A Three-arm Randomized Phase II Study of Dostarlimab Alone or with Bevacizumab Versus Nonplatinum Chemotherapy in Recurrent Gynecological Clear Cell Carcinoma: DOVE (APGOT-OV7/ ENGOT-ov80 Study)

Inclusion Criteria:

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

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

3. Patient with histologically proven confirmed recurrent or persistent clear cellcarcinoma of the ovary, endometrium, cervix, vagina, and vulva

• Local review by gynecologic pathologist required

• ≥50% clear cell histology in case of mixed carcinoma

• WT-1 neg (Only in case of ovarian cancer) Note: In the case of includingnon-ovarian clear cell carcinoma with more than 20 cases, the decision is madethrough discussion with the SPONSOR.

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

5. Disease progression within 12 months of completing platinum-based chemotherapy

6. 1-5 prior lines of therapies

7. Patient with measurable disease according RECIST 1.1 criteria

8. Availability of Tumor tissue for translational research . - A formalin-fixedparaffin-embedded (FFPE) tumor block(preferred) or at least 20 slides (unstained,freshly cut, serial sections) must be submitted.

9. Patients who consent to fresh tumor biopsies

• Confirmed with at least one lesion with location accessible to safely biopsyper the clinical judgement of the investigator

• Note: If mandatory biopsies cannot be performed as per investigator's clinicaljudgement, discussion and agreement between investigator and Sponsor arerequired.

10. Patient has adequate organ function, defined as follows:

11. Absolute neutrophil count ≥ 1,500 cells/μL

12. Platelets ≥ 100,000 cells/μL

13. Hemoglobin ≥ 9 g/dL or ≥ 5.6 mmol/L

14. Serum creatinine ≤ 1.5× upper limit of normal (ULN) or calculated creatinineclearance ≥ 50 mL/min using the Cockcroft-Gault equation for patients with × institutional ULN

15. Total bilirubin ≤ 1.5× ULN (≤ 2.0 x ULN in patients with known Gilbert'ssyndrome) or direct bilirubin ≤ 1× ULN

16. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5× ULNunless liver metastases are present, in which case they must be ≤ 5× ULN

17. International normalized ratio or prothrombin time (PT) ≤1.5× ULN and activatedpartial thromboplastin time ≤1.5× ULN.Participants taking anticoagulants may beincluded on a stable dose with a therapeutic INR <3.5. .

18. Patient must have a negative serum pregnancy test within 72 hours of the first doseof study medication, unless they are of non-childbearing potential. If a negativeresult cannot be confirmed by a urine test, a serum pregnancy test is required.Non-childbearing potential is defined as follows:

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

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

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

• Documented hysterectomy or oophorectomy must be confirmed with medicalrecords of the actual procedure or confirmed by an ultrasound, MRI, or CTscan.
• Tubal ligation must be confirmed with medical records of the actualprocedure.
• Information must be captured appropriately within the site's sourcedocuments.

12. Patient of childbearing potential must agree to use a highly effective method ofcontraception with their partners starting from time of consent through 180 daysafter the last dose of study treatment. Note: Abstinence is acceptable if this isthe established and preferred contraception for the patient (Information must becaptured appropriately within the site's source documents).

Exclusion Criteria:

1. Patient has had ≥ 6 prior lines of chemotherapy. Surgery of the recurrence isallowed.

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

3. Patient has received prior anticancer therapy (chemotherapy, targeted therapies,hormonal therapy, radiotherapy) within 21 days or < 5 times the half-life of themost recent therapy prior to Study Day 1, whichever is shorter. Note: Palliative radiation therapy to a small field ≥ 1 week prior to Day 1 of studytreatment may be allowed after discussion with the SPONSOR.

4. Patient with contraindication to chemotherapy or immune checkpoint inhibitortreatments or anti-angiogenic inhibitor

5. Patients with uncontrolled hypertension (defined as systolic blood pressure ≥ 160mmHg and/or diastolic blood pressure ≥100 mmHg) based on an average of ≥ 3 BPreadings on ≥ 2 sessions.

6. Patients with evidence of bleeding diathesis or significant coagulopathy (in theabsence of therapeutic anticoagulation)

7. Patients with current abdominal/pelvic fistula

8. Patient has a concomitant malignancy, or patient has a prior non-gynecologicalmalignancy who has been disease-free for < 3 years or who received any activetreatment in the last 3 years for that malignancy. Non-melanoma skin cancer isallowed.

9. Patient has known uncontrolled central nervous system metastases, carcinomatosismeningitis, or both. Note: Patients with previously treated brain metastases mayparticipate provided they are stable (without evidence of disease progression byimaging [using the identical imaging modality for each assessment, either MRI or CTscan] for at least 4 weeks prior to the first dose of study treatment and anyneurologic symptoms have returned to baseline), have no evidence of new or enlargingbrain metastases, and have not been using steroids for at least 7 days prior tostudy treatment. Carcinomatous meningitis precludes a patient from studyparticipation regardless of clinical stability.

10. Patient has a known history of human immunodeficiency virus (HIV; HIV ½ antibodies).Participants with known human immunodeficiency virus(HIV) are allowed if they meetall of the following criteria:

• Cluster of differentiation 4(CD4) ≥350/μL and viral load <50 copies/mL.

• No history of acquired immunodeficiency syndrome-defining opportunisticinfections within 12 months before enrollment.

• No history of HIV-associated malignancy for the past 5 years.

• Concurrent antiretroviral therapy as per the most current National Institutesof Health (NIH) Guidelines for the Use of Antiretroviral Agents in Adults andAdolescents with HIV started >4 weeks before study enrollment.

11. Patient with presence of hepatitis B surface antigen or a positive hepatitis Cantibody test result at screening or within 3 months before first dose ofdostarlimab treatment.

• Participants who are hepatitis B surface antigen positive may be enrolled iftheir HBV-DNA level is below the institutional lower limit.

• Participants with chronic hepatitis B virus (HBV) infection who meet thecriteria for anti-HBV therapy may be eligible if the participant is on asuppressive antiviral therapy before initiation of cancer therapy.

• Participants with positive hepatitis C antibody due to prior resolved diseasecan be enrolled only if a confirmatory negative hepatitis C RNA polymerasechain reaction is obtained. Hepatitis C participants may be eligible if theyboth have completed curative therapy and have a hepatitis C viral load <!-- NotAllowed Tag Filtered --><quantifiable limit.

12. Patient has an active autoimmune disease that required systemic treatment in thepast 2 years. Replacement therapy is not considered a form of (eg, thyroid hormoneor insulin).

13. diagnosis immunodeficiency receiving steroid any other immunosuppressive within 7days prior to first dose study treatment. Patients who have received acute and>/orlow-dose systemic immunosuppressive medications (e.g,, a one-time dose ofdexamethasone for nausea or chronic use of ≤ 10 mg/day of prednisone or doseequivalent corticosteroid) may be enrolled in the study after discussion with andapproval by the Sponsor. The use of inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone) is allowed.

14. Patient has not recovered (to Grade ≤ 1) from previous anti-cancer therapy-inducedadverse events (AEs). Note: Patients with Grade ≤ 2 neuropathy, Grade ≤ 2 alopecia, or Grade ≤ 2 fatigueare an exception to this criterion and may qualify for the study.

15. Patient has not recovered adequately from AEs or complications from any majorsurgery prior to starting therapy. Major surgical procedures, other than fordiagnosis, within 4 weeks prior to initiation of study treatment

16. Patient has a known hypersensitivity to bevacizumab or dostarlimab components orexcipients.

17. Patient is currently participating and receiving study treatment or has participatedin a study of an investigational agent and received study treatment or used aninvestigational device within 4 weeks of the first dose of treatment.

18. Patient is considered a poor medical condition 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 90days) myocardial infarction; uncontrolled major seizure disorder; unstable spinalcord compression; superior vena cava syndrome; or any psychiatric or substance abusedisorders that would interfere with cooperation with the requirements of the study (including obtaining informed consent).

19. Patients with known history of non-infectious pneumonitis that required steroids orhas current pneumonitis.

20. Use of any of the following immunomodulatory agents within 28 days prior to thefirst dose of study drug:

• Interferons

• Interleukins

• Live vaccine Note: Examples of live vaccines include, but are not limited to,the following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies,BCG, and typhoid vaccine. mRNA and adenoviral-based COVID-19 vaccines areconsidered non-live and are not exclusionary. Seasonal influenza vaccines forinjection are generally killed virus vaccines and are allowed as other killedvaccines, if done at least 2 weeks prior the first dose of study drug; however,intranasal influenza vaccines (eg, FluMist®) are live attenuated vaccines andare not allowed.

21. Patient who are pregnant or lactating, or plan to become pregnant or lactate duringthe expected duration of the study, from screening through 180 days after the lastdose of study drug.