Delving into the Latest Updates on OPB-111077 with Synapse

PURPOSEThe signal transducer and activator of transcription 3 (STAT3) signaling pathway might be a promising therapeutic target for hepatocellular carcinoma (HCC).MATERIALS AND METHODSThis study was a multicenter, open-label, non-comparative, dose escalating phase I study of OPB-111077, an oral STAT3 inhibitor, in patients with advanced HCC who failed on sorafenib. Continuous dosing (daily administration, 50 to 400 mg) and intermittent dosing (4-days on/3-days off administration: 300 to 900 mg) regimens were evaluated and the dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), and recommended dose (RD) were the primary endpoints.RESULTSA total of 33 patients (19 for continuous dosing and 14 for intermittent dosing) were enrolled. One patient experienced a DLT with grade 3 dizziness, but the MTD was identified in neither the continuous nor the intermittent dosing cohorts. The RDs were determined to be 250 mg for the continuous dosing regimen and 600 mg for the intermittent dosing regimen. There was no treatment-related death; five patients (15.2%) had grade 3-4 toxicities including thrombocytopenia (6%), fatigue (3%), and dizziness (3%). No patients achieved complete or partial responses and the median progression-free survival was 1.4 months (95% confidence interval, 0.8 to 2.8).CONCLUSIONOPB-111077 was well tolerated in patients with advanced HCC after sorafenib failure, but only showed limited preliminary efficacy outcomes. Further investigation of the role of the STAT3 signaling pathway in HCC and the development of biomarkers for STAT3 inhibitors are warranted.

01 Jun 2018·The Oncologist

A First-in-Human Phase I Study of OPB-111077, a Small-Molecule STAT3 and Oxidative Phosphorylation Inhibitor, in Patients with Advanced Cancers

Article

Author: Lin, Chester ; Rasco, Drew ; Flaherty, Keith ; Tolcher, Anthony ; Elekes, Agnes ; Ohi, Naoto ; Berlin, Jordan ; Smith, Lon ; Patnaik, Amita ; Kostic, Dusan ; Witzig, Thomas ; Rock, Edwin ; Habermann, Thomas ; Cote, Gregory M. ; Bullock, Andrea ; Shapiro, Geoffrey I. ; Papadopoulos, Kyriakos P.

AbstractLessons LearnedOPB-111077 is a novel inhibitor of STAT3 and mitochondrial oxidative phosphorylation that exhibited promising anticancer activity in preclinical models. In this first-in-human phase I study of OPB-111077 in unselected advanced cancers, treatment-emergent adverse events, most frequently nausea, fatigue, and vomiting, were generally mild to moderate in intensity and could be medically managed. Overall, only modest clinical activity was observed after OPB-111077 given as monotherapy. Notable antitumor activity was seen in a subject with diffuse large B-cell lymphoma.BackgroundOPB-111077 is a novel inhibitor of STAT3 and mitochondrial oxidative phosphorylation with promising anticancer activity in preclinical models.MethodsOpen-label, phase I trial of OPB-111077 in advanced cancers with no available therapy of documented benefit. Initial dose escalation in unselected subjects was followed by dose expansion. Patients received oral OPB-111077 daily in 28-day cycles until loss of clinical benefit.ResultsEighteen subjects enrolled in dose escalation, and 127 in dose expansion. Dose-limiting toxicities were observed at 300 mg and 400 mg QD; maximum tolerated dose was defined as 250 mg QD. Frequently reported treatment-emergent adverse events (TEAEs) included nausea, fatigue, and vomiting. TEAEs were generally mild to moderate and could be medically managed. OPB-111077 reached micromolar drug concentrations, had an elimination half-life of approximately 1 day, and reached steady-state by day 8. A durable partial response was observed in one subject with diffuse large B-cell lymphoma. Seven subjects with diverse tumor types had stable disease or minor responses for at least eight treatment cycles (224 days).ConclusionOPB-111077 is generally well tolerated, and its pharmacokinetic profile is sufficient for further clinical development. Notable clinical activity was observed in a subject with diffuse large B-cell lymphoma. Overall, modest efficacy was observed against unselected tumors.

Medicine International

Biomarker‑driven phase Ib clinical trial of OPB‑111077 in acute myeloid leukemia

Article

Author: Rojas‑Rudilla, José ; Acuña‑Cruz, Evelyn ; Boluda, Blanca ; Martínez‑Sánchez, Pilar ; Cano, Isabel ; Pérez De Oteyza, Jaime ; Pina, José ; Calbacho, María ; Gorrochategui, Julian ; López‑Muñoz, Nieves ; Ayala, Rosa ; Bergua‑Burgues, Juan-Miguel ; De La Fuente, Adolfo ; Martínez‑López, Joaquín ; Pérez‑Simón, José ; Montesinos, Pau ; Rodriguez‑Veiga, Rebeca ; Ballesteros, Juan ; Paciello Coronel, María ; Primo, Daniel

OPB-111077 is a novel, highly specific oral signal transducer and activator of transcription 3 inhibitor that has exhibited good efficacy against solid and blood cancers, including acute myeloid leukemia (AML), in preclinical models. In the present study, a phase 1b, two-stage, 3+3 dose-escalation clinical trial [dose level (DL)1 of 200 mg/day and DL2 of 250 mg/day on a once daily dose schedule in 28-day cycles] was conducted to assess the maximum tolerated dose (MTD), safety profile and the preliminary antitumor activity of OPB-111077 in patients with high-risk AML. A preliminary preclinical analysis evaluated the anti-proliferative activity of OPB-111077 in 19 patients with AML with a Vivia Biotech ex vivo PharmaFlow precision medicine test. A total of 12 patients were ultimately enrolled in the trial: 5 patients (42%) were treated with DL1, and 7 (58%) were escalated to DL2 of OPB-111077. Dose-limiting toxicities were not observed and the MTD was not reached. In addition, the most frequently reported treatment-emergent adverse events were nausea, vomiting and fatigue. Finally, clinical activity (overall response) was observed in 3 patients (25%). On the whole, the present study demonstrates that OPB-111077 exhibits a good safety and tolerability profile and an acceptable clinical response in patients with high-risk AML. A biomarker-driven design is useful for selecting the study population upfront.

100 Deals associated with OPB-111077

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Diffuse large B-cell lymphoma recurrent	Phase 1	JP	Otsuka Pharmaceutical Co., Ltd.	22 Nov 2019
Diffuse large B-cell lymphoma refractory	Phase 1	JP	Otsuka Pharmaceutical Co., Ltd.	22 Nov 2019
Refractory acute myeloid leukemia	Phase 1	US	Otsuka America Pharmaceutical, Inc.	17 Mar 2017
Relapsing acute myeloid leukemia	Phase 1	US	Otsuka America Pharmaceutical, Inc.	17 Mar 2017
Advanced Hepatocellular Carcinoma	Phase 1	KR	Korea Otsuka Pharmaceutical Co., Ltd.	29 May 2013
Advanced Malignant Solid Neoplasm	Discovery	SG	Otsuka Pharmaceutical Co., Ltd.	22 May 2017
Advanced cancer	Discovery	US	Otsuka Pharmaceutical Development & Commercialization, Inc.	01 Jun 2012
Solid tumor	Discovery	US	Otsuka Pharmaceutical Development & Commercialization, Inc.	01 Jun 2012

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Clinical Result

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT03063944 (ASH2020) Manual	Phase 1	Refractory acute myeloid leukemia First line	-	Decitabine+Venetoclax+OPB-111077	(ruyzyvptfy) = febrile neutropenia 56% wmfmghnqfb (ayouaqqtgk ) View more	Positive	05 Nov 2020
NCT01942083 (Pubmed) Manual	Phase 1	Advanced Hepatocellular Carcinoma	33	OPB-111077 (continuous dosing)	(kbpezuqxso) = rxgshduljw whigvyvfsf (xadhaniqjd )	Negative	01 Apr 2019
NCT01942083 (Pubmed) Manual	Phase 1	Advanced Hepatocellular Carcinoma	33	OPB-111077 (intermittent dosing)	(kbpezuqxso) = ybkotkatpr whigvyvfsf (xadhaniqjd )	Negative	01 Apr 2019
NCT01711034 (Pubmed) Manual	Phase 1	Neoplasms	145	OPB-111077	(grwezbwxil) = TEAEs were generally mild to moderate and could be medically managed. wcdgfcwxep (kjvjfhkhcw )	Positive	01 Jun 2018