Abstract C137: First-in-human dose escalation study of oral ONC201 in advanced solid tumors
Authors: Stein Mark N. , Moss Rebecca , Mayer Tina , Silk Ann W. , Chan Nancy , Zheng Ling , Beckett Yasmeen , Tenpenny Noelle , Bentlyewski Edward , DiPaola Robert , Tarapore Rohinton , Allen Joshua , Mehnert Janice 
Published: May 2016

Abstract
Background: ONC201 is an orally active first-in-class small molecule with strong antitumor activity in preclinical models of advanced cancers. In cancer cell lines and patient samples ONC201 induces activation of the integrated stress response (Ishizawa et al ASH, 2014) resulting in upregulation of ATF4 and CHOP which in turn regulates several proapoptotic genes namely DR5. ONC201 also causes late-stage inactivation of Akt and ERK, which also results in downstream activation of the apoptotic TRAIL pathway as part of innate immune surveillance (Allen J et al, Sci Trans Med, 2013). Activity of ONC201 is independent of p53 status and mutation agnostic. ONC201 is well tolerated at efficacious doses in animal models, crosses the blood brain barrier, is particularly effective in refractory tumors, depletes cancer stem cells (Ishizawa et al, ASH 2014; Prabhu et al, Blood 2014; Zhao et al, ASCO 2014), and is effective with infrequent dosing preclinically. Based on the compelling efficacy and safety profile of ONC201 as well as the engagement of signaling pathways critical for many cancers, the clinical introduction ONC201 in advanced cancer patients is warranted.
Methods: The first-in-human study of ONC201 (NCT02250781) began in January 2015 as an open-label single-site phase I trial enrolling adult patients with refractory advanced solid tumors and glioblastoma (GBM). Patients with symptomatic brain metastases or prior bevacizumab for treatment of GBM are excluded. The primary endpoint is determination of the recommended phase II dose (RP2D) of single agent ONC201 given orally once every 3 weeks (1 cycle). Secondary endpoints include assessment of pharmacodynamics using select biomarkers for ONC201 (Allen et al, 2015), pharmacokinetics, toxicity, and efficacy. The study employs an accelerated, single patient per cohort, dose escalation design with expansion to a standard 3+3 design if a subject has grade &gt; / = grade 2 toxicity or dose limiting toxicity within cycle 1. The maximum tolerated dose is the highest dose level in which 6 patients have been treated with &lt; / = 1 instance of DLT. Based on pre-clinical models doses for once every 3 week dosing were: dose leve1 (DL) 1- 125mg; 2- 250mg; 3- 375mg; 4- 500mg; 5- 626mg.
Results: Single patient dose escalation was completed in cohorts 1 to 4 and 6 patients completed at least 3 weeks of level 5 without any &gt; / = grade 2 drug related toxicity. At DL 6, Mean T1/2 = 7.91hours (7.01-9.42); Mean Cmax = 8.58 ug/mL (3.95 - 19.15) Mean AUC(0-24) = 28057 (15293 - 50597) hr-ng/mL. Ongoing radiographic stable disease is noted in a patient with metastatic castrate resistant prostate cancer.
Conclusions: The RP2D of ONC201 is 625mg on a once every 3 week schedule. Evaluation of PD markers of response and enrollment to a dose expansion safety cohort are ongoing.
Citation Format: Mark N. Stein, Rebecca Moss, Tina Mayer, Ann W. Silk, Nancy Chan, Ling Zheng, Yasmeen Beckett, Noelle Tenpenny, Edward Bentlyewski, Robert DiPaola, Rohinton Tarapore, Joshua Allen, Janice Mehnert. First-in-human dose escalation study of oral ONC201 in advanced solid tumors. [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 C137.