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A Phase IA, Open Label, Multiple Dose, Dose Escalation Study to Investigate the Safety and Pharmacokinetics of the BTK Inhibitor BGB-3111 in Subjects with Indolent B-Cell Lymphoid Malignancies
BeiGene Australia Pty Ltd
This is a multicentre, Phase I, open-label, multiple-dose, dose escalation, first-in-human study. It is to be conducted in two sequential parts: dose escalation, followed by safety and schedule expansion.
Part 1: Dose Escalation - this will follow a classic â€œ3+3â€ dose escalation schedule. The starting dose will be 40mg/day (once daily). The period for dose limiting toxicity (DLT) assessment is 21 days from first dose of BGB3111.
Evaluation of a cohort of at least three (3) subjects completing DLT assessment at any given dose level is required prior to determining the next dose level and dose regimen for the subsequent cohort. Pharmacodynamic effect of BGB3111 on BTK inhibition will be studied in peripheral blood mononuclear cells (PBMCs) and in bone marrow and lymph nodes if available. The continuous safety evaluation will be performed by the sponsor, the coordinating investigator, and investigators. A Safety Monitoring Committee (SMC) will be established for the determination of dose levels to be administered and dose regimen during dose escalation, and will utilize the data available from the previous dose levels.
In the event that a Maximal Tolerated Dose (MTD) is not identified due to paucity of DLTs, the dosing regimen used in the safety and schedule expansion will be based on pharmacodynamic studies of BTK inhibition in PBMCs, bone marrows and lymph nodes (if available).
Part 2: Safety and Schedule Expansion â€“ this will evaluate the MTD (or anticipated Phase 2 dose, if no MTD defined) in a further 20 subjects. Subjects will be assigned to the MTD on a once daily schedule, or 50% MTD given twice a day, by alternate allocation. Patients in this part will undergo a lymph node and bone marrow biopsy at screening stage and before their day 3 dose â€“ i.e. either 10-14 or 22-26 hours post dose, depending on assigned schedule for pharmacodynamic studies of BTK inhibition in lymph nodes and bone marrow in addition to that in PBMCs.
This study will be considered complete once all patients have either manifested disease progression, ceased BGB3111 due to intolerance, or completed a total of 12 months of BGB3111.
Patients in both parts of the study continuing to show clinical benefit at 12 months will be allowed to continue BGB3111 until disease progression or intolerance, on an extension study.