NKP-1339: Maximum tolerated dose defined for first-in-human GRP78 targeted agent.

Abstract

3033 Background: NKP-1339 is a first-in-class small molecule anti-cancer compound that down-regulates GRP78, a key regulator of misfolded protein processing and tumor survival/anti-apoptosis. GRP78 up-regulation occurs in many tumors, and is associated with intrinsic and chemotherapy-induced resistance. Preclinically, single agent NKP-1339 demonstrates activity against multiple tumor types, including chemoresistant lines. This phase I trial evaluates the safety, tolerability, maximum tolerated dose (MTD), pharmacokinetics, and pharmacodynamics (PD) of NKP-1339. Methods: Patients (pts) with advanced solid tumors, adequate organ function, ECOG 0-1 are enrolled. NKP-1339 is infused on day 1, 8, and 15 of 28 day cycles. Single pt cohorts are enrolled until grade 2 toxicity, then adjusted to standard 3+3 design. Doses from 20-780 mg/m2 are evaluated. PD samples for plasma GRP78 are collected. At MTD, an expanded cohort of 25 pts is enrolled. Results: 34 pts are enrolled for dose escalation: 30 evaluable for dose determination; 4 replaced due to tumor progression in cycle 1. Demographics: 19M/15F; median age 62 yrs (range 28 to 79). Tumor types: colorectal (CRC, 10), non-small cell lung (NSCLC, 8); neuroendocrine (NET, 5); head and neck (H&N, 3); and other cancer (8). Dose limiting toxicity of grade (gr) 2-3 nausea, with gr 2 creatinine in 1 pt, occurred at 780 mg/m2; MTD is 625 mg/m2. Gr 1 fever/chills is observed above 420 mg/m2, but is prevented by steroid premedication. The most common drug-related events are gr 1 nausea, gr 1-2 vomiting, and gr 1-2 fatigue. No lab abnormalities were noted except reversible creatinine elevation in 4 pts: 3 pt with gr 1; 1 pt with gr 2 secondary to DLT. Partial response was in 1 pt (NET); stable disease in 7 pts, including NET (2), NSCLC (2), CRC (1), sarcoma (1), and unknown primary (1). Therapy duration 14+-88+ weeks. Soluble GRP78 is detected in the plasma of patients at baseline. Conclusions: NKP-1339is well tolerated with manageable side effects. Single agent activity is noted in multiple tumors including NET. Results from the expanded cohort and pre/post-therapy PD will be presented. Phase II single agent NKP-1339 and phase I NKP-1339 combination trials are planned.