Agnes Elekes

Abstract B56: A phase 1, open-label, dose escalation, nonrandomized study to assess the maximum tolerated dose, dose limiting toxicity, and pharmacokinetics of OPB-31121 in subjects with advanced solid tumors.

Background: OPB-31121 is a novel compound exhibiting potent growth inhibition of cancer cell lines in vitro and xenografts in vivo. The exact mechanism of action of OPB-31121 has not been fully characterized, but studies indicate that a major effect is inhibition of STAT3 phosphorylation. STAT3 is frequently activated in a variety of solid and hematologic malignancies and may present an important target for antitumor therapy. Methods: Open-label, non-randomized, multi-center study in subjects with advanced solid tumors, using a 3+3 dose escalation design. OPB-31121 was administered orally for 21 days followed by 7 days rest per cycle (28-day cycle). The starting dose was 50 mg BID with escalations planned until the dose-limiting toxicity (DLT) was reached. The primary endpoint was determination of maximum tolerated dose (MTD). Additional endpoints included safety, pharmacokinetics, and anti-tumor effect of OPB-31121. Results: 30 subjects received treatment with OPB-31121. Most common tumor types were colorectal cancer (15), breast (3) and thyroid (2). Mean age was 55.9 (range 35–80) years and 17 of the patients were female. Most common adverse events (AEs) potentially attributed to treatment were gastrointestinal: nausea (80%), vomiting (73%), diarrhea (63%), anorexia (20%), and constipation (17%). Most AEs were CTCAE grades 1–2 and manageable with supportive treatment. Three DLTs were observed: one at 300 mg BID (grade 3 lactic acidosis), and two at 350 mg BID (a grade 3 diarrhea and a grade 3 vomiting); the MTD was 300 mg BID. All patients recovered from DLTs after discontinuing the drug. Six additional (9 total) subjects discontinued during the first cycle. Eight subjects completed only one cycle and 13 completed two cycles. No objective responses were observed. Disease progression was observed in all evaluable patients at first restaging. Pharmacokinetic measurements showed low and transient plasma levels of OPB-31121. Inter-patient variability was high. Exposure was low - area-under-the-curve (AUC) values were 2–3 orders of magnitude lower than those measured at active doses in mouse models. Analysis of metabolites in plasma samples indicates extensive CYP3A4 metabolism and suggests a large first-pass effect in humans, which had not been observed in rodents. Conclusions: OPB-31121 does not show potential as a therapeutic option for most malignancies. The extensive first-pass metabolism and dose-limiting gastrointestinal AEs limit the level of systemic exposure that can be achieved with this agent. Further studies may be warranted in cancers of organs where local concentrations of the compound may be higher (e.g., liver) and an exploratory study in hepatocellular carcinoma is ongoing in Asia. Because STAT3 remains an attractive antitumor target, chemically related compounds with similar pharmacologic activities are currently being evaluated preclinically. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B56.

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

Abstract Lessons Learned. OPB‐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. Background. OPB‐111077 is a novel inhibitor of STAT3 and mitochondrial oxidative phosphorylation with promising anticancer activity in preclinical models. Methods. Open‐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. Results. Eighteen 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). Conclusion. OPB‐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.

Abstract B118: A phase 1, open-label multiple dose escalation trial to determine safety and tolerability of once daily OPB-111077 in subjects with advanced cancer

Background: OPB-111077 is a new chemical entity with anticancer activity in vitro and in human tumor xenograft models. The compound modulates STAT3 phosphorylation but has no marked effect on activity of any of 69 tested human tyrosine or serine/threonine kinases. This P1 study evaluated safety, pharmacokinetics, and antitumor activity of OPB-111077 in subjects with advanced cancers. Methods: Primary objectives determined safety, tolerability, and maximum tolerated dose (MTD) of OPB-111077 given orally once daily to subjects with advanced cancer. Secondary objectives included pharmacokinetics (PK) and antitumor activity. In the first 2 cycles of dose escalation, Day 1 dose was followed by 2 days off study therapy for PK. The starting dose was 100 mg once daily. Single subject cohorts with dose level doublings were studied until the first ≥ Grade 2 AE that was possibly drug-related. Then a 3+3 design was used. After MTD determination, expansion cohorts were opened for subjects with malignancies possibly susceptible to inhibition by OPB-111077, including breast, cervical, colorectal, gastric, kidney, myeloma, non-small cell lung, non-Hodgkin9s lymphoma, ovarian, and prostate cancers, as well as “rare tumors” for which STAT3 inhibition might generate clinical activity. Results: Overall 145 subjects received OPB-111077. Mean age was 61 years (range 21-88), and 51% of subjects were female. Dose escalation occurred in 18 subjects. Four DLTs were observed: 2 at 400 mg QD (G3 nausea/vomiting), and 2 at 300 mg QD (G3 vertigo and G3 nausea/vomiting). The MTD was 250 mg QD. All subjects recovered from DLTs after drug discontinuation. Adverse events (AEs) that may be attributable to OPB-111077 include nausea (71%), vomiting (46%), fatigue (44%), dizziness/vertigo (26%), and hypothyroidism (19%). Most AEs were CTCAE Grades 1 or 2 and manageable with supportive treatment. OPB-111077 exposures increase dose proportionally and linearly with increasing single and multiple doses up to 250 mg. Median time to peak plasma concentration (tmax) is about 4 hours. Mean maximum plasma concentration (Cmax) is 16 μmol/L and mean trough concentration is 6 μmol/L after multiple doses of 250 mg QD. Terminal half-life is about 23 hours and steady state was reached by about 1 week. The major metabolites in plasma are pharmacologically inactive and unlikely to contribute to efficacy. Administration with a high fat meal did not significantly alter OPB-111077 bioavailability. Expansion cohorts enrolled 127 subjects, including NSCLC (13), breast (13), ovarian (11), kidney (11), colorectal (10), prostate (8), lymphoma (8), gastric (7), cervical (3) cancers, and myeloma (1). Rare tumors with STAT rationale included sarcomas (13), neuroendocrine tumors (7), squamous cell carcinomas (5), other carcinomas (12), and other malignant tumors (5). One RECIST Partial Response occurred in a subject with Diffuse Large B Cell Lymphoma. In addition, 7 subjects with had stable disease for at least 8 treatment cycles, including gastric (2), cholangiocarcinoma, kidney, prostate, K-Ras mutant colon cancer, and esthesioneuroblastoma. Conclusions: OPB-111077 can be given safely and achieves clinically active drug levels in humans. Single agent clinical activity was observed. Translational work is ongoing to determine factors driving clinical activity Citation Format: Gregory Cote, Kyriakos Papadopoulos, Amita Patnaik, Drew Rascoe, Lon Smith, Andrea Bullock, Keith Flaherty, Geoffrey Shapiro, Jordan Berlin, Manish Monga, Thomas Habermann, Thomas Witzig, Chester Lin, Lin-Feng Tsai, Agnes Elekes, Naoto Ohi, Kunihiko Tatsumi, Anthony Tolcher. A phase 1, open-label multiple dose escalation trial to determine safety and tolerability of once daily OPB-111077 in subjects with advanced cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B118.