GI-101 as a Single Agent or in Combination With Pembrolizumab, Lenvatinib or Local Radiotherapy in Advanced Solid Tumors

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety, tolerability, pharmacokinetics, and therapeutic activity of GI-101/GI-101A as a single agent or in combination with pembrolizumab, lenvatinib or local radiotherapy (RT) over a range of advanced and/or metastatic solid tumors.

Detailed Description
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This is a phase 1/2, open-label, dose-escalation and expansion study to evaluate the safety, tolerability and anti-tumor effect of GI-101/GI-101A as a single agent or in combination with pembrolizumab, lenvatinib or local RT over a range of advanced and/or metastatic solid tumors. This study will comprise six parts. Part A: Dose-escalation and expansion cohorts of GI-101 monotherapy Part B: Dose-escalation and expansion cohorts of GI-101 plus pembrolizumab Part C: Dose-optimization and expansion cohorts of GI-101 plus lenvatinib Part D: Dose-optimization and expansion cohorts of GI-101 plus local RT Part E: Dose-escalation and expansion cohorts of GI-101A monotherapy Part F: Dose-escalation and expansion cohorts of GI-101A plus pembrolizumab GI-101/GI-101A is a novel bi-specific Fc fusion protein containing the CD80 ectodomain as an N-terminal moiety and an interleukin (IL)-2 variant as a C-terminal moiety configurated via a human immunoglobulin G4 (IgG4) Fc. GI-101A is an abbreviation of advanced GI-101 with an improved formulation for manufacture consistency. Drug Information available for: Pembrolizumab (https://www.keytrudahcp.com), Lenvatinib (http://www.lenvima.com)

Official Title
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A Phase 1/2 Study to Evaluate Safety, Tolerability, PK, and Therapeutic Activity of GI-101 as a Single Agent and in Combination With Pembrolizumab, Lenvatinib or Local Radiotherapy in Patients With Advanced, Metastatic Solid Tumors

Conditions
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Melanoma, Sarcoma, Microsatellite Stable Colorectal Carcinoma, Merkel Cell Carcinoma, Esophageal Squamous Cell Carcinoma, Cervical Cancer, Vaginal Cancer, Vulvar Cancer, Advanced Solid Tumor, Metastatic Solid Tumor, Non-small Cell Lung Cancer, Head and Neck Squamous Cell Carcinoma, Renal Cell Carcinoma, Urinary Bladder Cancer

Intervention / Treatment
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* Drug: GI-101
* Drug: Pembrolizumab
* Drug: Lenvatinib
* Radiation: Local Radiotherapy
* Drug: GI-101A


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Males and females aged ≥ 18 years (or ≥ 19 years according to local regulatory guidelines) at the time of screening. Has adequate organ and marrow function as defined in protocol. Measurable disease as per RECIST v1.1. ECOG performance status 0-1. Adverse events related to any prior chemotherapy, radiotherapy, immunotherapy, other prior systemic anti-cancer therapy, or surgery must have resolved to Grade ≤1, except alopecia and Grade 2 peripheral neuropathy. HIV infected patients must be on anti-retroviral therapy (ART) and have a well-controlled HIV infection/disease as defined in protocol. Key Exclusion Criteria: Has known active CNS metastases and/or carcinomatous meningitis. An active second malignancy Has active or a known history of Hepatitis B or known active Hepatitis C virus infection. Has active tuberculosis or has a known history of active tuberculosis Active or uncontrolled infections, or severe infection within 4 weeks before study treatment administration. History of chronic liver disease or evidence of hepatic cirrhosis, except patients with liver metastasis. Has an active autoimmune disease that has required systemic treatment in past 2 years. Previous immunotherapies related to mode of action of GI-101. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy or any other form of immunosuppressive medications within 2 weeks prior to Cycle 1 Day 1. Administration of prior systemic anti-cancer therapy including investigational agents within 4 weeks prior to treatment. Radiotherapy within the last 2 weeks before start of study treatment administration, with exception of limited field palliative radiotherapy (except Part D). Administration of a live, attenuated vaccine within 4 weeks before Cycle 1 Day 1. Known hypersensitivity to any of the components of the drug products and/or excipients of GI-101, pembrolizumab or lenvatinib. Other protocol defined inclusion exclusion criteria may apply

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: GI-101<br>Dose escalation: GI-101, multiple ascending doses Dose expansion: | Drug: GI-101<br>* Recommended phase 2 dose of GI-101 will be administered via IV infusion Q3W up to 2 years (approximately 35 years).<br>|
| Experimental: GI-101 + Pembrolizumab<br>Dose escalation: GI-101, multiple ascending doses Dose expansion: | Drug: GI-101<br>* Recommended phase 2 dose of GI-101 will be administered via IV infusion Q3W up to 2 years (approximately 35 years).<br>Drug: Pembrolizumab<br>* Pembrolizumab will be administered at a dose of 200 mg as IV infusion Q3W.<br>* Other names: Keytruda®;|
| Experimental: GI-101 + Lenvatinib<br>Dose optimization: Dose expansion: | Drug: GI-101<br>* Recommended phase 2 dose of GI-101 will be administered via IV infusion Q3W up to 2 years (approximately 35 years).<br>Drug: Lenvatinib<br>* Lenvatinib will be administered at an approved dose orally.<br>* Other names: Lenvima®;|
| Experimental: GI-101 + Local Radiotherapy<br>Dose optimization: Dose expansion: | Drug: GI-101<br>* Recommended phase 2 dose of GI-101 will be administered via IV infusion Q3W up to 2 years (approximately 35 years).<br>Radiation: Local Radiotherapy<br>* Patients will receive SBRT prior to the first dose of GI-101<br>|
| Experimental: GI-101A<br>Dose escalation: GI-101A, multiple ascending doses Dose expansion: | Drug: GI-101A<br>* Recommended phase 2 dose of GI-101A will be administered via IV infusion Q3W up to 2 years (approximately 35 years).<br>|
| Experimental: GI-101A + Pembrolizumab<br>Dose escalation: GI-101A, multiple ascending doses Dose expansion: | Drug: Pembrolizumab<br>* Pembrolizumab will be administered at a dose of 200 mg as IV infusion Q3W.<br>* Other names: Keytruda®;Drug: GI-101A<br>* Recommended phase 2 dose of GI-101A will be administered via IV infusion Q3W up to 2 years (approximately 35 years).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence and nature of Dose-Limiting Toxicity (DLTs) | Based on toxicities observed. | Study Day 1, assessed up to approximately 24 months | 
| Incidence, nature, and severity of adverse events (AEs) and immune-related AEs (irAEs) | Based on toxicities observed. | Study Day 1, assessed up to approximately 24 months | 
| Objective Response Rate (ORR) according to RECIST version 1.1 | Based on Investigator review of radiographic imaging. | Study Day 1, assessed up to approximately 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Peak plasma concentration (Cmax) of GI-101/GI-101A | Based on the concentration vs time profile by dose level | Study Day 1, assessed up to approximately 24 months | 
| Half-life of GI-101/GI-101A (T1/2) | Based on the concentration vs time profile by dose level | Study Day 1, assessed up to approximately 24 months | 
| Area under the plasma concentration versus time curve (AUC) of GI-101/GI-101A | Based on the concentration vs time profile by dose level | Study Day 1, assessed up to approximately 24 months | 
| Disease control rate (DCR) according to RECIST version 1.1 | Based on Investigator review of radiographic imaging. | Study Day 1, assessed up to approximately 24 months | 
| Duration of objective Response (DoR) according to RECIST version 1.1 | Based on Investigator review of radiographic imaging. | Study Day 1, assessed up to approximately 24 months | 
| Time to Tumor Response (TTR) according to RECIST version 1.1 | Based on Investigator review of radiographic imaging. | Study Day 1, assessed up to approximately 24 months | 
| Progression-Free Survival (PFS) according to RECIST version 1.1 | Based on Investigator review of radiographic imaging. | Study Day 1, assessed up to approximately 24 months | 
| ORR per iRECIST guidelines | Based on Investigator review of radiographic imaging. | Study Day 1, assessed up to approximately 24 months | 
| DCR per iRECIST guidelines | Based on Investigator review of radiographic imaging. | Study Day 1, assessed up to approximately 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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IL-2, GI-101/GI-101A, CD80-IgG4 Fc-IL2 variant, Immunotherapy, Interleukin-2, Pembrolizumab, Lenvatinib, Radiotherapy