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Regular and Young Investigator Award Abstracts
Clinical Trials In Progress
678 A phase 1 study of GIGA-564, a minimally blocking anti-CTLA-4 monoclonal antibody
  1. Jason M Redman1,
  2. Kacy Stadtmiller2,
  3. Michael A Asensio2,
  4. Lisa Cordes1,
  5. Erica Redmond1,
  6. Jennifer Marte1,
  7. Renee Leong3,
  8. Dara Bracken-Clarke4,
  9. Elisabetta Xue4,
  10. Olga Titova5,
  11. Edward Garmey6,
  12. Carl Millward7,
  13. Kim Hanna8,
  14. Erica L Stone9 and
  15. James L Gulley1
  1. 1National Cancer Institute, Bethesda, MD, USA
  2. 2GigaGen, San Carlos, CA, USA
  3. 3GigaGen, South San Francisco, CA, USA
  4. 4National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
  5. 5Grifols, San Diego, CA, USA
  6. 6CMO Consulting, Concord, MA, USA
  7. 7Grifols, San Carlos, CA, USA
  8. 8Grifols, Durham, NC, USA
  9. 9GigaGen, San Diego, CA, USA

  • Journal for ImmunoTherapy of Cancer (JITC) preprint. The copyright holder for this preprint are the authors/funders, who have granted JITC permission to display the preprint. All rights reserved. No reuse allowed without permission.

Abstract

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

  1. 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).

http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/.

https://doi.org/10.1136/jitc-2024-SITC2024.0678

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