Neoplasms

All Conditions

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Carcinoma

Endometrial Neoplasms

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Uterine Neoplasms

Genital Neoplasms, Female

Urogenital Neoplasms

Uterine Diseases

Genital Diseases, Female

Genital Diseases

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

All Drugs and Chemicals

Antineoplastic Agents

Antibodies

Antibodies, Monoclonal

Paclitaxel

Carboplatin

Pembrolizumab

Albumin-Bound Paclitaxel

Immunomodulating Agents

Immunoglobulins

Tubulin Modulators

Antimitotic Agents

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

Standard Chemotherapy will be adminitred in 2 independant cohorts: Endometrial carcinoma or Cervix Carcinoma

Experimental double combination \[Standard Chemotherapy +NP137\] will be administred in 2 independant cohorts: Endometrial carcinoma or Cervix Carcinoma

Experimental double combination \[Pembrolizumab +NP137\] will be administred in 2 independant cohorts: Endometrial carcinoma or Cervix Carcinoma

Experimental triple combination \[Pembrolizumab+ Standard Chemotherapy + NP137\] will be administred in 2 independant cohorts: Endometrial carcinoma or Cervix Carcinoma

Recombinant humanized IgG1 monoclonal antibody against Netrin 1. NP137 will be administred IV, Q3W until disease progression, unacceptable toxicity, death, patient or physician decision to withdraw, pregnancy or SMPC guidance, whichever occurs first.

NP137

Humanised monoclonal anti-programmed cell death-1 (PD-1) antibody will be administred in IV Q3W. A maximum 35 cycles of treatments (approximately 2 years) with pembrolizumab can be administered to patients.

Standard Chemotherapy agent will be administred IV, Q3W, up to 6 cycles of treatment.

Ray-Coquard Isabelle, MD, PhD

Elsa KALBACHER, MD

Coriolan LEBRETON, MD

Florence JOLY, MD

Jean-David FUMET, MD

Cyril ABDEDDAIM, MD

Isabelle RAY COQUARD, MD,PhD

Magali PROVANSAL, MD

Michel FABBRO, MD

Jean-Sébastien FRENEL, MD

Frederic SELLE, MD

Alexandre DE MOURA, MD

Alexandra LEARY, MD

Jerome ALEXANDRE, MD, PhD

Thibault DE LA MOTTE ROUGE, MD

Laurence GLADIEFF, MD

The aim of this study is to investigate the safety and the clinical activities of NP137 when combined with pembrolizumab and/or chemotherapies in patients with advanced/metastatic gynecological cancers (2 types: endometrial carcinoma and cervix carcinoma).

The prognosis of patients with locally advanced/metastatic uterine (endometrial or cervical) cancer progressing/relapsing after at least one prior systemic treatment remains poor. The development of new innovative anti-tumor drug candidates as single agent or in combination with chemotherapy or check point inhibitors is needed.

NP137 is a first-in-class humanized monoclonal antibody targeting specifically and selectively Netrin-1. By blocking Netrin-1, NP137 is capable of restoring apoptosis in tumor cells in vitro and in vivo, leading to therapeutic activity in various animal cancer models.

Dependence receptors inhibitor such as NP137 might be a novel choice to improve the clinical outcomes of these patients.

The herein proposed study will be a multicenter, open-label, randomized, Phase I/II trial with:

A safety run in part to assess the safety of the therapeutic combinations for the first 6 patients enrolled in each of the therapeutic combinations independently of the tumor type. According to safety rules, these therapeutic combinations will be investigated or not in the Phase II part.

A Phase II part will be then conducted using an adaptive Bayesian approach allowing to quickly stop treatment cohorts without evidence of efficacy and/or select promising treatment cohorts. The Phase II part will be initiated with a preliminary step to assess the clinical activity of the proposed therapeutic combinations in 2 tumor types before proceeding to the activation of extension phase II part of the study. For each cohorts, clinical activity will be assessed through by sequential statistical analysis at specific timepoints.

GYNecological Cancers Treated With NETrin mAbs in Combination With Chemotherapy and /or Pembrolizumab

A Randomized, Multicenter, Open Label, Phase I/II Study to Evaluate the Safety, Clinical and Biological Activity of a Humanized Monoclonal Antibody Targeting Netrin-1 (NP137) in Combination With Carboplatin Plus Paclitaxel and/or Pembrolizumab in Patients With Locally Advanced/Metastatic Endometrial Carcinoma or Cervix Carcinoma Progressing/Relapsing After at Least One Prior Systemic Chemotherapy.

Any pre-definied toxicities graded by using NCI CTCAE Version 5.0 and assessed by the investigator to be possibly, probably, or definitely related to study treatments administration during the safety run in period

Rate of patients with CR or PR as per RECIST 1.1

The proportion of evaluable patients with an objective response according to RECIST 1.1.

Time interval from the date of first occurrence of a documented objective response (CR or PR, whichever status is recorded first) until the first date that disease progression or death is documented,

Time from first study drug intake until disease progression or death, whichever occurs first

Time from the first day of study treatment to the date of death due to any cause.

The best response designation between the date of the first study treatment and the date of objectively documented progression or the date of subsequent anti-cancer therapy

Area under the concentration-time curve from time zero to the last sample with the quantifiable concentration

Area under the concentration-time curve from time zero to infinity corresponding to the definite integral of a curve that describes the variation of a drug concentration in blood plasma as a function of time (drug exposure in plasma)

Clearance: volume of plasma from which NP137 is completely removed per unit time.

Terminal elimination half-life: time required for the amount of NP137 in the body to decrease by half.

Spots Global Cancer Trial Database for dependence receptors