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

Phase 1

Recruiting

• Conditions: Tumor, Solid; Metastatic Cancer; Cancer; Advanced Solid Tumor; Locally Advanced Solid Tumor
• Interventions: Drug: NTX-1088; Drug: Pembrolizumab

• Registration Number: NCT05378425
• Lead Sponsor: Nectin Therapeutics Ltd

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).

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 Timeline

• Study First Submitted: 2022-05-12
• Study First Submitted QC: 2022-05-12
• Study First Posted: 2022-05-18
• Study Start: 2022-09-01
• Status Verified: 2023-02
• Last Update Submitted: 2024-01-25
• Last Update Posted: 2024-01-29
• Primary Completion: 2025-06
• Study Completion: 2025-12

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 90

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.

Read More

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.

Read More

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Part 1 - Dose Escalation Phase (Monotherapy)	NTX-1088	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.
Part 2 - Dose Expansion (Combination Therapy)	NTX-1088	NTX-1088 administered at the RP2D as a 60-minute IV infusion in combination with pembrolizumab at the standard labeled dose.
Part 1 - Dose Escalation Phase (Combination Therapy)	NTX-1088	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.
Part 2 - Dose Expansion (Monotherapy)	NTX-1088	NTX-1088 administered at the RP2D as a 60-minute IV infusion as a monotherapy.
Part 1 - Dose Escalation Phase (Combination Therapy)	Pembrolizumab	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.
Part 2 - Dose Expansion (Combination Therapy)	Pembrolizumab	NTX-1088 administered at the RP2D as a 60-minute IV infusion in combination with pembrolizumab at the standard labeled dose.

Primary Outcome Measures

Name	Time	Method
Dose-Finding	Screening to 30 days from last dose.	Determination of the MTD or maximum tested dose, and the RP2D.
Frequency and Severity of Adverse Events (AE)	Screening to 30 days from last dose.	The incidences and percentages of patients experiencing AEs summarized by NCI CTCAE version 5.0 grade and by causality.
Dose-limiting Toxicity (DLT)	First 21 days of treatment.	The incidence of DLTs during the DLT assessment period.

Secondary Outcome Measures

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

Trial Locations

Locations (5)

Ochsner Clinic Foundation; 🇺🇸 New Orleans, Louisiana, United States

Hadassah Medical Center; 🇮🇱 Jerusalem, Israel

Sheba Medical Center; 🇮🇱 Ramat Gan, Israel

City of Hope; 🇺🇸 Duarte, California, United States

The University of Texas MD Anderson Cancer Center; 🇺🇸 Houston, Texas, United States