Phase I Study of OPB-31121, an Oral STAT3 Inhibitor, in Patients with Advanced Solid Tumors

다국어 초록 (Multilingual Abstract)

Purpose OPB-31121 is an oral STAT3 inhibitor with a good preclinical antitumor activity. This phaseI dose-escalation study of OPB-31121 was conducted to determine maximum-tolerateddose (MTD), safety, pharmacokinetics, and preliminary antitumor efficacy in patients withadvanced solid tumors.

Materials and MethodsPatients received OPB-31121 once daily for 28 days of each cycle followed by 2 weeks rest.

A standard 3+3 design was used for dose-escalation. Safety and response were evaluatedby the National Cancer Institute–Common Terminology Criteria for Adverse Events (NCICTCAE)ver. 3.0 and Response Evaluation Criteria in Solid Tumor (RECIST) ver. 1.0, respectively.

ResultsTwenty-five patients were treated with OPB-31121 at five dose levels: 100 mg (n=4), 200mg (n=3), 400 mg (n=3), 600 mg (n=7), and 800 mg (n=8). Seven patients discontinuedtreatment during cycle 1 for various reasons other than study drug-related adverse events.

Among 18 patients who were evaluable for dose-limiting toxicity (DLT), three DLTs wereobserved: one DLT (grade 3 vomiting) at 600 mg and two DLTs (grade 3 vomiting, grade 3diarrhea) at 800 mg. The MTD was determined as 800 mg/day. Common adverse eventswere gastrointestinal adverse event including nausea (84%), vomiting (80%), and diarrhea(72%). Pharmacokinetics did not demonstrate dose-proportionality of OPB-31121. Eightpatients had stable disease and 10 patients had disease progression. Two patients (1 coloncancer, 1 rectal cancer) showed tumor shrinkage. One gastric cancer patient continuedtreatment up to cycle 13 before disease progression.

ConclusionThis study demonstrates feasibility of STAT3 inhibition in patients with advanced solid tumor.

OPB-31121, at the MTD of 800 mg/day, was safe and relatively well tolerated, and has apreliminary antitumor activity.

참고문헌 (Reference)

1 Calvisi DF, "Ubiquitous activation of Ras and Jak/Stat pathways in human HCC" 130 : 1117-1128, 2006

2 Verstovsek S., "Therapeutic potential of JAK2 inhibitors" 636-642, 2009

3 Yu H, "The STATs of cancer : new molecular targets come of age" 4 : 97-105, 2004

4 Sansone P, "Targeting the interleukin-6/Jak/stat pathway in human malignancies" 30 : 1005-1014, 2012

5 Alvarez JV, "Signal transducer and activator of transcription 3 is required for the oncogenic effects of non-small-cell lung cancer-associated mutations of the epidermal growth factor receptor" 66 : 3162-3168, 2006

6 Mizutani Y, "Sensitization of human renal cell carcinoma cells to cis-diamminedichloroplatinum(II)by anti-interleukin 6monoclonal antibody or anti-interleukin 6 receptor monoclonal antibody" 55 : 590-596, 1995

7 Yu H, "STATs in cancer inflammation and immunity : a leading role for STAT3" 9 : 798-809, 2009

8 Lin L, "STAT3 is necessary for proliferation and survival in colon cancer-initiating cells" 71 : 7226-7237, 2011

9 Morikawa T, "STAT3 expression, molecular features, inflammation patterns, and prognosis in a database of 724 colorectal cancers" 17 : 1452-1462, 2011

10 Levy DE, "STAT3 : a multifaceted oncogene" 103 : 10151-10152, 2006

11 Deng JY, "STAT-3 correlates with lymph node metastasis and cell survival in gastric cancer" 16 : 5380-5387, 2010

12 Jove R, "Preface : STAT signaling" 19 : 2466-2467, 2000

13 Bendell JC, "Phase 1, open-label, dose-escalation, and pharmacokinetic study of STAT3 inhibitor OPB-31121 in subjects with advanced solid tumors" 74 : 125-130, 2014

14 Kim MJ, "OPB-31121, a novel small molecular inhibitor, disrupts the JAK2/STAT3 pathway and exhibits an antitumor activity in gastric cancer cells" 335 : 145-152, 2013

15 Motte N, "Mutations in JAK2V617F homologous domain of JAK genes are uncommon in solid tumors" 121 : 2113-2115, 2007

16 Li WC, "Inhibition of growth and metastasis of human hepatocellular carcinoma by antisense oligonucleotide targeting signal transducer and activator of transcription 3" 12 : 7140-7148, 2006

17 Alas S, "Inhibition of constitutive STAT3 activity sensitizes resistant non-Hodgkin's lymphoma and multiple myeloma to chemotherapeutic drug-mediated apoptosis" 9 : 316-326, 2003

18 Chen J, "Inhibition of STAT3 signaling pathway by nitidine chloride suppressed the angiogenesis and growth of human gastric cancer" 11 : 277-287, 2012

19 Mankan AK, "Inhibiting signal transducer and activator of transcription 3 : rationality and rationale design of inhibitors" 20 : 1263-1275, 2011

20 Gong W, "Expression of activated signal transducer and activator of transcription 3 predicts expression of vascular endothelial growth factor in and angiogenic phenotype of human gastric cancer" 11 : 1386-1393, 2005

21 Grandis JR, "Constitutive activation of Stat3 signaling abrogates apoptosis in squamous cell carcinogenesis in vivo" 97 : 4227-4232, 2000

22 Levine RL, "Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis" 7 : 387-397, 2005

23 Baxter EJ, "Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders" 365 : 1054-1061, 2005

24 James C, "A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera" 434 : 1144-1148, 2005

25 Kralovics R, "A gain-of-function mutation of JAK2 in myeloproliferative disorders" 352 : 1779-1790, 2005