Phase i trial of the human double minute 2 inhibitor MK-8242 in patients with advanced solid tumors

Andrew J. Wagner, Udai Banerji, Amit Mahipal, Neeta Somaiah, Heather Hirsch, Craig Fancourt, Amy O. Johnson-Levonas, Raymond Lam, Amy K. Meister, Giuseppe Russo, Clayton D. Knox, Shelonitda Rose, David S. Hong

Research output: Contribution to journalArticle

33 Scopus citations

Abstract

Purpose To evaluate MK-8242 in patients with wild-type TP53 advanced solid tumors. Patients and Methods MK-8242 was administered orally twice a day on days 1 to 7 in 21-day cycles. The recommended phase II dose (RP2D) was determined on the basis of safety, tolerability, pharmacokinetics (PK), and by mRNA expression of the p53 target gene pleckstrin homology-like domain, family A, member 3 (PHLDA3). Other objectives were to characterize the PK/pharmacodynamic (PD) relationship, correlate biomarkers with response, and assess tumor response. Results Forty-seven patients received MK-8242 across eight doses that ranged from 60 to 500 mg. Initially, six patients developed dose-limiting toxicities (DLTs): grade (G) 2 nausea at 120 mg; G3 fatigue at 250 mg; G2 nausea and G4 thrombocytopenia at 350 mg; and G3 vomiting and G3 diarrhea at 500 mg. DLT criteria were revised to permit management of GI toxicities. Dosing was resumed at 400 mg, and four additional DLTs were observed: G4 neutropenia and G4 thrombocytopenia at 400 mg and G4 thrombocytopenia (two patients) at 500 mg. Other drug-related G3 and G4 events included anemia, leukopenia, pancytopenia, nausea, hyperbilirubinemia, hypophosphatemia, and anorexia. On the basis of safety, tolerability, PK, and PD, the RP2D was established at 400 mg (15 evaluable patients experienced two DLTs). PK for 400 mg (day 7) showed Cmax 3.07 mM, Tmax 3.0 hours, t1/2 (half-life) 6.6 hours, CL/F (apparent clearance) 28.9 L/h, and Vd/F (apparent volume) 274 L. Blood PHLDA3 mRNA expression correlated with drug exposure (R2 = 0.68; P<001). In 41 patients with postbaseline scans, three patients with liposarcoma achieved a partial response (at 250, 400, and 500 mg), 31 showed stable disease, and eight had progressive disease. In total, 27 patients with liposarcoma had a median progression-free survival of 237 days. Conclusion At the RP2D of 400 mg twice a day, MK-8242 activated the p53 pathway with an acceptable safety and tolerability profile. The observed clinical activity (partial response and prolonged progression-free survival) provides an impetus for further study of HDM2 inhibitors in liposarcoma.

Original languageEnglish (US)
Pages (from-to)1304-1311
Number of pages8
JournalJournal of Clinical Oncology
Volume35
Issue number12
DOIs
StatePublished - Apr 20 2017
Externally publishedYes

    Fingerprint

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Wagner, A. J., Banerji, U., Mahipal, A., Somaiah, N., Hirsch, H., Fancourt, C., Johnson-Levonas, A. O., Lam, R., Meister, A. K., Russo, G., Knox, C. D., Rose, S., & Hong, D. S. (2017). Phase i trial of the human double minute 2 inhibitor MK-8242 in patients with advanced solid tumors. Journal of Clinical Oncology, 35(12), 1304-1311. https://doi.org/10.1200/JCO.2016.70.7117