A phase 1 trial in progress for in situ immunomodulation with CDX-301, radiation therapy, poly-ICLC, and CDX-1140 in patients with unresectable and metastatic solid tumors.
Authors: Ito Fumito , Bian Shelly , Lim Andrew S. , Jayachandran Priya , Sterrenberg Danielle R. , Roussos Torres Evanthia T. , Wallace William Dean , Vergara Rowena O. , Carr Azadeh A. , Siegel Emily L. , Woodworth Amanda M. , Yoo Stella , Nelson Maria E. , Sener Stephen Francis , Ling Diane C. , Stewart Daphne B. , Spicer Darcy V. , Hu James S , In Gino Kim , Ye Jason C. 
Published: July 2024

TPS2697 Background: The prognosis for patients with unresectable and metastatic solid tumors that progress on standard of care therapy remains poor due to limited treatment options. Compelling evidence suggests that the induction and activation of tumor-residing conventional type-1 dendritic cells (cDC1) is critical to elicit anti-tumor immunity. Recently, we have demonstrated that a combinatorial regimen comprised of in situ delivery of Fms-like tyrosine kinase 3 ligand (Flt3L), radiation therapy (9Gy), and dual TLR3/CD40 stimulation 1) mobilizes cDC1 to the tumor microenvironment; 2) induces maturation of cDC1; 3) facilitates trafficking of cDC1 carrying tumor antigens to tumor-draining lymph nodes; 4) elicits de novo adaptive T cell immunity; 5) triggers regression of primary tumors, as well as non-irradiated distant tumors; and 6) develops tumor-specific systemic immunological memory using multiple syngeneic orthotopic murine models (1-4). Based on results from preclinical studies, we have initiated a phase 1 study as below. Methods: This is a phase 1 study of in situ immunomodulation with CDX-301 (Flt3L), radiation therapy, CDX-1140 and Poly-ICLC (dual CD40/TLR3 stimulation) in patients with unresectable and metastatic solid tumors. Eligibility for this study includes patients ≥ 18 yrs who have clinically or pathologically confirmed diagnosis of unresectable and metastatic melanoma, cutaneous squamous cell carcinoma, Merkel cell carcinoma, high-grade bone and soft tissue sarcoma or HER2/neu (-) breast cancer with no curative treatment options, and progressed on at least one line of standard systemic therapy. The unresectable disease to be irradiated and injected with medications must be located in breast, dermal, subcutaneous, or soft tissue, or lymph nodes with the longest axis of the tumor 2-7 cm, and should be considered safe for injection by the investigator. The metastatic disease must be measurable per irRECIST criteria. Patients will be treated with daily intratumoral injection of CDX-301 for 5 days (Day 1-5), radiation therapy (9Gy, Day 8) followed by administration of CDX-1140 and Poly-ICLC (Day 9). Up to 4 cycles of this combination therapy can be given every 3 weeks. The primary endpoints are safety/tolerability and to evaluate the MTD of for injection (intratumoral in the cohort A and intratumoral and intravenous in the cohort B) of CDX-1140. A standard 3+3 design, allowing for dose de-escalation, will be used within each cohort. Secondary endpoints are to evaluate immune signatures in blood and the tumor. This phase 1 trial opened to enrollment at the University of Southern California Norris Comprehensive Cancer Center in January 2023 (recruitment is currently 4 on February 6, 2024). 1. Nature Communications 2020. 2. J. Immunology 2021. 3. Cancer Research 2021. 4. Scientific Reports 2022. Clinical trial information: NCT04616248 .