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.

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Purpose Pamiparib is an investigational, selective, oral poly(ADP-ribose) polymerase 1/2 (PARP1/2) inhibitor that has demonstrated PARP–DNA complex trapping and CNS penetration in preclinical models, as well as preliminary anti-tumor activity in early-phase clinical studies. We investigated whether the single-dose pharmacokinetic (PK) profile of pamiparib is altered by coadministration of a strong CYP3A inducer (rifampin) or a strong CYP3A inhibitor (itraconazole) in patients with solid tumors. Methods In this open-label, phase 1 study, adults with advanced solid tumors received either oral pamiparib 60 mg (days 1 and 10) and once-daily oral rifampin 600 mg (days 3–11) or oral pamiparib 20 mg (days 1 and 7) and once-daily oral itraconazole 200 mg (days 3–8). Primary endpoints included pamiparib maximum observed concentration (Cmax), and area under the plasma concentration–time curve from zero to last quantifiable concentration (AUC0–tlast) and infinity (AUC0–inf). Secondary endpoints included safety and tolerability. Results Rifampin coadministration did not affect pamiparib Cmax (geometric least-squares [GLS] mean ratio 0.94; 90% confidence interval 0.83–1.06), but reduced its AUC0–tlast (0.62 [0.54–0.70]) and AUC0–inf (0.57 [0.48–0.69]). Itraconazole coadministration did not affect pamiparib Cmax (1.05 [0.95–1.15]), AUC0–tlast (0.99 [0.91–1.09]), or AUC0–inf (0.99 [0.90–1.09]). There were no serious treatment-related adverse events. Conclusions Pamiparib plasma exposure was reduced 38–43% with rifampin coadministration but was unaffected by itraconazole coadministration. Pamiparib dose modifications are not considered necessary when coadministered with CYP3A inhibitors. Clinical safety and efficacy data will be used with these results to recommend dose modifications when pamiparib is coadministered with CYP3A inducers.

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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-Hodgkin's 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.