First-in-human dose-escalation study of NBF-006, a novel investigational siRNA targeting GSTP, in patients with non-small cell lung, pancreatic, or colorectal cancer.
Authors: Tolcher Anthony W. , Spira Alexander I. , Nemunaitis John J. , Vandross Andrae Lavon , Mamdani Hirva , O'Brien Zhihong , Huynh Annie , Albaugh Zachary , Gullbo Joachim , Zabludoff Sonya 
Published: June 2023

3084

Background: Glutathione S-transferase Pi (GSTP) has an important role in detoxification and anti-oxidative damage response. Additionally, GSTP has a chaperone function which regulates key oncogenic pathways such as the KRAS and JNK pathways. Targeting multiple pathways could lead to more effective therapy than agents inhibiting single downstream kinase pathways (i.e., a MEK inhibitor), as alternative or redundant pathways could compensate for the inhibition of a single kinase. NBF-006 is a novel drug product containing a GSTP siRNA encapsulated within a lipid nanoparticle. It has been designed to deliver siRNA to tumors of the lung and common sites of metastatic spread (liver and marrow) which has been demonstrated in preclinical efficacy models. Methods: NBF-006-001 is a first-in-man (FIM) dose escalation study evaluating safety, tolerability, and PK of NBF-006 administered intravenously over 70 minutes, QW4 followed by a 2-week rest period in patients with advanced non-small cell lung (NSCLC), pancreatic (PANC), or colorectal cancer (CRC). Results: Twenty-one patients (11 NSCLC, 5 CRC, and 5 PANC) received treatment in a standard 3+3 dose escalation design (0.15 mg/kg [n=2], 0.3 mg/kg [n=3], 0.6 mg/kg [n=3], 1.2 mg/kg [n=6], and 1.6 mg/kg [n=7]). NBF-006 was well tolerated with no treatment-related grade 4-5 AEs, SAEs nor DLTs. Only one grade 3 event (WBC decrease) was assessed as possibly related. The most common NBF-006-related AEs were Grade 1 or 2 arthralgia, diarrhea, fatigue, and vomiting (11% each). There was no dose relationship in the number of AEs or any observed AEs. No meaningful complement activation, cytokine elevation nor ADA response has been observed to date (20 patients). One patient had 2 infusion related reactions (Grade 1 and 2). PK analysis indicated a terminal half-life ranging from 26 to 55 hours with no accumulation. Cmax and AUC demonstrated dose-proportionality up to 1.2 mg/kg and no additional increase in exposure at 1.6 mg/kg. NSCLC patients had an average and median number of prior lines of therapy of 4 and 3, respectively, with a range from 1-7 prior lines. One patient with NSCLC (treated at 1.6 mg/kg) experienced a durable partial response and progressed after ten months on the study. Four additional patients with NSCLC experienced stable disease, and two of these stayed on study treatment for >6 months (both treated at 1.2 mg/kg). One patient remains on treatment. CRC and PANC patients had an average/median of 4 and 3 prior lines, respectively. In CRC and PANC, stable disease for 24 weeks was the best response (n=1 each). Conclusions: This FIM study with NBF-006 demonstrated a favorable safety profile with early signs of antitumor activity in NSCLC. No DLTs or treatment-related SAEs were observed. Dose expansion in NSCLC is ongoing and will not be presented. Clinical trial information: NCT03819387 .