Dose-Escalation and Dose-Expansion Study of IO-202 and IO-202+Pembrolizumab in Solid Tumors

Study Overview
=================
Brief Summary
-----------------
To assess safety and tolerability of increasing doses of IO-202 either as monotherapy or in combination with pembrolizumab in patients with advanced solid tumors, and select the recommended Phase 2 dose (RP2D).

Detailed Description
-----------------
This is a Phase 1, open-label, multicenter, dose-escalation and dose-expansion study of IO-202 in adult subjects with advanced relapsed or refractory solid tumors to study safety, tolerability, pharmacokinetic, pharmacodynamics and clinical activity of IO-202 as monotherapy or in combination with pembrolizumab and to estimate the maximum tolerated dose (MTD) or maximum administered dose (MAD), and to select the RP2D.

Official Title
-----------------
A Phase 1, Multicenter, Open-Label, Dose-Escalation, and Dose-Expansion Study of IO-202 in Combination With Pembrolizumab in Subjects With Advanced, Relapsed, or Refractory Solid Tumors

Conditions
-----------------
Solid Tumor, Adult

Intervention / Treatment
-----------------
* Biological: IO-202
* Biological: IO-202 + pembrolizumab combination therapy
* Biological: RP2D of IO-202 + pembrolizumab combination therapy in multiple solid tumor types


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Subject must be ≥18 years old. Part 1 - Dose Escalation: Subject must have any histologically or cytologically confirmed advanced or metastatic solid tumor and has received, has been intolerant to, or has been ineligible for standard systemic therapy known to confer clinical benefit. Part 2 - Dose Expansion: Subject must have failed at least one available therapy for the disease under study. Subject must have measurable disease per RECIST 1.1 as assessed by local clinical site. Subject must have an Eastern Cooperative Oncology Group performance status of 0 or 1. Exclusion Criteria: Subject who previously received leukocyte immunoglobulin-like receptor subfamily B (LILRB) or immunoglobulin-like transcript [ILT]) targeting agents including those targeting LILRB1 (ILT2), LILRB2 (ILT4), LILRB4 (ILT3), or leukocyte-associated immunoglobulin-like receptor 1 (LAIR1). Subject who received a biologic systemic anti-cancer therapy <4 weeks or 5 half-lives prior to their first day of study drug administration, or a small molecule systemic anti-cancer therapy or definitive radiotherapy <2 weeks or 5 half-lives prior to their first day of study drug administration or have not recovered to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0 Grade 1 or better from any adverse events (AEs) that were due to prior cancer therapeutics. Subject has symptomatic central nervous system (CNS) tumor. Requires systemic corticosteroids at a dose of >10 mg prednisone or the dose equivalent of other systemic corticosteroid. History of radiation pneumonitis, non-infectious pneumonitis or interstitial lung disease. History of Grade ≥3 immune-related AEs with any prior immunotherapy. Subjects with known hypersensitivity to any of the components of the IO-202 formulation or pembrolizumab. Active known malignancy with the exception of any of the following: Adequately treated basal cell carcinoma, squamous cell carcinoma of the skin, or in situ cervical cancer; Low-risk prostate cancer for which observation or hormonal therapy only is indicated; Any other malignancy treated with curative intent with the last treatment completed ≥ 6 months before study initiation (with the exception of hormonal therapies when indicated). Subjects with New York Heart Association (NYHA) Class III or IV congestive heart failure (CHF) or left ventricular ejection fraction (LVEF) <40% by ECHO or multi-gated acquisition (MUGA) scan ≤28 days prior to Cycle 1 Day 1 (C1D1). Any of the following in the previous 6 months: myocardial infarction, congenital long QT syndrome, Torsades de pointes, clinically significant arrhythmias (including sustained ventricular tachyarrhythmia and ventricular fibrillation), and left anterior hemiblock (bifascicular block), unstable angina, coronary/peripheral artery bypass graft, symptomatic CHF (NYHA class III or IV), cerebrovascular accident, transient ischemic attack, or pulmonary embolism. Patients with asymptomatic right bundle branch block or controlled atrial fibrillation are allowed. Ongoing cardiac dysrhythmias of Grade 2 or higher per NCI CTCAE, Version 5.0. Active bacterial, viral, and/or fungal infection including hepatitis B (HBV), hepatitis C, human immunodeficiency virus (HIV), severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) or acquired immunodeficiency syndrome (AIDS)-related illness. Subjects with any psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the subject before study entry. Subject with current active treatment in another interventional therapeutic clinical study. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the Investigator, would make the patient inappropriate for entry into this study.

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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: IO-202 Monotherapy (dose escalation)<br> | Biological: IO-202<br>* IO-202 given as monotherapy<br>|
| Experimental: IO-202 dose escalation + pembrolizumab<br>Increasing dose levels of IO-202 with fixed dose of pembrolizumab | Biological: IO-202 + pembrolizumab combination therapy<br>* IO-202 and fixed dose pembrolizumab combination therapy<br>* Other names: IO-202 + Keytruda combination therapy;|
| Experimental: IO-202 + pembrolizumab combination therapy (dose expansion)<br>RP2D + pembrolizumab combination therapy in solid tumor cohorts | Biological: RP2D of IO-202 + pembrolizumab combination therapy in multiple solid tumor types<br>* Expansion cohorts of the RP2D of IO-202 and fixed dose pembrolizumab combination therapy in multiple tumor types.<br>* Other names: RP2D of IO-202 + Keytruda combination therapy;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of treatment-emergent and serious adverse events in patients treated with IO-202 and IO-202 + pembrolizumab | safety and tolerability as measured by the incidence of treatment-emergent adverse events. | From first dose of IO-202 until the end of treatment which is up to 2 years from the first treatment date | 
| Dose-limiting toxicities (DLTs) with IO-202 and IO-202 + pembrolizumab | DLTs as measured by the incidence during Cycle 1. | From the first dose of IO-202 and IO-202 + pembrolizumab until 21 days after 1st treatment | 
| Study discontinuations due to adverse events (AEs) | The number of study discontinuations due to AEs | From the first dose of IO-202 IO-202 and IO-202 + pembrolizumab up to 2 years from the first treatment. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum serum concentration (Cmax) of IO-202 | Characterize the Cmax of IO-202 by successive sampling of blood at pre-specified times | From the first dose of IO-202 until Cycle 5, Day 1 | 
| Minimum concentration of IO-202 | Characterize minimum concentration of IO-202 by successive sampling of blood at pre-specified time points | From the first dose of IO-202 until the last treatment which is up to 2 years from the first treatment date | 
| Immunogenicity of IO-202 and IO-202 + pembrolizumab | Determine the incidence/titer of anti-drug antibodies (ADAs) against IO-202 and pembrolizumab (in combination treatment) | From the first dose until 24 months after the last treatment | 
| Anti-tumor activity of IO-202 and IO-202 + pembrolizumab | Determine preliminary rates of response after treatment with IO-202 | From the date of first treatment until the date of first documented progression or date of death from any cause, whichever comes first, assessed up to an estimated period of 24 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
IO-202