Treatment
toxicity, tumour
DISEASE PROGRESSION, EVENT, TUMOUR
SRA737 is a novel, weakly basic compound presented for oral clinical administration as its citrate salt. The molecular weight of SRA737 is 379.34 Da for the free base and 571.46 Da for the citrate salt. SRA737 capsules were be taken on an empty stomach, at the same time each day. Subjects were instructed to fast for 2 h before administration and for 1 h after administration. The instructions were to be followed throughout the study drug administration period including the PK assessment on Day −7 to −4. It was also instructed that the administration of antacids or H2 antagonists should occur 4 h before or 2 h after administration of SRA737. This latter instruction was due to the fact that preliminary in vitro studies suggest that the SRA737 citrate drug product may possess some minimal to moderate pH-dependent solubility over the physiological range.A single dose of SRA737 was given at one visit on Day −7 to Day −4 (prior to the start of Cycle 1) for PK assessments. SRA737 was then administered orally on a continuous daily dosing schedule in 28-day cycles. An accelerated titration design was used with single-patient dose-escalation cohorts starting with 20 mg SRA737 administered once daily (QD) in the first cohort, with dose doubling in subsequent single-patient cohorts. If a patient had SRA737-related Grade 2 toxicity in a dose level cohort during Cycle 1, that cohort was expanded to 3 to 6 patients, and subsequent cohorts followed a rolling six design.Patients were assessed for DLT from the first SRA737 dose (Day −7 to Day −4) until the end of Cycle 1 (up to 35 days). A DLT was defined as any highly probable or probably treatment-related event that met protocol-specified DLT criteria, including any drug-related toxicity that led to an inability to receive at least 75% of the planned dose in the first cycle (Supplementary Methods).Expansion cohorts including up to 20 patients with one of the 6 specified indication-specific tumour types, were treated at SRA737 doses selected by the cohort review committee based on all available safety and PK data; expansion doses were at or below the maximum tolerated dose (MTD) from the dose-escalation phase. Patients could continue treatment until disease progression or discontinuation from study due to unacceptable toxicity, investigator/sponsor decision, or withdrawal of consent.