The purpose of this clinical trial is to assess the safety and efficacy of ubamatamab in combination with first-line chemotherapy in patients with ovarian cancer. The main questions it aims to answer are:

• What is the safety profile of ubamatamab when administered with carboplatin-paclitaxel ± bevacizumab?
• What is the objective response rate after three cycles of ubamatamab in combination with carboplatin-paclitaxel ± bevacizumab?

Participants will:

• Receive three cycles of ubamatamab in combination with carboplatin-paclitaxel ± bevacizumab, followed by maintenance therapy with ubamatamab ± bevacizumab for up to 15 months, depending on HRD status and disease response after the initial treatment cycles.
• Attend regular clinic visits throughout the treatment period for checkups and tests

Inclusion Criteria:

1. Histologically confirmed high-grade epithelial (serous, endometrioid, or carcinosarcoma with a ≥30% epithelial tumor component) ovarian, primary peritoneal, or fallopian-tube carcinoma

2. Adult patient aged ≥ 18 years old

3. Advanced stage III or IV

4. Treated with 3 or 4 standard neo-adjuvant cycles of carboplatin-paclitaxel regimen, in first line, given every 3 weeks, and characterized by 2 unfavorable features (both are required):

   • A poorly chemosensitive disease defined by an unfavorable standardized KELIM score < 1.0 calculated on CA-125 KELIM™ calculator for patients treated with neo-adjuvant chemotherapy
   • A disease considered not amenable to complete interval cytoreductive surgery with no post-operative macroscopic residual lesion (either because the interval cytoreductive surgery attempt was incomplete CC2-CC3, or because the surgeon considers a complete interval cytoreductive surgery is not achievable based on imaging and/or laparoscopic explorations)

5. Disease measurable and assessable by imaging based on RECIST 1.1 criteria (thorax-abdomen-pelvis CT-scanner; FDG-PET-CT-scanner; and/or MRI)

6. Availability of a tumor tissue for translational research (archival tissue, or alternatively from fresh biopsy, and/or surgery)

7. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1

8. BRCA and HRD status known, or planned during the trial (before maintenance treatment)

9. Adequate bone marrow function

   • Red blood cells: baseline Hemoglobin ≥8 g/dL (without red blood cell transfusion within 3 weeks before the blood work)
   • White blood cells: Absolute neutrophil count (ANC) ≥1500 cells/mm3
   • Platelets: Platelet count ≥100,000/mm3

10. Adequate renal and liver functions

    • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 × upper limit of normal (ULN), or ≤5 × ULN in context of liver metastases
    • Total bilirubin ≤1.5 × ULN (patients with Gilbert's are eligible if total bilirubin ≤3 × ULN)
    • Albumin ≥3 g/dL
    • Creatinine clearance ≥40 mL/min/1.73 m2 (measured or estimated, ideally with CKD-EPI formula on https://www.kidney.org/professionals/kdoqi/gfr\_calculator )

11. Adequate heart function: LVEF ≥ 50%, measured by echocardiogram, and troponin levels above the upper limit of normal (ULN). The case of troponin level comprised between 1.0 and 2 ULN, inclusion may be discussed after cardiological assessment.

12. Life expectancy of at least 3 months

13. Patients who gave their written informed consent to participate to the study

14. Patients affiliated to a social insurance regime

15. Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow-up.

Non-inclusion Criteria:

1. Low-grade endometrioid, clear cell, mucinous, or sarcomatous histology, or mixed tumors containing any of these histologies, or low-grade or borderline ovarian tumor.

2. Patients with primary platinum-refractory disease, defined as disease that has radiologically progressed during the neo-adjuvant chemotherapy

3. Contraindication to ubamatamab

4. Contraindication to carboplatin, paclitaxel or bevacizumab

5. Previous treatment with bevacizumab during initial standard neo-adjuvant chemotherapy

6. Prior treatment with anti-PD-1 therapies or T-cell therapies, or any other experimental anti-cancer systemic therapy

7. Patients with second primary cancer, except: adequately treated non-melanoma skin cancer, curatively treated in-situ cancer of the cervix, or other solid tumors curatively treated with no evidence of disease for ≥ 2 years.

8. All trial participants with brain metastases, except those meeting the following criteria (all criteria are required):

   1. Brain metastases that have been treated locally, and are clinically asymptomatic for at least 4 weeks prior to enrolment,
   2. No ongoing neurological symptoms that are related to the brain localization of the disease (sequelae that are a consequence of the treatment of the brain metastases are acceptable).
   3. Trial participants with brain metastases must be either off steroids except a stable or decreasing dose of <10mg daily prednisone (or equivalent).

9. Encephalitis, meningitis, or uncontrolled seizures in the year prior to informed consent

10. Patients receiving any systemic chemotherapy, radiotherapy (except for symptomatic/palliative reasons), within 3 weeks before the first dose of ubamatamab. The patient can receive a stable dose of bisphosphonates for bone metastases, before and during the study if these were started at least 4 weeks prior to treatment with study drug.

11. Persistent toxicities (≥CTCAE grade 3), caused by previous cancer therapy

12. Treatment with other investigational agents.

13. Bowel occlusive syndrome, inflammatory bowel disease, immune colitis, or other gastro-intestinal disorder that does not allow oral medication, such as malabsorption.

14. Clinically significant (i.e., active) and severe cardiovascular disease according to investigator opinion such as myocardial infarction (< 6 months prior to enrollment); any history of myocarditis; significant arrhythmia including paroxysmal atrial fibrillation requiring intervention at any time or implantation of a pacemaker or defibrillator; signs or symptoms of active angina; arrhythmia or heart failure; LEVF < 50% with echocardiogram; QTc (Friedericia) interval >470 msec (in cases of asymptomatic prolonged QTc interval (>470 msec), the ECG can be repeated up to 2 times. If subsequent QTc interval is <470 msec, the patient may be enrolled but only after review and approval by a cardiologist); Evidence of Second-Degree AV block type II (Mobitz type II) or AV block type III (complete heart block); Baseline serum troponin above institutional upper limit of normal. In cases of minimally elevated troponin in absence of clinical symptoms, after clearance by a cardiologist, the patient may be enrolled.

15. Untreated pulmonary embolism (PE) or deep vein thrombosis (DVT), not currently managed with anticoagulant therapy. Ongoing or recent (within 5 years) evidence of significant autoimmune disease that required treatment with systemic immunosuppressive treatments, which may suggest risk for immunological adverse events. The following are not exclusionary: vitiligo, childhood asthma that has resolved, hypothyroidism that required only hormone replacement, type 1 diabetes or psoriasis that does not require systemic treatment

16. Uncontrolled infection with human immunodeficiency virus, hepatitis B or hepatitis C infection; or diagnosis of immunodeficiency or known latent tuberculosis infection.

    Participants will be tested for HCV and HBV at screening per Section 5.2

    • Patients with HIV who have controlled infection (undetectable viral load and CD4 count above 350 either spontaneously or on a stable antiviral regimen) are permitted.
    • Patients with hepatitis B surface antigen positive (HepBsAg+) who have controlled infection (serum hepatitis B virus DNA PCR that is below the limit of detection AND receiving antiviral therapy for hepatitis B) are permitted.
    • Participants with HBsAg negative but total HBV core antibody positive (HBc Ab+) are permitted with the following requirements: If serum HBV DNA PCR is above the limit of detection at screening, antiviral therapy for HBV must be initiated prior to study entry. If serum HBV DNA PCR is below the limit of detection periodic monitoring of HBsAg must be performed.
    • Patients who are Hepatitis C virus antibody positive (HCV Ab +) who have controlled infection (undetectable HCV RNA by PCR either spontaneously or in response to a successful prior course of anti-HCV therapy) are permitted.

17. Other active infections requiring hospitalization or IV anti-infectives within 2 weeks before starting study treatment.

18. Receipt of a live vaccine within 30 days of planned start of study medication.

19. Pregnant or lactating patients or patients expecting to conceive children within the projected duration of the trial.

20. Women of childbearing potential (WOCBP)* who are unwilling to practice highly effective contraception prior to the initial dose/start of the first treatment, during the study, and for at least 6 months after the last dose. Highly effective contraceptive measures include:

    1. stable use of combined (estrogen and progestogen containing) hormonal contraception (oral, intravaginal, transdermal) or progestogen-only hormonal contraception (oral, injectable, implantable) associated with inhibition of ovulation initiated 2 or more menstrual cycles prior to screening
    2. intrauterine device (IUD); intrauterine hormone-releasing system (IUS)
    3. bilateral tubal occlusion/ligation
    4. vasectomized partner (provided that the male vasectomized partner is the sole sexual partner of the study participant and that the vasectomized partner has obtained medical assessment of surgical success for the procedure) and/or e. sexual abstinence** *** * WOCBP are defined as women who are fertile following menarche until becoming postmenopausal, unless permanently sterile. Permanent sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy.

    A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle-stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient to determine the occurrence of a postmenopausal state. The above definitions are according to Clinical Trial Facilitation Group (CTFG) guidance.

    ** Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient.

    ***Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhea method (LAM) are not acceptable methods of contraception. Female condom and male condom should not be used together.

21. Known psychiatric disorder that would interfere with trial compliance.

22. Patient deprived of liberty, under guardianship, or under curatorship