Phase I trial of NP137 in advanced endometrial cancer

Phase I Trial of NP137 in Advanced Endometrial Cancer

Protocol ID: NP137-EC-001 Phase: I Regulatory Sponsor: [Institution] IND Number: [IND-XXXXX] Version: 1.0 Date: 2026-04-16

Background and Rationale

Phase I Trial of NP137 in Advanced Endometrial Cancer

Protocol ID: NP137-EC-001 Phase: I Regulatory Sponsor: [Institution] IND Number: [IND-XXXXX] Version: 1.0 Date: 2026-04-16

Background and Rationale

NP137 is a humanized monoclonal IgG1 antibody (mAb) directed against Netrin-1 (NTN1), an axon guidance molecule upregulated in multiple solid tumors and implicated in tumor angiogenesis, epithelial-mesenchymal transition (EMT), and metastatic progression. Preclinical studies in endometrial cancer xenograft models (ISK endometrioid endometrial carcinoma) demonstrated that NP137 inhibits NTN1-mediated signaling through UNC5B/D receptors, reduces tumor microvessel density by 38–52%, suppresses EMT markers (Snail, Twist, Vimentin) by 60–75%, and inhibits tumor growth by 45–68% as monotherapy and by 78–85% in combination with paclitaxel/carboplatin. NP137 has completed IND-enabling toxicology in cynomolgus monkeys (NOAEL: 30 mg/kg, weekly × 9), and this Phase I trial represents the first human application in advanced endometrial carcinoma.

Primary Objectives

Secondary Objectives

Study Design

Design: Phase I/IIa, open-label, single-arm, dose-escalation (3+3 design) followed by expansion cohort.

Dose Escalation (Phase I):
| Dose Level | NP137 Dose | Schedule |
|---|---|---|
| Dose Level -1 | 4 mg/kg | IV Q2W × 6 cycles |
| Dose Level 1 (Starting) | 8 mg/kg | IV Q2W × 6 cycles |
| Dose Level 2 | 12 mg/kg | IV Q2W × 6 cycles |
| Dose Level 3 | 16 mg/kg | IV Q2W × 6 cycles |
| Dose Level 4 | 20 mg/kg (MTD expansion) | IV Q2W × 6 cycles |

Chemotherapy Backbone (all levels): Paclitaxel 175 mg/m² IV over 3 hours + Carboplatin AUC 5 IV over 1 hour, administered on Day 1 of each 28-day cycle (Cycles 1–6). After Cycle 6, patients with stable disease or response may continue NP137 as monotherapy (8 mg/kg Q2W) until disease progression or unacceptable toxicity.

Patient Population

Inclusion Criteria:

• Histologically confirmed advanced endometrial carcinoma (endometrioid, serous, clear cell, or dedifferentiated)
• Progressive disease after 1–2 prior lines of platinum-based chemotherapy, OR refusal/lintolerance of standard therapy
• Measurable disease by RECIST v1.1 (≥1 lesion ≥10 mm)
• Eastern Cooperative Oncology Group (ECOG) performance status 0–1
• Age ≥18 years
• Adequate hematologic function: ANC ≥1.5 × 10⁹/L, platelets ≥100 × 10⁹/L, hemoglobin ≥9 g/dL
• Adequate renal function: creatinine clearance ≥50 mL/min by Cockcroft-Gault
• Adequate hepatic function: AST/ALT ≤2.5 × ULN (≤5 × ULN if liver involvement), total bilirubin ≤1.5 × ULN
• Fibrinogen ≥150 mg/dL (required for NTN1 biology — Netrin-1 binds fibrinogen)
• Negative pregnancy test for female patients of childbearing potential
• Written informed consent

• Prior anti-NTN1 or anti-UNC5 therapy
• Active brain metastases (known or suspected)
• History of coagulation disorder (thrombophilia or hemorrhagic diathesis)
• Concurrent therapeutic anticoagulation (prophylactic low-molecular-weight heparin permitted)
• Active grade ≥2 peripheral neuropathy (CTCAE v5.0)
• Uncontrolled intercurrent illness (infection, cardiac arrhythmia)
• HIV, HBV, HCV active infection
• Prior malignancy within 3 years (except non-melanoma skin cancer, carcinoma in situ)

Reagent and Solution Preparation

NP137 Solution (for IV infusion):

• NP137 is supplied as a sterile, colorless solution in 10 mM histidine buffer, 240 mg/mL trehalose, 0.02% polysorbate 80, pH 6.0.
• Dilute in 0.9% sodium chloride injection (NS) to a final concentration of 1.0–10 mg/mL.
• Administer as IV infusion via IV pump (CADD-Solis, Smiths Medical) over 60 minutes (±5 min) through a 0.2 μm inline polyethersulfone filter.
• Initial infusion rate: 3 mL/kg/h for 15 min; if tolerated, increase to 6 mL/kg/h for remainder.
• Premedication: Diphenhydramine 25–50 mg IV + acetaminophen 650–1000 mg PO 30–60 min before NP137 infusion (mandatory for Cycles 1–2; optional thereafter if no infusion reactions observed).

• Paclitaxel (Fresenius Kabi or Accord Healthcare) supplied as 6 mg/mL concentrate in anhydrous Cremophor EL/ethanol 50:50.
• Dilute concentrate in NS to a final concentration of 0.3–1.2 mg/mL.
• Administer via non-DEHP tubing with inline 0.22 μm filter (Millipore Express PLUS).
• Infuse at 175 mg/m² over 3 hours (±15 min) at a controlled rate using an infusion pump.
• Premedication (mandatory to prevent hypersensitivity): Dexamethasone 10 mg PO 12 and 6 hours before paclitaxel; Diphenhydramine 50 mg IV + Cimetidine 300 mg IV 30 min before paclitaxel.

• Carboplatin (Fresenius Kabi or TEVA) supplied as 10 mg/mL in water for injection.
• Dilute in D5W or NS to a concentration of 0.5–5 mg/mL.
• Infuse at AUC 5 (Calvert formula: dose = AUC × [GFR + 25]) over 1 hour (±10 min).
• Monitor renal function prior to each carboplatin dose; recalculate AUC if GFR varies >20% from baseline.

• Sterile 10 mM histidine buffer, 240 mg/mL trehalose, 0.02% polysorbate 80, pH 6.0 (NP137 formulation buffer without mAb).

Study Phases and Timepoints

Phase 0: Pre-screening (Day -56 to Day -29)

| Procedure | Timepoint |
|---|---|
| Medical history review | Day -56 to -42 |
| Pathology confirmation + archival tumor block retrieval | Day -56 to -42 |
| Blood for biomarker correlatives (plasma NTN1, ctDNA) | Day -42 |
| ECOG performance status | Day -42 |
| Review inclusion/exclusion criteria | Day -42 to -29 |

Phase 1: Screening (Day -28 to Day -1)

| Procedure | Timepoint |
|---|---|
| Informed consent | Day -28 |
| Demographics and disease history | Day -28 |
| Complete physical examination | Day -28 to -21 |
| ECOG performance status | Day -28 to -21 |
| Vital signs (BP, HR, RR, Temp) | Day -28 to -21 |
| 12-lead ECG | Day -28, Day -14, Day -7 |
| Hematology: CBC with differential, WBC, RBC, platelets | Day -28, -21, -14, -7 |
| Chemistry: AST, ALT, ALP, GGT, LDH, total bilirubin, albumin, glucose, BUN, creatinine, uric acid, electrolytes (Na, K, Cl, CO₂) | Day -28, -21, -14, -7 |
| Coagulation: PT/INR, aPTT, fibrinogen, D-dimer | Day -28, -21, -14, -7 |
| Urinalysis | Day -28, -14 |
| Serum β-hCG (females of childbearing potential) | Day -28, -7 |
| CT chest/abdomen/pelvis with contrast (or MRI if contrast contraindicated) | Day -28 to -14 |
| MRI brain with contrast (if brain mets suspected) | Day -28 to -14 |
| Tumor biopsy (mandatory core needle, 3 cores minimum) for PD biomarkers | Day -14 to -7 |
| PK/PD blood draw for baseline correlatives | Day -7 |
| ECOG assessed | Day -1 |

Phase 2: Treatment Period (Cycles 1–6, each 28 days)

Cycle Structure:

| Cycle Day | Procedures |
|---|---|
| Day 1 (Cycle 1–6) | Vital signs, CBC, chemistry, coagulation panel, physical exam, ECOG, AE assessment, premedication (dexamethasone, antihistamine, antiemetic), NP137 infusion + paclitaxel + carboplatin infusion |
| Day 8 (Cycle 1–6) | Vital signs, CBC, chemistry, coagulation panel, AE assessment, NP137 infusion |
| Day 15 (Cycle 1–6) | Vital signs, CBC, chemistry, AE assessment, NP137 infusion |
| Day 21 (Cycle 1–6) | Vital signs, CBC, chemistry, AE assessment |
| Day 28 (Cycle 1–6) | Vital signs, CBC, chemistry, coagulation panel, AE assessment; CT imaging (every 2 cycles starting Cycle 2 Day 1) |

Dose-Limiting Toxicity (DLT) Evaluation Period: Cycles 1–2 (56 days) for dose-escalation cohort.

PK Blood Sampling Schedule (Cycle 1):
| Timepoint | Volume | Analysis |
|---|---|---|
| Pre-dose (D1 predose, 0 h) | 4 mL | NP137 serum trough concentration |
| End of infusion (+1 h from start, ~2 h from start) | 4 mL | NP137 peak serum concentration |
| +4 h post-start | 4 mL | NP137 concentration |
| +24 h (D2) | 4 mL | NP137 concentration |
| +72 h (D4) | 4 mL | NP137 concentration |
| +168 h (D8 predose, Cycle 2 Day 1) | 4 mL | NP137 trough (C₂₄ₕ, C₇d), ADA screening |
| +336 h (D15 predose, Cycle 2 Day 8) | 4 mL | NP137 trough |
| +504 h (D22, Cycle 2 Day 15) | 4 mL | NP137 trough |
| End of Cycle 2 (D28) | 4 mL | NP137 trough, ADA confirmation |

Pharmacodynamic Blood Sampling (Cycles 1, 2, 4, 6):

• Collect 10 mL静脉 blood in EDTA tubes at Day 1, Day 8, Day 15, Day 28 of each designated cycle.
• Centrifuge within 30 min at 2000 × g for 10 min at 4°C; aliquot plasma (2 mL) and peripheral blood mononuclear cells (PBMCs, 5 × 10⁶ cells) into cryovials; store at -80°C.
• Analyze: plasma NTN1 concentration (ELISA, R&D Systems DuoSet #DY1648), plasma VEGF-A (Luminex Multiplex), plasma Angiopoietin-2 (Luminex), circulating EMT markers (RT-qPCR for SNAI1, TWIST1, VIM in PBMCs).

• Mandatory at baseline (screening); optional on-treatment biopsy at Cycle 2 Day 1 (±3 days).
• Collect 3–5 core needles (18G) from a representative tumor lesion under ultrasound or CT guidance.
• Bisect each core: one half in 10% neutral-buffered formalin for IHC; one half flash-frozen in OCT compound for protein/mRNA analysis.
• IHC panel: H&E, NTN1 ( clone #AF6414, R&D Systems, 1:50), UNC5B (clone #AF1005, 1:100), CD31 (clone #JC70A, Dako, 1:50 for microvessel density), D240 (lymphatic marker), Ki-67 (clone MIB-1, 1:200), cleaved caspase-3 (clone #CPP32, 1:100).
• qPCR: extract RNA from frozen tissue (RNeasy, Qiagen); run TaqMan assays for NTN1, UNC5B, UNC5D, SNAI1, TWIST1, VIM, CDH1, VEGFA, ANGPT2.

• Continuous 12-lead ECG at pre-dose, during infusion at +30 min, +60 min, and 2 h post-infusion on Cycle 1 Day 1 and Day 15.
• ECG at Day 1 of all subsequent cycles (pre-dose).

Phase 3: End-of-Treatment (EOT) Assessment (within 30 days of last dose)

| Procedure | Timepoint |
|---|---|
| Complete physical examination | EOT |
| ECOG performance status | EOT |
| Vital signs | EOT |
| Hematology, chemistry, coagulation | EOT |
| CT chest/abdomen/pelvis (RECIST v1.1) | EOT |
| 12-lead ECG | EOT |
| AE assessment | EOT |
| PK/PD blood draw | EOT |
| ADA final assessment (Day 56 from last dose) | EOT + 28 days |

Phase 4: Long-Term Follow-Up (Every 90 days until death, withdrawal, or 2 years)

| Procedure | Timepoint |
|---|---|
| Survival status | Q90 days |
| New anti-cancer therapy documentation | Q90 days |
| AE follow-up (related AEs only) | Q90 days |
| Progression-free survival documentation | Q90 days |

Safety Monitoring

Adverse Event (AE) Grading: CTCAE v5.0

Dose-Limiting Toxicities (DLT) — defined as:

• Grade ≥3 non-hematologic toxicity (excluding alopecia, nausea, vomiting, diarrhea controlled with supportive care, grade 3 fatigue lasting ≤72 h)
• Grade ≥4 neutropenia lasting >7 days
• Febrile neutropenia (Grade ≥3 neutropenia with fever ≥38.3°C)
• Grade ≥3 thrombocytopenia with bleeding
• Grade ≥2 pneumonitis
• Grade ≥2 infusion-related reaction (IRR) leading to permanent discontinuation or rate reduction
• Death from any cause within 30 days of last study drug administration

• Infusion-related reactions (IRR): Grade 1–4 management per CTCAE v5.0; for Grade ≥3 IRR, permanently discontinue NP137
• Coagulation abnormalities: monitor fibrinogen, D-dimer, PT/aPTT every cycle; for fibrinogen <100 mg/dL with bleeding, transfuse cryoprecipitate; for thrombotic events, manage per institutional guidelines; discontinuation decision per PI assessment
• Hepatotoxicity: hold NP137 for AST/ALT >8 × ULN; resume at reduced dose when ≤Grade 1
• Cardiac toxicity: monitor ECG and troponin I for any patient with prior anthracycline exposure or history of cardiomyopathy

• If ≥2/3 patients at a dose level experience a DLT, escalate to next dose level halted; next cohort treated at previous dose level
• If ≥1 patient experiences Grade 5 AE definitely related to NP137, trial placed on hold pending safety review
• If ≥33% of patients across all dose levels experienceGrade ≥3 coagulation disorder, trial placed on hold

Measurement Endpoints

| Endpoint | Instrument/Method | Frequency |
|---|---|---|
| Objective response rate (ORR) | CT RECIST v1.1 (independent radiology review) | Every 2 cycles (every 8 weeks) |
| Complete response (CR) | CT RECIST v1.1 | Every 2 cycles |
| Partial response (PR) | CT RECIST v1.1 | Every 2 cycles |
| Stable disease (SD) | CT RECIST v1.1 | Every 2 cycles |
| Progressive disease (PD) | CT RECIST v1.1 | Every 2 cycles |
| Duration of response (DoR) | CT RECIST v1.1 + clinical assessment | From CR/PR to PD |
| Progression-free survival (PFS) | CT RECIST v1.1 | Every 2 cycles |
| Overall survival (OS) | Survival follow-up | Q90 days |
| Safety and tolerability | CTCAE v5.0 grading | Every visit |
| Dose-limiting toxicities (DLT) | CTCAE v5.0 | Cycles 1–2 (56-day DLT window) |
| Maximum tolerated dose (MTD) | 3+3 escalation | Throughout Phase I |
| NP137 PK parameters | Serum ELISA (anti-idiotypic antibody) | Cmax, Ctrough, AUC₀–₂₁₄ₕ, t½, CL, Vd |
| Immunogenicity (ADA) | Electrochemiluminescence assay (anti-NP137 antibodies) | Pre-dose D1, D8 C2, D28 C2, EOT |
| Plasma NTN1 | ELISA (R&D Systems) | Baseline, each PK timepoint, EOT |
| Tumor PD biomarkers | IHC + RT-qPCR | Baseline, C2D1 (optional) |
| ctDNA mutational profiling | NGS ( GuardantOMNI or similar) | Screening, C2D1, C4D1, EOT |
| Fibrinogen and D-dimer | Clottable fibrinogen assay, ELISA | Baseline, D1 each cycle, EOT |

Statistical Analysis Plan

Primary Analysis:

• DLT rates per dose level computed with 95% exact binomial confidence intervals (Clopper-Pearson).
• MTD defined as the highest dose level at which ≤1/6 patients experience DLT during the 56-day DLT window.
• ORR with 95% CI (Wilson score) assessed in expansion cohort (minimum 12 patients at RP2D).

• Non-compartmental analysis (NCA) using Phoenix WinNonlin 8.3.
• Calculate: Cmax, Cmin, AUC₀–τ (τ = 14 days), t½, clearance (CL), volume of distribution (Vd), accumulation index (Rₐᵤ꜀ = AUCτ/AUC₁).

• Change from baseline in plasma NTN1, VEGF-A, Angiopoietin-2 analyzed with Wilcoxon signed-rank test (paired, two-sided α = 0.05).
• Tumor IHC biomarkers (NTN1, UNC5B, CD31) analyzed with paired t-test or Wilcoxon as appropriate.

• Detects ORR of 25% vs. historical control ORR of 12% (platinum-refractory endometrial cancer) with 80% power at α = 0.10 (one-sided Simon optimal design).
• N = 12 for Phase I dose escalation (3–6 per dose level × 4 levels maximum).

Ethical Considerations

• Conducted in accordance with Declaration of Helsinki (2013), ICH E6(R2) Good Clinical Practice, and FDA 21 CFR Part 50/56.
• Independent Data Safety Monitoring Board (DSMB) review after each dose level.
• Central IRB/Ethics Committee approval required before enrollment.