First In-Human Phase I Trial of NHS-IL12 in Subjects With Metastatic Solid Tumors
- Interleukin-12 (IL-12) is a proinflammatory cytokine produced by activated phagocytes
and dendritic cells (DCs) that plays a critical role in regulating the transition from
innate to adaptive immunity.
- IL-12 has shown some promising clinical activity in phase I trials, including
stabilization of disease in renal cancer patients with partial regression of a
metastatic lesion, but has not proceeded further in clinical development due to
- The NHS-IL12 concept is a strategy to reduce the toxicity associated with systemic
administration of recombinant human IL-12 by selectively targeting delivery to tumors.
The NHS-IL12 immunocytokine is composed of 2 IL-12 heterodimers, each fused to one of the
H-chains of the NHS76 antibody, which has affinity for both single- and double-stranded DNA.
Thus, NHS-IL12 targets delivery to regions of tumor necrosis where DNA has become exposed.
- To determine the dose-limiting toxicities (DLTs) and Maximum Tolerated Dose (MTD) of
NHS-IL12 administered subcutaneously as a onetime dose in patients with metastatic or
locally advanced solid epithelial or mesenchymal tumors
- Secondary objectives include exploring the pharmacokinetics, immunogenicity and immune
response of subcutaneously administered NHS-IL12. Based on analysis of immune response,
in a preliminary fashion in two expansion cohorts after repeated treatments, the tumor
response (irRC) and progression free survival and overall survival will be described.
- Adults with histologically or cytologically proven metastatic or locally advanced solid
epithelial or mesenchymal tumors, except unstable brain metastases, for which standard
curative or palliative measures do not exist or are no longer effective.
- Adequate organ function as defined by liver, kidney, and hematologic laboratory
- Patients with acquired immune defects, systemic autoimmune disease, history of organ
transplant, history of chronic infections, or history of active inflammatory bowel
disease will be excluded.
- This is a phase I, open-label, dose-escalation study designed to assess the safety,
tolerability, PK, and biological and clinical activity of NHS-IL12. Goals are to
determine the MTD of a single dose NHS-IL12 and to define the biologically optimal
- Patients will be enrolled in cohorts of 3 to 6 patients using a standard 3+3 approach
until MTD is reached.
- The trial will include a planned schedule-optimization amendment with up to 12 patients
at each of the 2 dose levels that are of greater biologic interest (MTD and dose below
MTD), which will be submitted as soon as a clear biological response (changes in
circulating cytokine levels) is measured in at least 3 patients at a given dose level.
- With a maximum accrual ceiling of 78 participants, this study will be completed within
2-3 years, enrolling up to 2 participants per month.
Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
To determine the dose-limiting toxicities (DLTs) and Maximum Tolerated Dose (MTD) of NHS-IL12 administered subcutaneously as a onetime dose in patients with metastatic or locally advanced solid epithelial or mesenchymal tumors.
James L Gulley, M.D.
National Cancer Institute (NCI)
United States: Federal Government
|National Institutes of Health Clinical Center, 9000 Rockville Pike||Bethesda, Maryland 20892|