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

A Phase 1/2, Open-label, Dose-escalation, and Expansion Study to Evaluate Safety, Tolerability, Pharmacokinetics, and Therapeutic Activity of GI-101 as a Single Agent and in Combination With Pembrolizumab, Lenvatinib or Local Radiotherapy in Patients With Advanced or Metastatic Solid Tumors (Keynote B59)

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.

Study Overview

• Status: Recruiting
• Conditions: Melanoma; Sarcoma; Renal Cell Carcinoma; Cervical Cancer; Urinary Bladder Cancer; Vulvar Cancer; Advanced Solid Tumor; Metastatic Solid Tumor; Non-small Cell Lung Cancer; Head and Neck Squamous Cell Carcinoma; Esophageal Squamous Cell Carcinoma; Merkel Cell Carcinoma; Vaginal Cancer; Microsatellite Stable Colorectal Carcinoma
• Intervention / Treatment: Drug: GI-101; Drug: Lenvatinib; Radiation: Local Radiotherapy; Drug: GI-101A; Drug: Pembrolizumab (KEYTRUDA®)

Detailed Description

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)

• Study Type: Interventional
• Enrollment (Estimated): 430
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Recruiting sites have contact information. Please contact the sites directly.; Phone Number: +82-2-404-2003; Email: clinical@gi-innovation.com

Study Locations

• Korea, Republic of
  • Daejeon, Korea, Republic of, 65015
    • Recruiting
    • Chungnam national university hospital
    • Principal Investigator: HyoJin Lee, M.D., Ph.D.
  • Seoul, Korea, Republic of, 05505
    • Recruiting
    • Asan Medical Center
    • Principal Investigator: Jae Lyun Lee, M.D., Ph.D.
  • Seoul, Korea, Republic of, 03722
    • Recruiting
    • Yonsei University Health system, Severance Hospital
    • Principal Investigator: Jung-Yun Lee, M.D., Ph.D.
  • Kyeonggi-do
    • Suwon-si, Kyeonggi-do, Korea, Republic of, 16247
      • Recruiting
      • The Catholic University Of Korea St. Vincent's Hospital
      • Principal Investigator: Byoung-Yong Shim, M.D., Ph.D.
  • Seongbuk-gu
    • Seoul, Seongbuk-gu, Korea, Republic of, 02841
      • Recruiting
      • Korea University Anam Hospital
      • Principal Investigator: Soohyeon Lee, M.D., Ph.D.
• United States
  • New York
    • New York, New York, United States, 10029-5674
      • Recruiting
      • Tisch Cancer Institute (TCI), Icahn School of Medicine
      • Principal Investigator: Thomas Marron, MD, PhD
  • North Carolina
    • Huntersville, North Carolina, United States, 28078
      • Recruiting
      • Carolina BioOncology Institute
      • Principal Investigator: John Powderly, M.D., Ph.D.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: GI-101; Dose escalation: GI-101, multiple ascending doses Dose expansion:	Drug: GI-101; Recommended phase 2 dose of GI-101 will be administered via IV infusion Q3W up to 2 years (approximately 35 years).
Experimental: GI-101 + Pembrolizumab; Dose escalation: GI-101, multiple ascending doses Dose expansion:	Drug: GI-101; Recommended phase 2 dose of GI-101 will be administered via IV infusion Q3W up to 2 years (approximately 35 years).; Drug: Pembrolizumab (KEYTRUDA®); Pembrolizumab will be administered at a dose of 200 mg as IV infusion Q3W.; Other Names: KEYTRUDA®
Experimental: GI-101 + Lenvatinib; Dose optimization: Dose expansion:	Drug: GI-101; Recommended phase 2 dose of GI-101 will be administered via IV infusion Q3W up to 2 years (approximately 35 years).; Drug: Lenvatinib; Lenvatinib will be administered at an approved dose orally.; Other Names: Lenvima®
Experimental: GI-101 + Local Radiotherapy; Dose optimization: Dose expansion:	Drug: GI-101; Recommended phase 2 dose of GI-101 will be administered via IV infusion Q3W up to 2 years (approximately 35 years).; Radiation: Local Radiotherapy; Patients will receive SBRT prior to the first dose of GI-101
Experimental: GI-101A; Dose escalation: GI-101A, multiple ascending doses Dose expansion:	Drug: GI-101A; Recommended phase 2 dose of GI-101A will be administered via IV infusion Q3W up to 2 years (approximately 35 years).
Experimental: GI-101A + Pembrolizumab; Dose escalation: GI-101A, multiple ascending doses Dose expansion:	Drug: GI-101A; Recommended phase 2 dose of GI-101A will be administered via IV infusion Q3W up to 2 years (approximately 35 years).; Drug: Pembrolizumab (KEYTRUDA®); Pembrolizumab will be administered at a dose of 200 mg as IV infusion Q3W.; Other Names: KEYTRUDA®

What is the study measuring?

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
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
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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Immunophenotyping of peripheral blood mononuclear cells will be performed by flow cytometry at various time points	Peripheral immune cell subpopulation (e.g., CD4+ T cells, CD8+ T cells, regulatory T cells) will be assessed.	Study Day 1, assessed up to approximately 24 months
Incidence of anti-GI-101/GI-101A antibody (ADA) and neutralizing antibody (Nab)	Serum will be assessed for the presence of ADA and Nab based on the appropriate assay.	Study Day 1, assessed up to approximately 24 months

Collaborators and Investigators

• Sponsor: GI Innovation, Inc.
• Collaborators: Merck Sharp & Dohme LLC
• Investigators: Study Director: Nari Yun, PhD, GI Innovation

Study record dates

Study Major Dates

• Study Start (Actual): August 2, 2021
• Primary Completion (Estimated): October 1, 2025
• Study Completion (Estimated): October 1, 2026

Study Registration Dates

• First Submitted: July 9, 2021
• First Submitted That Met QC Criteria: July 26, 2021
• First Posted (Actual): July 27, 2021

Study Record Updates

• Last Update Posted (Estimated): February 22, 2024
• Last Update Submitted That Met QC Criteria: February 20, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: Immunotherapy; Radiotherapy; Pembrolizumab; Lenvatinib; IL-2; Interleukin-2; CD80-IgG4 Fc-IL2 variant; GI-101/GI-101A
• Additional Relevant MeSH Terms: Digestive System Diseases; Virus Diseases; Infections; Neoplasms by Histologic Type; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Urologic Diseases; Adenocarcinoma; Neoplasms, Glandular and Epithelial; Urinary Bladder Diseases; Genital Neoplasms, Female; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Head and Neck Neoplasms; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Colonic Diseases; Intestinal Diseases; DNA Virus Infections; Intestinal Neoplasms; Rectal Diseases; Tumor Virus Infections; Esophageal Diseases; Neuroendocrine Tumors; Vaginal Diseases; Neoplasms, Squamous Cell; Vulvar Diseases; Esophageal Neoplasms; Polyomavirus Infections; Carcinoma, Neuroendocrine; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Genital Diseases; Genital Diseases, Female; Neoplasms; Carcinoma; Colorectal Neoplasms; Urinary Bladder Neoplasms; Carcinoma, Squamous Cell; Squamous Cell Carcinoma of Head and Neck; Vulvar Neoplasms; Esophageal Squamous Cell Carcinoma; Carcinoma, Merkel Cell; Vaginal Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Antineoplastic Agents, Immunological; Protein Kinase Inhibitors; Immune Checkpoint Inhibitors; Pembrolizumab; Lenvatinib
• Other Study ID Numbers: GII-101-P101 (MK-3475-B59); KEYNOTE-B59 (Other Identifier: Merck Sharpe and Dohme LLC)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No