Phase 1 Multicenter Open-Label Study of Niraparib Tosilate Monohydrate and Dostarlimab in Pediatric Patients with Recurrent or Refractory Solid Tumors
- Trial ID
- 2024-511071-16-00
- Protocol
- 213406
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to establish the recommended Phase 2 dose (**RP2D**) of the combination of **niraparib** and **dostarlimab** in pediatric participants with recurrent or refractory **solid tumours**. This is clinically relevant as determining the RP2D is crucial for optimizing therapeutic efficacy while minimizing adverse effects in this vulnerable population.
Secondary objectives include:
- Evaluation of additional measures of anticancer activity, including objective response rate (ORR) and duration of response (DOR) in pediatric participants.
- Evaluation of the safety and tolerability of the combination of niraparib (tablet or tablet for oral suspension) and dostarlimab in pediatric participants.
- Characterization of the pharmacokinetics (PK) of the combination of niraparib and dostarlimab in pediatric participants.
- Assessment of the immunogenicity of dostarlimab in pediatric participants.
Participants
The clinical trial involves a total of **37 participants** diagnosed with **solid tumours**. The study population comprises both male and female **paediatric** subjects, ranging in age from 6 months to less than 18 years. Participants were selected based on specific inclusion criteria, including the presence of radiologically measurable disease or evaluable disease in the case of neuroblastoma, and a performance status of at least 60% on the Karnofsky or Lansky scale, depending on age. The trial includes a vulnerable population, as it involves children and adolescents. Participants are required to have adequate organ function and must not be pregnant or breastfeeding. The study does not specify any particular lifestyle considerations such as diet or physical activity. The selection process ensures that participants have a baseline body weight and the ability to swallow medication, although recent protocol amendments have adjusted these criteria. The trial aims to establish the recommended phase 2 dose (RP2D) of a combination therapy involving niraparib and dostarlimab.
Plans and Procedures
The clinical trial is designed as a **Phase 1**, multicenter, open-label, dose-escalation and cohort expansion study. The primary objective is to establish the recommended phase 2 dose (RP2D) of the combination of **niraparib tosilate monohydrate** and **dostarlimab** in pediatric patients with recurrent or refractory **solid tumors**. The trial is expected to run from October 12, 2020, to August 31, 2031. Participants will be involved in the study for varying durations depending on their response to treatment and the specific cohort they are assigned to.
The trial includes several key phases: Part 1A and Part 1B, which focus on dose escalation to determine the RP2D, and Part 2, which involves cohort expansion. The study is not randomized or blinded, as it is an open-label trial. Participants will be required to attend multiple study visits, starting with an inclusion (screening) visit to assess eligibility based on criteria such as age, disease status, and organ function. Follow-up visits will be scheduled to monitor safety, efficacy, and any dose-limiting toxicities (DLTs) to establish the RP2D. The end-of-study visit will conclude the participant's involvement, assessing the overall outcomes and any long-term effects of the treatment.
Participants are expected to remain in the study until the completion of their assigned cohort or until they experience unacceptable toxicity, disease progression, or withdrawal of consent. Conditions that may lead to early termination from the study include non-compliance with study procedures, adverse events that compromise safety, or any other medical reasons deemed significant by the investigator. The study aims to provide valuable data on the safety and efficacy of the drug combination in a pediatric population, contributing to the development of new therapeutic options for solid tumors.
Treatment
The clinical trial involves the administration of **Niraparib Tosilate Monohydrate**, an investigational medication provided in various pharmaceutical forms. The primary form is a **tablet** intended for oral administration. This formulation is not specifically designed for pediatric use. The dosage and frequency of administration are determined based on the study protocol, with the aim of establishing the recommended phase 2 dose (RP2D) in pediatric participants. Compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the protocol.
Another formulation of **Niraparib Tosilate Monohydrate** used in the trial is the **tablet for oral suspension**. This formulation is specifically designed for pediatric use, allowing for easier administration in younger participants. The route of administration remains oral, and the dosing schedule is tailored to establish the RP2D in pediatric patients. Participant compliance is closely monitored to ensure accurate dosing and adherence to the study protocol.
The trial also includes the use of **Zejula 100 mg film-coated tablets**, which contain **Niraparib Tosilate Monohydrate**. These tablets are administered orally and are not specifically formulated for pediatric use. The trial aims to determine the RP2D for this formulation in pediatric participants. The study protocol outlines the dosing schedule, and participant compliance is monitored to ensure adherence.
In addition to the oral formulations, the trial involves the administration of **Jemperli 500 mg concentrate for solution for infusion**, which contains the active substance **Dostarlimab**. This medication is administered via intravenous use. The trial protocol specifies the dosing schedule and frequency of administration, with the objective of determining the RP2D in pediatric patients. Compliance with the infusion schedule is monitored to ensure protocol adherence.
No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified in the trial data provided. The focus of the trial is on the investigational medications and their administration in pediatric patients with recurrent or refractory solid tumors. The study protocol includes detailed instructions for drug administration, dosing schedules, and participant compliance monitoring to ensure the integrity of the trial data.
Efficacy
Efficacy in this clinical trial will be assessed using several primary and secondary endpoints. The primary endpoint for Parts 1A and 1B is to assess the incidence of dose-limiting toxicities (DLTs) to establish the recommended phase 2 dose (RP2D) of the combination of **niraparib** and **dostarlimab**. This will be evaluated by study part and cohort for the DLT-evaluable population. Secondary endpoints include the overall response rate (ORR) based on investigator assessment, defined as the proportion of participants with a best overall response (BOR) of confirmed complete response (CR) or partial response (PR) as determined by the investigator using RECIST v1.1 or the International Neuroblastoma Response Criteria (INRC) for participants with neuroblastoma. Additionally, the duration of response (DOR) is defined as the time from the first documentation of response (CR or PR) until the time of first documented progressive disease (PD) by RECIST v1.1 or INRC, or death, whichever occurs first.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Participant is child or adolescent ≥6 months to <18 years old at the time of informed consent/assent. If a participant is enrolled under Protocol Amendment 04, the participant must be ≥6 months to <8 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 International Neuroblastoma Response Criteria (INRC) at the time of study enrolment. Neuroblastoma participants with recurrent/relapsed bone metastasis that is MIBG-positive (or FDG positive, for MIBG-nonavid tumours) as only site of disease are eligible.
- Under Protocol Amendment 03 (or earlier), a participant in Part 1A must be able to swallow the "CCI" and have a baseline body weight of ≥20 kg. Participants in Part 1A who are unable to swallow the "CCI" or who have a baseline body weight <20 kg are eligible to receive "CCI" only. As of Protocol Amendment 04, there are no inclusion criteria addressing ability to swallow niraparib tablets.
- Performance status must be ≥60% on the Karnofsky scale for participants >16 years of age and ≥60% on the Lansky scale for participants ≤16 years of age. Note: Neurologic deficits in participants with brain metastases must have been stable for at least 7 days prior to study enrolment. Participants who are unable to walk because of paralysis, but who are upright in a wheelchair, will be considered ambulatory for the purpose of assessing the performance status.
- Participant has adequate organ function, defined as follows: a. absolute neutrophil count (ANC) ≥1000/μL b. platelets ≥100000/μL c. haemoglobin ≥8 g/dL or ≥5.0 mmol/L d. serum creatinine ≤1.5 × upper limit of normal (ULN) for age or calculated creatinine clearance or radioisotope glomerular filtration rate ≥60 mL/min/1.73 m2 e. total bilirubin ≤1.5 × ULN or direct bilirubin ≤1 × ULN f. aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 × ULN unless liver metastases are present, in which case AST and ALT must be ≤5 × ULN g. international normalised ratio or prothrombin time (PT) ≤1.5 × ULN unless the participant is receiving anticoagulant therapy as long as PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants h. activated PTT ≤1.5 × ULN unless the participant is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants
- A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the conditions per protocol.
Exclusion Criteria
- Participation presents unacceptable risk to the prospective participant based on the Investigator's judgment.
- Participant has known hypersensitivity to dostarlimab or niraparib, their components, or their excipients
- Participant has a known history of myelodysplastic syndrome or acute myeloid leukaemia.
- Participant has active autoimmune disease that has required systemic treatment in the past 2 years (i.e., with use of disease-modifying antirheumatic drugs, corticosteroids, or immunosuppressive drugs). Replacement therapy (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. Note: Participants with previously treated brain metastases may participate provided they are clinically stable and have no evidence of new, enlarging, or progressing brain metastases (using the identical imaging modality for each assessment, either MRI or CT scan) for at least 4 weeks (28 days) prior to the first dose of study treatment. In addition, the participant must not have been using steroids for at least 7 days prior to the first dose of study treatment. 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, nonmalignant systemic disease, or active infection that requires systemic therapy. Specific examples include, but are not limited to, history of (noninfectious) pneumonitis that required steroids or current pneumonitis, uncontrolled ventricular arrhythmia, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, or any psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study (including obtaining assent/consent).
- Participant has a condition (such as transfusion-dependent anaemia 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 is pregnant, breastfeeding, or expecting to conceive within the projected duration of the study, starting with the Screening Visit through 180 days after the last dose of study treatment. No data are available regarding the presence of dostarlimab or niraparib or its metabolites in human milk, or on its effects on the breastfed infant or milk production. Because of the potential for serious adverse reactions in breastfed infants from dostarlimab and/or niraparib, female participants should not breastfeed during treatment with dostarlimab and/or niraparib and for at least 4 months after the last dose of dostarlimab or at least 30 days after the last dose of niraparib, whichever is longer.
- 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 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 anaemia, neutropenia, and/or thrombocytopenia that was related to the most recent prior anticancer treatment and that persisted >4 weeks (28 days).
- Exclusion criteria for Part 2 of the study are described in each cohort-specific supplement
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Czechia | Not Recruiting | 12 Oct 2020 | 14 |
 France | Not Recruiting | 12 Oct 2020 | 23 |
 Germany | Not Recruiting | 12 Oct 2020 | 30 |
 Hungary | Not Recruiting | 12 Oct 2020 | 17 |
 Spain | Not Recruiting | 12 Oct 2020 | 37 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Zejula 100 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL | — | — | PRD9709363 |
Zejula 100 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL | — | — | PRD9709386 |
JEMPERLI 500 mg concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS USE | — | — | PRD8877508 |