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

Neoplasms Clinical Trial

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

Clinical Trial Details — Status: Suspended

Administrative data

• NCT number: NCT04544995
• Other study ID #: 213406
• Secondary ID: 2020-002359-39
• Status: Suspended
• Phase: Phase 1
• Start date: October 6, 2020
• Est. completion date: April 12, 2029

Study information

• Verified date: August 2023
• Source: GlaxoSmithKline
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Suspended
• Enrollment: 116
• Est. completion date: April 12, 2029
• Est. primary completion date: September 28, 2028
• Accepts healthy volunteers: No
• Gender: All
• Age group: 6 Months to 17 Years

Eligibility

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).

Related Conditions & MeSH terms

• Neoplasms

Intervention

Drug:
• Niraparib
Niraparib will be administered as tablet
• Dostarlimab
Dostarlimab will be administered as IV infusion
• Niraparib
Niraparib will be administered as AAOLF (once available)

Locations

Country	Name	City	State
Czechia	GSK Investigational Site	Brno
Czechia	GSK Investigational Site	Prague
France	GSK Investigational Site	Lille
France	GSK Investigational Site	Lyon
France	GSK Investigational Site	Marseille
France	GSK Investigational Site	Paris
France	GSK Investigational Site	Paris cedex 05
France	GSK Investigational Site	Villejuif
Germany	GSK Investigational Site	Duesseldorf	Nordrhein-Westfalen
Germany	GSK Investigational Site	Essen	Nordrhein-Westfalen
Germany	GSK Investigational Site	Frankfurt	Hessen
Germany	GSK Investigational Site	Hamburg
Germany	GSK Investigational Site	Heidelberg	Baden-Wuerttemberg
Germany	GSK Investigational Site	Muenchen	Bayern
Germany	GSK Investigational Site	Rostock	Mecklenburg-Vorpommern
Hungary	GSK Investigational Site	Budapest
Spain	GSK Investigational Site	Barcelona
Spain	GSK Investigational Site	Esplugues De Llobregat. Barcelona
Spain	GSK Investigational Site	Madrid
Spain	GSK Investigational Site	Madrid
Spain	GSK Investigational Site	Valencia
United Kingdom	GSK Investigational Site	Birmingham
United Kingdom	GSK Investigational Site	Glasgow
United Kingdom	GSK Investigational Site	London
United Kingdom	GSK Investigational Site	Manchester
United Kingdom	GSK Investigational Site	Sutton

Sponsors (1)

Lead Sponsor	Collaborator
GlaxoSmithKline

Countries where clinical trial is conducted

Czechia,  France,  Germany,  Hungary,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Part 1A: Number of participants with dose limiting toxicities (DLTs)	Number of participants with DLTs will be reported.	Up to 42 days
Primary	Part 1B: Number of participants with DLTs	Number of participants with DLTs will be reported.	Up to 42 days
Primary	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
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Part 1A, Part 1B, Part 2A and Part 2B: Number of subjects with positive ADAs against dostarlimab		Up to 2 years
Secondary	Part 1A, Part 1B, Part 2A and Part 2B: Titers of neutralizing anti-bodies to dostarlimab		Up to 2 years
Secondary	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