Clinical trial NCT05824975: 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)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Advanced Solid Tumor
Metastatic Solid Tumor
Soft Tissue Sarcoma (STS)
Platinum-resistant Ovarian Cancer (PROC)
Hepatocellular Carcinoma (HCC)
Colorectal Cancer (CRC)
HER2 Negative Breast Cancer
Cutaneous Melanoma
Renal Cell Carcinoma (RCC)
Keywords: GI-102
CD80-IgG4 Fc-IL2 variant
Immunotherapy
IL-2
Interleukin-2
bispecific protein
immunocytokine
CD80
CTLA-4
Pembrolizumab
T-DXd
Trastuzumab deruxtecan
Doxorubicin
Paclitaxel
Bevacizumab
Eribulin
Lead sponsor: GI Innovation, Inc.
Sponsor class: INDUSTRY
Collaborators: name: Merck Sharp & Dohme LLC
First posted: 2023-04-24
Enrollment: 358
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Incidence and nature of Dose-Limiting Toxicity (DLTs) (dose escalation phase of Part A and B)
timeFrame: Study Day 1, assessed up to DLT period (3 weeks after treatment)
measure: Incidence, nature, and severity of adverse events (AEs) and immune-related AEs (irAEs) (dose escalation phase of Part A and B)
timeFrame: Study Day 1, assessed up to approximately 24 months
measure: Objective Response Rate (ORR) (dose optimization phase of Part A, dose expansion phase of Part B, Part C and D)
timeFrame: Study Day 1, assessed up to approximately 24 months
Secondary outcomes:
measure: Objective Response Rate (ORR) (dose escalation phase of Part A and B)
timeFrame: Study Day 1, assessed up to approximately 24 months
measure: Incidence and nature of Dose-Limiting Toxicity (DLTs) (dose optimization phase of Part A, dose expansion phase of Part B, Part C and D)
timeFrame: Study Day 1, assessed up to DLT period (3 weeks after treatment)
measure: 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)
timeFrame: Study Day 1, assessed up to approximately 24 months
measure: Disease Control Rate (DCR)
timeFrame: Study Day 1, assessed up to approximately 24 months
measure: Duration of objective response (DoR)
timeFrame: Study Day 1, assessed up to approximately 24 months
measure: Progression-free survival (PFS)
timeFrame: 6-month, 12-month, and 18-month
measure: Overall survival (OS)
timeFrame: 12-month and 18-month
measure: Peak plasma concentration (Cmax) of GI-102
timeFrame: Study Day 1, assessed up to approximately 24 months
measure: Half-life of GI-102 (T1/2)
timeFrame: Study Day 1, assessed up to approximately 24 months
measure: Area under the plasma concentration versus time curve (AUC) of GI-102
timeFrame: Study Day 1, assessed up to approximately 24 months
measure: Clearance of GI-102
timeFrame: Study Day 1, assessed up to approximately 24 months
measure: Volume of distribution (Vd) of GI-102 after administration
timeFrame: Study Day 1, assessed up to approximately 24 months
Other outcomes:
measure: Incidence of anti-GI-102 antibody (ADA) and neutralizing antibody (Nab)
timeFrame: Study Day 1, assessed up to approximately 24 months
measure: Immunophenotyping of peripheral blood CD4+ T cells
timeFrame: Study Day 1, assessed up to approximately 24 months
measure: Immunophenotyping of peripheral blood CD8+ T cells
timeFrame: Study Day 1, assessed up to approximately 24 months
measure: Immunophenotyping of peripheral blood Treg cells
timeFrame: Study Day 1, assessed up to approximately 24 months
Locations:
city: Scottsdale
country: United States
facility: Mayo Clinic in Arizona
state: Arizona
city: Jacksonville
country: United States
facility: Mayo Clinic in Florida
state: Florida
city: Rochester
country: United States
facility: Mayo Clinic in Minnesota
state: Minnesota
city: New York
country: United States
facility: Memorial Sloan-Kettering Cancer Center
state: New York
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Seoul
country: Korea, Republic of
facility: Yonsei University Health System, Severance Hospital
city: Seoul
country: Korea, Republic of
facility: Yonsei University Health System, Severance Hospital
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Suwon
country: Korea, Republic of
facility: St. Vincent's Hospital
Study officials:
affiliation: GI Innovation, Inc.
name: Nari Yun, PhD
role: STUDY_DIRECTOR
References: