Dose Escalation and Cohort Expansion Study of Niraparib and Dostarlimab in Paediatric Participants With Solid Tumors (SCOOP)
- Conditions
- Neoplasms
- Interventions
- Registration Number
- NCT04544995
- Lead Sponsor
- GlaxoSmithKline
- 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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 116
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.
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).
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description Part 1A: Dose Escalation Dostarlimab Participants with body weight of ≥ 20 kilogram (kg) and who can swallow niraparib tablets will receive niraparib tablets and dostarlimab. Part 1A: Dose Escalation Niraparib (Tablet) Participants with body weight of ≥ 20 kilogram (kg) and who can swallow niraparib tablets will receive niraparib tablets and dostarlimab. Part 2A: Cohort Expansion for Osteosarcoma Niraparib (Tablet) Participants with osteosarcoma will receive the RP2D of the combination of niraparib and dostarlimab. Part 1B: Dose Escalation Niraparib (Tablet for oral suspension) Participants who are \<8 years of age will receive niraparib TfOS and dostarlimab. Part 1B: Dose Escalation Dostarlimab Participants who are \<8 years of age will receive niraparib TfOS and dostarlimab. Part 2 Safety Run-in Niraparib (Tablet for oral suspension) Participants with osteosarcoma or neuroblastoma who are ≥8 years of age will receive niraparib TfOS and dostarlimab. Part 2 Safety Run-in Dostarlimab Participants with osteosarcoma or neuroblastoma who are ≥8 years of age will receive niraparib TfOS and dostarlimab. Part 2A: Cohort Expansion for Osteosarcoma Niraparib (Tablet for oral suspension) Participants with osteosarcoma will receive the RP2D of the combination of niraparib and dostarlimab. Part 2A: Cohort Expansion for Osteosarcoma Dostarlimab Participants with osteosarcoma will receive the RP2D of the combination of niraparib and dostarlimab. Part 2B: Cohort Expansion for Neuroblastoma Niraparib (Tablet for oral suspension) Participants with neuroblastoma will receive the RP2D of the combination of niraparib and dostarlimab. Part 2B: Cohort Expansion for Neuroblastoma Dostarlimab Participants with neuroblastoma will receive the RP2D of the combination of niraparib and dostarlimab. Part 2B: Cohort Expansion for Neuroblastoma Niraparib (Tablet) Participants with neuroblastoma will receive the RP2D of the combination of niraparib and dostarlimab.
- Primary Outcome Measures
Name Time Method Part 1A: Number of participants with dose limiting toxicities (DLTs) for the DLT-evaluable Population Up to 42 days Number of participants with DLTs will be reported for the DLT-evaluable Population.
Part 1B: Number of participants with DLTs for the DLT-evaluable Population Up to 42 days Number of participants with DLTs will be reported for the DLT-evaluable Population.
Part 2 Safety Run-in: Number of participants with DLTs for the DLT-evaluable Population Up to 42 days Number of participants with DLTs will be reported for the DLT-evaluable Population.
Part 2 Safety Run-in: Number of participants with Grade ≥3 thrombocytopenia AEs for the DLT-evaluable Population Up to 42 days Number of participants with Grade ≥3 thrombocytopenia AEs will be reported for the DLT-evaluable Population.
Part 2A: Progression-free survival rate at 6 months (PFS6) in participants with osteosarcoma Up to 6 months PFS6 is defined as the proportion 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.
Part 2B: Objective response rate (ORR) in participants with neuroblastoma Up to 8 years ORR is defined as the proportion 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).
- Secondary Outcome Measures
Name Time Method Part 1A, Part 1B, Part 2 Safety Run-in and Part 2A: ORR Up to 8 years ORR 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.
Part 1A, Part 1B, Part 2 Safety Run-in, Part 2A and Part 2B: Plasma concentration of niraparib Up to 3 years Blood samples will be collected for the concentrations of niraparib.
Part 1A, Part 1B, Part 2 Safety Run-in, Part 2A, and Part 2B: Duration of response (DOR) Up to 8 years DOR is defined as the time from first documentation of confirmed response (CR or PR) until the time of first documented PD by RECIST v1.1 or by INRC for participants with neuroblastoma only based on Investigator assessment or death (whichever occurs first).
Part 2 Safety Run-in, Part 2A, and Part 2B: Disease control rate (DCR) in participants Up to 8 years DCR is defined as the percentage of participants who have achieved a BOR of confirmed CR, confirmed PR, or stable disease by RECIST v1.1 or by INRC for participants with neuroblastoma only based on Investigator assessment.
Part 2 Safety Run-in, Part 2A, and Part 2B: Progression free survival (PFS) Up to 8 years 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 by INRC for participants with neuroblastoma only based on Investigator assessment, or death from any cause (whichever occurs first).
Part 1A, Part 1B, Part 2 Safety Run-in, Part 2A and Part 2B: Number of participants with Treatment emergent adverse events (TEAEs), Serious AEs (SAEs), immune-mediated AEs (imAEs), TEAEs leading to death and AEs leading to treatment discontinuation Up to 8 years TEAEs, SAEs, imAEs, TEAEs leading to death and AEs leading to treatment discontinuation will be collected.
Part 1A, Part 1B, Part 2A and Part 2B: Serum concentration of dostarlimab Up to 3 years Blood samples will be collected for the concentrations of dostarlimab
Part 1A, Part 1B, Part 2A and Part 2B: Number of subjects with positive ADAs against dostarlimab Up to 3 years Blood samples will be collected for the determination of anti-dostarlimab antibodies
Part 1A, Part 1B, Part 2A and Part 2B: Niraparib Acceptability and Palatability in paediatric participants Day 1 of first two weeks of Cycle 1 (cycle duration is of 3 weeks) Acceptability and Palatability of niraparib as tablets and as TfOS will be assessed using the acceptability and palatability questionnaires
Trial Locations
- Locations (1)
GSK Investigational Site
🇬🇧Sutton, United Kingdom