GYNecological Cancers Treated with NETrin MAbs in Combination with Chemotherapy and /or Pembrolizumab

Inclusion Criteria:

• Be women ≥ 18 years at time of inform consent signature.

• Patient with histologically confirmed locally advanced / metastatic endometrialcarcinoma (Endometrial sarcoma are excluded) or patient with histologicallyconfirmed locally advanced / metastatic cervix adeno- or epidermoid- carcinoma.

• Previously treated by at least one line of platinum based chemotherapy, but no morethan 3 lines of chemotherapies whatever the nature. If the previous based platinumchemotherapy was given as neoadjuvant or adjuvant chemotherapy for a local disease (stage I or II), inclusion must be performed no more than one year after the end ofthis chemotherapy, except if an advanced or metastatic relapse has been documentedand treated by a systemic anti-cancer agent during this time interval.

In all cases, a minimal wash-out period of 6 months after completion of last chemotherapy with [platinum + paclitaxel] is required prior to entering the study.

Platinum chemotherapy concomitant to RT can not be considered as a line of previous platinum based chemotherapy.

• For endometrium carcinoma: mutational profile (MSI/MSS status) available beforerandomization (see St Paul de Vence 2019- ARCAGY - GINECO Group recommendation).

• Documented disease progression as per RECIST V1.1 after prior systemic chemotherapyregimen and presence of at least one lesion evaluable for response according toRECIST 1.1.

• Have provided a representative archival tumor sample in formalin-fixed paraffinembedded (FFPE) block (primary tumor or metastasis) or newly obtained core orexcisional biopsy of a tumor lesion together with an associated pathology report.

Note: If submitting unstained cut slides, newly cut slides should be submitted to the testing laboratory within 14 days from the date slides are cut (details pertaining to tumor tissue submission can be found in the laboratory manual).

• Optional for patients having consented to tumor biopsies: presence of at least onetumor lesion visible by medical imaging and accessible to repeatable percutaneoussampling that permits core needle biopsy without unacceptable risk of a significantprocedural complications, and suitable for retrieval of 4 cores using a 16-gaugediameter needle or larger.

Note: lesions to be biopsied should not be selected as RECIST target lesions. Bone lesions are not adequate lesions for biopsies and lymph nodes lesions should not be considered as prime targets.

• Life expectancy ≥ 3 months.

• Eastern Cooperative Oncology GrougGroup performance status (ECOG PS) of 0 to 1.

• Demonstrate adequate cardiovascular function:

• QTcF < 470ms

• Resting BP systolic <160mmHg and diastolic < 100mmHg

• LVEF > 50% as determined by transthoracic echocardiogram.

• Demonstrate adequate organ function as defined in protocol, all screening laboratorytests should be performed within 7 days prior C1D1:

• Women of child-bearing potential must have a negative urine pregnancy test atscreening (within 72 hours prior C1D1) and must agree to use 2 effective forms ofcontraception from the time of the treatment period and of the negative pregnancytest up 6 months after the end of their treatment.

• Patient should understand, sign, and date the written voluntary informed consentform prior to any protocol-specific procedures.

• Patient should be able and willing to comply with study visits and procedures as perprotocol.

Exclusion Criteria:

• Patients with progression during previous chemotherapy with [platinum +paclitaxel]

• Persistence of CTCAE ≥ Grade 2 toxicity due to prior anti-cancer therapy (exceptalopecia (any grades).

• History of severe (≥Grade 3) allergic anaphylactic reactions to one of thecomponents of NP137, pembrolizumab, paclitaxel, carboplatin and/or any of theirexcipients.

• Has known active CNS metastases and/or carcinomatous meningitis. Participants withpreviously treated brain metastases may participate provided they are radiologicallystable, i.e., without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening),clinically stable and without requirement of steroid treatment for at least 14 daysprior to first dose of study treatment.

• Has a known additional malignancy that is progressing or has required activetreatment within the past 2 years.

Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (e.g., breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy are not excluded.

• Prior/concomitant Therapy:

• Have received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD-L2 agentor with an agent directed to another stimulatory or co-inhibitory T-cellreceptor (e.g., CTLA-4, OX 40, CD137) and was discontinued from that treatmentdue to a Grade ≥ 3 irAE

• Have received prior systemic anti-cancer therapy :

• Chemotherapy or targeted therapies (approved or investigational) within 2 weeks or 5* t1/2 whichever is longer prior C1D1.

• Hormonal therapy within 1 week prior to C1D1

• Biological therapy within 4 weeks prior to C1D1

• Are currently participating in or have participated in a study of aninvestigational agent or have used an investigational device within 4 weeksprior to the first dose of study treatment. Note: Participants who have enteredthe follow-up phase of an investigational study may participate as long as ithas been 4 weeks after the last dose of the previous investigational agent.Have received prior radiotherapy within 4 weeks of start of study treatment.Participants must have recovered from all radiation-related toxicities, notrequire corticosteroids, and not have had radiation pneumonitis. A 1-weekwashout is permitted for palliative radiation (≤ 2 weeks of radiotherapy) tonon-CNS disease.

• Have had major surgery within 4 weeks of start of study treatment. Participantsmust have recovered adequately from the toxicity and/or complications from theintervention prior to starting study treatment, C1D1.

• Have received a live or live-attenuated vaccine within 30 days prior to thefirst dose of study drug. Note: killed vaccinesare allowed.

• Have received immunosuppressive medication within 2 weeks with the exceptionsof intranasal, topical and inhaled corticosteroids or systemic corticosteroidsat doses which are not to exceed 10 mg/day of prednisone, or equivalent dosesof another corticosteroid.

• Have a history of autoimmune disease that has required systemic treatment in past 2years (i.e., with use of disease modifying agents, corticosteroids orimmunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, orphysiologic corticosteroid replacement therapy for adrenal or pituitaryinsufficiency) is not considered a form of systemic treatment and is allowed.History of autoimmune disease which include but not limited to myasthenia gravis,myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis,inflammatory bowel disease, vascular thrombosis associated with antiphospholipidsyndrome, Wegener's granulomatosis, Sjögren's syndrome, Guillain-Barre syndrome,multiple sclerosis, vasculitis, or glomerulonephritis with the following exceptions:

• Patients with a history of autoimmune-related hypothyroidism who are on stablethyroid replacement hormone therapy,

• Patients with controlled Type 1 diabetes mellitus,

• patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo withdermatologic manifestations only (e.g., patients with psoriatic arthritis wouldbe excluded) are eligible provided that they meet the following conditions:

• Rash must cover less than 10% of body surface area (BSA).

• Disease is well controlled at baseline and only requiring low potencytopical steroids.

• No acute exacerbations of underlying condition within the previous 12months requiring PUVA [psoralen plus ultraviolet A radiation],methotrexate, retinoid, biologic agents, oral calcineurin inhibitors, highpotency or oral steroids.

• Patients with HIV, active B or C hepatitis infection. Notes: Active hepatitis B i.e.chronic or acute; defined as having a positive hepatitis B surface antigen [HBsAg]test at screening before C1D1. Patients with past hepatitis B virus (HBV) infectionor resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. HBV DNA test must be performed inthese patients prior to C1D1. Patients with a positive HBcAb test must have anegative HBV DNA test at screening. Active hepatitis C i.e. Patients positive forhepatitis C virus (HCV) antibody are eligible only if PCR is negative for HCV RNA atscreening.

• Patients with active tuberculosis.

• Prior allogeneic bone marrow transplantation or solid organ transplant for anothermalignancy in the past.

• History of idiopathic pulmonary fibrosis, non-infectious pneumonitis / interstitiallung disease that required steroids or has current pneumonitis / interstitial lungdisease , drug-induced pneumonitis, organizing pneumonia (i.e. bronchiolitisobliterans, cryptogenic organizing pneumonia), or evidence of active pneumonitis onscreening chest CT scan.

• Have an active infection requiring systemic therapy.