An International Multicentric Randomized Phase II Evaluating Dostarlimab in Combination With Niraparib Versus Niraparib Alone Compared to Chemotherapy in the Treatment of Metastatic or Recurrent Endometrial or Ovarian Carcinosarcoma After at Least One Line of Chemotherapy
Carcinosarcomas (CS) (malignant mixed Müllerian tumors) are highly aggressive and rare tumors with a worldwide annual incidence between 0.5-3.3 cases/100.000 women. Gynecological CS, i.e. ovarian CS (OCS) and uterine CS (UCS), have a 5-year overall survival (OS) \< 10% and a poor prognosis. After initial treatment (surgery +/- adjuvant radiotherapies +/- chemotherapies (CT)), vast majority of patients relapsed and received diverse CT producing modest benefits, and nearly all patients will die. After first line CT including platinum salt, monotherapy (doxorubicin or paclitaxel) is frequently used for relapsed patients, but the response rate (RR) is \<20%, progression-free survival (PFS) \<4 months, and OS \<1 year. In this unmet need situation, a better knowledge of these aggressive neoplasms is essential to propose new therapeutic options.
• Progressive or recurrent uterine or ovarian carcinosarcoma (Malignant Mixed Mullerian Tumor-MMMT).
• The primary diagnosis must be histologically confirmed and central pathological review of the initial tumor or biopsy at relapse will be done.
• Mandatory tumor samples: Availability of tumor sample(s) from a recently (not older than 3 months) obtained archival FFPE tumor tissue block or agreement for having a new tumor biopsy if lesion amenable, with ≥ 20% cellularity and tumoral surface ≥ 8 mm².
• Progressive disease as defined by RECIST 1.1., within 12 months from last chemotherapy cycle.
• 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 radiotherapy, 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 ≤2.
⁃ Life expectancy of \> 2 months.
⁃ Adequate bone marrow function:
∙ Platelet count greater than or equal to 100,000/mm3
‣ Absolute neutrophil count (ANC) greater than or equal to 1,500/mm3
‣ Hemoglobin \> 9g/dL
⁃ Adequate hepatic and renal function:
∙ 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)
‣ Serum creatinine ≤1.5x upper limit of normal (ULN) or calculated creatinine clearance ≥ 60 mL/min using Cockcroft-Gault equation
‣ Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5x ULN unless liver metastases are present, in which case they must be ≤5x ULN
‣ Alkaline phosphatase \< 2.5 times ULN
‣ 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.
⁃ Left ventricular ejection fraction (LVEF) \> Lower Limit of Normal (LLN) as assessed by either multigated acquisition (MUGA) scan or echocardiogram (ECHO), for patients planned to receive Anthracycline based therapy.
⁃ 18\. Patient has a negative urine or serum pregnancy test within 7 days 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.
∙ Non-childbearing potential is defined as follows:
⁃ ≥45 years of age and has not had menses for \>1 year
• Patients who have been amenorrhoeic for \<2 years without history of a hysterectomy and oophorectomy must have a follicle stimulating hormone value in the postmenopausal range upon screening evaluation
• Post-hysterectomy, post-bilateral oophorectomy, or post-tubal ligation. Documented hysterectomy or oophorectomy must be confirmed with medical records of the actual procedure or confirmed by an ultrasound. Tubal ligation must be confirmed with medical records of the actual procedure.
‣ For women of childbearing potential: the patient must be willing to use a highly effective contraception measure throughout the study, starting with the screening visit through 180 days after the last dose of study treatment. See Section 4.3. for a list of highly effective contraception methods. Information must be captured appropriately within the site's source documents. Note: Abstinence is acceptable if this is the established and preferred contraception for the patient.
⁃ 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.
⁃ 21\. 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.