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

A Phase 1, First-in-Human Study of NTX-1088, a Monoclonal Antibody Targeting the Poliovirus Receptor (PVR, CD155), as Monotherapy and Combined With Pembrolizumab, in Patients With Advanced Solid Malignancies

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).

Study Overview

• Status: Recruiting
• Conditions: Cancer; Metastatic Cancer; Advanced Solid Tumor; Tumor, Solid; Locally Advanced Solid Tumor
• Intervention / Treatment: Drug: NTX-1088; Drug: Pembrolizumab

Detailed Description

This is a Phase 1, open-label, multi-center study whose principal Part 1 stage objective is to determine the recommended Phase 2 dose (RP2D) of the anti-PVR monoclonal antibody (mAb) as a single agent and combined with the anti-PD-1 mAb pembrolizumab in patients with advanced solid malignancies.

In the Part 2 stage, the antitumor activity of NTX-1088 alone or combined with pembrolizumab will be evaluated in patients with malignancies known to express PVR.

• Study Type: Interventional
• Enrollment (Estimated): 90
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Keren Paz, PhD; Phone Number: 201-218-1774; Email: keren@nectintx.com

Study Locations

• Israel
  • Jerusalem, Israel, 9574425
    • Recruiting
    • Hadassah Medical Center
    • Contact: Jonathan Cohen, MD/PhD
  • Ramat Gan, Israel, 5262131
    • Recruiting
    • Sheba Medical Center
    • Contact: Shirly Grynberg, MD
• United States
  • California
    • Duarte, California, United States, 91010
      • Recruiting
      • City of Hope
      • Contact: Miguel Villalona-Calero, MD
  • Louisiana
    • New Orleans, Louisiana, United States, 70121
      • Recruiting
      • Ochsner Clinic Foundation
      • Contact: Marc Matrana, MD
  • Texas
    • Houston, Texas, United States, 77030
      • Recruiting
      • The University of Texas MD Anderson Cancer Center
      • Principal Investigator: Sarina A Piha-Paul, MD
      • Contact: Sarina A Piha-Paul, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Histologic or cytologic evidence of an advanced (locally advanced or metastatic) malignant solid cancer known to express PVR, or if the patient's cancer has been documented to express PVR.
2. 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.
3. Tumor tissue or paraffin block, ideally from the patient's most recent biopsy within 1 year of study treatment. A fresh tumor biopsy will be obtained if archival samples are not available or from tumor sampled more than 1 year prior to enrollment. Patient must be amenable to on treatment biopsy.
4. Disease that is measurable by Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1.
5. A least 18 years old.
6. An Eastern Cooperative Oncology Group (ECOG) performance status of ≤1.
7. Adequate baseline hematopoietic, kidney and liver function.
8. A left ventricular ejection fraction (LVEF) ≥ 45%.
9. Female participants are eligible to participate if not pregnant, not breastfeeding, and must agree to follow contraceptive guidance during the treatment period and for at least 120 days after the last dose of study treatment.
10. Male subjects must agree to follow contraceptive guidance during the study period and for at least 120 days after the last dose of study treatment.
11. Patient must give informed written consent for the study.
12. Patient must adhere to the study visit schedule and other protocol requirements.
13. Patient has sufficient venous access for protocol defined plasma/blood sampling.

Exclusion Criteria:

1. The patient was discontinued from prior treatment with an immuno-oncology therapeutic due to a Grade 3 or higher immune-related adverse event.
2. Received radiotherapy within 2 weeks of treatment.
3. Received radiation therapy to the lung that is greater than 30 Gray within 6 months of the first dose of study medication.
4. The patient is concurrently receiving treatment with anticancer therapies (cytotoxic chemotherapy, monoclonal antibodies, and/or small molecule tyrosine kinase inhibitors).
5. Received an allogeneic tissue/solid organ transplant.
6. Received a live or live-attenuated vaccine within 30 days prior to the first dose of study intervention.
7. Received prior treatment with NTX-1088 or another investigational agent targeting PVR.
8. The participant must have recovered adequately from any major surgery and/or any complications from the surgery prior to starting study intervention.
9. Currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment.
10. The patient must have recovered from all AEs due to previous therapies to Grade ≤1 or baseline.
11. The patient has an active autoimmune disease that required systemic treatment in the past.
12. Presence of an uncontrolled endocrine disorder.
13. Presence of clinically significant cardiovascular disease.
14. History of (non-infectious) pneumonitis or interstitial pulmonary disease that required steroids or has current pneumonitis or interstitial pulmonary disease.
15. Presence of uncontrolled, clinically significant pulmonary disease.
16. A previous severe hypersensitivity reaction (Grade ≥3) to pembrolizumab and/or any of its excipients.
17. A diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior the first dose of study drug. Inhaled or topical steroids are permitted in the absence of active autoimmune disease.
18. An uncontrolled intercurrent illness that would limit compliance with study requirements.
19. History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study or interfere with participation in the study.
20. A positive status for human immunodeficiency virus (HIV).
21. A known history of Hepatitis B (defined as HBsAg reactive) or known active Hepatitis C virus (defined as HCV RNA detected) infection.
22. Oxygen dependent.
23. The patient has any medical condition which, in the opinion of the Investigator, places the patient at an unacceptably high risk for toxicities.
24. Additional active malignancy that is progressing or has required active treatment within the past 3 years.
25. Known active CNS metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable.
26. Patient is pregnant or breast feeding.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part 1 - Dose Escalation Phase (Monotherapy); 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; IgG4 mAb targeting the poliovirus receptor (PVR, CD155).
Experimental: Part 2 - Dose Expansion (Monotherapy); NTX-1088 administered at the RP2D as a 60-minute IV infusion as a monotherapy.	Drug: NTX-1088; IgG4 mAb targeting the poliovirus receptor (PVR, CD155).
Experimental: Part 2 - Dose Expansion (Combination Therapy); NTX-1088 administered at the RP2D as a 60-minute IV infusion in combination with pembrolizumab at the standard labeled dose.	Drug: NTX-1088; IgG4 mAb targeting the poliovirus receptor (PVR, CD155).; Drug: Pembrolizumab; 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).; Other Names: KEYTRUDA®
Experimental: Part 1 - Dose Escalation Phase (Combination Therapy); 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; IgG4 mAb targeting the poliovirus receptor (PVR, CD155).; Drug: Pembrolizumab; 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).; Other Names: KEYTRUDA®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetics of NTX-1088	Maximum Plasma Concentration (Cmax)	Day 1 of dosing through 21 days post last dose.
Pharmacokinetics of NTX-1088	Area Under the Curve (AUC)	Day 1 of dosing through 21 days post last dose.
Objective Response Rate (ORR)	ORR according to RECIST v1.1.	Day 1 of dosing through 90 days after the last dose.
Duration of Response (DoR)	Time from the date measurement criteria are first met for PR or CR to the date measurement criteria are first met for progressive disease.	Day 1 of dosing through 90 days after the last dose.
Progression Free Survival (PFS)	Time from the date of initiation of study therapy to the date measurement criteria are first met for progressive disease or death from any cause, whichever occurs first.	Day 1 of dosing through 90 days after the last dose.
Overall Survival (OS)	Time from the date of initiation of study therapy to the date of death from any cause.	Day 1 of dosing through 90 days after the last dose.

Collaborators and Investigators

• Sponsor: Nectin Therapeutics Ltd
• Collaborators: Merck Sharp & Dohme LLC

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2022
• Primary Completion (Estimated): June 1, 2025
• Study Completion (Estimated): December 1, 2025

Study Registration Dates

• First Submitted: May 12, 2022
• First Submitted That Met QC Criteria: May 12, 2022
• First Posted (Actual): May 18, 2022

Study Record Updates

• Last Update Posted (Estimated): January 29, 2024
• Last Update Submitted That Met QC Criteria: January 25, 2024
• Last Verified: February 1, 2023

More Information

Terms related to this study

• Keywords: PVR; IO; Immune Oncology
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplastic Processes; Neoplasms; Neoplasm Metastasis; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Pembrolizumab
• Other Study ID Numbers: NTX 1088-01; KEYNOTE-E92 (Other Identifier: Merck Sharp & Dohme, LLC); MK-3475-E92 (Other Identifier: Merck Sharp & Dohme, LLC)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No