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

Study Overview
=================
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.

Official Title
-----------------
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

Conditions
-----------------
Cancer, Tumor, Solid, Advanced Solid Tumor, Metastatic Cancer, Locally Advanced Solid Tumor

Intervention / Treatment
-----------------
* Drug: NTX-1088
* Drug: Pembrolizumab


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: 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. 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. 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. Disease that is measurable by Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. A least 18 years old. An Eastern Cooperative Oncology Group (ECOG) performance status of ≤1. Adequate baseline hematopoietic, kidney and liver function. A left ventricular ejection fraction (LVEF) ≥ 45%. 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. 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. Patient must give informed written consent for the study. Patient must adhere to the study visit schedule and other protocol requirements. Patient has sufficient venous access for protocol defined plasma/blood sampling. Exclusion Criteria: The patient was discontinued from prior treatment with an immuno-oncology therapeutic due to a Grade 3 or higher immune-related adverse event. Received radiotherapy within 2 weeks of treatment. Received radiation therapy to the lung that is greater than 30 Gray within 6 months of the first dose of study medication. The patient is concurrently receiving treatment with anticancer therapies (cytotoxic chemotherapy, monoclonal antibodies, and/or small molecule tyrosine kinase inhibitors). Received an allogeneic tissue/solid organ transplant. Received a live or live-attenuated vaccine within 30 days prior to the first dose of study intervention. Received prior treatment with NTX-1088 or another investigational agent targeting PVR. The participant must have recovered adequately from any major surgery and/or any complications from the surgery prior to starting study intervention. 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. The patient must have recovered from all AEs due to previous therapies to Grade ≤1 or baseline. The patient has an active autoimmune disease that required systemic treatment in the past. Presence of an uncontrolled endocrine disorder. Presence of clinically significant cardiovascular disease. History of (non-infectious) pneumonitis or interstitial pulmonary disease that required steroids or has current pneumonitis or interstitial pulmonary disease. Presence of uncontrolled, clinically significant pulmonary disease. A previous severe hypersensitivity reaction (Grade ≥3) to pembrolizumab and/or any of its excipients. 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. An uncontrolled intercurrent illness that would limit compliance with study requirements. 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. A positive status for human immunodeficiency virus (HIV). A known history of Hepatitis B (defined as HBsAg reactive) or known active Hepatitis C virus (defined as HCV RNA detected) infection. Oxygen dependent. The patient has any medical condition which, in the opinion of the Investigator, places the patient at an unacceptably high risk for toxicities. Additional active malignancy that is progressing or has required active treatment within the past 3 years. Known active CNS metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable. Patient is pregnant or breast feeding.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

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

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. | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
PVR, IO, Immune Oncology