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)

Official title

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)

Overview

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.

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.

Interventions

• 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).
• 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 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.
• 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.
• 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.
• 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.
• Drug pembrolizumab
  pembrolizumab will be administered at a dose of 200 mg as IV infusion Q3W.
• 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).

Primary outcome measures

• Incidence and nature of Dose-Limiting Toxicity (DLTs) (dose escalation phase of Part A and B) [Time frame: 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) [Time frame: 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) [Time frame: Study Day 1, assessed up to approximately 24 months]

Secondary outcome measures (12)

• Objective Response Rate (ORR) (dose escalation phase of Part A and B) [Time frame: 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) [Time frame: 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) [Time frame: Study Day 1, assessed up to approximately 24 months]
• Disease Control Rate (DCR) [Time frame: Study Day 1, assessed up to approximately 24 months]
• Duration of objective response (DoR) [Time frame: Study Day 1, assessed up to approximately 24 months]
• Progression-free survival (PFS) [Time frame: 6-month, 12-month, and 18-month]
• Overall survival (OS) [Time frame: 12-month and 18-month]
• Peak plasma concentration (Cmax) of GI-102 [Time frame: Study Day 1, assessed up to approximately 24 months]
• Half-life of GI-102 (T1/2) [Time frame: Study Day 1, assessed up to approximately 24 months]
• Area under the plasma concentration versus time curve (AUC) of GI-102 [Time frame: Study Day 1, assessed up to approximately 24 months]
• Clearance of GI-102 [Time frame: Study Day 1, assessed up to approximately 24 months]
• Volume of distribution (Vd) of GI-102 after administration [Time frame: Study Day 1, assessed up to approximately 24 months]

Eligibility criteria

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.

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Sequential

Masking

Open label

Primary purpose

Treatment

Study locations

South Korea · 6 centers

• Seoul National University Hospital — Seoul
• St. Vincent's Hospital — Suwon
• Yonsei University Health System, Severance Hospital — Seoul
• Yonsei University Health System, Severance Hospital — Seoul
• Asan Medical Center — Seoul
• Samsung Medical Center — Seoul

United States · 5 centers

• Mayo Clinic in Arizona — Scottsdale
• Mayo Clinic in Florida — Jacksonville
• Mayo Clinic in Minnesota — Rochester
• Memorial Sloan-Kettering Cancer Center — New York
• Cleveland Clinic — Cleveland

Identifiers

NCT: NCT05824975 · GII-102-P101 · KEYNOTE-G08, MK3475-G08

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗