A Study to Evaluate the Safety and Therapeutic Activity of GI-102 As a Single Agent and in Combination with Conventional Anti-cancer Drugs, Pembrolizumab or Trastuzumab Deruxtecan(T-DXd) in Patients with Advanced Solid Tumors (KEYNOTE-G08)

An Open-label, Multicenter, Dose Escalation and Expansion Phase 1/2 Study to Evaluate the Safety, Tolerability and Pharmacokinetics, and Anti-tumor Activity of GI-102, a CD80-IgG4 Fc-IL-2v Bispecific Fusion Protein, As a Single Agent and in Combination with Conventional Anti-cancer Drugs, Pembrolizumab or Trastuzumab Deruxtecan(T-DXd) in Patients with Advanced or Metastatic Solid Tumors (KEYNOTE-G08)

The purpose of this study is to evaluate the safety, tolerability, pharmacokinetics, and therapeutic activity of GI-102 as a single agent and in combination with conventional anti-cancer drugs, pembrolizumab or trastuzumab deruxtecan(T-DXd) over a range of advanced and/or metastatic solid tumors.

Study Overview

• Status: Recruiting
• Conditions: Hepatocellular Carcinoma (HCC); Advanced Solid Tumor; Metastatic Solid Tumor; Cutaneous Melanoma; Renal Cell Carcinoma (RCC); HER2 Negative Breast Cancer; Platinum-resistant Ovarian Cancer (PROC); Colorectal Cancer (CRC); Soft Tissue Sarcoma (STS)
• Intervention / Treatment: Drug: GI-102; Drug: GI-102; Drug: GI-102 subcutaneous (SC); Drug: doxorubicin; Drug: paclitaxel; Drug: bevacizumab; Drug: eribulin; Drug: trastuzumab deruxtecan (T-DXd); Drug: pembrolizumab

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-102 as a single agent and in combination with conventional anti-cancer drugs, pembrolizumab or trastuzumab deruxtecan(T-DXd) over a range of advanced and/or metastatic solid tumors. This study is adaptive in nature.

The study is composed of four parts:

• Part A: Dose escalation and optimization phase of GI-102 intravenous (IV) monotherapy

  • Part A dose escalation phase
  • Part A dose optimization phase: Dose optimization cohorts in patients with 2L+, CPI-refractory metastatic melanoma
• Part B: Dose escalation and expansion phase of GI-102 subcutaneous (SC) monotherapy
• Part C: Indication specific cohorts of GI-102 IV in combination with conventional anti-cancer drugs or trastuzumab deruxtecan (T-DXd)
• Part D: Indication specific cohorts of GI-102 IV in combination with pembrolizumab

GI-102 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-102 has unique characteristics by having bispecificity to CD80 and IL2Rβγ. The CD80 portion is responsible for targeting tumor/immune cells while blocking CTLA-4 expressed on the Treg cells. The IL-2v of GI-102 is designed to abolish IL-2Rα affinity and therefore minimize the effect on Treg while it has very outstanding effect on NK and CD8 T cell proliferation and activity through IL-2Rbr affinity.

• Study Type: Interventional
• Enrollment (Estimated): 358
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Woosun Lee; Phone Number: +82-2-404-2003; Email: Clinical-102@gi-innovation.com
• Study Contact Backup: Name: Jay Kim; Phone Number: +82-2-404-2003; Email: Clinical-102@gi-innovation.com

Study Locations

• Korea, Republic of
  • Seoul, Korea, Republic of, 03080
    • Recruiting
    • Seoul National University Hospital
    • Contact: Seock-Ah Im, MD, PhD
  • Seoul, Korea, Republic of, 05505
    • Recruiting
    • Asan Medical Center
    • Contact: Jae-Lyun Lee, MD, PhD
  • Seoul, Korea, Republic of, 06351
    • Recruiting
    • Samsung Medical Center
    • Contact: Seung Tae Kim, MD, PhD
  • Seoul, Korea, Republic of, 03722
    • Recruiting
    • Yonsei University Health System, Severance Hospital
    • Contact: Jung-Yun Lee, MD, PhD
  • Suwon, Korea, Republic of, 12647
    • Recruiting
    • St. Vincent's Hospital
    • Contact: Byoung Yong Shim, MD, PhD
• United States
  • Arizona
    • Scottsdale, Arizona, United States, 85259
      • Recruiting
      • Mayo Clinic in Arizona
      • Contact: Mahesh Seetharam, MD
  • Florida
    • Jacksonville, Florida, United States, 32224
      • Recruiting
      • Mayo Clinic in Florida
      • Contact: Yujie Zhao, MD, PhD
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Recruiting
      • Mayo Clinic in Minnesota
      • Contact: Jian Li Campian, MD, PhD
  • New York
    • New York, New York, United States, 10065
      • Recruiting
      • Memorial Sloan-Kettering Cancer Center
      • Contact: Viswatej Avutu, MD
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Recruiting
      • Cleveland Clinic
      • Contact: Wen Wee Ma, MBBS

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 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-102.
• 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.
• 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-102.

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

7

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: GI-102; Dose escalation: GI-102 intravenous (IV), multiple ascending doses Dose optimization: GI-102 intravenous (IV), sRP2D Dose optimization: GI-102 intravenous (IV), sRP2D-1 (or sRP2D+1)	Drug: GI-102; Dose level will be escalated from 0.06 mg/kg to 0.45 mg/kg and Recommended phase 2 dose (or RP2D-1, RP2D+1) of GI-102 will be administered via IV infusion Q3W up to 2 years (approximately 35 years).; Drug: GI-102; Recommended phase 2 dose (or RP2D-1, RP2D-2) of GI-102 will be administered via IV infusion Q3W up to 2 years (approximately 35 years).
Experimental: GI-102 subcutaneous (SC); Dose escalation: GI-102 subcutaneous (SC), multiple ascending doses Dose expansion: GI-102 subcutaneous (SC), sRP2D	Drug: GI-102 subcutaneous (SC); 0.12 mg/kg, 0.24 mg/kg or Recommended phase 2 dose of GI-102 will be administered via SC injection Q3W up to 2 years (approximately 35 years).
Experimental: GI-102 + doxorubicin	Drug: GI-102; Dose level will be escalated from 0.06 mg/kg to 0.45 mg/kg and Recommended phase 2 dose (or RP2D-1, RP2D+1) of GI-102 will be administered via IV infusion Q3W up to 2 years (approximately 35 years).; Drug: GI-102; Recommended phase 2 dose (or RP2D-1, RP2D-2) of GI-102 will be administered via IV infusion Q3W up to 2 years (approximately 35 years).; Drug: doxorubicin; Doxorubicin will be administered intravenously at a dose of 75 mg/m2 on Day 3 every 3-week (21-day) cycle for up to 6 cycles.
Experimental: GI-102 + paclitaxel + bevacizumab	Drug: GI-102; Dose level will be escalated from 0.06 mg/kg to 0.45 mg/kg and Recommended phase 2 dose (or RP2D-1, RP2D+1) of GI-102 will be administered via IV infusion Q3W up to 2 years (approximately 35 years).; Drug: GI-102; Recommended phase 2 dose (or RP2D-1, RP2D-2) of GI-102 will be administered via IV infusion Q3W up to 2 years (approximately 35 years).; Drug: paclitaxel; Paclitaxel will be administered intravenously over 1 hour at a dose of 80 mg/m2 each time weekly as a diluted solution according to the prescribing information.; Drug: bevacizumab; Bevacizumab will be administered intravenously at a dose of 10 mg/kg every 2 weeks.
Experimental: GI-102 + eribulin	Drug: GI-102; Dose level will be escalated from 0.06 mg/kg to 0.45 mg/kg and Recommended phase 2 dose (or RP2D-1, RP2D+1) of GI-102 will be administered via IV infusion Q3W up to 2 years (approximately 35 years).; Drug: GI-102; Recommended phase 2 dose (or RP2D-1, RP2D-2) of GI-102 will be administered via IV infusion Q3W up to 2 years (approximately 35 years).; Drug: eribulin; Eribulin will be administered intravenously at a dose of over 1.4 mg/m2 over 2 to 5 minutes on Days 3 and 10 every 3-week (21-day) cycle.
Experimental: GI-102 + trastuzumab deruxtecan (T-DXd)	Drug: GI-102; Dose level will be escalated from 0.06 mg/kg to 0.45 mg/kg and Recommended phase 2 dose (or RP2D-1, RP2D+1) of GI-102 will be administered via IV infusion Q3W up to 2 years (approximately 35 years).; Drug: GI-102; Recommended phase 2 dose (or RP2D-1, RP2D-2) of GI-102 will be administered via IV infusion Q3W up to 2 years (approximately 35 years).; Drug: trastuzumab deruxtecan (T-DXd); T-DXd will be administered initially as a 5.4 mg/kg (or 6.4 mg/kg only for gastric cancer) IV over 30 - 90 minutes every 3 weeks.; Other Names: ENHERTU®
Experimental: GI-102 + pembrolizumab	Drug: GI-102; Dose level will be escalated from 0.06 mg/kg to 0.45 mg/kg and Recommended phase 2 dose (or RP2D-1, RP2D+1) of GI-102 will be administered via IV infusion Q3W up to 2 years (approximately 35 years).; Drug: GI-102; Recommended phase 2 dose (or RP2D-1, RP2D-2) of GI-102 will be administered via IV infusion Q3W up to 2 years (approximately 35 years).; Drug: pembrolizumab; 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) (dose escalation phase of Part A and B)	A DLT is defined as a clinically significant AE (classified according to the NCI CTCAE version 5) or significant laboratory abnormality that occur during the DLT assessment periods, during dose escalation and dose expansion, and is considered by the Investigator to be related to GI-102.	Study Day 1, assessed up to DLT period (3 weeks after treatment)
Incidence, nature, and severity of adverse events (AEs) and immune-related AEs (irAEs) (dose escalation phase of Part A and B)	An adverse event (AE) is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as AEs. All AE events will be graded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.	Study Day 1, assessed up to approximately 24 months
Objective Response Rate (ORR) (dose optimization phase of Part A, dose expansion phase of Part B, Part C and D)	ORR is defined as the percentage of participants with investigator-assessed objective response of complete response (CR) or partial response (PR). PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. CR was defined as disappearance of all target and non-target lesions and normalization of tumor marker levels (as applicable to non-target lesions).	Study Day 1, assessed up to approximately 24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Disease Control Rate (DCR)	DCR is defined as the percentage of patients who have achieved CR, PR and stable disease (SD), per RECIST v1.1 guideline as determined by the investigators.	Study Day 1, assessed up to approximately 24 months
Duration of objective response (DoR)	DCR is defined as the time from the first occurrence of a documented objective response to the time of the first document disease progression or death from any cause, whichever occurs first, per RECIST v1.1 as determined by the investigator.	Study Day 1, assessed up to approximately 24 months
Progression-free survival (PFS)	PFS is defined as the time from the first study treatment (Day 1) to the first occurrence of progression or death from any cause, whichever occurs first, per RECIST v1.1 guideline as determined by the investigator	6-month, 12-month, and 18-month
Overall survival (OS)	OS is defined as the time from the first study treatment to death from any cause	12-month and 18-month
Peak plasma concentration (Cmax) of GI-102	Based on the concentration vs time profile by dose level	Study Day 1, assessed up to approximately 24 months
Half-life of GI-102 (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-102	Based on the concentration vs time profile by dose level	Study Day 1, assessed up to approximately 24 months
Clearance of GI-102	Based on the concentration vs time profile by dose level	Study Day 1, assessed up to approximately 24 months
Volume of distribution (Vd) of GI-102 after administration	Based on the concentration vs time profile by dose level	Study Day 1, assessed up to approximately 24 months
Objective Response Rate (ORR) (dose escalation phase of Part A and B)	ORR is defined as the percentage of participants with investigator-assessed objective response of complete response (CR) or partial response (PR). PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. CR was defined as disappearance of all target and non-target lesions and normalization of tumor marker levels (as applicable to non-target lesions).	Study Day 1, assessed up to approximately 24 months
Incidence and nature of Dose-Limiting Toxicity (DLTs) (dose optimization phase of Part A, dose expansion phase of Part B, Part C and D)	A DLT is defined as a clinically significant AE (classified according to the NCI CTCAE version 5) or significant laboratory abnormality that occur during the DLT assessment periods, during dose escalation and dose expansion, and is considered by the Investigator to be related to GI-102.	Study Day 1, assessed up to DLT period (3 weeks after treatment)
Incidence, nature, and severity of adverse events (AEs) and immune-related AEs (irAEs) (dose optimization phase of Part A, dose expansion phase of Part B, Part C and D)	An adverse event (AE) is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as AEs. All AE events will be graded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.	Study Day 1, assessed up to approximately 24 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of anti-GI-102 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
Immunophenotyping of peripheral blood CD4+ T cells	CD4+ T cells in peripheral blood will be assessed by flow cytometry at various time points	Study Day 1, assessed up to approximately 24 months
Immunophenotyping of peripheral blood CD8+ T cells	CD8+ T cells in peripheral blood will be assessed by flow cytometry at various time points	Study Day 1, assessed up to approximately 24 months
Immunophenotyping of peripheral blood Treg cells	Treg cells in peripheral blood will be assessed by flow cytometry at various time points	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, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): May 30, 2023
• Primary Completion (Estimated): November 12, 2025
• Study Completion (Estimated): April 24, 2027

Study Registration Dates

• First Submitted: March 28, 2023
• First Submitted That Met QC Criteria: April 20, 2023
• First Posted (Actual): April 24, 2023

Study Record Updates

• Last Update Posted (Estimated): November 25, 2024
• Last Update Submitted That Met QC Criteria: November 21, 2024
• Last Verified: November 1, 2024

More Information

Terms related to this study

• Keywords: Immunotherapy; Bevacizumab; Pembrolizumab; Doxorubicin; Eribulin; Paclitaxel; IL-2; Interleukin-2; CTLA-4; T-DXd; Trastuzumab deruxtecan; CD80-IgG4 Fc-IL2 variant; immunocytokine; CD80; GI-102; bispecific protein
• Additional Relevant MeSH Terms: Urogenital Diseases; Urogenital Neoplasms; Neoplasms by Site; Male Urogenital Diseases; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Adenocarcinoma; Urologic Neoplasms; Kidney Neoplasms; Neoplasms, Connective and Soft Tissue; Neoplasms; Carcinoma; Carcinoma, Renal Cell; Sarcoma; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Antibiotics, Antineoplastic; Antineoplastic Agents; Immunologic Factors; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Topoisomerase Inhibitors; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Immunoconjugates; Trastuzumab; Bevacizumab; Trastuzumab deruxtecan; Pembrolizumab; Doxorubicin; Paclitaxel
• Other Study ID Numbers: GII-102-P101; KEYNOTE-G08, MK3475-G08 (Other Identifier: Merck Sharp & 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
• product manufactured in and exported from the U.S.: No