Clinical Trials /

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

NCT04544995

Description:

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.

Related Conditions:
  • Adrenal Cortex Carcinoma
  • Ewing Sarcoma
  • Malignant Solid Tumor
  • Neuroblastoma
  • Osteosarcoma
  • Rhabdomyosarcoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Dose Escalation and Cohort Expansion Study of Niraparib and Dostarlimab in Pediatric Participants With 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

Clinical Trial IDs

  • ORG STUDY ID: 213406
  • NCT ID: NCT04544995

Conditions

  • Neoplasms

Interventions

DrugSynonymsArms
Niraparib TabletPart 1A: Dose escalation phase: Niraparib tablet+ Dostarlimab
Niraparib AAOLFPart 1B: Dose escalation phase: Niraparib AAOLF + Dostarlimab
DostarlimabPart 1A: Dose escalation phase: Niraparib tablet+ Dostarlimab

Purpose

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.

Trial Arms

NameTypeDescriptionInterventions
Part 1A: Dose escalation phase: Niraparib tablet+ DostarlimabExperimentalIn Part 1A, participants will receive niraparib tablet in combination with dostarlimab. Up to 4 dose-level cohorts are planned and the starting dose of niraparib tablet will be 100 milligrams (mg) daily. Additional dose levels will be determined with consideration to comprehensive safety data and exposure data from population PK. The dostarlimab starting dose will be 3 milligrams per kilograms (mg/kg), administered every 3 weeks with possible escalation to 7.5 mg/kg (with maximum dose of 500 mg) or de-escalation to 1 mg/kg.
  • Niraparib Tablet
  • Dostarlimab
Part 1B: Dose escalation phase: Niraparib AAOLF + DostarlimabExperimentalIn Part 1B, participants will receive niraparib AAOLF in combination with dostarlimab. Up to 3 dose-level cohorts are planned and the starting dose level for niraparib AAOLF will be determined by population PK modelling using the RP2D from Part 1A. The starting dose level for dostarlimab will be the RP2D as determined from Part 1A.
  • Niraparib AAOLF
  • Dostarlimab
Part 2: DE phase: Participants with osteosarcoma (tablets)ExperimentalIn Part 2, participants with osteosarcoma who are able to swallow tablets and weigh >=20 kg will be eligible to receive the RP2D of niraparib along with dostarlimab once the RP2D for the niraparib tablets or dostarlimab is determined in Part 1A of the study.
  • Niraparib Tablet
  • Dostarlimab
Part 2: DE phase: Participants with osteosarcoma (AAOLF)ExperimentalIn Part 2, participants with osteosarcoma who are not able to swallow tablets or weigh <20 kg will be eligible to receive the RP2D of niraparib AAOLF with dostarlimab once the RP2D for the niraparib AAOLF and dostarlimab is determined in Part 1B of the study.
  • Niraparib AAOLF
  • Dostarlimab
Part 2: DE phase: Participants with neuroblastoma (tablet)ExperimentalIn Part 2, participants with neuroblastoma who are able to swallow tablets and weigh >=20 kg will be eligible to receive the RP2D of niraparib along with dostarlimab once the RP2D for the niraparib tablets and dostarlimab is determined in Part 1A of the study.
  • Niraparib Tablet
  • Dostarlimab
Part 2: DE phase: Participants with neuroblastoma (AAOLF)ExperimentalIn Part 2, participants with neuroblastoma who are not able to swallow tablets or weigh <20 kg will be eligible to receive the RP2D of niraparib AAOLF with dostarlimab once the RP2D for the niraparib AAOLF and dostarlimab is determined in Part 1B of the study.
  • Niraparib AAOLF
  • Dostarlimab

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.

          -  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 body weight of >=20 kg.
             Participants who are unable to swallow the 100 mg niraparib tablet or who have a body
             weight <20 kg are eligible to receive the niraparib AAOLF only.

          -  Performance status must be >=70 percent on the Karnofsky scale for participants >16
             years of age and >=50 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]) previously documented to have 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 prior to enrolment. 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 BRCA1/2 and
             other homologous recombination DNA repair (HRR) pathway genes, mutational signatures
             including signature 3, and tumor mutational burden (TMB).

        For Part 2 (osteosarcoma expansion cohort) only:

          -  Participant has recurrent or refractory osteosarcoma.

          -  Participant has radiographically measurable disease that can be tracked as RECIST v1.1
             target lesion(s).

          -  Participant must provide tumor tissue sample at screening for retrospective
             exploratory biomarker analysis.

        For Part 2 (neuroblastoma expansion cohort) only:

          -  Participant has recurrent or refractory neuroblastoma.

          -  Participant has radiographically measurable disease at the time of study enrolment;
             participants with neuroblastoma who do not have measurable disease but have
             metaiodobenzylguanidine-positive (+) evaluable disease are eligible. Measurable
             disease in participants with CNS involvement is defined as a tumor that is measurable
             in 2 perpendicular diameters on magnetic resonance imaging (MRI) and visible on more
             than 1 slice.

          -  Participant must provide tumor tissue sample at screening.

        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 (ie, with use of disease-modifying anti-rheumatic 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.

          -  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 including the following: Participants who received a transfusion
             (platelets or red blood cells) within 6 weeks of the first dose of study drug are not
             eligible. 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 drug are
             not eligible.

          -  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 drug.

          -  Participant has a known history of human immunodeficiency virus (HIV) (type 1 or 2
             antibodies).

          -  Participant has known active hepatitis B (eg, hepatitis B surface antigen reactive) or
             hepatitis C (eg, hepatitis C virus ribonucleic acid [qualitative] is detected).

          -  Participant has had any known Grade 3 or 4 anemia, neutropenia, or thrombocytopenia
             due to prior chemotherapy that persisted >4 weeks related to the most recent prior
             treatment.

          -  Participant had treatment with prior systemic anticancer therapy within the 3 weeks
             prior to the first dose of study drug, radiation therapy encompassing >20 percent of
             the bone marrow within 2 weeks prior to the first dose of study drug, or any radiation
             therapy within 1 week prior to the first dose of study drug.

          -  Participant has received a live vaccine within 14 days of planned start of study drug.

          -  Participant has clinically significant cardiovascular disease (eg, 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 >480 milliseconds at
             screening. The participant may be eligible to participate in the study following
             discussion with the Sponsor's Medical Monitor.

        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).
      
Maximum Eligible Age:17 Years
Minimum Eligible Age:6 Months
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Part 1A: Number of participants with dose limiting toxicities (DLTs)
Time Frame:Up to 42 days from start of the treatment (Day 0)
Safety Issue:
Description:An event is considered to be a DLT if the event occurs within the first 42 days of treatment and meets protocol defined DLT criteria. Number of participants with DLTs will be reported.

Secondary Outcome Measures

Measure:Part 1A and Part 1B: ORR
Time Frame:Up to 6 months from start of the treatment (Day 0)
Safety Issue:
Description:ORR based on Investigator assessment is defined as the percentage of participants with a BOR of confirmed CR or PR as determined by the Investigator using RECIST v1.1 criteria or INRC (for participants with neuroblastoma only).
Measure:Part 1A and Part 1B: Duration of response (DOR)
Time Frame:Up to 6 months
Safety Issue:
Description: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 or INRC (for participants with neuroblastoma only) based on Investigator assessment or death (whichever occurs first).
Measure:Part 2: ORR in participants with osteosarcoma
Time Frame:Up to 6 months from start of the treatment (Day 0)
Safety Issue:
Description:ORR is defined as the percentage of participants who have a BOR of confirmed CR or PR as determined by the Investigator using RECIST v1.1.
Measure:Part 2: DOR in participants with osteosarcoma
Time Frame:Up to 6 months
Safety Issue:
Description: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).
Measure:Part 2: Disease control rate (DCR) in participants with osteosarcoma
Time Frame:Up to 6 months from start of the treatment (Day 0)
Safety Issue:
Description: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.
Measure:Part 2: PFS in participants with osteosarcoma
Time Frame:Up to 6 months from start of the treatment (Day 0)
Safety Issue:
Description: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).
Measure:Part 2: DOR in participants with neuroblastoma
Time Frame:Up to 6 months
Safety Issue:
Description: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).
Measure:Part 2: DCR in participants with neuroblastoma
Time Frame:Up to 6 months from start of the treatment (Day 0)
Safety Issue:
Description:DCR is defined as the percentage of participants who have achieved a BOR of confirmed CR, confirmed PR, or stable disease by INRC based on Investigator assessment.
Measure:Part 2: PFS in participants with neuroblastoma
Time Frame:Up to 6 months from start of the treatment (Day 0)
Safety Issue:
Description: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).
Measure:Part 1A and Part 1B: Number of participants with adverse events (AEs), Serious AEs (SAEs), immune-related AEs (irAEs), AEs leading to death, AEs leading to discontinuation
Time Frame:Up to 2 years
Safety Issue:
Description:An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. An SAE is defined as any SAE that, at any dose that results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/ incapacity, is a congenital anomaly/ birth defect or any other situations as per Medical or scientific judgment. Number of participants with AEs, SAEs, irAEs, AEs leading to death, and AEs leading to discontinuation will be summarized.
Measure:Part 1A and Part 1B: Plasma concentration of niraparib
Time Frame:Cycle 1 Week 2 (Cycle duration: 21 days)
Safety Issue:
Description:Blood samples will be collected at indicated time points to analyze plasma concentration of niraparib.
Measure:Part 1A and Part 1B: Serum concentration of dostarlimab
Time Frame:Cycle 1, 3, 4, 6 and every 6 cycles thereafter (Up to maximum 2 years) (Each Cycle of 21 days)
Safety Issue:
Description:Blood samples will be collected at indicated time points to analyze serum concentration of dostarlimab.
Measure:Part 1A: Number of participants compliant based on 'Acceptability and Palatability questionnaire'
Time Frame:Cycle 1 Week 1 (Cycle duration: 21 days)
Safety Issue:
Description:The Acceptability and Palatability questionnaire addresses and intends to collect information on the 100 mg niraparib tablet formulation. Acceptability of niraparib tablets is defined based on overall experience of participants swallowing the tablet. Participants will select appropriate reasons from following such as due to taste, size, shape, color, medical condition or any other reason in cases where the tablet is unable to be swallowed.
Measure:Part 2: Number of participants with AEs, SAEs, irAEs, AEs leading to death, AEs leading to discontinuation in participants with osteosarcoma
Time Frame:Up to 2 years
Safety Issue:
Description:An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. An SAE is defined as any SAE that, at any dose that results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/ incapacity, is a congenital anomaly/ birth defect or any other situations as per Medical or scientific judgment. Number of participants with AEs, SAEs, irAEs, AEs leading to death, and AEs leading to discontinuation will be summarized.
Measure:Part 2: Plasma concentration of niraparib in participants with osteosarcoma
Time Frame:Cycle 1 Week 2 (Cycle duration: 21 days)
Safety Issue:
Description:Blood samples will be collected at indicated time points to analyze plasma concentration of niraparib.
Measure:Part 2: Serum concentration of dostarlimab in participants with osteosarcoma
Time Frame:Cycle 1, 3, 4, 6 and every 6 cycles thereafter (Up to maximum 2 years) (Each Cycle of 21 days)
Safety Issue:
Description:Blood samples will be collected at indicated time points to analyze serum concentration of dostarlimab.
Measure:Part 2: Number of participants compliant based on 'Acceptability and Palatability questionnaire' in participants with osteosarcoma
Time Frame:Cycle 1 Week 1 (Cycle duration: 21 days)
Safety Issue:
Description:The Acceptability and Palatability questionnaire addresses and intends to collect information on the 100 mg niraparib tablet formulation. Acceptability of niraparib tablets is defined based on overall experience of participants swallowing the tablet. Participants will select appropriate reasons from following such as due to taste, size, shape, color, medical condition or any other reason in cases where the tablet is unable to be swallowed.
Measure:Part 2: Number of participants with AEs, SAEs, irAEs, AEs leading to death, AEs leading to discontinuation in participants with neuroblastoma
Time Frame:Up to 2 years
Safety Issue:
Description:An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. An SAE is defined as any SAE that, at any dose that results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/ incapacity, is a congenital anomaly/ birth defect or any other situations as per Medical or scientific judgment. Number of participants with AEs, SAEs, irAEs, AEs leading to death, and AEs leading to discontinuation will be summarized.
Measure:Part 2: Plasma concentration of niraparib in participants with neuroblastoma
Time Frame:Cycle 1 Week 2 (Cycle duration: 21 days)
Safety Issue:
Description:Blood samples will be collected at indicated time points to analyze plasma concentration of niraparib.
Measure:Part 2: Serum concentration of dostarlimab in participants with neuroblastoma
Time Frame:Cycle 1, 3, 4, 6 and every 6 cycles thereafter (Up to maximum 2 years) (Each Cycle of 21 days)
Safety Issue:
Description:Blood samples will be collected at indicated time points to analyze serum concentration of dostarlimab.
Measure:Part 2: Number of participants compliant based on 'Acceptability and Palatability questionnaire' in participants with neuroblastoma
Time Frame:Cycle 1 Week 1(Cycle duration: 21 days)
Safety Issue:
Description:The Acceptability and Palatability questionnaire addresses and intends to collect information on the 100 mg niraparib tablet formulation. Acceptability of niraparib tablets is defined based on overall experience of participants swallowing the tablet and parent's or caregiver's observation on the result of the intake if not swallowed. Participants will have to select appropriate reasons from following in cases where the tablet is unable to be swallowed such as due to taste, size, shape, color, medical condition or any other reason.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:GlaxoSmithKline

Trial Keywords

  • Dose escalation
  • Dostarlimab
  • Niraparib
  • Osteosarcoma
  • Neuroblastoma

Last Updated

September 13, 2020