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Background: Locally advanced cervical cancer accounts for most deaths from disease. Standard of care includes treatment with cisplatin-based chemoradiation with a 70% response rate. The addition of intravenous (IV) triapine to chemoradiation has shown promising clinical activity in phase 1 and 2 studies but comes with a more intensive treatment regimen. An ongoing phase 1 trial has finished the escalation phase, and we report the pharmacokinetics (PK) and pharmacodynamics (PD) of oral (PO) triapine. Methods: This phase 1 study followed a 3+3 design for dose escalation of oral triapine, starting with initial dose of 100 mg five days a week for five weeks combined with external beam pelvic radiation and weekly IV cisplatin. PK was determined by LC-MS/MS, and PD included methemoglobin levels at 4 h post dose. Within patient PK variability after IV and PO dosing and PO bioavailability were calculated. Results: PK data were available for 10 patients at 100 (the MTD) and 150 mg. PO parameter values were Tmax 1.3 h, t1/2 1.4 h, CL/F 104 L/h, and Vz/F 214 L. There was no discernable difference between triapine exposure at 100 vs. 150 mg PO (Cmax 520 (2.5) vs. 344 (1.9) µg/L; AUC 1209 (2.53) vs. 1034 (1.41) µg/L•h), and between patient variability at each dose level was substantial. The correlation of PO Vz/F vs Cl/F was high at R2=0.86, suggesting that the apparent clearance and volume variability is primarily due to variability in the oral bioavailability F. PO within patient variability of Cmax and AUC was also large at 43% and 55%. IV PK was less variable with lower geometric standard deviations across all parameters, including within patients where variability of Cmax and AUC was modest at 10 and 12% coefficient of variation, respectively. Oral bioavailability was estimated at 66%. We found a non-significant trend of smoking almost doubling triapine oral clearance from 68 to 156 L/h (p=0.056). There was no apparent relationship between occurrence of DLT and either IV or PO triapine AUC. Methemoglobin levels directly correlated with triapine exposure expressed as AUC or Cmax. Conclusions: Triapine PK parameter values for PO and IV administration and PO bioavailability values observed in this trial were comparable to previous reports. Correlation of methemoglobin with exposure highlights the importance of optimizing triapine exposure. Additional data may support the exploration of a dose specific to current smokers. Citation Format: Jan H. Beumer, Sarah Behr, Holly Gallion, John Vargo, Frederick Ueland, Haider Mahdi, Brian Orr, Eugenia Girda, Susan Christner, Edward Chu, Charles Kunos, Percy S. Ivy, Sarah Taylor. Pharmacokinetics, bioavailability, and pharmacodynamics of oral triapine [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2800.

ONC201 is a small molecule DRD2 antagonist and ClpP agonist that has prolonged antitumor efficacy and immunomodulatory properties in preclinical models. The enhanced immune modulatory nature of ONC201 was observed in a Phase I study that revealed increased infiltration of granzyme B+ and CD56+ cells, corroborating preclinical reports of NK cell intratumoral infiltration in response to ONC201. A broad induction of immune cytokines and effector molecules was observed in patients treated with ONC201, in particular among patients who experienced at least stable disease by RECIST for 12 or more weeks. Patients who had a > 50% induction in serum perforin, a cytolytic protein found in the granules of cytotoxic T lymphocytes (CTLs) and NK cells, upon ONC201 administration had better outcomes. Regressions in individual metastatic lesions were noted in a small number of EC patients. A multi-center Phase 2 study to explore the efficacy of weekly ONC201 in recurrent or metastatic Type II EC enrolled 5 patients with recurrent EC who underwent paired tumor biopsies before and 9 days after ONC201 initiation. Four of the 5 patients exhibited a 2-5-fold increase in CD4+ Thelper cells in their tumors and the majority of these patients also had CD4+FoxP3+ cells, indicating a significant population of Tregulatory cells (Treg). One patient exhibited an 80% increase in CD8+ T-cells in their tumor 8 days after initiating ONC201. Two of the patients had >2 fold induction of intratumoral granzyme B expression that was surprisingly not accompanied by NK cell infiltration, as assessed by CD56 staining. These results may be consistent with innate immune system activation by ONC201 that results in T-cell modulation. The multi-fold increase in Treg expression could be suppressing tumor cell death. As such, ONC201 dose intensification or combination with immunotherapy are being evaluated for ONC201 in the context of endometrial cancer. Citation Format: Rohinton S. Tarapore, Varun V. Prabhu, Samuel C. Mok, Chilam Au Yeung, Lorna Rodriguez, Eugenia Girda, Gina Mantia-Smaldone, Victoria Bae-Jump, Guangrong Lu, Wolfgang Oster, Joshua E. Allen. Immunomodulatory activity of selective DRD2 antagonist ONC201, an imipridone, in metastatic endometrial cancer (mEC) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-145.