Module 1A
toxicity, malignancy, tumor, breast cancer
TUMOR, SOLID TUMORS, SECONDARY, BREAST CANCER
In this Phase I study (ClinicalTrials.gov: NCT03363893), male and female patients with locally advanced/metastatic solid tumors received samuraciclib in dose escalation cohorts (at least 3 and up to 6 evaluable patients permitted per dose cohort) to determine the MTD (see Supplementary Information for definition). An additional 6 to 12 male or female patients with breast cancer were enrolled to a paired biopsy cohort to evaluate the pharmacodynamic effects of samuraciclib in tumor tissue, initiated after determining the minimally biologically active dose, defined by a 25-30% reduction in signal for pPolII in lymphocytes after 21 days of dosing or more.Patients aged 18 or over, ECOG performance status 0 or 1, estimated life expectancy of >12 weeks, and histological, radiological, or cytological confirmation of advanced non-hematological malignancy not considered appropriate for further standard treatment were eligible. For inclusion in the paired biopsy cohort, only patients with breast cancer with lesions amenable to biopsy were recruited. A full list of inclusion/exclusion criteria is provided in the Supplementary Information.Patients initially received an oral dose of samuraciclib at Cycle 0, Day 1 for PK evaluation, followed by a 48-hour interval then continuous daily dosing for 21 days (Cycle 1). Dosing continued in 21-day cycles until the patient no longer gained clinical benefit or had intolerable toxicity. At least 3 evaluable patients in a cohort had to complete Cycle 1 before any dose escalation was considered.The primary endpoint was safety and tolerability, with secondary endpoints to characterize the PK of samuraciclib and to assess biological and anti-tumor activity.