First in Human Evaluation of Safety, Pharmacokinetics, and Clinical Activity of a Monoclonal Antibody Targeting Netrin 1 in Patients With Advanced/Metastatic Solid Tumors

NCT02977195 | Completed Phase 1 DMC

• 2 other identifiers: ET15-098 (NP137)2015-003907-41
• Study Type: interventional
• Target: 70
• Locations: 1 country
• Sites: 3

Brief Summary

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.

Conditions

Advanced Solid Tumor; Endometrial Carcinoma; Hormone Receptor Positive

Keywords

First in Human; monoclonal antibody; Netrin-1

Outcome Measures

Primary Outcomes (3)

• 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.

  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).

  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).

  12 weeks of treatment (=3 months)

Secondary Outcomes (10)

• Adverse events reporting

  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)

  from the date of first study drug intake until until first documented progression, assessed up to 52 weeks

• Duration of Response (DoR)

  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)

  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)

  from the date of first study drug intake until disease progression or death, whichever occurs first, up to 52 weeks

Study Arms (1)

Dose escalation part, biological cohort and expansion Parts

EXPERIMENTAL

Dose Escalation and Biological Cohort: NP137 was administrated in patients with locally advanced or metastatic solid tumors Expansion Parts: NP137 was administrated in patients with locally advanced or metastatic solid tumors (Expansion part 1) and in patients with RH+ endometrial cancers (Expansion part 2)

Drug: NP137 DL and RP2D

Interventions

NP137 DL and RP2D DRUG

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.

Dose escalation part, biological cohort and expansion Parts

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Adult men and women ≥ 18 years at time of inform consent signature.
• For dose escalation cohorts, biological cohorts ans extension parts: Histological confirmed locally advanced/metastatic solid tumors of any histological types.
• For second expansion part only: patients with histologically confirmed locally advanced / metastatic endometrial carcinoma and who positively expressed Hormone Receptors (with a positivity threshold value ≥ 10%). Estrogene receptors (ER) and Progesterone Receptors (PR) expression rates must be assessed by immunohistochemistry and fully documented.
• Documented disease progression after at least one prior line of treatment in the metastatic/advanced setting.
• Patient must be, in the judgment of the investigator, an appropriate candidate for an experimental therapy i.e. with no available curative options.
• At least one measurable lesion as per RECIST 1.1.
• For Expansion part only: Availability of at least 2 pre-treatment scans prior to C1D1 including the screening scan (i.e. within 28 days before C1D1) and the most recent scan prior to screening to evaluate tumor growth kinetics.
• Mandatory for Biological collection cohorts and Expansion part #1 and #2 only (optional for dose escalation): Availability of a representative archival tumor specimen in formalin-fixed paraffin embedded (FFPE) block with an associated pathology report. Optional for Expansion part #2 only (RH+ endometrial carcinoma\] Biopsable disease i.e. at least one lesion with a diameter ≥10 mm, visible by medical imaging and accessible to percutaneous sampling.
• Life expectancy ≥ 12 weeks.
• ECOG PS 0-1
• Adequate hematological function: Hemoglobin ≥ 9 g/dL, Absolute neutrophil count (ANC) ≥ 1.5 x 109/L, Platelet count ≥ 100 x 109/L (without transfusion within 21 days before C1D1).
• Adequate renal function: Calculated creatinine clearance by MDRD or CDK-EPI ≥50 mL/min/1.73m2 or serum creatinine ≤ 1.5 ULN
• Adequate liver function: AST and ALT ≤ 2.5 ULN (up to 5 ULN may be tolerated in case of liver metastases), Total serum bilirubin ≤ 1.5 x ULN (except for patients with Gilbert disease for whom a total serum bilirubin ≤3mg/dL is acceptable).
• Adequate coagulation function: INR≤ 1.5, aPTT≤ 1.5 ULN.
• Adequate cardiovascular function: QTc ≤470ms, Resting BP systolic \<160mmHg and diastolic\<100mmHg, LVEF ≥50% as determined by multiple-gated acquisition (MUGA) scan or transthoracic echocardiogram

You may not qualify if:

• History of severe allergic anaphylactic reactions to one of the components of the study drug or to humanized mAbs
• Any known neurodegenerative (Alzheimer's disease, Parkinson's disease and related disorders, amyotrophic lateral sclerosis, prion disease, motor neuron diseases, Huntington's disease, spinocerebellar ataxia, spinal muscular atrophy,) or neuroinflammatory disease (multiple sclerosis, …).
• Active or untreated CNS metastases. Patients with radiographically stable, asymptomatic previously irradiated lesions are eligible provided that patient is ≥ 4 weeks beyond completion of cranial irradiation and ≥ 3 weeks off of corticosteroid therapy are eligible.
• Any uncontrolled intercurrent illness that would limit compliance with protocol requirements including, but not limited to: Ongoing or active infection including acute or chronic hepatitis B, hepatitis C or human immunodeficiency virus (HIV), History of chronic liver disease or hepatic cirrhosis, Impaired cardiovascular function or clinically significant cardiovascular diseases including but not limited to symptomatic congestive heart failure, history of acute myocardial infection, acute coronary syndromes; history or current evidence of clinically significant cardiac arrhythmia and/or conduction abnormality within 6 months prior to C1D1, Psychiatric illness / specific social situations.
• Other invasive malignancy in the last 2 years except for those with a minimal risk of metastasis or death such as adequately managed in-situ carcinoma of the cervix, basal or squamous cell skin cancer, localized prostate cancer or ductal carcinoma in situ treated with curative intent.
• Needs to be treated with a forbidden concomitant/concurrent therapies/procedures including: Any investigational anticancer therapy other than the study drug , Any concurrent chemotherapy, radiotherapy (except palliative radiotherapy performed on non-target lesion and following sponsor's approval), immunotherapy, biologic or hormonal therapy\* for cancer treatment. \*: for prostate cancer patients, treatment with GnrH analogs is allowed, Immunosuppressive medications including methotrexate, azathioprine, and TNF-α blockers. Use of immunosuppressive medications including steroids for the management of AEs or in subjects with contrast allergies is acceptable, Major surgery, Any hematopoietic growth factor (during the DLT period)
• Female subjects who are pregnant or breast-feeding.

Sponsors & Collaborators

• Centre Leon Berard: lead
• NETRIS Pharma: collaborator

Study Sites (3)

Centre Léon Bérard

Lyon, 69008, France

Location

Ico - Rene Gauducheau

Nantes, 44805, France

Location

IUCT-Oncopôle de Toulouse

Toulouse, 31059, France

Location

Related Publications (2)

• Lengrand J, Pastushenko I, Vanuytven S, Song Y, Venet D, Sarate RM, Bellina M, Moers V, Boinet A, Sifrim A, Rama N, Ducarouge B, Van Herck J, Dubois C, Scozzaro S, Lemaire S, Gieskes S, Bonni S, Collin A, Braissand N, Allard J, Zindy E, Decaestecker C, Sotiriou C, Salmon I, Mehlen P, Voet T, Bernet A, Blanpain C. Pharmacological targeting of netrin-1 inhibits EMT in cancer. Nature. 2023 Aug;620(7973):402-408. doi: 10.1038/s41586-023-06372-2. Epub 2023 Aug 2.

  PMID: 37532929 DERIVED

• Sun Y, Manceau A, Frydman L, Cappuccio L, Neves D, Basso V, Wang H, Fombonne J, Maisse C, Mehlen P, Paradisi A. Delta40p53 isoform up-regulates netrin-1/UNC5B expression and potentiates netrin-1 pro-oncogenic activity. Proc Natl Acad Sci U S A. 2021 Sep 7;118(36):e2103319118. doi: 10.1073/pnas.2103319118.

  PMID: 34470826 DERIVED

MeSH Terms

Conditions

Endometrial Neoplasms

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

Study Officials

• Philippe CASSIER, MD

  Centre Leon Berard

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 25, 2016
• First Posted: November 30, 2016
• Study Start: January 9, 2017
• Primary Completion: December 1, 2021
• Study Completion: June 1, 2022
• Last Updated: July 25, 2022

Record last verified: 2022-05

Data Sharing

• IPD Sharing: Will not share

Locations

FR (3)