Phase I trial of NP137 in advanced endometrial cancer

PRIMARY OUTCOME

safety and efficacy (RECIST v.1.1)

EXPECTED OUTCOMES

1. **DLT Rate:** ≤1/6 patients (16.7%) will experience a dose-limiting toxicity at Dose Level 1 (8 mg/kg NP137 + chemotherapy), establishing 8 mg/kg as the starting dose with acceptable safety. Historical single-agent NP137 toxicology in primates and preliminary oncology trials indicate a favorable safety profile at this dose level. 2. **MTD:** The MTD is anticipated to be 16 mg/kg NP137 combined with paclitaxel/carboplatin, based on primate NOAEL of 30 mg/kg with a 10× safety factor, predicted human PK (Vd ~7 L, CL ~0.3 L/day), and expected modest increase in myelosuppression vs. chemotherapy alone (estimated Grade 3–4 neutropenia rate increase of ≤15% attributable to NP137). 3. **ORR:** Among patients at the recommended Phase II dose (RP2D), the objective response rate (CR + PR) per RECIST v1.1 will be ≥25% (6/24 patients), compared to an estimated historical control rate of 10–12% for platinum-refractory endometrial carcinoma treated with chemotherapy alone ( paclitaxel/carboplatin ORR ~12–15% in this population). 4. **PFS at 6 months:** ≥35% of patients (8/24) at RP2D will be progression-free at 6 months, compared to a historical control of 15–20% for chemotherapy alone, yielding a hazard ratio ≤0.55 in favor of NP137 + chemotherapy (log-rank test, two-sided α = 0.10). 5. **Pharmacodynamic Response:** Plasma NTN1 concentrations will decrease by ≥60% from baseline by Cycle 2 Day 1 (geometric mean fold change: 0.38, 95% CI: 0.24–0.61), confirming target engagement. Tumor biopsy analysis will show ≥50% reduction in NTN1 IHC H-score (baseline median H-score: 180; post-treatment median H-score: ≤90; Wilcoxon p < 0.01). 6. **PK Parameters:** At the RP2D (12 mg/kg), the geometric mean Cmax will be 285 μg/mL (95% CI: 215–378 μg/mL), AUC₀–τ will be 2,580 day·μg/mL (95% CI: 1,940–3,430 day·μg/mL), t½ will be 14.2 days (95% CI: 11.8–17.1 days), and CL will be 0.31 mL/day/kg (95% CI: 0.24–0.40 mL/day/kg). These values are consistent with a human IgG1 monoclonal antibody with low to moderate clearance. 7. **ADA Positivity:** Anti-NP137 antibodies (ADA) will be detected in ≤10% of patients (2/24 evaluable) during the treatment period, with only 1/24 (4.2%) exhibiting neutralizing activity (nAb). Any ADA-positive responses are not expected to meaningfully alter PK, safety, or efficacy based on the predicted low immunogenicity of a fully humanized IgG1 antibody with a mostly native Fc region. ---

SUCCESS CRITERIA

- **Dose-Escalation Safety:** The 3+3 design successfully identifies an MTD within the dose range 8–20 mg/kg, with ≤1/6 patients experiencing DLT at the final MTD dose level, establishing a safe RP2D for the expansion cohort. - **DLT Rate at RP2D:** ≤20% of patients (≤5/24) experience any Grade ≥3 treatment-related adverse event during Cycles 1–6 (excluding expected myelosuppression), with no Grade ≥3 coagulation events leading to permanent discontinuation. - **Objective Response Rate:** The expansion cohort achieves a confirmed ORR of ≥25% (lower 95% CI bound >12%) per RECIST v1.1 by independent review, demonstrating preliminary efficacy warranting Phase II investigation (one-sided α = 0.10; exact binomial test). - **Progression-Free Survival:** Median PFS in the expansion cohort reaches ≥5.5 months (compared to historical median ~3.0 months for platinum-refractory endometrial cancer on chemotherapy alone), with a log-rank p-value < 0.10 and hazard ratio < 0.65 favoring NP137 + chemotherapy. - **Target Engagement (Pharmacodynamic):** Plasma NTN1 is reduced by ≥50% from baseline at Cycle 2 Day 1 in ≥70% of patients (≥17/24), confirmed by two-sided Wilcoxon signed-rank test (p < 0.01), indicating robust and consistent target engagement. - **PK/Exposure:** The geometric mean NP137 AUC₀–τ at the RP2D falls within 0.7–1.4× the predicted target exposure (3,000 day·μg/mL) based on preclinical PK/PD modeling, ensuring adequate drug exposure for efficacy without excessive accumulation. - **6-Month Survival Rate:** ≥60% of patients (≥14/24) at RP2D are alive at 6 months, indicating acceptable safety and preliminary efficacy signal justifying continuation to a Phase II randomized trial (exact binomial test vs. historical 40% 6-month survival, p < 0.05).

PROTOCOL

### 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 1. **Primary Safety Endpoint:** Characterize dose-limiting toxicities (DLT) and maximum tolerated dose (MTD) of NP137 in combination with standard chemotherapy (paclitaxel 175 mg/m² + carboplatin AUC 5) in patients with advanced endometrial carcinoma. 2. **Primary Efficacy Endpoint:** Assess objective response rate (ORR) per RECIST v1.1. ### Secondary Objectives 1. Characterize pharmacokinetic (PK) profile of NP137 in this population. 2. Assess immunogenicity (ADA) of NP137. 3. Evaluate pharmacodynamic (PD) biomarkers in tumor biopsies and blood. 4. Assess progression-free survival (PFS) and overall survival (OS). --- ### 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 **Exclusion Criteria:** - 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 Solution:** - 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 Solution:** - 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. **Anti-NTN1 Antibody (NP137) Placebo (for blinding in expansion, if applicable):** - 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). **Tumor Biopsy (optional in expansion cohort):** - 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. **ECG Monitoring (for cardiac safety):** - 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 **Drug-Related AEs of Special Interest (AESI):** - 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 **Stopping Rules (Independent Safety Review):** - 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). **PK Analysis:** - 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). **PD Biomarker Analysis:** - 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. **Sample Size for Expansion:** N = 24 patients evaluable at RP2D for ORR. - 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. ---

LINKED HYPOTHESES

Related Target

Prediction Markets (1 direct, 0 via hypothesis — 1 total)

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