A Study of NTX-1088, a Monoclonal Antibody Targeting the Poliovirus Receptor (PVR, CD155), as Monotherapy and Combined With Pembrolizumab

NCT05378425 | Active Not Recruiting Phase 1 DMC FDA Drug

• 3 other identifiers: NTX 1088-01KEYNOTE-E92MK-3475-E92
• Study Type: interventional
• Target: 90
• Locations: 3 countries
• Sites: 6

Brief Summary

This is a Phase 1,open-label, multi-center, first-in-human, 2-part (Part 1: dose escalation and Part 2: expansion) study, evaluating multiple doses and schedules of intravenously (IV) administered NTX-1088, with or without pembrolizumab, in patients with advanced solid malignancies (i.e., locally advanced or metastatic).

Conditions

Cancer; Tumor, Solid; Advanced Solid Tumor; Metastatic Cancer; Locally Advanced Solid Tumor

Keywords

PVR; IO; Immune Oncology

Outcome Measures

Primary Outcomes (3)

• Dose-limiting Toxicity (DLT)

  The incidence of DLTs during the DLT assessment period.

  First 21 days of treatment.

• Dose-Finding

  Determination of the MTD or maximum tested dose, and the RP2D.

  Screening to 30 days from last dose.

• Frequency and Severity of Adverse Events (AE)

  The incidences and percentages of patients experiencing AEs summarized by NCI CTCAE version 5.0 grade and by causality.

  Screening to 30 days from last dose.

Secondary Outcomes (6)

• Pharmacokinetics of NTX-1088

  Day 1 of dosing through 21 days post last dose.

• Pharmacokinetics of NTX-1088

  Day 1 of dosing through 21 days post last dose.

• Objective Response Rate (ORR)

  Day 1 of dosing through 90 days after the last dose.

• Duration of Response (DoR)

  Day 1 of dosing through 90 days after the last dose.

• Progression Free Survival (PFS)

  Day 1 of dosing through 90 days after the last dose.

Study Arms (4)

Part 1 - Dose Escalation Phase (Monotherapy)

EXPERIMENTAL

NTX-1088 administered as a 60-minute IV infusion at escalating doses as a monotherapy. NTX-1088 will be administered on Day 1 of a 21-day cycle.

Drug: NTX-1088

Part 1 - Dose Escalation Phase (Combination Therapy)

EXPERIMENTAL

NTX-1088 administered as a 60-minute IV infusion in escalating doses in combination with pembrolizumab. NTX-1088 will be administered on Day 1 of a 21-day cycle. Pembrolizumab will be administered as a 30-minute IV infusion, within 2 hours prior to NTX-1088 administration, at a dose of 200 mg on Day 1 of every 21-day cycle.

Drug: NTX-1088; Drug: Pembrolizumab

Part 2 - Dose Expansion (Monotherapy)

EXPERIMENTAL

NTX-1088 administered at the RP2D as a 60-minute IV infusion as a monotherapy.

Drug: NTX-1088

Part 2 - Dose Expansion (Combination Therapy)

EXPERIMENTAL

NTX-1088 administered at the RP2D as a 60-minute IV infusion in combination with pembrolizumab at the standard labeled dose.

Drug: NTX-1088; Drug: Pembrolizumab

Interventions

NTX-1088 DRUG

IgG4 mAb targeting the poliovirus receptor (PVR, CD155).

Part 1 - Dose Escalation Phase (Combination Therapy); Part 1 - Dose Escalation Phase (Monotherapy); Part 2 - Dose Expansion (Combination Therapy); Part 2 - Dose Expansion (Monotherapy)

Pembrolizumab DRUG

IgG4 mAb with high specificity of binding to the PD-1 receptor, thus inhibiting its interaction with programmed cell death ligand 1 (PD-L1) and programmed cell death ligand 2 (PD-L2).

Also known as: KEYTRUDA®

Part 1 - Dose Escalation Phase (Combination Therapy); Part 2 - Dose Expansion (Combination Therapy)

Eligibility Criteria

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

You may qualify if:

• The patient must have histologic or cytologic evidence of an advanced (locally advanced or metastatic) malignant solid cancer known to express PVR, including colorectal carcinoma (MSI-H and MSS with no liver mets), hepatocellular carcinoma, gastric/gastroesophageal junction/esophageal carcinoma, Non-Small Cell Lung Cancer (NSCLC), endometrial carcinoma, cervical carcinoma, Squamous Cell Carcinoma of the Head and Neck (SCCHN), Renal Cell Carcinoma (RCC), cutaneous melanoma, Basal Cell Carcinoma (BCC) or another tumor type approved by the Medical Monitor.
• Except for dose escalation with pembrolizumab for patients in whom mAbs targeting PD-1 as monotherapy are the standard of care, patients enrolled in the dose-escalation parts must have disease that is resistant to or relapsed following available standard systemic therapy, or for which there is no standard systemic therapy or reasonable therapy in the physician's judgment likely to result in clinical benefit, or if such therapy has been refused by the patient. Documentation of the reason must be provided for patients who have not received a standard therapy likely to result in clinical benefit.
• Patient must have received no more than 4 prior systemic therapies. Special cases of \>4 prior systemic therapies will be discussed between the investigator and the Sponsor's medical team.
• A fresh tumor biopsy will be required if the biopsy procedure is not a significant risk procedure defined as one without mortality or major morbidity in the patient's clinical setting and at the institution completing the procedure is estimated to be ≥2%. The Medical Monitor must be contacted to review documentation of biopsy risk.
• Patients enrolled in the dose-escalation part at relevant NTX-1088 doses (i.e., NTX-1088 at a dose \>400 mg) will be required to undergo a tumor biopsy during the screening period and at the end of Cycle 2 (±7 days from C3D1), if the procedure is not a significant risk procedure as defined above.
• Patients enrolled in the expansion part will be required to undergo a tumor biopsy during the screening period and at the end of Cycle 2 (±7 days from C3D1), if the procedure is not a significant risk procedure as defined above.
• The patient must have disease that is measurable by RECIST, version 1.1 (APPENDIX A) as assessed by the local site Investigator/radiology. For patients with prior radiation therapy, measurable lesions must be outside of any prior radiation field(s), unless disease progression has been documented at that site after radiation.
• The patient is ≥18 years old on the day of signing the consent form.
• The patient has an ECOG PS of ≤1.
• The patient has life expectancy of \>3 months
• The patient has adequate baseline organ function, as demonstrated by the following:
• a. CrCL ≥30 mL/min as calculated by the Cockcroft-Gault formula: i. CrCl (male) = (\[140-age\] × weight in kg)/ (serum creatinine ×72) ii. CrCl (female) = CrCl (male)×0.85 b. Bilirubin ≤1.5×ULN. c. AST and ALT ≤2.5×ULN. Patients may have ALT and AST \<5×ULN if the patient has hepatic metastases.
• d. Corrected calcium \<11g/dL e. Albumin \>3g/dL
• For patients not taking warfarin or other oral anticoagulants: international normalized ratio (INR) ≤1.5 or prothrombin time (PT) ≤1.5×ULN; and either partial thromboplastin time or activated partial thromboplastin time (PTT or aPTT) ≤1.5×ULN. Patients taking warfarin should be on a stable dose that results in a stable INR \<3.5. Among patients receiving other oral anticoagulant therapy, PT or aPTT must be within the intended therapeutic range of the anticoagulant and/or subcutaneous therapies should be monitored as standard per institution.
• The patient has adequate baseline hematologic function, as demonstrated by the following:

You may not qualify if:

• The patient (for combination arm only) was discontinued from treatment with an immuno-oncology therapeutic due to a Grade 3 or higher immune-related adverse event (irAE) except endocrine disorders that can be treated with replacement therapy or was discontinued from that treatment due to Grade 2 myocarditis or recurrent Grade 2 pneumonitis. This does not apply to irAEs due to prior treatment with cell therapy.
• The patient has received prior radiotherapy within 2 weeks of treatment. Patients 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 with a limited port ≤2 weeks of radiotherapy to non-central nervous system (CNS) disease.
• The patient has received radiation therapy to the lung that is \>30 Gy within 6 months of the first dose of study medication.
• The patient has received treatment with approved anticancer therapies including cytotoxic chemotherapy, monoclonal antibodies, and/or small molecule tyrosine kinase inhibitors within 14 days prior to study therapy administration or 5 half-lives, whichever is shorter (42 days for nitrosourea or mitomycin-C); patients with advanced prostate cancer who are receiving luteinizing hormone releasing hormone (LHRH) agonists are permitted onto the study and should continue use of these agents during study treatment.
• The patient has had an allogeneic tissue/solid organ transplant.
• The patient has received a live or live-attenuated vaccine within 30 days prior to the first dose of study intervention.
• The patient has received prior treatment with another investigational agent that targets PVR.
• If the patient had major surgery, the patient must have recovered adequately from the procedure and/or any complications from the surgery prior to starting study intervention.
• The patient is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks or 5 half-lives, whichever is shorter, prior to the first dose of study treatment.
• The patient has an active autoimmune disease that required systemic treatment in the past. Patients who have not required systemic treatment for at least two years may be enrolled if permission is provided after discussion with the Medical Monitor (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).
• The patient has an uncontrolled endocrine disorder.
• The patient has clinically significant cardiovascular disease (e.g., uncontrolled or any New York Heart Association Class 3 or 4 heart failure \[see Section 8.2.7\]), uncontrolled angina, history of myocardial infarction, unstable angina or stroke within 6 months prior to study entry, uncontrolled hypertension, or clinically significant arrhythmias not controlled by medication).
• The patient has a history of (non-infectious) pneumonitis or interstitial pulmonary disease that required steroids or has current pneumonitis or interstitial pulmonary disease.
• The patient has uncontrolled, clinically significant pulmonary disease (e.g., chronic obstructive pulmonary disease, pulmonary hypertension) that in the opinion of the Investigator would put the patient at significant risk for pulmonary complications during the study.
• The patient has had a severe hypersensitivity reaction (Grade ≥3) to pembrolizumab and/or any of its excipients (pembrolizumab combination enrollment only).

Sponsors & Collaborators

• Nectin Therapeutics Ltd: lead
• Merck Sharp & Dohme LLC: collaborator

Study Sites (6)

City of Hope

Duarte, California, 91010, United States

Location

Ochsner Clinic Foundation

New Orleans, Louisiana, 70121, United States

Location

The University of Texas MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Hadassah Medical Center

Jerusalem, 9574425, Israel

Location

Sheba Medical Center

Ramat Gan, 5262131, Israel

Location

Maria Skłodowska-Curie National Research Institute of Oncology

Warsaw, Poland

Location

MeSH Terms

Conditions

Neoplasms; Neoplasm Metastasis

Interventions

pembrolizumab

Condition Hierarchy (Ancestors)

Neoplastic Processes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Design

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

Study Record Dates

• First Submitted: May 12, 2022
• First Posted: May 18, 2022
• Study Start: September 1, 2022
• Primary Completion (Estimated): December 1, 2026
• Study Completion (Estimated): December 1, 2026
• Last Updated: April 30, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will not share

Locations

IL (2); PL (1); US (3)