Safety, Tolerability, and Pharmacokinetics of EVT801 in Patients With Advanced Solid Tumours

Stage 1 - Dose Escalation Cohorts:

Stage 1 is a multiple ascending dose escalation of EVT801 in patients with advanced solid tumours to determine MTD / RP2D for further investigation.

After completing screening and signing informed consent, subjects will be enrolled. The first dose of study drug will be administered at the site, and patients will undergo intensive PK assessment for 48 hours before receiving the second and subsequent doses.

The first subject in Stage 1 will receive EVT801 at a dose of 50 mg QD (Quaque Die: once daily) (Dose Level 1). If no Doses Limiting Toxicity (DLTs) are observed in a 28-day period, the second subject may be enrolled at Dose Level 2. The study will proceed by way of single-patient cohorts until (a) treatment-related toxicity of at least Grade 2 is observed, or (b) Dose Level 5 is reached, or (c) the Principal Investigator, in consultation with the sponsor, determines that it is appropriate to transition to larger cohorts. At this point, the study will move to a conventional 3+3 design.

If a DLT is observed in any cohort, that cohort will expand to six patients. If two DLTs are observed at a given dose level, the prior dose level will be declared the MTD, and Stage 1 will be deemed complete. If the prior dose level had recruited only a single patient, then that dose level will be expanded to three patients, such that the MTD will have been administered to a minimum of three patients.

If two DLTs are observed at Dose Level 2 (100 mg QD), a de-escalation cohort (Dose Level -1) will enrol three patients in order to establish the viability of twice-daily dosing.

Once the MTD has been established, the sponsor will evaluate, in consultation with the investigators, whether that dose or a lower dose should be used for subsequent investigation (the RP2D). This evaluation will be based on a consideration of broader factors than safety, including PK and PD. The RP2D shall under no circumstances be greater than the MTD.

The sequence of doses examined will be:

50 mg QD → 100 mg QD (→50 mg BID \[Bis In Die (i.e. twice daily)\] if 2 DLTs / 6 patients @ 100 mg QD) → 100 mg BID → 200 mg BID → 400 mg BID → 500 mg BID → 600 mg BID → 800 mg BID (up to 8 cohorts).

After completion of at least two cycles at the dose level to which they were initially assigned, individual subjects may escalate to higher dose levels, providing the higher dose level has (a) been administered to at least one patient for at least 28 days without grade 2 treatment-related toxicity, or (b) been administered to at least three subjects for at least 28 days without a DLT, or (c) been administered to at least six subjects for at least 28 days with no more than one DLT. A given subject may escalate through multiple dose levels in this fashion, providing the aforementioned criteria continue to be satisfied and the patient has no ongoing clinically significant adverse event \> grade 1.