For most advanced solid tumors, current therapy is inadequate at improving quality of life, slowing progression of disease, prolonging survival, and providing a cure. Hence, there is a continuous need for innovative, safer and more effective anti-cancer therapies. Our study is based on the dependence receptor paradigm and the associated therapeutic strategy. In preclinical models, preventing Netrin-1 interaction with its receptors is sufficient to trigger Netrin-1-expressing tumor cell death in vitro as well as tumor growth and metastasis inhibition in vivo. This indicates that a therapeutic approach based on Netrin-1/Netrin-1 receptors interaction inhibition is both feasible and promising. NP137 is a "first-in-class" humanized monoclonal antibody targeting the Netrin-1 ligand, a secreted protein recently described as a driver of tumor initiation and progression. NP137 demonstrated anti-tumor activity as a single agent in several pre-clinical models of cancer, including breast and lung cancer. Taken together, several studies strongly support the rational for preclinical development and clinical evaluation of a highly potent and selective anti-Netrin-1 antibody in cancer patients. The proposed study is an open label, multicenter, Phase I dose escalation study to assess the safety, tolerability, pharmacokinetic (PK), pharmacodynamic (PD) and preliminary anti-tumor activity of NP137 administered every 2 weeks (Q2W) as single agent in patients with locally advanced or metastatic solid tumors. This trial will be the First in Human (FIH) study for NP137; there is no clinical experience with this antibody in the clinic. The study consists of 3 parts: Part 1) a dose escalation part to define the Maximum tolerated dose and the Recommended Phase II dose (MTD /RP2D) of NP137 as well as to research some PD biomarkers (Biological collection cohorts) - This part is now completed with Last Patient In on December 20th 2018 - Part 2) an expansion part#1 to investigate NP137 clinical activity as a single agent by collecting the 3-month objective response rate (ORR3m). Part 3) an expansion part#2 to investigate NP137 clinical activity as a single agent by collecting the 3-month objective response rate (ORR3m) in RH+ patients with endometrial carcinoma.
The dose escalation part (NP137 administered as a single agent by intravenous injection with 7 ascending dose levels) has been initiated with an accelerated dose titration with 1 patient per DL until the occurrence of a ≥ Grade 2 drug-related AE. Following the occurrence of such moderate toxicity, patients have been enrolled in a slower dose escalation design with at least 3 patients per DL using a Modified Continual Reassessment Method. Of note, in case no toxicity occurs up to the DL4, the classical 3+3 design has been initiated. Cohorts of patients with biopsable disease have been added in order to assess the impact of NP137 treatment on epithelial phenotype signature (assessed by RNAseq and subsequent bioinformatic profiling using published E vs M score). Up to 4 additional and independent cohorts of patients (n= up to 6 pts/ cohort) with biopsable disease have been enrolled. Starting from DL4, the enrolment in such cohort will be allowed at highest DL that has cleared its DLT assessment window. Such cohorts will allow to collect pre and on-treatment tumor biopsies in order to identify PD biomarkers correlated to NP137 clinical activity. In expansion parts, patients are treated at the RP2D defined in Part 1 (14 mg/kg). In both parts, NP137 will continue to be administered as long as patient experience clinical benefit in the opinion of the investigator or until unacceptable toxicity or symptomatic deterioration attributed to disease progression as determined by the investigator after an integrated assessment of radiographic data and clinical status or withdrawal of consent or patient willingness to stop the treatment.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
70
DOSE ESCALATION PART: 7 DL: NP137 was administrated every 2 weeks, as single agent by intravenous injection over 90 min with up to 7 ascending dose levels: Dose level 1: 1 mg/kg Dose level 2: 2 mg/kg Dose level 3: 4 mg/kg Dose level 4: 6 mg/kg Dose level 5: 9 mg/kg Dose level 6: 14 mg/kg Dose level 7: 20 mg/kg EXPANSION PARTS: NP137 was administered every 2 weeks, as single agent by intravenous injection over 180 min at 14 mg/kg (RP2D defined in the Dose escalation part). FOR ALL PARTS AND COHORT: Treatment will be administered as long as patient experiences clinical benefit in the opinion of the investigator or until unacceptable toxicity or symptomatic deterioration attributed to disease progression as determined by the investigator after an integrated assessment of radiographic data and clinical status or withdrawal of consent.
Centre Léon Bérard
Lyon, France
Ico - Rene Gauducheau
Nantes, France
IUCT-Oncopôle de Toulouse
Toulouse, France
Part 1 (dose escalation part): DLT occurrence
Dose Limiting toxicities (DLTs) are any pre-defined toxicities graded by using NCI-CTCAE v4.0 occurring during the DLT period (i.e . 28 days) and assessed as related to study drug and any other study drug related toxicity considered significant enough to be qualified as DLT in the opinion of the investigators after discussion with the sponsor. Indeed, as a principle in this first in Man study, any toxicity that the investigator or the sponsor determines to be dose-limiting, regardless of the grade, may be considered as a DLT.
Time frame: At the end of Cycle 2 (each cycle is 14 days)
Part 2 (expansion part #1): Objective response rate after 3 months
Objective response rate after 3 months (ORR3m) is defined as the rate of patients with complete response (CR) or partial response (PR) after 3 months of treatment (measurements according to RECIST 1.1 criteria).
Time frame: 12 weeks of treatment (=3 months)
Part 3 (expansion part #2): Objective response rate after 3 months in RH+ patients with endometrial carcinoma
Objective response rate after 3 months (ORR3m) is defined as the rate of patients with complete response (CR) or partial response (PR) after 3 months of treatment (measurements according to RECIST 1.1 criteria).
Time frame: 12 weeks of treatment (=3 months)
Adverse events reporting
Any adverse events (AEs) graded according to NCI-CTCAE, Version 4.03.
Time frame: from the date of first intake of study drug until 90 days after study drug discontinuation or at time of initiation of a new anti-cancer treatment
Overall response Rate (ORR)
Overall response Rate (ORR) is the proportion of evaluable patients with objective response i.e. CR or PR according to RECIST 1.1.
Time frame: from the date of first study drug intake until until first documented progression, assessed up to 52 weeks
Duration of Response (DoR)
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: from the time of first objective response (CR or PR as per RECIST 1.1 criteria) until first documented progression, assessed up to 52 weeks
Clinical Benefit Rate (CBR)
Clinical Benefit Rate (CBR) is the proportion of evaluable patients with an objective response i.e. CR, PR or SD according to RECIST 1.1.
Time frame: from the date of first study drug intake until until first documented progression, assessed up to 52 weeks
Progression-free survival (for expansion part only)
Time from first study drug intake until disease progression or death, whichever occurs first
Time frame: from the date of first study drug intake until disease progression or death, whichever occurs first, up to 52 weeks
PFS2/PFS1 (for expansion part only)
PFS2/PFS1 is defined as the ratio of the PFS of the current treatment (PFS2) versus the PFS of previous treatment before inclusion (PFS1).
Time frame: From the date of first intake of previous treatment before inclusion until disease progression or death, whichever occurs first, up to 52 weeks
Tumor Growth Kinetics (growth rate)
An exploratory assessment of tumor growth kinetics will be made by comparing post-treatment scans with at least 2 pre-treatment scans.
Time frame: from date of progression under previous treatment before inclusion until disease progression, up to 52 weeks
Area under the NP137 plasma concentration (AUC) versus time curve
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 14 days) and 30 days after last study drug intake
Peak NP137 plasma concentration (Cmax)
Plasma peak concentration of NP137
Time frame: Over the first 6 cycles (each cycle is 14 days) and 30 days after last study drug intake
NP137 terminal elimination half-time (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 (each cycle is 14 days) and 30 days after last study drug intake
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.