This phase I trial evaluates the safety and effectiveness of in situ immunomodulation with CDX-301, radiotherapy, CDX-1140 and Poly-ICLC (Cohort A) and these with intravenous (IV) pembrolizumab and subcutaneous (SC) tocilizumab (Cohort B) in treating patients with unresectable and measurable metastatic melanoma, cutaneous squamous cell carcinoma (SCC), basal cell carcinoma (BCC), Merkel cell carcinoma, high-grade bone and soft tissue sarcoma or HER2/neu(-) breast cancer. CDX-301 may induce cross-presenting dendritic cells, master regulators in the immune system. Radiation therapy uses high energy to kill tumor cells and release antigens that may be picked up, processed and presented by cross-presenting dendritic cells. CDX-1140 and Poly-ICLC may activate tumor antigen-loaded,cross-presenting dendritic cells, and generate tumor-specific T lymphocytes, a type of immune cells, that can search out and attack cancers. Giving immune modulators and radiation therapy may stimulate tumor cell death and activate the immune system.
PRIMARY OBJECTIVE: I. To evaluate the safety profile of in situ immunomodulation with CDX-301, radiotherapy, CDX-1140, and Poly-ICLC (Cohort A) and these with pembrolizumab (IV) and tocilizumab (SC) (Cohort B) in unresectable and metastatic melanoma, cutaneous squamous cell carcinoma, basal cell carcinoma, Merkel cell carcinoma, high-grade bone and soft tissue sarcoma or breast cancer patients with injectable palpable disease by determining the maximum tolerated dose (MTD) of CDX-1140 that has an acceptable adverse event profile. SECONDARY OBJECTIVE: I. To evaluate the immune signatures in the tumor microenvironment before and after in situ immunomodulation with CDX-301, radiotherapy, CDX-1140, and Poly-ICLC (Cohort A) and these with pembrolizumab (IV) and tocilizumab (SC) (Cohort B). EXPLORATORY OBJECTIVES: I. To record the overall response rate (ORR) (complete response \[CR\] and partial response \[PR\]) of injected as well as distant uninjected metastatic lesions in metastatic melanoma, cutaneous SCC, basal cell carcinoma, Merkel cell carcinoma, high-grade bone and soft tissue sarcoma or breast cancer patients with injectable palpable disease treated with in situ immunomodulation with CDX-301, radiotherapy, CDX-1140, and Poly-ICLC (Cohort A) and these with pembrolizumab (IV) and tocilizumab (SC) (Cohort B) by immune-related Response Evaluation Criteria In Solid Tumors (irRECIST) response assessment. II. To record the overall survival (OS) and progression free survival (PFS) in unresectable and metastatic melanoma, cutaneous SCC, basal cell carcinoma, Merkel cell carcinoma, high-grade bone and soft tissue sarcoma or breast cancer patients with injectable palpable disease treated with in situ immunomodulation with CDX-301, radiotherapy, CDX-1140, and Poly-ICLC (Cohort A) and these with pembrolizumab (IV) and tocilizumab (SC) (Cohort B). III. Examine changes in the levels of T-cell subsets/myeloid derived suppressor cells (MDSC)/cytokines in peripheral blood (PB) of unresectable and metastatic melanoma, cutaneous SCC, basal cell carcinoma, Merkel cell carcinoma, high-grade bone and soft tissue sarcoma or breast cancer patients with injectable palpable disease treated with in situ immunomodulation with CDX-301, radiotherapy, CDX-1140, and Poly-ICLC (Cohort A) and these with pembrolizumab (IV) and tocilizumab (SC) (Cohort B). OUTLINE:Cohort A will evaluate safety of intratumoral administration of CDX-1140 in combination with CDX-301, radiotherapy and Poly-ICLC. Once cohort A is finished, patients will be enrolled to cohort B to evaluate safety of intratumoral + intravenous administration of CDX-1140 in combination with CDX-301, radiotherapy, pembrolizumab, tocilizumab, and Poly-ICLC. COHORT A: Patients receive recombinant Flt3 ligand intratumorally (IT) on days 1-5 and agonistic anti-CD40 monoclonal antibody CDX-1140 IT with Poly-ICLC IT on day 9 or 10. Patients also undergo radiation therapy on day 8 or 9. Treatment repeats every 21 days for 4 cycles in the absence of disease progression or unacceptable toxicity. COHORT B: Patients receive recombinant Flt3 ligand IT on days 1-5 and agonistic anti-CD40 monoclonal antibody CDX-1140 IT and intravenously (IV) over 90 minutes with Poly-ICLC IT on day 9 or 10. Patients also receive pembrolizumab (IV), tocilizumab (SC), as well as undergo radiation therapy on day 8 or 9. Treatment repeats every 21 days for 4 cycles in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 30 days and then every 3-6 months for 2 years.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
14
Given IT
Given IT
Undergo radiation therapy
Given IT
Given IV
Given SC
Los Angeles General Medical Center
Los Angeles, California, United States
USC/Norris Comprehensive Cancer Center
Los Angeles, California, United States
Incidence of adverse events
Time frame: Up to 30 days
Maximum tolerated dose or maximum administered dose
The dose limiting toxicity rate will be estimated by cohort and dose-level (if appropriate) using 90% confidence intervals obtained by Jeffrey's prior method.
Time frame: Up to 30 days
Changes in Immune signatures in the tumor microenvironment
Will examine changes in the immune biomarkers levels from baseline to end of treatment
Time frame: Baseline up to 2 years
Changes in the levels of infiltrating CD4+ and CD8+ T cells
Will examine changes in the levels of infiltrating CD4+ and CD8+ T cells and their proteomic, genomic and transcriptomic signatures in the tumor microenvironment. The immune biomarker levels are treated as continuous variables and will be summarized in the overall sample and within treatment-arm by time-point using the mean and standard error, and graphically using dot-plots.
Time frame: Baseline up to 2 years
Changes in the levels of infiltrating myeloid cell subsets
Will examine changes in the levels of infiltrating myeloid cell subsets including dendritic cells (DCs), macrophages, and monocytes, and their proteomic, genomic and transcriptomic signatures in the tumor microenvironment. The immune biomarker levels are treated as continuous variables and will be summarized in the overall sample and within treatment-arm by time-point using the mean and standard error, and graphically using dot-plots.
Time frame: Baseline up to 2 years
Changes in the levels of PD-L1 expression
Will examine changes in the levels of PD-L1 expression within both neoplastic and nonneoplastic stromal elements of the tumor microenvironment. The immune biomarker levels are treated as continuous variables and will be summarized in the overall sample and within treatment-arm by time-point using the mean and standard error, and graphically using dot-plots.
Time frame: Baseline up to 2 years
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