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)
Conditions
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
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.
Interventions
DRUGGI-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).
DRUGGI-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).
DRUGdoxorubicin
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.
DRUGbevacizumab
Bevacizumab will be administered intravenously at a dose of 10 mg/kg every 2 weeks.
DRUGpaclitaxel
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.
DRUGeribulin
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.
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.
DRUGpembrolizumab
pembrolizumab will be administered at a dose of 200 mg as IV infusion Q3W.
Sponsors
Merck Sharp & Dohme LLC
GI Innovation, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence and nature of Dose-Limiting Toxicity (DLTs) (dose escalation phase of Part A and B) | Study Day 1, assessed up to DLT period (3 weeks after treatment) | 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. |
| Objective Response Rate (ORR) (dose optimization phase of Part A, dose expansion phase of Part B, Part C and D) | Study Day 1, assessed up to approximately 24 months | 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). |
| Incidence, nature, and severity of adverse events (AEs) and immune-related AEs (irAEs) (dose escalation phase of Part A and B) | Study Day 1, assessed up to approximately 24 months | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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) | Study Day 1, assessed up to approximately 24 months | 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. |
| Disease Control Rate (DCR) | Study Day 1, assessed up to approximately 24 months | 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. |
| Duration of objective response (DoR) | Study Day 1, assessed up to approximately 24 months | 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. |
| Progression-free survival (PFS) | 6-month, 12-month, and 18-month | 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 |
| Objective Response Rate (ORR) (dose escalation phase of Part A and B) | Study Day 1, assessed up to approximately 24 months | 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). |
| Incidence and nature of Dose-Limiting Toxicity (DLTs) (dose optimization phase of Part A, dose expansion phase of Part B, Part C and D) | Study Day 1, assessed up to DLT period (3 weeks after treatment) | 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. |
| Half-life of GI-102 (T1/2) | Study Day 1, assessed up to approximately 24 months | Based on the concentration vs time profile by dose level |
| Area under the plasma concentration versus time curve (AUC) of GI-102 | Study Day 1, assessed up to approximately 24 months | Based on the concentration vs time profile by dose level |
| Clearance of GI-102 | Study Day 1, assessed up to approximately 24 months | Based on the concentration vs time profile by dose level |
| Volume of distribution (Vd) of GI-102 after administration | Study Day 1, assessed up to approximately 24 months | Based on the concentration vs time profile by dose level |
| Overall survival (OS) | 12-month and 18-month | OS is defined as the time from the first study treatment to death from any cause |
| Peak plasma concentration (Cmax) of GI-102 | Study Day 1, assessed up to approximately 24 months | Based on the concentration vs time profile by dose level |
Other
| Measure | Time frame | Description |
|---|---|---|
| Incidence of anti-GI-102 antibody (ADA) and neutralizing antibody (Nab) | Study Day 1, assessed up to approximately 24 months | Serum will be assessed for the presence of ADA and Nab based on the appropriate assay. |
| Immunophenotyping of peripheral blood Treg cells | Study Day 1, assessed up to approximately 24 months | Treg cells in peripheral blood will be assessed by flow cytometry at various time points |
| Immunophenotyping of peripheral blood CD8+ T cells | Study Day 1, assessed up to approximately 24 months | CD8+ T cells in peripheral blood will be assessed by flow cytometry at various time points |
| Immunophenotyping of peripheral blood CD4+ T cells | Study Day 1, assessed up to approximately 24 months | CD4+ T cells in peripheral blood will be assessed by flow cytometry at various time points |
Countries
South Korea, United States
Contacts
Primary ContactJay Kim
Backup ContactWoosun Lee
Outcome results
None listed