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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
240
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.
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.
CHRU BESANCON - Hopital Jean Minjoz
Besançon, France
Institut Bergonié
Bordeaux, France
Centre François Baclesse
Caen, France
DLT occurrence
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
Time frame: Safety run in Period: At the end of Cycle 2 (each cycle is 21 days) for the first 6 to 12 patients per arm
Overall response Rate (ORR)
Rate of patients with CR or PR as per RECIST 1.1
Time frame: At 3 months of treatement and then every 12 weeks, up to 2 years
Clinical Benefit Rate (CBR)
The proportion of evaluable patients with an objective response according to RECIST 1.1.
Time frame: Every 12 weeks, up to 2 years
Duration of Response
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 frame: Every 12 weeks, up to 2 years
Progression-free Survival
Time from first study drug intake until disease progression or death, whichever occurs first
Time frame: Every 12 weeks, up to 2 years
Overall Survival
Time from the first day of study treatment to the date of death due to any cause.
Time frame: Every 12 weeks, up to 2 years
Best Overall Response
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
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Standard Chemotherapy agent will be administred IV, Q3W, up to 6 cycles of treatment.
Centre Georges François Leclerc
Dijon, France
Primary Completion Date
Lille, France
Centre Léon Bérard
Lyon, France
Primary Completion Date
Marseille, France
ICM - Val d'Aurelle
Montpellier, France
Insitut de cancérologie de l'ouest
Nantes, France
Hopital de la Croix Saint Simon
Paris, France
...and 5 more locations
Time frame: Every 12 weeks, up to 2 years
Pharmacokinetic parameter: Cmax
Plasma peak concentration
Time frame: Over the first 6 cycles (each cycle is 21 days) of patients treated with NP137 and enrolled during the Safety run in period
Pharmacokinetic parameter: tmax
Time to reach the peak concentration
Time frame: Over the first 6 cycles (each cycle is 21 days) of patients treated with NP137 and enrolled during the Safety run in period
Pharmacokinetic parameter: AUCt
Area under the concentration-time curve from time zero to the last sample with the quantifiable concentration
Time frame: Over the first 6 cycles (each cycle is 21 days) of patients treated with NP137 and enrolled during the Safety run in period
Pharmacokinetic parameter: AUC∞
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)
Time frame: Over the first 6 cycles (each cycle is 21 days) of patients treated with NP137 and enrolled during the Safety run in period
Pharmacokinetic parameter: CL
Clearance: volume of plasma from which NP137 is completely removed per unit time.
Time frame: Over the first 6 cycles (each cycle is 21 days) of patients treated with NP137 and enrolled during the Safety run in period
Pharmacokinetic parameter: t1/2
Terminal elimination half-life: time required for the amount of NP137 in the body to decrease by half.
Time frame: Over the first 6 cycles of the patients Treated with NP137 and enrolled during the Safety run in period