nonavid tumors) as only site of disease are eligible. * Performance status must be \>=60 percent on the Karnofsky scale for participants \>16 years of age and \>=60 percent on the Lansky scale for participants less than or equal to (\<=) 16 years of age. * Participant has adequate organ function. * A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies: Is not a woman of childbearing potential (WOCBP) or Is a WOCBP and using a contraceptive method that is highly effective. * A male participant of reproductive potential is eligible to participate if he agrees to refrain from donating sperm plus, either be abstinent from heterosexual intercourse or must agree to use a male condom starting with the first dose of study treatment through at least 90 days after the last dose of study treatment. For Part 1 only: • Participant has recurrent or refractory osteosarcoma, neuroblastoma, adrenocortical carcinoma, Ewing sarcoma, rhabdomyosarcoma, or any other solid tumor (excluding tumors of the central nervous system \[CNS\]) and must not be eligible for alternative curative treatment: i. Participants with non-CNS solid tumours other than osteosarcoma, neuroblastoma, adrenocortical carcinoma, Ewing sarcoma or rhabdomyosarcoma are required to have prior documented breast cancer susceptibility gene (BRCAness) mutational signature (mutational signature 3) on deoxyribonucleic acid (DNA) sequencing of tumor obtained in the relapsed/recurrent disease setting, within 6 (preferably 3) months of Cycle 1 Day 1. ii. For participants with documented BRCAness mutational signature: Existing information on molecular profiling of the participant's tumor 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 BRCA1 and BRCA 2 and other homologous recombination DNA repair (HRR) pathway genes, mutational signatures including mutational signature 3, and tumor mutational burden (TMB). iii. NOTE: Participants with recurrent or refractory osteosarcoma, neuroblastoma, adrenocortical carcinoma, Ewing sarcoma, or rhabdomyosarcoma are asked to provide documentation, if available, of the BRCAness mutational signature analysis on DNA sequencing of their tumour. For Part 2A: • Participant has recurrent or refractory osteosarcoma and must not be eligible for alternative curative treatment. Documentation of BRCAness mutational signature 3 will be requested, but not required, for enrollment. • Participant must confirm at screening that an archival or fresh tumor tissue sample is available for use, in retrospective exploratory biomarker analysis. Otherwise, enrolling site must discuss with Sponsor. For Part 2B: * Participant has recurrent or refractory neuroblastoma and must not be eligible for alternative curative treatment. Documentation of BRCAness mutational signature 3 will be requested, but not required, for enrollment. * Participant must confirm at screening that an archival or fresh tumor tissue sample is available for use, in retrospective exploratory biomarker analysis. Otherwise, enrolling site must discuss with Sponsor.
Exclusion criteria
For Part 1 and Part 2: * Participant has known hypersensitivity to dostarlimab or niraparib, their components, or their excipients. * Participant has a known history of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). * Participant has active autoimmune disease that has required systemic treatment in the past 2 years (that is \[i.e.\], with use of disease-modifying anti-rheumatic drugs, corticosteroids, or immunosuppressive drugs). Replacement therapy (for example \[e.g.\], thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment. * Participant has known active CNS metastases, carcinomatous meningitis, or both. Carcinomatous meningitis precludes a participant from study participation regardless of clinical stability. * Participant had a known additional (second primary) malignancy that progressed or required active treatment within the last 2 years. * Participant is considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease, or active infection that requires systemic therapy. * Participant has a condition (such as transfusion-dependent anemia 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. * 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. * Participant has a known history of human immunodeficiency virus (HIV) (type 1 or 2 antibodies). * 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. * 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. * Participant has had any known Grade 3 or 4 anemia, neutropenia, and/or thrombocytopenia that was related to the most recent prior anti-cancer treatment and that persisted \>4 weeks (28 days). * Participant has not recovered (i.e., to Grade ≤1 or to baseline) from prior systemic anticancer therapy-induced AEs. Note: Participants with alopecia, hearing impairment, Grade ≤2 neuropathy, Grade ≤2 fatigue, Grade ≤ 2 anaemia, and/or Grade ≤2 neutropenia are an exception to this criterion and may qualify for participation in the study. * Participant had toxicity related to prior immunotherapy that led to study treatment discontinuation. * Participant had treatment with systemic anticancer therapy (investigational agent or device, or approved chemotherapy, targeted therapy, immunotherapy, or other systemic therapy) within 3 weeks or 5 half-lives, whichever is shorter, prior to the first dose of study treatment, radiation therapy encompassing \>20 percent of the bone marrow within 2 weeks prior to the first dose of study treatment, or any radiation therapy within 1 week prior to the first dose of study treatment. * Participant has not recovered adequately from AEs or complications from any major surgery prior to starting study treatment. * Participant has received a live vaccine within 30 days of planned start of study treatment. * Participant has clinically significant cardiovascular disease (e.g., significant cardiac conduction abnormalities, uncontrolled hypertension, cardiac arrhythmia or unstable angina, New York Heart Association Grade 2 or greater congestive heart failure, serious cardiac arrhythmia requiring medication, and history of cerebrovascular accident) within 6 months of enrolment. * Participant has heart rate-corrected QT interval prolongation at screening \>450 milliseconds (msec) or \>480 msec for participants with bundle branch block. * Participant has received a solid organ transplant. * Participant has a documented presence of HCV antibody at Screening or within 3 months prior to first dose of study intervention. NOTE: Participants with a positive HCV antibody test result due to prior resolved disease can be enrolled, if a confirmatory HCV RNA test is negative and the participant otherwise meets entry criteria. * Participant has a documented presence of HCV RNA at Screening or within 3 months prior to first dose of study intervention. NOTE: The HCV RNA test is optional and participants with negative HCV antibody test are not required to undergo HCV RNA testing as well. For Part 2: * Participant has received prior therapy with an anti-PD-1, anti-programmed cell death ligand 1, anti-programmed cell death-ligand 2, anti-cytotoxic T-lymphocyte-associated antigen-4 antibody (including ipilimumab), or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways (with the exception of participants rolling over from Part 1 of the study: these participants are allowed to have received dostarlimab). * Participant has had prior treatment with a known poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor (with the exception of participants rolling over from Part 1 of the study: these participants are allowed to have received niraparib).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part 2B: Objective Response Rate (ORR) by the Investigator Using International Neuroblastoma Response Criteria (INRC) | Up to approximately 196 weeks | ORR is defined as the percentage of participants who have a best overall response (BOR) of confirmed complete response (CR) or partial response (PR) as determined by the Investigator using International Neuroblastoma Response Criteria (INRC). CR is resolution of all detectable disease, including soft tissue, bone, and bone marrow, with residual lesion measurements \<10 mm and no tumor infiltration in the bone marrow or abnormal MIBG/FDG uptake. PR: Significant reduction in tumor burden, including a ≥30% decrease in primary or metastatic lesion size and ≥50% reduction in bone involvement (MIBG/FDG), with no new lesions and bone marrow infiltration ≤5%. |
| Part 2 Safety-run in: Number of Participants With Dose-limiting Toxicities (DLT) | Up to 42 days | DLT referred to adverse effects within the first 42 days of treatment, indicating the maximum tolerated dose. DLTs included treatment-related Grade (G) 4 non-haematologic AEs or G3 AEs unresolved to G≤1 within 48 hours. G3/4 non-haematologic lab abnormalities were DLTs if causing hospitalization or persisting ≥7 days with symptoms or requiring intervention. Haematologic DLTs included prolonged G4 thrombocytopenia, G3/4 thrombocytopenia with bleeding or transfusion needs, prolonged G4 neutropenia, G3/4 neutropenia with infection, and G3/4 anemia requiring transfusion. Other criteria included Cycle 2 delays \>2 weeks, unresolved G≥2 uveitis/endocrine toxicity, persistent colitis/diarrhea, unresolved G3/4 immune-related AEs, G≥3 infusion reactions, hemophagocytic lymphohistiocytosis, posterior reversible encephalopathy syndrome, and treatment-related G5 AE. DLT-evaluable participants completed ≥2 cycles with ≥80% of planned niraparib and ≥2 dostarlimab infusions or had a DLT. |
| Part 2 Safety-run in: Number of Participants With Grade ≥3 Thrombocytopenia Adverse Events | Up to 42 days | Thrombocytopenia events were defined as treatment-related toxicities of Grade 3 or Grade 4 thrombocytopenia occurring within the first 42 days of study treatment. AEs were graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version (v) 5.0. |
| Part 2A: Progression-Free Survival at 6 Months Per Response Evaluation Criteria in Solid Tumours (RECIST) v1.1 | At Month 6 | PFS6 is defined as the percentage of participants without progressive disease (PD) per Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1 or death at 6 months from the date of the first dose of study treatment. PD was defined as at least a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started (e.g. percent change from nadir, where nadir is defined as the smallest sum of diameters recorded since treatment start). |
| Part 1A and Part 1B: Number of Participants With Dose-limiting Toxicities (DLT) | Up to 42 days | DLT referred to adverse effects within the first 42 days of treatment, indicating the maximum tolerated dose. DLTs included treatment-related Grade (G) 4 non-haematologic AEs or G3 AEs unresolved to G≤1 within 48 hours. G3/4 non-haematologic lab abnormalities were DLTs if causing hospitalization or persisting ≥7 days with symptoms or requiring intervention. Haematologic DLTs included prolonged G4 thrombocytopenia, G3/4 thrombocytopenia with bleeding or transfusion needs, prolonged G4 neutropenia, G3/4 neutropenia with infection, and G3/4 anemia requiring transfusion. Other criteria included Cycle 2 delays \>2 weeks, unresolved G≥2 uveitis/endocrine toxicity, persistent colitis/diarrhea, unresolved G3/4 immune-related AEs, G≥3 infusion reactions, hemophagocytic lymphohistiocytosis, posterior reversible encephalopathy syndrome, and treatment-related G5 AE. DLT-evaluable participants completed ≥2 cycles with ≥80% of planned niraparib and ≥2 dostarlimab infusions or had a DLT. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part 1A and Part 1B: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious AEs (SAEs) | Up to approximately 196 weeks | An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. A TEAE is any event that emerged during treatment and was not present prior to the initiation of study treatment or any event already present that worsens in either intensity or frequency following exposure to study treatment. SAE is defined as any untoward medical occurrence that, at any dose resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent disability/incapacity, or is a congenital anomaly/birth defect, other situations which involved medical or scientific judgment or is associated with liver injury and impaired liver function. SAEs are subset of AEs. AEs were coded using the Medical Dictionary for Regulatory Activities (MedDRA dictionary). |
| Part 1A and Part 1B: Number of Participants With Dostarlimab-Related Immune-Mediated Adverse Events (imAEs) | Up to approximately 196 weeks | Dostarlimab-Related Immune-Mediated AEs were reported. AEs were coded using the Medical Dictionary for Regulatory Activities (MedDRA dictionary). |
| Part 1A and Part 1B: Number of Participants With TEAEs Leading to Death and Treatment Discontinuation | Up to approximately 196 weeks | An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. A TEAE is any event that emerged during treatment and was not present prior to the initiation of study treatment or any event already present that worsens in either intensity or frequency following exposure to study treatment. |
| Part 1A and Part 1B: Niraparib Concentrations | 2.5 hours (HR) and 7 HR post-dose on Cycle 1 Week 1, 168 HR post-dose on Cycle 1 Week 2 | Blood samples were obtained to analyze niraparib concentration levels. |
| Part 1A and Part 1B: Dostarlimab Concentrations | Pre-dose on Day 1; 1 HR post-dose on Cycle 1 Week 1; 168 HR post-dose on Cycle 1 Week 2; 504 HR post-dose) on Cycle 2 Week 1; Pre-dose on Week 1 of Cycles 4, 6, 12, 18, 24, 30, 36; End of Treatment (Up to approximately 196 weeks) | Blood samples were collected for PK analysis of Dostarlimab. |
| Part 2 Safety-run in: Objective Response Rate (ORR) | Up to approximately 196 weeks | ORR is the percentage of participants with a best overall response (BOR) of confirmed CR or PR, using RECIST v1.1 or INRC (neuroblastoma only) as determined by the Investigator. Per RECIST v1.1: CR is disappearance of all target lesions, with pathological lymph nodes \<10 mm in short axis. PR is ≥30% decrease in sum of diameters of target lesions, referencing baseline sum (percent change from baseline). Per INRC: CR is resolution of all detectable disease, including soft tissue, bone, and bone marrow, with residual lesion measurements \<10 mm and no tumor infiltration in the bone marrow or abnormal MIBG/FDG uptake. PR: Significant reduction in tumor burden, including a ≥30% decrease in primary or metastatic lesion size and ≥50% reduction in bone involvement (MIBG/FDG), with no new lesions and bone marrow infiltration ≤5%. |
| Part 2 Safety-run in: Duration of Response (DOR) | Up to approximately 196 weeks | DOR is the time from first documented response (CR or PR) to first PD by RECIST v1.1 or INRC (neuroblastoma only), based on Investigator assessment, or death (whichever occurs first). It is calculated for participants with a BOR of confirmed CR or PR. If no PD or death occurs post-response, participants are censored at their last tumor assessment date. Per RECIST v1.1, CR is disappearance of all target lesions; PR is ≥30% decrease in lesion diameters from baseline; PD is ≥20% increase in lesion sum from nadir plus ≥5 mm absolute increase. Per INRC, CR is resolution of detectable disease, including soft tissue, bone, and bone marrow, with residual lesions \<10 mm, no bone marrow infiltration, and normal MIBG/FDG uptake. PR is a ≥30% decrease in lesion size, ≥50% reduction in bone involvement (MIBG/FDG), no new lesions, and bone marrow infiltration ≤5%. PD is \>20% lesion size increase, new lesions, or increased infiltration in bone marrow. |
| Part 2 Safety-run in: Disease Control Rate (DCR) | Up to approximately 196 weeks | DCR is the percentage of participants achieving a BOR of confirmed CR, PR, or stable disease (SD) by RECIST v1.1 or INRC (neuroblastoma only). Per RECIST v1.1: CR is disappearance of all target lesions and pathological lymph nodes \<10 mm in short axis; PR is ≥30% decrease in lesion diameters from baseline; SD is neither sufficient shrinkage for PR nor sufficient increase for PD. Per INRC: CR is resolution of all detectable disease (soft tissue, bone, marrow) with residual lesion \<10 mm, no tumor infiltration in the bone marrow, and no abnormal MIBG or FDG/PET uptake. PR is ≥30% decrease in lesion size, ≥50% bone involvement reduction (MIBG/FDG uptake), no new lesions, and bone marrow infiltration ≤5%. SD was defined as neither sufficient shrinkage for PR nor sufficient increase for PD at the primary site. Bone marrow infiltration remains \>5%. |
| Part 2 Safety-run in: Progression-free Survival (PFS) | Up to approximately 196 weeks | PFS is defined as the time from the date of the first dose of study treatment to the first documented PD, as determined by RECIST v1.1 or INRC (in participants with neuroblastoma only) based on Investigator assessment, or death from any cause (whichever occurs first). Per RECISTv1.1: PD was defined as At least a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started (e.g., percent change from nadir, where nadir is defined as the smallest sum of diameters recorded since treatment start). In addition, the sum must have an absolute increase from nadir of 5 mm. Per INRC: PD is \>20% lesion size increase, new lesions, or increased marrow tumor infiltration (\>5%). |
| Part 2 Safety-run in: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious AEs (SAEs) | Up to approximately 196 weeks | An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. A TEAE is any event that emerged during treatment and was not present prior to the initiation of study treatment or any event already present that worsens in either intensity or frequency following exposure to study treatment. SAE is defined as any untoward medical occurrence that, at any dose resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent disability/incapacity, or is a congenital anomaly/birth defect, other situations which involved medical or scientific judgment or is associated with liver injury and impaired liver function. SAEs are subset of AEs. AEs were coded using the Medical Dictionary for Regulatory Activities (MedDRA dictionary). |
| Part 2 Safety-run in: Number of Participants With Dostarlimab-Related Immune-Mediated Adverse Events (imAEs) | Up to approximately 196 weeks | Dostarlimab-Related Immune-Mediated AEs were reported. AEs were coded using the Medical Dictionary for Regulatory Activities (MedDRA dictionary). |
| Part 2 Safety-run in: Number of Participants With TEAEs Leading to Death and Treatment Discontinuation | Up to approximately 196 weeks | An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. A TEAE is any event that emerged during treatment and was not present prior to the initiation of study treatment or any event already present that worsens in either intensity or frequency following exposure to study treatment. |
| Part 2 Safety-run in: Niraparib Concentrations | 2.5 HR and 7 HR post-dose on Cycle 1 Week 1, Pre-dose on Cycle 1 Week 2 and Pre-dose and 5 HR post-dose on Cycle 2 Week 1 | Blood samples were obtained to analyze niraparib concentration levels. |
| Part 2A: Objective Response Rate (ORR) by the Investigator Using RECIST v1.1 | Up to approximately 196 weeks | ORR is defined as the percentage of participants who have a best overall response (BOR) of confirmed complete response (CR) or partial response (PR) as determined by the Investigator using RECIST v1.1. CR was defined as disappearance of all target and any pathological lymph nodes must be \<10 millimeter (mm) in the short axis. PR was defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the baseline sum of the diameters (e.g. percent change from baseline). |
| Part 2A: Duration of Response (DOR) by the Investigator Using RECIST v1.1 | Up to approximately 196 weeks | 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 , based on Investigator assessment, or death (whichever occurs first). CR was defined as disappearance of all target lesions and any pathological lymph nodes must be \<10 millimeter (mm) in the short axis. PR was defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the baseline sum of the diameters (e.g. percent change from baseline). PD was defined as At least a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started (e.g., percent change from nadir, where nadir is defined as the smallest sum of diameters recorded since treatment start). In addition, the sum must have an absolute increase from nadir of 5 mm. |
| Part 2A: Disease Control Rate (DCR) by the Investigator Using RECIST v1.1 | Up to approximately 196 weeks | DCR is defined as the percentage of participants who have achieved a BOR of confirmed CR, confirmed PR, or stable disease (SD) by RECIST v1.1. CR was defined as disappearance of all target lesions and any pathological lymph nodes must be \<10 millimeter (mm) in the short axis. PR was defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the baseline sum of the diameters (e.g. percent change from baseline). SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. |
| Part 2A: Progression-free Survival (PFS) by the Investigator Using RECIST v1.1 | Up to approximately 196 weeks | PFS is defined as the time from the date of the first dose of study treatment to the first documented PD, as determined by RECIST v1.1 , based on Investigator assessment, or death from any cause (whichever occurs first). PD was defined as at least a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started (e.g. percent change from nadir, where nadir is defined as the smallest sum of diameters recorded since treatment start). |
| Part 2A: Number of Participants With of Treatment Emergent Adverse Events (TEAEs) and Serious AEs (SAEs) | Up to approximately 196 weeks | An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. A TEAE is any event that emerged during treatment and was not present prior to the initiation of study treatment or any event already present that worsens in either intensity or frequency following exposure to study treatment. SAE is defined as any untoward medical occurrence that, at any dose resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent disability/incapacity, or is a congenital anomaly/birth defect, other situations which involved medical or scientific judgment or is associated with liver injury and impaired liver function. SAEs are subset of AEs. AEs were coded using the Medical Dictionary for Regulatory Activities (MedDRA dictionary). |
| Part 2A: Number of Participants With Dostarlimab-Related Immune-Mediated Adverse Events (imAEs) | Up to approximately 196 weeks | Dostarlimab-Related Immune-Mediated AEs were reported. AEs were coded using the Medical Dictionary for Regulatory Activities (MedDRA dictionary). |
| Part 2A: Number of Participants With TEAEs Leading to Death and Treatment Discontinuation | Up to approximately 196 weeks | An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. A TEAE is any event that emerged during treatment and was not present prior to the initiation of study treatment or any event already present that worsens in either intensity or frequency following exposure to study treatment. |
| Part 2A: Niraparib Concentrations | 2.5 HR and 7 HR post-dose on Cycle 1 Week 1, 168 HR post-dose on Cycle 1 Week 2 | Blood samples were obtained to analyze niraparib concentration levels. |
| Part 2A: Dostarlimab Concentrations | Pre-dose on Day 1; 1 HR post-dose on Cycle 1 Week 1; 168 HR post-dose on Cycle 1 Week 2; 504 HR post-dose) on Cycle 2 Week 1; Pre-dose on Week 1 of Cycles 4 and 6; End of Treatment (Up to approximately 196 weeks) | Blood samples were collected for PK analysis of Dostarlimab. |
| Part 2A: Number of Participants With Positive Anti-Drug Antibody (ADAs) to Dostarlimab | Up to approximately 196 weeks | Blood samples were collected for the analysis of the presence of ADAs using electrochemiluminescence. All samples were tested in screening and confirmatory assay, and positive samples were further characterized for antibody titers. |
| Part 2A: Number of Participants Answered Acceptability and Palatability of Niraparib Via Questionnaires | At Week 1 of Cycle 1 | The acceptability and palatability for participants who received niraparib tablet were evaluated by using a questionnaire. |
| Part 2B: Duration of Response (DOR) by the Investigator by INRC | Up to approximately 196 weeks | DOR is defined as the time from first documentation of response (CR or PR) until the time of first documented PD by INRC , based on Investigator assessment, or death (whichever occurs first). CR is resolution of all detectable disease, including soft tissue, bone, and bone marrow, with residual lesion measurements \<10 mm and no tumor infiltration in the bone marrow or abnormal MIBG/FDG uptake. PR: Significant reduction in tumor burden, including a ≥30% decrease in primary or metastatic lesion size and ≥50% reduction in bone involvement (MIBG/FDG), with no new lesions and bone marrow infiltration ≤5%. PD is \>20% lesion size increase,new lesions or increased tumor infiltration in bone marrow. |
| Part 2B: Disease Control Rate (DCR) by the Investigator by INRC | Up to approximately 196 weeks | DCR is defined as the percentage of participants who have achieved a BOR of confirmed CR, confirmed PR, or SD by INRC. CR is resolution of all detectable disease (soft tissue, bone, marrow) with residual lesion \<10 mm, no tumor infiltration in the bone marrow, and no abnormal MIBG or FDG/PET uptake. PR is ≥30% decrease in lesion size, ≥50% bone involvement reduction (MIBG/FDG uptake), no new lesions, and bone marrow infiltration ≤5%. SD was defined as neither sufficient shrinkage for PR nor sufficient increase for PD at the primary site. Bone marrow infiltration remains \>5%. |
| Part 2B: Progression-free Survival (PFS) by the Investigator by INRC | Up to approximately 196 weeks | PFS is defined as the time from the date of the first dose of study treatment to the first documented PD, as determined by INRC , based on Investigator assessment, or death (whichever occurs first). PD is \>20% lesion size increase, new lesions, or increased tumor infiltration in bone marrow. |
| Part 2B: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious AEs (SAEs) | Up to approximately 196 weeks | An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. A TEAE is any event that emerged during treatment and was not present prior to the initiation of study treatment or any event already present that worsens in either intensity or frequency following exposure to study treatment. SAE is defined as any untoward medical occurrence that, at any dose resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent disability/incapacity, or is a congenital anomaly/birth defect, other situations which involved medical or scientific judgment or is associated with liver injury and impaired liver function. SAEs are subset of AEs. AEs were coded using the Medical Dictionary for Regulatory Activities (MedDRA dictionary). |
| Part 2B: Number of Participants With Dostarlimab-Related Immune-Mediated Adverse Events (imAEs) | Up to approximately 196 weeks | Dostarlimab-Related Immune-Mediated AEs were reported. AEs were coded using the Medical Dictionary for Regulatory Activities (MedDRA dictionary). |
| Part 2B: Number of Participants With TEAEs Leading to Death and Treatment Discontinuation | Up to approximately 196 weeks | A TEAE is any event that emerged during treatment and was not present prior to the initiation of study treatment or any event already present that worsens in either intensity or frequency following exposure to study treatment. |
| Part 2B: Niraparib Concentrations | 2.5 HR and 7 HR post-dose on Cycle 1 Week 1, 168 HR post-dose on Cycle 1 Week 2 | Blood samples were obtained to analyze niraparib concentration levels. |
| Part 2B: Dostarlimab Concentrations | Pre-dose on Day 1; 1 HR post-dose on Cycle 1 Week 1; 168 HR post-dose on Cycle 1 Week 2; 504 HR post-dose on Cycle 2 Week 1; Pre-dose on Week 1 of Cycles 4, 6, 12 and 18; End of Treatment (Up to approximately 196 weeks) | Blood samples were collected for PK analysis of Dostarlimab. |
| Part 2B: Number of Participants With Positive Anti-Drug Antibody (ADAs) to Dostarlimab | Up to approximately 196 weeks | Blood samples were collected for the analysis of the presence of ADAs using electrochemiluminescence. All samples were tested in screening and confirmatory assay, and positive samples were further characterized for antibody titers. |
| Part 2B: Number of Participants Answered Acceptability and Palatability of Niraparib Via Questionnaires | At Week 1 of Cycle 1 | The acceptability and palatability for participants who received niraparib tablet were evaluated by using a questionnaire. |
| Part 1A and Part 1B: Number of Participants With Positive Anti-Drug Antibody (ADAs) to Dostarlimab | Up to approximately 196 weeks | Blood samples were collected for the analysis of the presence of ADAs using electrochemiluminescence. All samples were tested in screening and confirmatory assay, and positive samples were further characterized for antibody titers. |
| Part 1A and Part 1B: Number of Participants Answered Acceptability and Palatability of Niraparib Via Questionnaires | At Week 1 of Cycle 1 | The acceptability and palatability for participants who received niraparib tablet or TfOS were evaluated by using a questionnaire. |
| Part 1A and Part 1B: Objective Response Rate (ORR) | Up to approximately 196 weeks | ORR is the percentage of participants with a best overall response (BOR) of confirmed CR or PR using RECIST v1.1 or INRC (for neuroblastoma participants only) as determined by the Investigator. Per RECIST v1.1: CR is disappearance of all target lesions, with pathological lymph nodes \<10 mm in short axis. PR is ≥30% decrease in sum of diameters of target lesions, referencing baseline sum (percent change from baseline). Per INRC: CR is resolution of all detectable disease, including soft tissue, bone, and bone marrow, with residual lesion measurements \<10 mm and no tumor infiltration in the bone marrow or abnormal MIBG/FDG uptake. PR: Significant reduction in tumor burden, including a ≥30% decrease in primary or metastatic lesion size and ≥50% reduction in bone involvement (MIBG/FDG), with no new lesions and bone marrow infiltration ≤5%. |
| Part 1A and Part 1B: Duration of Response (DOR) | Up to approximately 196 weeks | DOR is the time from first documented response (CR or PR) to first PD by RECIST v1.1 or INRC (neuroblastoma only), based on Investigator assessment, or death (whichever occurs first). If no PD or death occurs post-response, participants are censored at their last tumor assessment date. Per RECIST v1.1, CR is disappearance of all target lesions; PR is ≥30% decrease in lesion diameters from baseline; PD is ≥20% increase in lesion sum from nadir plus ≥5 mm absolute increase. Per INRC, CR is resolution of detectable disease, including soft tissue, bone, and bone marrow, with residual lesions \<10 mm, no bone marrow infiltration, and normal MIBG/FDG uptake. PR is a ≥30% decrease in lesion size, ≥50% reduction in bone involvement (MIBG/FDG), no new lesions, and bone marrow infiltration ≤5%. PD is \>20% lesion size increase, new lesions, or increased infiltration in bone marrow. |
Countries
United Kingdom
Contacts
STUDY_DIRECTORGSK Clinical Trials
GlaxoSmithKline
Participant flow
Pre-assignment details
This study was performed in two parts: Part 1: Dose Escalation and Part 2: Safety Run-in and Cohort Expansion.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 13.7 YEARS STANDARD_DEVIATION 3.99 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 43 Participants |
| Sex: Female, Male Female | 1 Participants |
| Sex: Female, Male Male | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 7 / 11 | 3 / 7 | 3 / 5 | 3 / 3 | 2 / 11 | 2 / 7 | 1 / 3 |
| other Total, other adverse events | 11 / 11 | 7 / 7 | 5 / 5 | 3 / 3 | 11 / 11 | 7 / 7 | 3 / 3 |
| serious Total, serious adverse events | 6 / 11 | 2 / 7 | 2 / 5 | 2 / 3 | 4 / 11 | 4 / 7 | 2 / 3 |
Outcome results
None listed