GYNET : A randomized, multicenter, open label, Phase I/II study to evaluate the safety (Phase I - safety run in), clinical and biological activity (Phase II) 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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Netris Pharma

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Female

Therapeutic area

Diseases [C] - Pathological Conditions, Signs and Symptoms [C23], Diseases [C] - Neoplasms [C04]

Trial duration

10 Dec 2020 → ongoing

Decision date (initial)

2024-09-05

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2024-510714-32-00

EudraCT number

2020-000172-38

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy

Safety run in part: To assess the safety of the proposed therapeutic combinations according to the incidence of DLT
Phase II part: To investigate the clinical activity of the proposed therapeutic combinations as defined by the 3-month objective response rate (ORR-3m) as per RECIST V1.1 assessment by blinded independent central review

Secondary objectives 5

1. Both parts: To further document the safety profile of the proposed therapeutic combinations.
2. Both parts: To assess the PK parameters of NP137.
3. Both parts: To further assess the anti-tumor activity of the proposed combination (in terms of Best overall response, Duration of response, Clinical Benefit rate at 3 months [CBR-3m], PFS and OS).
4. Both parts: Tumor response will be assessed using RECIST V1.1 and iRECIST by both BICR and investigator.
5. Translational program, the exploratory objectives include but are not limited to assess: The expression of Netrin-1 and its receptors. * The expression of PD-1/PD-L1 and other immune check point receptors or ligands (only for Arms C and D). * The expression of immunomodulatory enzyme on tumor cells. * The level of apoptosis. * The impact of combined treatment on immune cell infiltration. * The signature linked to NP137 ± pembrolizumab ± CT biological effects. * Specific mutational status associated to patient’s benefit or response. * Investigate the prognosis value of numerous of circulating biomarkers identified from the RNA sequencing. * Phenotype circulating immune cells by Flow Cytometry on PBMC.

Conditions and MedDRA coding

Patiens with locally advanced/metastatic endometrial carcinoma or cervix carcinoma progressing/relapsing after at least one prior systemic chemotherapy.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 14

1. I1. Be women ≥ 18 years at time of inform consent signature.
2. I2. 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.
3. I3. 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 platinum based 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.
4. I4. For endometrium carcinoma: Mutational profile (MSI/MSS status) available before randomization (see St Paul de Vence 2019- ARCAGY – GINECO Group recommendation).
5. I5. 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.
6. I6. 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.
7. I7. Optional for patient 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 and lymph nodes lesions should not be considered ad prime targets for biopsies.
8. I8. Life expectancy ≥ 3 months.
9. I9. Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 to 1.
10. I10. Demonstrate adequate cardiovascular function: o QTcF < 470ms o Resting BP systolic <160mmHg and diastolic < 100mmHg o LVEF > 50% as determined by transthoracic echocardiogram.
11. I11. Demonstrate adequate organ function as defined in table below, all screening laboratory tests should be performed within 7 days prior C1D1: HEMATOLOGICAL: Absolute neutrophil count ≥ 1.5G/L (1500/µL) ; Platelets ≥ 100G/L (100000/µL) (without transfusion within 21 days before C1D1); Hemoglobin ≥ 9 g/dL or ≥ 5.6 mmol/L-1 without packed red blood cell (pRBC) transfusion within last 2 weeks. Patient can be on stable dose of erythropoietin (≥ approximately 3 months). RENAL: Serum creatinine OR Creatinine clearance according to CKD-EPI : ≤ 1.5 X upper limit of normal (ULN) OR ≥ 30mL/min/1.73m2 for patient with creatinine levels > 1.5 ULN ; HEPATIC: Serum total bilirubin ≤ 1.5 X ULN OR Direct bilirubin ≤ ULN for patients with total bilirubin levels > 1.5 ULN ; AST (SGOT) and ALT (SGPT) :≤ 2.5 X ULN (up to 5 ULN may be tolerated in case of liver metastases) ; COAGULATION: International Normalized Ratio (INR) and Activated Partial Thromboplastin Time (aPTT) ≤ 1.5 X ULN Note: This is applicable only for patients not receiving an anticoagulant treatment: patients receiving therapeutic anticoagulation must be on stable dose.
12. I12. 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. Effective forms of contraception will be listed in protocol.
13. I13. Patient should understand, sign, and date the written voluntary informed consent form prior to any protocol-specific procedures.
14. I14. Patient should be able and willing to comply with study visits and procedures as per protocol.

Exclusion criteria 14

1. E1: Patients with progression during previous chemotherapy with [platinum + paclitaxel] .
2. E2. Persistence of CTCAE ≥ Grade 2 toxicity due to prior anti-cancer therapy (except alopecia (any grades)).
3. E3. History of severe (≥ Grade 3) allergic anaphylactic reactions to one of the components of NP137, pembrolizumab, paclitaxel, carboplatin, premedication and/or any of their excipients.
4. E4. 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.
5. E5. 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.
6. E6. 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 coinhibitory 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:. o Chemotherapy or targeted therapies (approved or investigational) within 2 weeks or 5* t1/2 whichever is longer prior C1D1. o Hormonal therapy within 1 week prior to C1D1 o 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, C1D1. 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. * 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.
7. E7. 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: o patients with a history of autoimmune-related hypothyroidism who are on stable thyroid replacement hormone therapy, o patients with controlled Type 1 diabetes mellitus, o 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.
8. E8. 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.
9. E9. Patients with active tuberculosis.
10. E10. Prior allogeneic bone marrow transplantation or solid organ transplant for another malignancy in the past.
11. E11. 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.
12. E12. Have an active infection requiring systemic therapy.
13. E13. Pregnant or breastfeeding women. A WOCBP who has a positive urine pregnancy test (e.g. within 72 hours) prior to treatment. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
14. E14. Patients placed under a legal protection regimen: Judicial Safeguards, curatorship or guardianship.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Phase II part: Overall response Rate (ORR) after 3 months (ORR3m) is defined as the rate of patients with CR or PR. Response will be evaluated as per RECIST 1.1 (Eisenhauer et al., 2009) by BICR after 3 months of treatment.

Secondary endpoints 3

1. Part II part, both part safety endpoints: Safety will be assessed by the following assessments: adverse events (AEs), vital signs, ECG, physical examination, laboratory safety assessments (hematological and biochemical parameters). All AEs will be graded according to NCI-CTCAE V5.0. In case of Infusion Related Reaction, blood samples will be collected to monitor the PK profile and Immunogenicity using ADA for NP137 assays.
2. Phase II part, both part efficacy endpoints: Objective response Rate (ORR) after 3 months of treatment will be also assessed as per modified criteria for immunotherapies iRECIST. Overall objective response Rate beyond 3 months of treatment will be assessed as per RECIST V1.1 and iRECIST (assessment by both BICR and investigator). Duration of Response (DoR). *Best Overall Response Rate. *Clinical Benefit Rate (CBR). *Progression-free survival (PFS). *Overall survival (OS)
3. Pharmacokinetic endpoints: The following PK parameters will be determined for NP137 treated patients during the safety run in period only: Cmax, tmax, AUCt, AUC, CL, t½ based on both individual PK and popPK models.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Auxiliary 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Netris Pharma

Sponsor organisation

Netris Pharma

Address

28 Rue Laennec

City

Lyon

Postcode

69008

Country

France

Scientific contact point

Organisation

Netris Pharma

Contact name

Isabelle RAY COQUARD

Public contact point

Organisation

Netris Pharma

Contact name

Laure BOUGAREL

Locations

1 EU/EEA country · 15 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 10 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

3 submissions — initial application plus substantial / non-substantial modifications