Phase II Randomized Study of Dostarlimab and Niraparib Versus Niraparib Monotherapy and Chemotherapy in Metastatic or Recurrent Endometrial or Ovarian Carcinosarcoma
- Trial ID
- 2024-516782-36-00
- Protocol
- GINECO-EN203b
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the efficacy of the best experimental strategy in patients with **metastatic or recurrent endometrial or ovarian carcinosarcoma** after at least one line of chemotherapy. This involves a two-step process: initially selecting the optimal experimental strategy between **dostarlimab** combined with **niraparib** and niraparib monotherapy, followed by assessing the efficacy of the selected strategy. This is clinically relevant as it aims to identify a more effective treatment regimen for a challenging and aggressive cancer type, potentially improving patient outcomes.
Secondary objectives include:
- Evaluating the median overall survival in the best experimental strategy.
- Further assessing the overall safety profile of the best experimental arm.
- Evaluating the anti-tumor activity of the best experimental strategy, including objective response rate (ORR) and duration of response (DoR).
- Assessing the clinical benefit of the best experimental strategy.
- Further assessing progression-free survival (PFS) and PFS2 in the best experimental strategy.
- Evaluating the effects of treatments on patient-reported outcomes and quality of life (QoL).
- Exploring the biological mechanisms of response and resistance.
Participants
The clinical trial involves a study population exclusively composed of **female** participants aged 18 years and older, diagnosed with **metastatic or recurrent endometrial or ovarian carcinosarcoma**. The sponsor has not provided the total number of participants. The trial population was selected based on specific inclusion criteria, including a confirmed diagnosis of progressive or recurrent uterine carcinosarcoma, adequate bone marrow, hepatic, and renal function, and a life expectancy of more than two months. Participants must have experienced failure after at least one prior platinum-containing regimen and must be free of active infections requiring antibiotics. The study does not include male participants or vulnerable populations. Lifestyle considerations such as diet and physical activity are not specified, but participants must be able to take oral medications and agree to not donate blood or breastfeed during and after the study period. The trial requires participants to have an ECOG Performance Status of 0 or 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. The trial does not include any information on the participants' general health status beyond the specified criteria.
Plans and Procedures
The clinical trial is designed as an international multicentric **randomized** phase II study evaluating the efficacy of **dostarlimab** in combination with **niraparib** versus **niraparib** alone, compared to chemotherapy, in the treatment of metastatic or recurrent endometrial or ovarian carcinosarcoma. The trial is structured into two phases: a selection phase to determine the optimal experimental strategy and an extension phase to assess the efficacy of the selected strategy. The study is expected to run from July 2020 to December 2026, with a maximum treatment period of 24 months for participants.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as adequate bone marrow, hepatic, and renal function, and a life expectancy of more than two months. Following the screening, participants will be randomized into one of the treatment arms. Regular follow-up visits will be scheduled to monitor the response to treatment, assess safety and tolerability, and evaluate progression-free survival and overall survival rates. The end-of-study visit will conclude the participant's involvement, which is anticipated to last up to 24 months unless early termination criteria are met.
Early termination from the study may occur if a participant experiences unacceptable toxicity, disease progression, or withdraws consent. The primary endpoints include the response rate at four months and the six-month overall survival rate, while secondary endpoints focus on progression-free survival, time to subsequent treatment or death, and quality of life assessments. The trial employs a double-blind methodology to ensure unbiased results, with neither participants nor investigators aware of the treatment allocations. This rigorous design aims to provide robust data on the comparative efficacy of the treatment regimens in this patient population.
Treatment
The clinical trial involves the administration of **JEMPERLI** (dostarlimab), a **concentrate for solution for infusion**. This experimental medication is provided in a pharmaceutical form suitable for **intravenous use**. Each vial contains 500 mg of the active substance, dostarlimab, which is a protein-based therapeutic agent. The maximum daily and total dose is set at 1000 mg, with a treatment period extending up to 24 months. The administration schedule is designed to ensure optimal therapeutic efficacy while monitoring participant compliance through regular assessments.
In addition to JEMPERLI, the trial also includes the use of **Zejula** (niraparib tosilate monohydrate), which is provided in the form of **hard capsules** for **oral use**. Each capsule contains 100 mg of the active chemical substance, niraparib tosilate monohydrate. The maximum daily and total dose is 300 mg, with a treatment duration of up to 24 months. Bottles containing 72 hard capsules are supplied for the study, and dosing schedules are structured to maintain consistent therapeutic levels. Participant adherence to the dosing regimen is monitored through scheduled follow-ups and capsule counts.
The trial aims to evaluate the efficacy of dostarlimab in combination with niraparib versus niraparib alone, compared to chemotherapy, in the treatment of metastatic or recurrent endometrial or ovarian carcinosarcoma. The study is conducted under the sponsorship of GlaxoSmithKline (Ireland) Limited, ensuring compliance with regulatory standards and ethical guidelines. No non-experimental treatments, such as placebo or standard-of-care therapy, are utilized in this study.
Efficacy
Efficacy in the clinical trial will be assessed using specific primary and secondary endpoints. The primary endpoints include the **Response Rate** at 4 months (W16-RR) as per RECIST 1.1 during the Selection Phase (Step 1) and the 6-months **Overall Survival** (OS) rate during the Extension Phase (Step 2). Secondary endpoints encompass **Progression-Free Survival** (PFS), **Time To Subsequent Treatment or Death**, **Progression-Free Survival 2** (PFS2), **Overall Survival**, **Objective Response Rate** (ORR), **Disease Control Rate** (DCR), **Duration of response**, **Safety and Tolerability**, and **Quality of Life** (QoL) & symptom benefit evaluation.
The trial will evaluate the efficacy of dostarlimab in combination with niraparib versus niraparib alone compared to chemotherapy in patients with metastatic or recurrent endometrial or ovarian carcinosarcoma after at least one line of chemotherapy. The efficacy parameters will be measured and collected at specified timepoints, including 4 months and 6 months, using validated scales and criteria such as RECIST 1.1. The analysis will focus on determining the best experimental strategy and evaluating its effectiveness in improving patient outcomes.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Progressive or recurrent uterine carcinosarcoma (Malignant Mixed Mullerian Tumor-MMMT).
- The primary diagnosis must be histologically confirmed by pathological expert review of the initial tumor or biopsy at relapse.
- Mandatory tumor samples: Availability of an archival FFPE tumor sample(s) from diagnosis, or if not available from relapse setting.
- Progressive disease as defined by RECIST 1.1.
- Failure after ≥1 prior platinum containing regimen, which may have been given in the adjuvant setting.
- Patient must have had 1 prior chemotherapeutic regimen for management of carcinosarcoma that may have included chemotherapy, chemotherapy and radio-chemotherapy, and/or consolidation/maintenance therapy.
- Patient must be free of active infection requiring antibiotics.
- Any hormonal therapy directed at the malignant tumor must be discontinued at least one week prior to beginning protocol chemotherapy; continuation of hormone replacement therapy is permitted.
- Patient must have ECOG Performance Status ≤1.
- Life expectancy of > 2 months.
- Adequate bone marrow function:o Platelet count greater than or equal to 100,000/mm3 o Absolute neutrophil count (ANC) greater than or equal to 1,500/mm3 o Hemoglobin > 9g/dL
- Adequate hepatic and renal function/ o Total bilirubin ≤1.5x Upper Limit of Normal (ULN) unless liver metastases are present, in which case they must be ≤3x ULN (≤2.0 in patients with known Gilberts syndrome OR direct bilirubin ≤ 1 x ULN) o Serum creatinine ≤1.5x upper limit of normal (ULN) or calculated creatinine clearance ≥ 60 mL/min using Cockcroft-Gault equation o Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5x ULN unless liver metastases are present, in which case they must be ≤5x ULN o Alkaline phosphatase < 2.5 times ULN o Serum albumin > 3 g/dL
- International normalized ratio (INR) or prothrombin time (PT) ≤1.5× ULN unless patient is receiving anticoagulant therapy as long as PT or partial thromboplastin (PTT) is within therapeutic range of intended use of anticoagulants. Activated partial thromboplastin time (aPTT) ≤1.5× ULN unless patient is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants.
- Patient must have normal BP or adequately treated and controlled hypertension (systolic BP≤140 mmHg and/or diastolic BP ≤90 mmHg)
- Patient receiving corticosteroids may continue as long as their dose is stable and ≤10mg/day (prednisone equivalent) for at least 4 weeks prior to initiating protocol therapy.
- Patient must agree to not donate blood during the study or for 90 days after the last dose of study treatment
- Patient has a negative urine or serum pregnancy test within 72 hours prior to taking study treatment if of childbearing potential and agrees to abstain from activities that could result in pregnancy from screening through 180 days after the last dose of study treatment, or is of nonchildbearing potential.
- Patient must agree to not breastfeed during the study and for 180 days after the last dose of study treatment.
- Patient able to take oral medications
- Female aged ≥18 years at time of signing ICF.
- Patient must have signed an approved informed consent.
- For France only: patient affiliated to, or a beneficiary of, a social security category.
Exclusion Criteria
- Not enrolled in any interventional clinical trial (except to biological trials that must be validated by the sponsor)
- Prior treatment with niraparib or other PARPi therapy or PD1/PDL-1 inhibitors.
- Patient has had investigational therapy, immunotherapy, chemotherapy or biological therapy administered within 4 weeks or within a time interval less than at least 5 half-lives of the investigational agent, whichever is longer, prior to treatment initiation. Patient has had radiotherapy within 4 weeks prior to treatment initiation.
- Patients must not have had major surgery ≤ 3 weeks prior to initiating protocol therapy and participant must have recovered from any surgical effects
- Patient who has received more than 3 prior cytotoxic chemotherapies for management of uterine carcinosarcoma.
- Patient with persistent, clinically significant > Grade 1 toxicity.
- Patient has clinically significant cardiovascular disease (eg, significant cardiac conduction abnormalities, uncontrolled hypertension, myocardial infarction, uncontrolled cardiac arrhythmia or unstable angina < 6 months to enrollment, NYHA grade 2 or greater congestive heart failure, serious cardiac arrhythmia requiring medication, Grade 2 or greater peripheral vascular disease, and history of cerebrovascular accident within 6 months)
- Patient with any other severe concurrent disease, which may increase the risk associated with study participation or study drug administration and, in the judgment of the investigator, would make the patient inappropriate for entry into this study, including significant neurologic, psychiatric, infectious, hepatic, renal, or gastrointestinal diseases or laboratory abnormalities. Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 90 days) myocardial infarction, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, or any psychiatric disorder that prohibits obtaining informed consent.
- Symptoms or signs of gastrointestinal obstruction requiring parenteral nutrition or hydration or any other gastro-intestinal disorders or abnormalities, including difficulty swallowing, that would interfere with drug absorption.
- Patient experienced ≥ Grade 3 immune-related AE with prior immunotherapy, with the exception of non-clinically significant lab abnormalities
- Participant has had radiation therapy encompassing >20% of the bone marrow within 2 weeks prior to Day 1 of protocol therapy or any radiation therapy within 1 week prior to Day 1 of protocol therapy.
- Patient has a diagnosis of immunodeficiency or has received systemic steroid therapy >10mg/day (prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to initiating protocol therapy
- Participants with known HIV infection are allowed with the following requirements: Documented evidence of plasma HIV-1 RNA persistently <50 copies/mL ≤3 months prior to AND at Screening. In the >3 to 12 months prior to Screening, plasma HIV-1 RNA consistently <50 c/mL required; if single increases ≥50 c/mL occurred, they cannot have been persistent nor associated with antiretroviral resistance per investigator assessment AND CD4 cell count >350 cells/mm3 over past 12 months and at Screening (and no measurement ≤350 cells/mm3 during that time period) AND Must be on an uninterrupted combination antiretroviral therapy regimen for at least 3 months prior to Screening, with combination antiretroviral therapy regimen consistent with locally recommended guidelines Participants with history of CDC Stage 3 AIDS-defining disease (CDC, 2014; also known as acquired immunodeficiency syndrome - defining disease) are allowed if AIDS-defining disease has been treated and cured or is stable for ≥3 months prior to study entry. Cutaneous Kaposi’s sarcoma not requiring systemic therapy is allowed. No history of HIV-associated non-Hodgkin lymphoma ≤5 years prior to study entry. No treatment with an HIV-1 immunotherapeutic vaccine within 90 days of Screening
- Patient has known active hepatitis B (e. g., hepatitis B surface antigen [HBsAg] reactive and HBcAb reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [qualitative] is detected).
- Patient has an active autoimmune disease that has required systemic treatment in the past 2 years (ie, with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
- Patient must not have a history of interstitial lung disease.
- Patient has received a live vaccine within 30 days of initiating protocol therapy.
- Patient must not have received a transfusion (platelets or red blood cells) ≤ 4 weeks prior to initiating protocol therapy.
- Patient must not have received colony-stimulating factors (e.g, granulocyte colony-stimulating factor, granulocyte macrophage colony-stimulating factor, or recombinant erythropoietin) within 4 weeks prior initiating protocol therapy.
- Patient must not have any known history of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML)
- Symptomatic CNS metastasis or leptomeningeal carcinomatosis.
- Patients with a history of other invasive malignancies (any evidence of other malignancy being present within the last 3 years) or with a concomitant invasive malignancy, with the exception of non-melanoma skin cancer; patients are also ineligible if their previous cancer treatment contraindicates this protocol therapy.
- Known hypersensitivity reactions or allergy to investigational drugs or their excipients that contraindicates the subject’s participation.
- Any psychological, familial, sociological or geographical consideration potentially hampering compliance with the study protocol and follow up schedule; those considerations should be discussed with the patient before registration in the trial.
- Patients under psychiatric care and patients admitted to a health or social institution.
- Patients deprived of their liberty by judicial or administrative decision.
- Patients under a legal protection measure or unable to express their consent.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Recruiting | 15 Jul 2020 | 100 |
 Italy | Not Yet Recruiting | 15 Jul 2020 | 25 |
 Spain | Recruiting | 15 Jul 2020 | 10 |
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 hard capsules | Test | HARD CAPSULE | ORAL USE | 300 | 24 | PRD5625301 |
Zejula 100 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL USE | 300 | 24 | PRD9709363 |
JEMPERLI 500 mg concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS USE | 1000 | 24 | PRD8877508 |