| Eligibility |
Inclusion Criteria:
1. Progressive or recurrent uterine or ovarian carcinosarcoma (Malignant Mixed Mullerian
Tumor-MMMT).
2. The primary diagnosis must be histologically confirmed and central pathological review
of the initial tumor or biopsy at relapse will be done.
3. 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.
4. Progressive disease as defined by RECIST 1.1., within 12 months from last chemotherapy
cycle.
5. Failure after =1 prior platinum containing regimen, which may have been given in the
adjuvant setting.
6. 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.
7. Patient must be free of active infection requiring antibiotics.
8. 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.
9. Patient must have ECOG Performance Status =2.
10. Life expectancy of > 2 months.
11. 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
12. 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
13. 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.
14. Patient must have normal BP or adequately treated and controlled hypertension
(systolic BP=140 mmHg and/or diastolic BP =90 mmHg)
15. 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.
16. Patient must agree to not donate blood during the study or for 90 days after the last
dose of study treatment.
17. 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. 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.
19. Patient must agree to not breastfeed during the study and for 180 days after the last
dose of study treatment.
20. Patient able to take oral medications.
21. 21. Female aged =18 years at time of signing ICF.
22. Patient must have signed an approved informed consent.
23. For France only: patient affiliated to, or a beneficiary of, a social security
category.
Exclusion Criteria:
1. Not enrolled in any interventional clinical trial (except to biological trials that
must be validated by the sponsor).
2. Prior treatment with niraparib or other PARPi therapy or PD1/PDL-1 inhibitors.
3. 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 randomization.
Patient has had radiotherapy within 4 weeks prior to randomization.
4. Patient must not have had major surgery = 3 weeks prior to initiating protocol therapy
and participant must have recovered from any surgical effect.
5. Previous treatment with the chemotherapy regimen selected as the control arm by the
investigator.
- Prior therapy with paclitaxel given on a three-weekly regimen is permitted for
patients receiving weekly Paclitaxel.
- Prior treatment with weekly paclitaxel is permitted where this has been used as
part of first line therapy and it is greater than 6 months since the last dose of
weekly paclitaxel.
- Prior weekly paclitaxel for relapsed disease is not permitted.
6. Patients who have received more than 3 prior cytotoxic chemotherapies for management
of uterine or ovarian carcinosarcoma.
7. Patients with persistent, clinically significant > Grade 1 toxicity.
8. 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, NHYA
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)
9. Patients 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 abnormality. 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.
10. 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.
11. Patient experienced = Grade 3 immune-related AE with prior immunotherapy, with the
exception of non-clinically significant lab abnormalities
12. 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.
13. Patient has a diagnosis of immunodeficiency or has received systemic steroid therapy
or any other form of immunosuppressive therapy within 7 days prior to initiating
protocol therapy
14. Patient has a known history of human immunodeficiency virus (type 1 or 2 antibodies).
15. Patient has known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg]
reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [qualitative]
is detected).
16. 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.
17. Patient must not have a history of interstitial lung disease.
18. Patient has received a live vaccine within 14 days of initiating protocol therapy.
19. Patient must not have received a transfusion (platelets or red blood cells) = 4 weeks
prior to initiating protocol therapy.
20. Patient must not have received colony stimulating factors (eg, granulocyte
colony-stimulating factor, granulocyte macrophage colony stimulating factor, or
recombinant erythropoietin) within 4 weeks prior initiating protocol therapy.
21. Patient has had any known Grade 3 or 4 anemia, neutropenia or thrombocytopenia due to
prior chemotherapy that persisted > 4 weeks and was related to the most recent
treatment.
22. Patient must not have any known history of myelodysplastic syndrome (MDS) or acute
myeloid leukemia (AML)
23. Symptomatic CNS metastasis or leptomeningeal carcinomatosis.
24. 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.
25. Known, hypersensitivity reactions or allergy to investigational drugs or their
excipients that contraindicates the subject's participation.
26. 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.
27. Patients under psychiatric care and patients admitted to a health or social
institution.
28. Patients deprived of their liberty by judicial or administrative decision.
29. Patients under a legal protection measure or unable to express their consent.
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