A phase I dose-escalation study of NKP-1339 in patients with advanced solid tumors refractory to treatment.

Abstract

2607 Background: NKP-1339 is a novel transferrin targeted ruthenium based anti-cancer compound which is intravenously administered. Its intracellular targets include GRP78, a key regulator of misfolded protein processing. In nonclinical anti-tumor studies, NKP-1339 showed activity against different tumor types, including those resistant to platinum and other standard anti-cancer agents. This Phase I trial evaluates the safety, tolerability, maximum tolerated dose, pharmacokinetics, and pharmacodynamics of NKP-1339. Methods: NKP-1339 is administered as a 30-90 minute infusion (based on volume to be infused) on days 1, 8, and 15 of a 28 day cycle. Full PK sampling in blood and urine is performed on Day 1; trough plasma and urine samples are obtained predose on Cycle 1 Day 8 and Cycle 2 Day 1. PD samples, including transferrin, transferrin receptor, ferritin, serum iron, and TIBC are also collected. Results: A total of 16 patients with various solid tumors have been treated at 6 different dose levels (20, 40, 80, 160, 320, and 420 mg/m2). Tumor types represented in this population include: lung (5); neuroendocrine (3); colon (4) and 1 each of ovarian, cervical, pancreatic, and head and neck cancer. All patients have a performance score of 0 or 1. Demographics: 7 female /9 male; 14 white /2 black; median age 63.5 years (range 51 to 75). At 420 mg/m2 an unusual finding of a transient green discoloration to the plasma in the absence of clinical jaundice or other signs/symptoms has been noted. This is probably due to the complex chemical state of ruthenium in plasma. Unrelated to the plasma discoloration, Grade 1-2 pyrexia and/or rigors has been observed in 2 of 5 patients at the 420 mg/m2 dose level, but has been prevented in subsequent infusions with steroid-based premedications. Preliminary PK results on the first 16 patients show dose proportionality of Cmax and AUC 0-192 (AUC of first dosing interval). Two patients with Stage IV neuroendocrine tumors have experienced stable disease for up to 9 cycles. Conclusions: Promising anti-cancer activity in neuroendocrine tumors has been observed with this novel ruthenium based compound. The toxicity profile is manageable and the PK profile is consistent with preclinical predictions.