First-in-human (FIH) trial evaluating immune activation and safety of PIN- 2 administered intravenously to patients with advanced solid tumors.

Abstract

2600 Background: Innate immunity is an integral component necessary to initiate systemic anti-tumor immunity in patients with progressive malignancy. PIN-2 is a novel immunomodulating agent derivatized from a transactivator (Tat) protein that stimulates innate immunity in vivo by promoting differentiation of peripheral blood monocytes into activated APC’s linking the innate and adaptive immune systems resulting in endogenous T-cell priming against a multitude of tumor associated antigens unique to the individual. Methods: A FIH clinical trial was conducted in patients (pts) with extensively pretreated solid tumors to evaluate the pharmacodynamics (PD) and safety of PIN-2. 8 pts (2 men), mean age 62.7 (±7.9) years, and a median of 4.5 prior treatment lines, were enrolled in 2 Australian centers. 2 pts received 1 cycle of treatment and 6 received 2 cycles. Pts were given 300 µg of PIN-2 IV 3 times/wk for 2 wks followed by a 1 wk rest period. A 2nd cycle of treatment was offered based on pt and investigator preference. Plasma was collected at 6 and 24H post-infusion 1 to evaluate immune activation. Th1 cytokines (TNF-α, IFN-γ, IL-12, CSF-2) were analyzed to assess PD activity. Results: A significant increase in TNF-α was seen 6H following PIN-2 infusion (p = 0.0142), demonstrating rapid onset of immune activation. There were no clear changes in the other parameters evaluated. PIN-2 was rapidly cleared from plasma, with mean T1/2 = 24.0 (8.07) min, Tmax = 1.06 (0.665) min, Cmax= 77,500 (61,600) pg/mL, and AUC0-inf = 690,000 (493,000) pg•min/mL. 3 pts discontinued treatment, 2 for adverse events (1 gr 2 infusion reaction, 1 unrelated SAE of abdominal pain) and 1 for disease progression on day 12. Treatment related AEs were grade 1 and 2, and readily managed. There was a single unrelated gr 3 event (anemia) and no AEs > gr3. 2 pts developed anti-drug antibodies; however, these did not result in changes in the immuno-PD profile. Conclusions: PIN-2 was generally well tolerated with an acceptable safety profile. PIN-2 caused an early increase in TNF-α, consistent with PD activity predicted by preclinical data. Further study alone and in combination with other agents in pts with advanced solid tumors is warranted. Clinical trial information: ACTRN12617001597381.