Safety and Efficacy of KY1044 and Atezolizumab in Advanced Cancer

Study Overview
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Brief Summary
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A Phase 1/2, open label, multi-center study to evaluate the safety, efficacy and tolerability of KY1044 as single agent and in combination with anti-PD-L1 (atezolizumab) in adult patients with selected advanced malignancies, who are ineligible for or there are no available therapies known to confer a clinical benefit for their disease, or they have exhausted all such available options in each indication and therefore will be patients for whom a clinical trial is appropriate.

Official Title
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A Phase 1/2, Open-label, Multi-center Study of the Safety and Efficacy of KY1044 as Single Agent and in Combination With Anti-PD-L1 (Atezolizumab) in Adult Patients With Selected Advanced Malignancies

Conditions
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Squamous Cell Carcinoma of Head and Neck, Non-small Cell Lung Cancer, Hepatocellular Carcinoma, Esophageal Cancer, Gastric Cancer, Melanoma, Renal Cell Carcinoma, Pancreatic Cancer, Cervical Cancer, Triple Negative Breast Cancer, Advanced Cancer, Metastatic Cancer

Intervention / Treatment
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* Drug: KY1044
* Drug: KY1044 and atezolizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥18 years (≥20 years in Taiwan) Histologically documented advanced/metastatic malignancies Phase 1 and Phase 2 participants with advanced/metastatic malignancies who have measurable disease (non-measurable disease is allowed only in Phase 1) as determined by RECIST 1.1 will be eligible if, according to the National Comprehensive Cancer Network (NCCN) guidelines, there are no available therapies known to confer a clinical benefit for their disease, or they have exhausted all such available options. Additionally, the following specific tumor indications will be enrolled: Phase 1: Participants with advanced/metastatic malignancies, and preferred indications (non-small cell lung cancer (NSCLC), head and neck squamous cell carcinoma (HNSCC), hepatocellular carcinoma (HCC), melanoma, cervical, esophageal, gastric, renal, pancreatic, and triple negative breast cancer) Phase 2 KY1044 single agent: Participants with advanced/metastatic malignancies in indications in which signs of anti-tumor activity (Complete Response (CR), Partial Response (PR) or durable stable disease (SD) with tumor shrinkage that does not qualify for PR) were seen during the dose escalation of KY1044 as single agent Phase 2 KY1044 in combination with atezolizumab: Participants with advanced/metastatic malignancies in the selected indications below, and/or indications which have shown promising activity in Phase 1: NSCLC (anti-PD-(L)1 therapy naïve and pre-treated between 1 and 2 prior lines of systemic therapy for advanced disease) Gastric (anti-PD-(L)1 therapy naïve and pre-treated) Recurrent and/or metastatic HNSCC (anti-PD-(L)1 therapy naïve and pre-treated between 1 and 2 prior lines of systemic therapy for advanced disease) Esophageal (anti-PD-(L)1 therapy naïve and pre-treated) Cervical (anti-PD-(L)1 therapy naïve and pre-treated) Indications, in which signs of anti-tumor activity has been observed in Phase 1 with KY1044 in combination with atezolizumab Prior therapy with anti-PD-(L)1 inhibitors is allowed provided any toxicity attributed to prior anti-PD-(L)1-directed therapy did not lead to discontinuation of therapy Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1 Life expectancy longer than 12 weeks Must have a site of disease amenable to biopsy, and be a candidate for tumor biopsy according to the treating institution's guidelines. Participants must be willing to undergo a new tumor biopsy at screening, and during therapy on the study Exclusion Criteria: Presence of symptomatic central nervous system (CNS) metastases, or CNS metastases that require local CNS-directed therapy, or increasing doses of corticosteroids within the prior 2 weeks of first dose of study treatment History of severe hypersensitivity reactions to other monoclonal antibodies and/or their excipients Known presence of neutralizing anti-atezolizumab antibodies (for patients previously treated with atezolizumab) Having out of range laboratory values: creatinine, bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), absolute neutrophil count (ANC), platelet count, hemoglobin Impaired cardiac function or clinically significant cardiac disease, including any of the following: Clinically significant and/or uncontrolled heart disease such as congestive heart failure requiring treatment (New York Heart Association [NYHA] Grade ≥2), uncontrolled hypertension or clinically significant arrhythmia QTcF >470 msec on screening (electrocardiogram) ECG using Fridericia's formula (QTcF) or congenital long QT syndrome Acute myocardial infarction or unstable angina pectoris Known human immunodeficiency virus (HIV), active hepatitis B virus (HBV) or active hepatitis C virus (HCV) infection Malignant disease, other than that being treated in this study Any medical condition that would, in the Investigator's judgment, prevent participation in the clinical study due to safety concerns, compliance with clinical study procedures or interpretation of study results Active autoimmune disease or a documented history of autoimmune disease Participants previously exposed to anti-PD-(L)1 treatment who are not adequately treated for skin rash or had no replacement therapy for endocrinopathies should be excluded Participants with a history of drug-induced pneumonitis or current pneumonitis Systemic steroid therapy or any immunosuppressive therapy. Topical, inhaled, nasal, and ophthalmic steroids are not prohibited Use of live attenuated vaccines against infectious diseases within 4 weeks of the first dose of study treatment. SARS-CoV-2 vaccines authorized for use by the competent local regulatory health authorities for active immunization to prevent COVID 19 are allowed (unless the vaccine is live or live attenuated) and must be given in accordance with the prevailing immunization guidelines. Anti-CTLA4, anti-PD-(L)1 treatment within 4 weeks of the first dose of study treatment Pre-treatment with anti-CTLA4 antibodies in combination with any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathway Presence of Common Terminology Criteria for Adverse Events version 5 (CTCAE v5) ≥Grade 2 toxicity (except alopecia, peripheral neuropathy and ototoxicity, which are excluded if CTCAE v5 ≥Grade 3) due to prior cancer therapy Radiotherapy within 2 weeks of the first dose of study treatment, except for palliative radiotherapy to a limited field, such as for the treatment of bone pain or a focally painful tumor mass. To allow evaluation for response to treatment, participants enrolled in the Phase 2 part must have remaining measurable disease that has not been irradiated Pregnant or lactating women

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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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: KY1044 monotherapy phase 1<br>KY1044 monotherapy dose escalation | Drug: KY1044<br>* A human anti-ICOS monoclonal antibody<br>|
| Experimental: KY1044 and atezolizumab phase 1<br>KY1044 and atezolizumab combination dose escalation | Drug: KY1044 and atezolizumab<br>* A human anti-ICOS monoclonal antibody in combination with anti-PD-L1 monoclonal antibody (atezolizumab)<br>|
| Experimental: KY1044 monotherapy phase 2<br>KY1044 monotherapy | Drug: KY1044<br>* A human anti-ICOS monoclonal antibody<br>|
| Experimental: KY1044 and atezolizumab phase 2<br>KY1044 and atezolizumab combination | Drug: KY1044 and atezolizumab<br>* A human anti-ICOS monoclonal antibody in combination with anti-PD-L1 monoclonal antibody (atezolizumab)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety: Incidence and severity of adverse events (AEs) and serious adverse events (SAEs) (Phase 1) |  | Up to 48 months | 
| Tolerability: Number of dose interruptions, reductions and dose intensity (Phase 1) |  | Up to 48 months | 
| Overall response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 (Phase 2) |  | Up to 48 months | 
| Incidence of Dose Limiting Toxicities (DLTs) with KY1044 as single agent (Phase 1) |  | Within first 21 days of treatment | 
| Incidence of DLTs with KY1044 in combination with atezolizumab (Phase 1) |  | Within first 21 days of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best overall response (BOR) per RECIST 1.1 |  | Up to 48 months | 
| Progression Free Survival (PFS) per RECIST 1.1 |  | Up to a PFS event, approximately every 3 months | 
| Duration of Response (DOR) per RECIST 1.1 |  | Up to a PFS event, approximately every 3 months | 
| ORR per Immune-Related Response Evaluation Criteria in Solid Tumors (iRECIST) (Phase 1 and Phase 2) |  | Up to 48 months | 
| PFS per iRECIST (Phase 1 and Phase 2) |  | Up to 48 months | 
| ORR per RECIST 1.1 (Phase 1) |  | Up to 48 months | 
| Survival rate |  | At 12 and 24 months | 
| Safety: Incidence and severity of AEs and SAEs (Phase 2) |  | Up to 48 months | 
| Number of dose interruptions, reductions and dose intensity (Phase 2) |  | Up to 48 months | 
| Maximum Concentration (Cmax) of KY1044 and of atezolizumab if in combination |  | Up to 48 months | 
| Half-life (t1/2) of of KY1044 and of atezolizumab if in combination |  | Up to 48 months | 
| Number of participants with anti-KY1044 and anti-atezolizumab antibodies |  | Up to 48 months | 
| Number of participants with presence of tumor-infiltrating lymphocytes (TILs) as determined by expression of ICOS (Inducible T cell Costimulator), FOXP3 (Forkhead box P3) and CD8 cells |  | Up to 48 months |