Chen Ren

Phase I clinical trial of oral rigosertib in patients with myelodysplastic syndromes.

The multi‐kinase inhibitor rigosertib (ON 01910.Na) induces mitotic arrest and apoptosis in myeloblasts, while sparing normal cells. The purpose of this study was to determine the pharmacokinetic profile, maximum‐tolerated dose (MTD), safety, and clinical activity of an oral formulation of rigosertib in patients with myelodysplastic syndromes (MDS). For pharmacokinetic studies, patients received rigosertib in single escalating weekly doses. To determine the MTD, patient cohorts received escalating doses of rigosertib twice daily for 14 d of a 21‐d cycle. Overall, 37 patients were treated. Rigosertib exposure increased with escalating oral doses. Mean absolute oral bioavailability ranged from 13·9% (fed) to 34·8% (fasting) in 12 patients treated at the 560 mg b.i.d. dose level. Dose‐limiting toxicity (grade 3 dysuria and shortness of breath) occurred at the 700 mg b.i.d. dose. Five patients experienced grade 3 non‐haematological toxicity, including symptoms of urothelial inflammation, hypotension and syncope, fatigue and abdominal pain. Encouraging signs of clinical activity included two bone marrow complete remissions in refractory anaemia with excess blasts type 1 patients previously treated with azacitidine. In addition, four patients each achieved transfusion independence and haematological improvements. In conclusion, oral rigosertib is bioavailable and well tolerated, and has clinical activity in patients with MDS.

Phase I Study of Rigosertib, an Inhibitor of the Phosphatidylinositol 3-Kinase and Polo-like Kinase 1 Pathways, Combined with Gemcitabine in Patients with Solid Tumors and Pancreatic Cancer

Purpose: Rigosertib, a dual non-ATP inhibitor of polo-like kinase 1 (Plk1) and phosphoinositide 3-kinase pathways (PI3K), and gemcitabine have synergistic antitumor activity when combined in preclinical studies. This phase I study aimed to determine the recommended phase II dose (RPTD) of the combination of rigosertib and gemcitabine in patients with cancer. Experimental Design: Patients with solid tumors who failed standard therapy or were candidates for gemcitabine-based therapy were eligible. Gemcitabine was administered on days 1, 8, and 15 on a 28-day cycle and rigosertib on days 1, 4, 8, 11, 15, and 18. Pharmacokinetic studies were conducted during an expansion cohort of patients with advanced pancreatic ductal adenocarcinoma (PDA). Results: Forty patients were treated, 19 in the dose-escalation phase and 21 in the expansion cohort. Dose levels evaluated were (gemcitabine/rigosertib mg/m2): 750/600 (n = 4), 750/1,200 (n = 3), 1,000/600 (n = 3), 1,000/1,200 (n = 3), and 1,000/1,800 (n = 6 + 21). One dose-limiting toxicity (death) occurred at the highest dose level (1,000/1,800) tested. Non–dose-limiting ≥grade II/III toxicities included neutropenia, lymphopenia, thrombocytopenia, fatigue, and nausea. Grade III/IV neutropenia, thrombocytopenia, and fatigue were seen in two, one, and two patients in the expansion cohort. Partial responses were observed in PDA, thymic cancer, and Hodgkin lymphoma, including gemcitabine-pretreated PDA. The pharmacokinetic profile of rigosertib was not affected by gemcitabine. Conclusion: The RPTD established in this study is rigosertib 1,800 mg/m2 and gemcitabine 1,000 mg/m2. This regimen is well tolerated with a toxicity profile of the combination similar to the profile of gemcitabine alone. Antitumor efficacy was observed in patients who previously progressed on gemcitabine-based therapy. Clin Cancer Res; 18(7); 2048–55. ©2012 AACR.

Phase I study of oral rigosertib (ON 01910.Na), a dual inhibitor of the PI3K and Plk1 pathways, in adult patients with advanced solid malignancies.

Purpose: To determine the pharmacokinetics (PK), maximum tolerated dose (MTD), safety, and antitumor activity of an oral formulation of rigosertib, a dual phosphoinositide 3-kinase (PI3K) and polo-like kinase 1 (Plk1) pathway inhibitor, in patients with advanced solid malignancies. Experimental Design: Patients with advanced solid malignancies received rigosertib twice daily continuously in 21-day cycles. Doses were escalated until intolerable grade ≥2 toxicities, at which point the previous dose level was expanded to define the MTD. All patients were assessed for safety, PK, and response. Urinary PK were performed at the MTD. Archival tumors were assessed for potential molecular biomarkers with multiplex mutation testing. A subset of squamous cell carcinomas (SCC) underwent exome sequencing. Results: Forty-eight patients received a median of 2 cycles of therapy at 5 dose levels. Rigosertib exposure increased with escalating doses. Dose-limiting toxicities were hematuria and dysuria. The most common grade ≥2 drug-related toxicities involved urothelial irritation. The MTD is 560 mg twice daily. Activity was seen in head and neck SCCs (1 complete response, 1 partial response) and stable disease for ≥12 weeks was observed in 8 additional patients. Tumors experiencing ≥partial response had PI3K pathway activation, inactivated p53, and unique variants in ROBO3 and FAT1, two genes interacting with the Wnt/β-catenin pathway. Conclusions: The recommended phase II dose of oral rigosertib is 560 mg twice daily given continuously. Urinary toxicity is the dose-limiting and most common toxicity. Alterations in PI3K, p53, and Wnt/β-catenin pathway signaling should be investigated as potential biomarkers of response in future trials. Clin Cancer Res; 20(6); 1656–65. ©2014 AACR.

Disposition of ON 01210.Na (Ex-RAD(R)), a novel radioprotectant, in the isolated perfused rat liver: Probing metabolic inhibition to increase systemic exposure

ON 01210.Na (Ex-RAD) is a novel benzyl styryl sulfone analog, developed as a radioprotectant by Onconova Therapeutics Inc. The objectives of this research were to evaluate the hepatobiliary disposition of ON 01210.Na in the isolated perfused rat liver (IPRL) and to determine the effect of coadministration of ethacrynic acid (EA) on the pharmacokinetic profile of ON 01210.Na. EA acid was used as a prototypical inhibitor of glutathione-S-transferase inhibitor. ON 01210.Na was highly bound in IPRL perfusate proteins, and binding was significantly lower in the presence of EA. Dose-escalation studies (bolus dose, target concentrations 10-250 μg/mL) showed that ON 01210.Na followed nonlinear pharmacokinetics with hepatic clearance decreasing from 3.14 to 1.99 mL/min with increasing dose. ON 01210.Na underwent extensive metabolic degradation to its glutathione (GSH) adduct in liver. The GSH metabolite was mainly excreted into the bile. Coadministration of EA (1 mM) significantly inhibited the conversion of ON 01210.Na to its GSH conjugate, resulting in decreased clearance (approx. fivefold lower), and prolonged elimination from the perfusate. These preclinical studies suggest that EA is a potential pharmacoenhancer that can reduce the metabolism of ON 01210.Na in vivo, thereby increasing drug exposure and boosting radioprotective activity.

Determination of Degradation Kinetics and Effect of Anion Exchange Resin on Dissolution of Novel Anticancer Drug Rigosertib in Acidic Conditions

Rigosertib is a novel anticancer drug in clinical development by Onconova therapeutics, Inc. Currently, it is in pivotal phase III clinical trials for myelodysplastic syndrome (MDS) patients. Chemically, it is a sodium salt of weak acid with low solubility in lower pH solutions. In the preliminary studies, it was found that rigosertib is unstable in acidic conditions and forms multiple degradation products. In this research, drug degradation kinetics of rigosertib were studied in acidic conditions. Rigosertib follows pseudo-first-order general acid catalysis reaction. Cholestyramine, which is a strong anion exchange resin, was used to form complex with drug to improve stability and dissolution in acidic conditions. Drug complex with cholestyramine showed better dissolution profile compared to drug alone. Effect of polyethylene glycol was investigated on the release of drug from the drug resin complex. Polyethylene glycol further improved dissolution profile by improving drug solubility in acidic medium.

Abstract LB-A21: Single-agent activity and favorable pharmaceutical properties of orally bioavailable next-generation CDK4/6 inhibitor, ON 123300

Introduction: Recent proof-of-concept for targeting cyclin dependent kinases 4 and 6 (CDK4/6) culminated in the approval for breast cancer of the first-in-class CDK4/6 inhibitor, palbociclib (Ibrance®). Palbociclib and other potent but narrowly targeted CDK4/6 inhibitors are cytostatic rather than cytotoxic (Leonard et al, 2012), and require combination therapy for optimal activity. ON 123300 is a next-generation CDK4/6 inhibitor with improved single-agent cytotoxicity. This novel compound is a potent CDK4 and CDK6 inhibitor (IC50 = 3.9 nM and 9.8 nM, respectively) that is cytotoxic against breast and other cancer cell lines (Reddy et al, 2014). We present pre-IND profiling pharmacology, physicochemical and ADME studies to support ON 123300 as a clinical candidate and next-generation CDK4/6 inhibitor. Methods and Results: Non-clinical studies were conducted in order to assess the drug-like properties of ON 123300 and its pharmaceutical salts. Physicochemical parameters were determined for the compound. ON 123300 was highly soluble below pH 4.0, with reduced solubility in more basic conditions. Predicted intestinal absorption, as measured by Caco-2 permeability, was 1.95×10-5 cm/s with a low efflux ratio. Based on these characteristics, the compound was advanced to lead profiling against 68 primary molecular targets. Radioligand binding studies revealed limited receptor inhibition (11/68 targets) with 10 μM of ON 123300. Human Ether-a-go-go (hERG) inhibition testing revealed no significant effect (IC50 > 25 μM). In vitro metabolism studies indicated metabolism through CYP3A4 and CYP2C8. Finally, in silico based modeling (Cloe® PK) integrating all key non-clinical parameters was carried out in order to estimate the potential for oral absorption in humans. Preliminary analysis suggests good oral bioavailability and the potential to establish an acceptable therapeutic window. Conclusions: The well differentiated biochemical, anticancer and pharmaceutical properties of ON 123300 provide the basis for pre-clinical toxicology testing, leading to an investigational new drug (IND) filing and clinical exploration of this compound across tumor types that share targets accessed by this next-generation CDK inhibitor. Citation Format: Benjamin Hoffman, Ramana Reddy, Muralidhar Mallireddigari, Daniel Fox, Chen Ren, Manoj Maniar. Single-agent activity and favorable pharmaceutical properties of orally bioavailable next-generation CDK4/6 inhibitor, ON 123300. [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 LB-A21.

Abstract 3534: Proposed pathway of disposition of ON 01910. Na, a novel clinical trial stage anti-cancer agent: Implicaton of Mrp2 in biliary excretion in the isolated perfused rat liver system

Introduction: ON 01910. Na is a novel targeted anti-cancer agent under clinical investigation in Phase I and Phase II trials. Preclinical studies indicate that the compound preferentially distributes to the liver but is not extensively metabolized in vivo The purpose of this study was to evaluate the disposition of ON 01910. Na employing the isolated perfused rat liver (IPRL) model. The specific goals were to 1) Assess the dose-linearity of ON 01910. Na disposition; 2) Probe the role of the Mrp2 transporter on ON 01910. Na biliary excretion; and 3) Establish the effect of concurrent dosing with oxaliplatin and doxorubicin on ON 01910. Na hepatobiliary disposition. Methods: Perfusion experiments (n=3/group) were performed at 4 doses (0.8, 4, 8, 20 mg), targeting a range of perfusate levels between 10 and 250 ug/ml. ON 01910. Na (10 ug/ml) disposition was then studied in the presence of doxorubicin (2.5 ug/ml) and oxaliplatin (2 ug/ml). IPRL experiments were also conducted using livers from Mrp2 deficient rats. ON 01910. Na was assayed in perfusate and bile samples by HPLC. Results: ON 01910. Na parameter estimates are provided in the table below. The compound displayed nonlinear excretion in the IPRL, and ON 01910. Na disposition was altered in mrp2-deficient rats. The effect of co-administered chemotherapeutic agents is being investigated. Conclusions: ON 01910. Na showed extensive biliary excretion in the IPRL, and IPRL findings correlated with in vivo data in rats. ON 01910. Na biliary transport appears to be mediated in part by Mrp2. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3534.