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

NCT04652076 | Active Not Recruiting Phase 1 DMC

• 5 other identifiers: NP137CT022020-000172-38/ET20-049ANR-18-RHUS-0009KEYNOTE-A92
• Study Type: interventional
• Target: 240
• Locations: 1 country
• Sites: 15

Brief Summary

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).

Conditions

Endometrial Carcinoma; Cervix Carcinoma

Keywords

anti-Netrin 1; anti-PD-1; Immunotherapy; Check Point Inhibitors; Dependence Receptors

Outcome Measures

Primary Outcomes (2)

• 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

  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

  At 3 months of treatement and then every 12 weeks, up to 2 years

Secondary Outcomes (11)

• Clinical Benefit Rate (CBR)

  Every 12 weeks, up to 2 years

• Duration of Response

  Every 12 weeks, up to 2 years

• Progression-free Survival

  Every 12 weeks, up to 2 years

• Overall Survival

  Every 12 weeks, up to 2 years

• Best Overall Response

  Every 12 weeks, up to 2 years

Study Arms (4)

Arm A: Standard Chemotherapy alone (Paclitaxel + Carboplatin)

OTHER

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

Drug: Paclitaxel; Drug: Carboplatin

Arm B: Experimental double combination [Standard Chemotherapy +NP137]

OTHER

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

Drug: NP137; Drug: Paclitaxel; Drug: Carboplatin

Arm C: Experimental double combination [Pembrolizumab +NP137]

OTHER

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

Drug: NP137; Drug: Pembrolizumab

Arm D: Experimental triple therapeutical combination [Pembrolizumab+ Standard Chemotherapy + NP137]

OTHER

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

Drug: NP137; Drug: Pembrolizumab; Drug: Paclitaxel; Drug: Carboplatin

Interventions

NP137 DRUG

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.

Arm B: Experimental double combination [Standard Chemotherapy +NP137]; Arm C: Experimental double combination [Pembrolizumab +NP137]; Arm D: Experimental triple therapeutical combination [Pembrolizumab+ Standard Chemotherapy + NP137]

Pembrolizumab DRUG

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.

Also known as: KEYTRUDA

Arm C: Experimental double combination [Pembrolizumab +NP137]; Arm D: Experimental triple therapeutical combination [Pembrolizumab+ Standard Chemotherapy + NP137]

Paclitaxel DRUG

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

Arm A: Standard Chemotherapy alone (Paclitaxel + Carboplatin); Arm B: Experimental double combination [Standard Chemotherapy +NP137]; Arm D: Experimental triple therapeutical combination [Pembrolizumab+ Standard Chemotherapy + NP137]

Carboplatin DRUG

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

Arm A: Standard Chemotherapy alone (Paclitaxel + Carboplatin); Arm B: Experimental double combination [Standard Chemotherapy +NP137]; Arm D: Experimental triple therapeutical combination [Pembrolizumab+ Standard Chemotherapy + NP137]

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• NETRIS Pharma: lead
• Merck Sharp & Dohme LLC: collaborator
• Centre Leon Berard: collaborator

Study Sites (15)

CHRU BESANCON - Hopital Jean Minjoz

Besançon, France

Location

Institut Bergonié

Bordeaux, France

Location

Centre François Baclesse

Caen, France

Location

Centre Georges François Leclerc

Dijon, France

Location

Primary Completion Date

Lille, France

Location

Centre Léon Bérard

Lyon, France

Location

Primary Completion Date

Marseille, France

Location

ICM - Val d'Aurelle

Montpellier, France

Location

Insitut de cancérologie de l'ouest

Nantes, France

Location

Hopital de la Croix Saint Simon

Paris, 75020, France

Location

Institut Curie (Site Saint Cloud)

Paris, 92210, France

Location

Institut Gustave Roussy

Paris, 94800, France

Location

Aphp Cochin

Paris, France

Location

Centre Eugène Marquis

Rennes, France

Location

Institut claudius Regaud

Toulouse, France

Location

MeSH Terms

Conditions

Endometrial Neoplasms; Uterine Cervical Neoplasms

Interventions

netrin-1 inhibitor NP137; pembrolizumab; Paclitaxel; Carboplatin

Condition Hierarchy (Ancestors)

Uterine Neoplasms; Genital Neoplasms, Female; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Uterine Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases; Uterine Cervical Diseases

Intervention Hierarchy (Ancestors)

Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Diterpenes; Terpenes; Coordination Complexes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 5, 2020
• First Posted: December 3, 2020
• Study Start: December 14, 2020
• Primary Completion: October 30, 2025
• Study Completion (Estimated): July 30, 2026
• Last Updated: October 8, 2024

Record last verified: 2024-10

Locations

FR (15)