Dose Escalation and Cohort Expansion Study of Niraparib and Dostarlimab in Pediatric Participants With Solid Tumors (SCOOP)

Study Overview
=================
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 pediatric 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 pediatric participants with recurrent or refractory solid tumors.

Official Title
-----------------
A PHASE 1, MULTICENTRE, OPEN-LABEL, DOSE-ESCALATION AND COHORT EXPANSION STUDY OF NIRAPARIB AND DOSTARLIMAB IN PAEDIATRIC PATIENTS WITH RECURRENT OR REFRACTORY SOLID TUMOURS

Conditions
-----------------
Neoplasms

Intervention / Treatment
-----------------
* Drug: Niraparib
* Drug: Dostarlimab
* Drug: Niraparib


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: For Part 1 and Part 2 (osteosarcoma and neuroblastoma expansion cohorts): 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 that can be tracked as RECIST v1.1. Participant with neuroblastoma has measurable/evaluable disease by INRC at the time of study enrolment. Neuroblastoma participants with recurrent/relapsed bone metastasis that is MIBG-positive (or FDG-PET positive, for MIBG-nonavid tumors) as only site of disease are eligible. Participant will receive niraparib tablet or age-appropriate oral liquid formulation based on body weight and ability to swallow tablet. 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. 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 local curative treatment: 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. 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). For Part 2A (osteosarcoma expansion cohort) only: Participant has recurrent or refractory osteosarcoma and must not be eligible for local curative treatment. Documentation of BRCAness mutational signature 3 will be requested, but not required, for enrollment. Participant has radiographically measurable disease that can be tracked as RECIST v1.1 target lesion(s). 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 (neuroblastoma expansion cohort) only: Participant has recurrent or refractory neuroblastoma and must not be eligible for local curative treatment. Documentation of BRCAness mutational signature 3 will be requested, but not required, for enrollment. Participant has measurable/ evaluable disease by INRC at the time of study enrollment. Participants with recurrent/relapsed bone metastasis that is metaiodobenzylguanidine-positive (or FDG-PET positive, for MIBG nonavid tumors) as only site of disease are eligible. 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 (osteosarcoma and neuroblastoma expansion cohorts): 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 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), 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 known active hepatitis B (e.g., hepatitis B surface antigen reactive) or hepatitis C (e.g., hepatitis C virus ribonucleic acid [qualitative] is detected). 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. 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. For Part 2 (osteosarcoma expansion cohort and neuroblastoma expansion cohort): 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).

Ages Eligible for Study
-----------------
Minimum Age: 6 Months
Maximum Age: 17 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: In Part 1 (dose escalation phase), the RP2D of the combination of niraparib and dostarlimab will be determined in participants with recurrent or refractory osteosarcoma, neuroblastoma, adrenocortical carcinoma, Ewing sarcoma,or rhabdomyosarcoma, or any other solid tumor (excluding tumors of the central nervous system [CNS]) with a previously documented BRCAness mutational signature. Part 1 will be followed by Part 2 (dose expansion phase), in which the RP2D established in Part 1 will be evaluated for efficacy and safety in disease-specific expansion cohorts (osteosarcoma and neuroblastoma).
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1A: Dose Escalation<br>Participants with body weight of ≥ 20 kilogram (kg) and who can swallow niraparib tablets will receive niraparib tablets and dostarlimab. | Drug: Niraparib<br>* Niraparib will be administered as tablet<br>Drug: Dostarlimab<br>* Dostarlimab will be administered as IV infusion<br>|
| Experimental: Part 1B: Dose Escalation<br>Participants who are not able to swallow niraparib tablets or who have a body weight of <20 kg will receive niraparib age-appropriate oral liquid formulation (AAOLF) (once available) and dostarlimab. | Drug: Dostarlimab<br>* Dostarlimab will be administered as IV infusion<br>Drug: Niraparib<br>* Niraparib will be administered as AAOLF (once available)<br>|
| Experimental: Part 2A: Cohort Expansion for Osteosarcoma<br>Participants with osteosarcoma who are not able to swallow niraparib tablets or have a body weight of < 20 kg, will receive the RP2D of niraparib AAOLF (when available) and dostarlimab. Participants with osteosarcoma who are able to swallow niraparib tablets and have a body weight ≥20 kg will receive the RP2D of niraparib tablets and dostarlimab. | Drug: Niraparib<br>* Niraparib will be administered as tablet<br>Drug: Dostarlimab<br>* Dostarlimab will be administered as IV infusion<br>Drug: Niraparib<br>* Niraparib will be administered as AAOLF (once available)<br>|
| Experimental: Part 2B: Cohort Expansion for Neuroblastoma<br>Participants with neuroblastoma who are not able to swallow niraparib tablets or who have a body weight of <20 kg will receive the RP2D of niraparib AAOLF (when available) and dostarlimab. Participants with neuroblastoma who are able to swallow niraparib tablets and have a body weight of ≥ 20 kg, will receive the RP2D of niraparib tablets and dostarlimab, when available. | Drug: Niraparib<br>* Niraparib will be administered as tablet<br>Drug: Dostarlimab<br>* Dostarlimab will be administered as IV infusion<br>Drug: Niraparib<br>* Niraparib will be administered as AAOLF (once available)<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1A: Number of participants with dose limiting toxicities (DLTs) | Number of participants with DLTs will be reported. | Up to 42 days | 
| Part 1B: Number of participants with DLTs | Number of participants with DLTs will be reported. | Up to 42 days | 
| Part 2A: Progression-free survival rate at 6 months (PFS6) in participants with osteosarcoma | PFS6 is defined as the proportion of participants without progressive disease (PD) per Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1 criteria or death at 6 months from the date of the first dose of study treatment. | Up to 6 months | 
| Part 2B: Objective response rate (ORR) in participants with neuroblastoma | 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). | Up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1A, Part 1B and Part 2A: ORR | 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 criteria. | Up to 2 years | 
| Part 1A, Part 1B and Part 2A: Duration of response (DOR) | 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). | Up to 2 years | 
| Part 2B: DOR | 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). | Up to 2 years | 
| Part 1A, Part 1B and Part 2A: Disease control rate (DCR) in participants | 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 based on Investigator assessment. | Up to 2 years | 
| Part 2B: DCR | DCR is defined as the proportion of participants who have achieved a BOR of confirmed CR, confirmed PR, or stable disease by INRC based on Investigator assessment. | Up to 2 years | 
| Part 2A: PFS | 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). | Up to 2 years | 
| Part 2B: PFS | 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 from any cause (whichever occurs first). | Up to 2 years | 
| Part 1A, Part 1B, Part 2A and Part 2B: Number of participants with Treatment emergent adverse events (TEAEs), adverse events (AEs, Serious AEs (SAEs), immune-related AEs (irAEs), TEAEs leading to death and AEs leading to discontinuation | TEAEs, AEs, SAEs, irAEs, TEAEs leading to death and AEs leading to discontinuation will be collected. | Up to 5 years | 
| Part 1A, Part 1B, Part 2A and Part 2B: Plasma concentration of niraparib | Blood samples will be collected for the concentrations of niraparib. | Up to Week 2 | 
| Part 1A, Part 1B, Part 2A and Part 2B: Serum concentration of dostarlimab | Blood samples will be collected for the concentrations of dostarlimab | Up to 2 years | 
| Part 1A, Part 1B, Part 2A and Part 2B: Number of subjects with positive ADAs against dostarlimab |  | Up to 2 years | 
| Part 1A, Part 1B, Part 2A and Part 2B: Titers of neutralizing anti-bodies to dostarlimab |  | Up to 2 years | 
| Part 1A, Part 1B, Part 2A and Part 2B: Acceptability and Palatability questionnaire score in pediatric participants | Acceptability and Palatability of niraparib as tablets and as AAOLF will be assessed using the acceptability and palatability questionnaires | Day 1 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Dose escalation, Dose Expansion, Dostarlimab, Niraparib, Osteosarcoma, Neuroblastoma