Endometrial Cancer Patientes MMR Deficient Comparing Chemotherapy vs Dostarlimab in First Line

Inclusion Criteria:

• Patients must fulfil all the following criteria:

1. Female patient is at least 18 years of age,

2. Patient has signed the Informed Consent (ICF) and is able to comply withprotocol requirements.

3. Patient with histologically proven endometrial adenocarcinoma with recurrent oradvanced disease.

4. Patient with an Eastern Cooperative Oncology Group (ECOG) performance statusscore of 0 or 1.

5. Patient must have primary Stage IIIA to C2 or Stage IV disease or firstrecurrent endometrial cancer (see International Federation of Gynecology andObstetrics staging FIGO Staging 18.1) without curative treatment by radiationtherapy or surgery alone or in combination, and meet at least one of thefollowing situations:

6. Patient has patient has primary Stage IIIA-IIIC1 with no amenable curativeintent surgery or radiation.

7. Patient has first recurrent disease and is chemotherapy naïve for this 1strecurrence or metastatic setting.

8. Patient has recurrent disease and is chemotherapy naïve for recurrence oradvanced /metastatic setting.

9. Patient may have received prior irradiation for advanced endometrialcancer with or without radio-sensitizing chemotherapy if > 3 weeks beforethe start of the study

10. Patient with evaluable disease (measurable and not measurable disease)according to RECIST 1.1

11. Patient may have received prior neo-adjuvant/adjuvant systemic chemotherapy forthe primary cancer and had a recurrence ≥ 6 months after completing treatment (first recurrence only).

12. All histologic subtypes of endometrial adenocarcinoma could be included ifMMRd/MSI-H

13. MMRd/MSI-H tumor (first diagnosed by routine local IHC performed either onprimitive tumour tissue or on relapse/metastatic tumour sample) is mandatoryfor inclusion. A central confirmation will be done before inclusion; in case ofambiguous result of central IHC (lack of positive internal control,heterogeneous loss of MMR protein expression), MSI-H status will be assessed byPCR/NGS

14. Availability of 1 block for MMR/MSI status centralized confirmation for IHC orPCR/ NGS

15. . Patient could have been previously treated with hormone therapy, for themetastatic/advanced disease 12) Patient may have received pelvic andlombo-aortic external beam +/- vaginal brachytherapy

16. Patient has adequate organ function, defined as follows: a) Absolute neutrophil count ≥ 1,500 cells/μL b) Platelets ≥ 100,000 cells/μL c)Haemoglobin ≥ 9 g/dL or ≥ 5.6 mmol/L d) Serum creatinine ≤ 1.5× upper limit ofnormal (ULN) or calculated creatinine clearance ≥ 50 mL/min using theCockcroft-Gault equation for patients with creatinine levels > 1.5× institutionalULN e) Total bilirubin ≤ 1.5× ULN (≤ 2.0 x ULN in patients with known Gilbert'ssyndrome) or direct bilirubin ≤ 1× ULN f) Aspartate aminotransferase (AST) andalanine aminotransferase (ALT) ≤ 2.5× ULN unless liver metastases are present, inwhich case they must be ≤ 5× ULN g) International normalized ratio or prothrombintime (PT) ≤1.5× ULN and activated partial thromboplastin time ≤1.5× ULN. Patientsreceiving anticoagulant therapy must have a PT or partial thromboplastin within thetherapeutic range of intended use of anticoagulants.

17. Patient must have a negative serum pregnancy test within 72 hours of the firstdose of study medication, unless they are of nonchildbearing potential.Nonchildbearing potential is defined as follows:

18. Patient is ≥ 45 years of age and has not had menses for > 1 year.

19. A follicle-stimulating hormone value in the postmenopausal range upon screeningevaluation if amenorrhoeic for < 2 years without a hysterectomy andoophorectomy.

20. Post-hysterectomy, post-bilateral oophorectomy, or post-tubal ligation:

• Documented hysterectomy or oophorectomy must be confirmed with medical records ofthe actual procedure or confirmed by an ultrasound, MRI, or CT scan.

• Tubal ligation must be confirmed with medical records of the actual procedure;otherwise, the patient must fulfil the criteria in Inclusion Criterion 14.

• Information must be captured appropriately within the site's source documents. 15.Patient of childbearing potential must agree to use a highly effective method ofcontraception (section 18.9) with their partners starting from time of consentthrough 150 days after the last dose of study treatment. Note: Abstinence isacceptable if this is the established and preferred contraception for the patient (Information must be captured appropriately within the site's source documents).

Exclusion Criteria:

• Patients are to be excluded from the study if they meet any of the followingcriteria:

1. Patient has received neoadjuvant/adjuvant systemic chemotherapy for primaryStage III or IV disease and has had a recurrence or PD within 6 months ofcompleting this chemotherapy treatment prior to entering the study.Note: Low-dose cisplatin given as a radiation sensitizer or hormonal therapiesdo not exclude patients from study participation.

2. Patient has had > 1 recurrence of endometrial cancer, treated withchemotherapy. Surgery of the recurrence is allowed.

3. Patient previously treated with systemic chemotherapy for non-curable advanceddisease or metastatic disease

4. Patient has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2agent.

5. Patient has received prior anticancer therapy for (advanced or metastaticdisease (targeted therapies, hormonal therapy, radiotherapy) within 21 days or < 5 times the half-life of the most recent therapy prior to Study Day 1,whichever is shorter Note: Palliative radiation therapy to a small field ≥ 1week prior to Day 1 of study treatment may be allowed.

6. Patient with contraindication to chemotherapy or checkpoint inhibitortreatments

7. Patient has a concomitant malignancy, or patient has a prior non-endometrialinvasive malignancy who has been disease-free for < 3 years or who received anyactive treatment in the last 3 years for that malignancy. Non-melanoma skincancer is allowed.

8. Patient has known uncontrolled central nervous system metastases,carcinomatosis meningitis, or both. Note: Patients with previously treatedbrain metastases may participate provided they are stable (without evidence ofdisease progression by imaging [using the identical imaging modality for eachassessment, either MRI or CT scan] for at least 4 weeks prior to the first doseof study treatment and any neurologic symptoms have returned to baseline), haveno evidence of new or enlarging brain metastases, and have not been usingsteroids for at least 7 days prior to study treatment. Carcinomatous meningitisprecludes a patient from study participation regardless of clinical stability.

9. Patient has a known history of human immunodeficiency virus (HIV; HIV 1 or 2antibodies).

10. Patient has known active viral infection of hepatitis B (eg, hepatitis Bsurface antigen reactive) or hepatitis C (eg, hepatitis C virus ribonucleicacid [qualitative] detection).

11. Patient has an active autoimmune disease that has required systemic treatmentin the past 2 years. Replacement therapy is not considered a form of systemictherapy (eg, thyroid hormone or insulin).

12. Patient has a diagnosis of immunodeficiency or is receiving systemic steroidtherapy or any other form of systemic immunosuppressive therapy within 7 daysprior to the first dose of study treatment.

13. Patient has not recovered (ie, to Grade ≤ 1 or to baseline) from cytotoxictherapy-induced adverse events (AEs).Note: Patients with Grade ≤ 2 neuropathy, Grade ≤ 2 alopecia, or Grade ≤ 2fatigue are an exception to this criterion and may qualify for the study.

14. Patient has not recovered adequately from AEs or complications from any majorsurgery prior to starting therapy.

15. Patient has a known hypersensitivity to carboplatin, paclitaxel, or dostarlimabcomponents or excipients.

16. Patient is currently participating and receiving study treatment or hasparticipated in a study of an investigational agent and received studytreatment or used an investigational device within 4 weeks of the first dose oftreatment.

17. Patient is considered a poor medical risk due to a serious, uncontrolledmedical disorder, non-malignant systemic disease, or active infection requiringsystemic therapy. Specific examples include, but are not limited to, active,non-infectious pneumonitis; uncontrolled ventricular arrhythmia; recent (within 90 days) myocardial infarction; uncontrolled major seizure disorder; unstablespinal cord compression; superior vena cava syndrome; or any psychiatric orsubstance abuse disorders that would interfere with cooperation with therequirements of the study (including obtaining informed consent).

18. Use of any of the following immunomodulatory agents within 30 days prior to thefirst dose of study drug:

• Systemic corticosteroids (at dose higher than 10 mg/day equivalentprednisone); if systemic corticoid use at higher dose than 10 mg/day,corticoid must be stopped at least 7 days before study treatment start
• Interferons
• Interleukins
• Live vaccine Note: Examples of live vaccines include, but are not limitedto, the following: measles, mumps, rubella, varicella/zoster, yellowfever, rabies, BCG, and typhoid vaccine. Seasonal influenza vaccines forinjection are generally killed virus vaccines and are allowed as otherkilled vaccines, if done at least 2 weeks prior the first dose of studydrug; however, intranasal influenza vaccines (eg, FluMist®) are liveattenuated vaccines and are not allowed.

19. Patient is pregnant or breastfeeding or is expecting to conceive childrenwithin the projected duration of the study, starting with the screening visitthrough 180 days after the last dose of study treatment, or lactating woman.

20. Patients who had an allogenic tissue/solid organ transplant