Today’s blog post—part three of a four-part series on attempts to target p53—goes into more detail on Kevetrin, the company’s first-in-class, Orphan Drug-designated (three times), anti-cancer drug candidate entering a mid-stage trial for the treatment of platinum-resistant ovarian cancer.
Kevetrin (thioureidobutyronitrile) is small molecule belonging to a class of compounds called thioureals. In its early development, laboratory testing in animals revealed the drug exhibited robust anti-cancer activity across multiple drug-resistant cell lines by activating wild type p53 and degrading mutant p53. Toxicology studies showed Kevetrin largely had a benign profile. Likely to be well-tolerated by patients (non-genotoxic), coupled with compelling signs of efficacy in pre-clinical work, Cellceutix filed a new drug application with the FDA to begin testing Kevetrin human trials.
Cellceutix completed a Phase 1 dose-escalation study, conducted at Dana-Farber Cancer Institute and Beth Israel Deaconess Medical Center, in patients with advanced solid tumors. Each patient received one dose of Kevetrin, intravenously, each week for three weeks over a four-week treatment period. Over the course of the study, dosing amounts ranged from 10mg/m2 to 750mg/m2of Kevetrin. The primary objective was to evaluate the safety and tolerability of Kevetrin. Secondary objectives were to determine the pharmacokinetic (PK) profile and assess anti-tumor activity of Kevetrin.
In the trial, investigators measured p53 activity by increased expression of the protein p21, a downstream biomarker of p53, in peripheral blood lymphocytes. Samples were collected from patients at 7 and 24 hours after the initiation of the first Kevetrin infusion.
Regardless of tumor type, a total of 27 of 40 evaluable patients (67.5%) had an increase in p21 expression relative to pre-treatment levels. For patients with the greatest increases at either 7 hours or 24 hours, the mean percent increase at 7 hours (10 patients) was 38.5% (median 22%) and at 24 hours (17 patients) the mean percent increase was 24.5% (median 17%). For patients who received Kevetrin at doses of ≤ 165 mg/m2, the mean percent increase was 21.7% (n=11). For patients who received Kevetrin at doses ranging from 215 mg/m2 to 750 mg/m2, the mean percent increase was 35.2% (n=17). In ovarian cancer, analyses indicated a particularly pronounced increase in p21 expression.
The Phase 1 study met its primary endpoint by showing no clinically significant adverse effects of Kevetrin in patients based on clinical laboratory parameters through all dosing levels and across the duration of treatment. Some patients also saw disease stabilization and reduction of cancerous lesions. Further data analyses revealed Kevetrin exhibited a dose-dependent response and had a relatively short half-life (~2 hours), clearing the body within one day—on average, between 8 and 10 hours, though the drug remained in the body up to approximately 24 hours based on individual patient variations.
As a result of these findings, Cellceutix’s believes the impact of Kevetrin when administered to patients with repeated dosing—3 times per week over 3 weeks (with dose escalation in the 2nd cohort)—as planned in the Phase 2a trial in late-stage ovarian cancer, likely will achieve more steady systemic levels of the drug, thereby increasing its therapeutic efficacy. Patients will receive Kevetrin, at a starting dose of 250 mg/m2 followed by "standard of care" regimen for 6 months. Lab work is under way to better establish the molecular mechanisms by which Kevetrin modulates p53. Cellceutix also is exploring an oral formulation of Kevetrin, with promising early indications based on bioavailability studies.
In the final part of this series on pharmaceutical efforts to drug p53, we will discuss what the future might hold for patients, clinicians and shareholders, as Kevetrin advances toward possibly becoming the first p53-activating drug approved by the FDA—a potential daily oral medicine for treating and defeating cancer.
““Kevetrin is unique in that it is not a chemotherapy and acts by targeting multiple biochemical pathways to control tumor development in cells with diverse mutational background. Kevetrin has now shown at this stage of its development its enormous potential. We are extremely excited about Kevetrin’s prospects moving forward and feel we have a solid foundation upon which to proceed into advanced trials. To see disease stabilization in the Phase 1 trial with Kevetrin, let alone when optimal dosing has yet to be achieved, is exceptional.”
Leo Ehrlich, Cellceutix CEO