Background
It has been assumed that the primary mechanism of action of first generation anti-CTLA-4 therapies is blocking the interaction between CTLA-4 and its B7 ligands, leading to enhanced T cell costimulation and activity. However, in preclinical studies CTLA-4 mAbs can induce effective anti-tumor activity via an Fc receptor dependent mechanism of action, suggesting that depletion of intratumoral Tregs may be a major mechanism of action of CTLA-4 mAbs. Additionally, there is evidence to suggest that CTLA-4 blockade contributes to the immune related adverse events induced by CTLA-4 mAbs. It is hypothesized, and supported by nonclinical studies, that an anti-CTLA-4 mAb with minimal blocking of CTLA-4 binding to its B7 ligands, such as GIGA-564, may increase efficacy while reducing toxicity compared to first generation anti-CTLA-4 therapies.1 Overall, the data support testing this mechanism of action in patients.
Methods
This is a First-In-Human Phase 1 study of GIGA-564 consisting of Phase 1A dose escalation and Phase 1B dose expansion parts. Participants will receive up to 4 cycles of GIGA-564 on Day 1 of each 3-week cycle. Select eligibility criteria: locally advanced or metastatic solid tumor malignancies ineligible for, refractory to or relapsing after at least one line of standard systemic therapy; ECOG ≤1; and measurable disease. Major exclusion criteria: prior receipt of therapy directed against CTLA-4 and brain metastases with growth after radiotherapy. Phase 1A will enroll up to 5 escalating dose cohorts. Cohort 1 (0.3 mg/kg) will initially enroll 1 participant but will expand to 6 participants if the first experiences a grade ≥2 adverse event. Cohorts 2–5 (1, 3, 10, 20 mg/kg) will enroll in a standard 3+3 design. Phase 1B will expand up to two tolerable doses (10 participants each). Phase 1B requires pre- and on-treatment biopsies if considered low or moderate risk. Primary endpoints: safety and tolerability, identify maximum tolerated dose and recommended Phase 2 dose level(s). Secondary endpoints: characterize preliminary anti-tumor activity (RECISTv1.1) and PK. Exploratory endpoints: characterize preliminary anti-tumor activity (iRECIST) and immunogenicity, and investigate pharmacodynamics.
Trial Registration
NCT06258304.
Reference
Stone E, Carter K, Wagner E. Lack of blocking activity in anti-CTLA-4 antibodies reduces toxicity, but not anti-tumor efficacy. BioRxiv. 2021;07.12.452090.
Ethics Approval
This study was approved by NIH Clinical Centers Institutional Review Board (IRBIRB001776/MOD007447).