Phase I study of onapristone, a type I antiprogestin, in female patients with previously treated recurrent or metastatic progesterone receptor-expressing cancers.

INTRODUCTION: Onapristone is a type I progesterone receptor (PR) antagonist, which prevents PR- mediated DNA transcription. Onapristone is active in multiple preclinical models and two prior studies demonstrated promising activity in patients with breast cancer. We conducted a study of extended release (ER) Onapristone to determine a recommended dose and explore the role of transcriptionally-activated PR (APR), detected as an aggregated subnuclear distribution pattern, as a predictive biomarker. METHODS: An open-label, multicenter, randomized, parallel-group, phase 1 study (target n = 60; NCT02052128) included female patients ≥18 years with PRpos tumors. APR analysis was performed on archival tumor tissue. Patients were randomized to five cohorts of extended release (ER) onapristone tablets 10, 20, 30, 40 or 50 mg BID, or immediate release 100 mg QD until progressive disease or intolerability. Primary endpoint was to identify the recommended phase 2 dose. Secondary endpoints included safety, clinical benefit and pharmacokinetics. RESULTS: The phase 1 dose escalation component of the study is complete (n = 52). Tumor diagnosis included: endometrial carcinoma 12; breast cancer 20; ovarian cancer 13; other 7. Median age was 64 (36-84). No dose limiting toxicity was observed with reported liver function test elevation related only to liver metastases. The RP2D was 50 mg ER BID. Median therapy duration was 8 weeks (range 2-44), and 9 patients had clinical benefit ≥24 weeks, including 2 patients with APRpos endometrial carcinoma. CONCLUSION: Clinical benefit with excellent tolerance was seen in heavily pretreated patients with endometrial, ovarian and breast cancer. The data support the development of Onapristone in endometrial endometrioid cancer. Onapristone should also be evaluated in ovarian and breast cancers along with APR immunohistochemistry validation.

A Multicenter Phase I Study Evaluating Dual PI3K and BRAF Inhibition with PX-866 and Vemurafenib in Patients with Advanced BRAF V600-Mutant Solid Tumors.

Purpose: The objectives of the study were to evaluate the safety of daily oral PX-866 in combination with twice daily vemurafenib and to identify potential predictive biomarkers for this novel combination.Experimental Design: We conducted a phase I, open-label, dose-escalation study in patients with advanced BRAF V600-mutant solid tumors. PX-866 was administered on a continuous schedule in combination with vemurafenib. Patients underwent a baseline and on-treatment biopsy after 1-week of PX-866 monotherapy for biomarker assessment.Results: Twenty-four patients were enrolled. The most common treatment-related adverse events were gastrointestinal side effects. One dose-limiting toxicity (DLT) of grade 3 rash and one DLT of grade 3 pancreatitis were observed in cohort 2 (PX-866 6 mg daily; vemurafenib 960 mg twice daily) and cohort 3 (PX-866 8 mg daily; vemurafenib 960 mg twice daily), respectively. Of 23 response-evaluable patients, seven had confirmed partial responses (PR), 10 had stable disease, and six had disease progression. Decreases in intratumoral pAKT expression were observed following treatment with PX-866. Patients who achieved PRs had higher rates of PTEN loss by IHC (80% vs. 58%) and pathogenic PTEN mutations and/or deletions (57% vs. 25%). Two patients with durable PRs had an increase in intratumoral CD8+ T-cell infiltration following treatment with PX-866.Conclusions: PX-866 was well tolerated at its maximum tolerated single-agent dose when given in combination with a modified dose of vemurafenib (720 mg twice daily). Response to treatment appeared to be associated with PTEN loss and treatment with PX-866 seemed to increase CD8+ T-cell infiltration in some patients. Clin Cancer Res; 24(1); 22-32. ©2017 AACR.

A single-dose PK study of onapristone including the effect of food on absorption.

PURPOSE: Onapristone is an antiprogestin with activity in breast cancer and is under investigation for use in endometrial, ovarian and prostate cancers. Megestrol acetate and abiraterone generally show variability in absorption and, depending on the formulation, food effect. This study was conducted to determine the effect of food on 10 mg oral immediate-release (IR) onapristone and to help identify a formulation to minimize variability. METHODS: This is an open-label, randomized, crossover study to determine the pharmacokinetic profile of onapristone and its main metabolite, N-mono-desmethyl onapristone. Twelve healthy female subjects received 10 mg of oral IR onapristone after an overnight fast, or within 30 min of a high-fat, high-calorie meal with a 2-week washout between dosing periods. RESULTS: Onapristone plasma t1/2 (mean ± SD) was 4.36 ± 0.81 h for the fasted state and 3.76 ± 0.36 h for the fed state. Following food, onapristone tmax was delayed from 1 to 4 h. Food intake was also associated with a small increase in AUC0-∞ of approximately 13 % and a statistically significant decrease in Cmax of approximately 18 %. One subject experienced a 23-day delay in menses after one 10 mg onapristone dose, while another subject experienced transient grade 2 NCI-CTCAE liver enzyme elevation 3 weeks post dose. CONCLUSION: The results are consistent with previous observations, indicating that there is a small increase in onapristone exposure and a significant decrease in Cmax when taken with food. These changes are within acceptable limits set out by the FDA. Thus, our findings indicate that onapristone could be administered without regard to food.

A multicenter phase I trial of PX-866, an oral irreversible phosphatidylinositol 3-kinase inhibitor, in patients with advanced solid tumors.

PURPOSE: The objectives of the study were to evaluate the maximum tolerated dose (MTD), safety, pharmacodynamics, pharmacokinetics, and antitumor activity of PX-866 in patients with incurable cancers. EXPERIMENTAL DESIGN: This was a phase I, open-label, dose-escalation study. Drug was administered orally once per day either on an intermittent (arm 1; days 1-5 and 8-12 of a 28-day cycle) or continuous (arm 2; days 1-28 of a 28-day cycle) schedule. Additional patients were treated at the arm 2 MTD in a food effects substudy. RESULTS: Eighty-four patients were treated in the arm 1 (n = 51), arm 2 (n = 20), and food effects (n = 13) cohorts. The most frequent study drug-related adverse events were gastrointestinal disorders (69.0%), with diarrhea being the most common (48.8%). The MTD was 12 and 8 mg for arm 1 and 2, respectively. The dose-limiting toxicities (DLT) consisted of grade III diarrhea (n = 3) and grade III elevated aspartate aminotransferase (AST; n = 1). The pharmacokinetics profile was dose proportional, with no evidence of drug accumulation. PX-866-associated inhibition of platelet pAKTSER473 was observed at the arm 2 MTD. The best response per Response Evaluation Criteria in Solid Tumors (RECIST) was stable disease in 22% of evaluable patients in arm 1, 53% in arm 2, and 11% in the food effects cohort. Eight patients were on study for 4 or more months. CONCLUSIONS: This first-in-human study shows that PX-866, an irreversible small-molecule inhibitor of phosphatidylinositol 3-kinase (PI3K), was well tolerated and was associated with prolonged stable disease, particularly when using a continuous dosing schedule.

Antiprogestin pharmacodynamics, pharmacokinetics, and metabolism: implications for their long-term use.

Antiprogestins represent a relatively new and promising class of therapeutic agents that could have significant impact on human health and reproduction. In the present work, the pharmacodynamics, pharmacokinetics, and metabolism of mifepristone (MIF), lilopristone (LIL), and onapristone (ONA) in humans are reviewed, and characteristics bearing important clinical implications are discussed. Although MIF has gained notoriety as an "abortion pill," antiprogestins may more importantly prove effective in the treatment of endometriosis, uterine leiomyoma, meningioma, cancers of the breast and prostate, and as contraceptive agents. MIF pharmacokinetics display nonlinearities associated with saturable plasma protein (alpha 1-acid glycoprotein, AAG) binding and characterized by lack of dose dependency for parent drug plasma concentrations (for doses greater than 100 mg) and a zero-order phase of elimination. LIL and ONA pharmacokinetics are less well characterized but ONA does not appear to bind AAG and displays a much shorter t1/2 than the other agents. The three antiprogestins are substrates of cytochrome P450 (CYP) 3A4, an enzyme exceedingly important in human xenobiotic metabolism. Even more implicative of likely drug-drug interactions subsequent to their long-term administration are recent data from our laboratory indicating that they inactivate CYP3A4 in a cofactor- and time-dependent manner, suggesting that complexation and induction of the enzyme may occur in vivo via protein stabilization. Moreover, it has been demonstrated that MIF increases CYP3A4 mRNA levels in human hepatocytes in primary culture, indicative of message stabilization and/or transcriptional activation of CYP3A4 expression. Finally, MIF has also been shown to inhibit P-glycoprotein function. Whether LIL and ONA share these latter two characteristics with MIF has not yet been determined but they illustrate properties that, in addition to diminished antiglucocorticoid activities and altered pharmacokinetic characteristics, warrant consideration during the development of these and never antiprogestational agents.

Discovery of novel intracellular receptor modulating drugs.

Utilizing the co-transfection assay as a guide to determining structure activity relationships, we have been pursuing the discovery of non-steroidal hPR modulators. Small molecule, non-steroidal lead structures have been identified. Optimization of these structures has yielded more potent hPR modulators. Improved cross-reactivity profiles with other intracellular receptors are a feature of these compounds owing to their non-steroidal nature.

The in vitro metabolic activation of the 11-trifluoromethyl analogue of the potent carcinogen 15,16-dihydro-11-methyl-cyclopenta[a]-phenanthren-17-one to mutagens.

A strongly electronegative, bay-region analogue of the potent carcinogen 15,16-dihydro-11-methylcyclopenta[a]phenanthren-17-one, namely 15,16-dihydro-11-trifluoromethylcyclopenta[a]phenanthren-17-one, is mutagenic to Salmonella typhimurium TA100. Also it is metabolized at the 1,2- and 3,4-positions in the A-ring as well as C-15 in the D-ring to give 3,4-dihydroxy-3,4,15,16-tetrahydro-11-trifluoromethyl- cyclopenta[a]phenanthren-17-one as the only mutagenic metabolite. In these respects its behaviour is closely similar to that of the 11-methyl compound, suggesting that the electronic nature of the bay-region substituent is rather less critical than its spatial configuration in influencing metabolism to genotoxic intermediates. It remains to be seen, however, whether the trifluoromethyl compound is also a carcinogen.

Determination of onapristone and its N-desmethyl metabolite in human plasma or serum by high-performance liquid chromatography.

An automated reversed-phase high-performance liquid chromatographic method for the determination of the antiprogestin onapristone and its N-desmethyl metabolite in human plasma or serum is described. Ultraviolet detection was performed at 315 nm, with a limit of detection of 1 ng/ml at a signal-to-noise ratio of 3. The intra- and inter-assay precision were less than or equal to 6% and less than or equal to 7%, respectively. Onapristone and its N-desmethyl metabolite were stable in human plasma. The method was successfully applied to serum samples obtained from human volunteers after oral administration of onapristone.