Interim open-label phase 1 results of misetionamide (GP-2250): A small molecule antineoplastic targeting three major transcription factors.

Abstract

4177 Background: GP-2250 is a novel antineoplastic agent demonstrating effective activity on preclinical pancreatic cancer models alone or in combination with gemcitabine, and inhibits c-MYC, NFκB, and HIFα in cancer cells at clinically achievable concentrations. This open-label phase 1 trial (NCT03854110) evaluates the safety and tolerability of escalating doses of GP-2250 in combination with gemcitabine as a second-line treatment in adults with advanced pancreatic adenocarcinoma that experienced disease progression with 5-FU based chemotherapy. Methods: GP-2250 dose escalation (starting dose 250 mg escalating up to 40 g IV once weekly) followed a Bayesian Optimal Interval design which transitioned to a 3+3 design. A 1-week run-in of GP-2250 was followed by a full cycle (3 weeks on, 1 week off) of GP-2250 plus gemcitabine treatment for each of 11 dose cohorts. Single-patient cohorts with 100% escalation between cohorts were enrolled until the first DLT (or cohort 4), followed by 3 patient cohorts with 35%−45% escalation between cohorts. The DLT assessment period was 5 weeks at each dose. Patients were treated until disease progression or development of unacceptable toxicity. Primary endpoints were safety and tolerability of GP-2250 monotherapy and in combination with gemcitabine. Secondary and exploratory endpoints were preliminary efficacy, pharmacokinetics, and pharmacodynamic blood markers. Results: To date, 52 patients have been enrolled. Five serious adverse events were reported in 3 patients (2 CVAs, pneumonia, and abdominal and flank pain in 2 patients), none attributed to GP-2250. Three patients discontinued treatment: 1 disease hyperprogression (at 11 g GP-2250) and 2 neutropenia (at 21 g GP-2250), with only 1 event of grade 3 neutropenia “possibly” attributed to GP-2250. In summary, the addition of GP-2250 did not significantly alter the safety and tolerability expected of gemcitabine alone. Twelve patients (23%) had progression-free survival (PFS) of ≥16 weeks, or twice as long as historical gemcitabine treatment alone; 7 patients (13%) had PFS of 24 weeks, and 4 (8%) had PFS of 32 weeks. One patient survived > 2 years while receiving treatment. Seventeen patients (33%) achieved stable disease and 6 (12%) achieved a partial response by RECIST criteria. While the blood half-life of GP-2250 is ~5 hours, mTOR and AKT biomarker data indicate that the biological half-life is longer, at 4–5 days. These data are within the concentrations and times required for cytotoxicity in all cancer cell lines tested with GP-2250. Conclusions: GP-2250/gemcitabine combination therapy showed encouraging safety and tolerability and favorable PFS outcomes compared to gemcitabine alone. These promising results in a historically difficult to treat pancreatic cancer population warrant progress to later-stage studies. This study is funded by Geistlich Pharma AG. Clinical trial information: NCT03854110 .