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 endometrial carcinoma (Endometrial sarcoma are excluded) or patient with histologically confirmed locally advanced / metastatic cervix adeno- or epidermoid- carcinoma.
* Previously treated by at least one line of platinum based chemotherapy, but no more than 3 lines of chemotherapies whatever the nature. If the previous based platinum chemotherapy 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 of this chemotherapy, except if an advanced or metastatic relapse has been documented and 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 before randomization (see St Paul de Vence 2019- ARCAGY - GINECO Group recommendation).
* Documented disease progression as per RECIST V1.1 after prior systemic chemotherapy regimen and presence of at least one lesion evaluable for response according to RECIST 1.1.
* Have provided a representative archival tumor sample in formalin-fixed paraffin embedded (FFPE) block (primary tumor or metastasis) or newly obtained core or excisional 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 one tumor lesion visible by medical imaging and accessible to repeatable percutaneous sampling that permits core needle biopsy without unacceptable risk of a significant procedural complications, and suitable for retrieval of 4 cores using a 16-gauge diameter 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 laboratory tests should be performed within 7 days prior C1D1:
* Women of child-bearing potential must have a negative urine pregnancy test at screening (within 72 hours prior C1D1) and must agree to use 2 effective forms of contraception from the time of the treatment period and of the negative pregnancy test up 6 months after the end of their treatment.
* Patient should understand, sign, and date the written voluntary informed consent form prior to any protocol-specific procedures.
* Patient should be able and willing to comply with study visits and procedures as per protocol.

Exclusion Criteria:

* Patients with progression during previous chemotherapy with \[platinum +paclitaxel\]
* Persistence of CTCAE ≥ Grade 2 toxicity due to prior anti-cancer therapy (except alopecia (any grades).
* History of severe (≥Grade 3) allergic anaphylactic reactions to one of the components of NP137, pembrolizumab, paclitaxel, carboplatin and/or any of their excipients.
* Has known active CNS metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable, 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 days prior to first dose of study treatment.
* Has a known additional malignancy that is progressing or has required active treatment 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 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4, OX 40, CD137) and was discontinued from that treatment due 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 an investigational agent or have used an investigational device within 4 weeks prior to the first dose of study treatment. Note: Participants who have entered the follow-up phase of an investigational study may participate as long as it has 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, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤ 2 weeks of radiotherapy) to non-CNS disease.
  * Have had major surgery within 4 weeks of start of study treatment. Participants must have recovered adequately from the toxicity and/or complications from the intervention prior to starting study treatment, C1D1.
  * Have received a live or live-attenuated vaccine within 30 days prior to the first dose of study drug. Note: killed vaccinesare allowed.
  * Have received immunosuppressive medication within 2 weeks with the exceptions of intranasal, topical and inhaled corticosteroids or systemic corticosteroids at doses which are not to exceed 10 mg/day of prednisone, or equivalent doses of another corticosteroid.
* Have a history of autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) 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 antiphospholipid syndrome, 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 stable thyroid replacement hormone therapy,
  * Patients with controlled Type 1 diabetes mellitus,
  * patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis would be 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 potency topical steroids.
    * No acute exacerbations of underlying condition within the previous 12 months requiring PUVA \[psoralen plus ultraviolet A radiation\], methotrexate, retinoid, biologic agents, oral calcineurin inhibitors, high potency 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) infection or 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 in these patients prior to C1D1. Patients with a positive HBcAb test must have a negative HBV DNA test at screening. Active hepatitis C i.e. Patients positive for hepatitis C virus (HCV) antibody are eligible only if PCR is negative for HCV RNA at screening.
* Patients with active tuberculosis.
* Prior allogeneic bone marrow transplantation or solid organ transplant for another malignancy in the past.
* History of idiopathic pulmonary fibrosis, non-infectious pneumonitis / interstitial lung disease that required steroids or has current pneumonitis / interstitial lung disease , drug-induced pneumonitis, organizing pneumonia (i.e. bronchiolitis obliterans, cryptogenic organizing pneumonia), or evidence of active pneumonitis on screening chest CT scan.
* Have an active infection requiring systemic therapy.