This is a Phase I, multicenter, open-label, two-stage study of APG-3288 monotherapy, aiming to determine the Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) of APG-3288 administered orally once daily in patients with relapsed/refractory (R/R) hematologic malignancies.
Part 1 (Dose Escalation Phase): Patients will receive orally administered APG-3288 at specified doses once daily in 28-day cycles. This phase aims to determine the MTD or RP2D of APG-3288 for patients who have failed standard therapy and for whom no standard therapy offering clinical benefit is available. Part 2 (Dose Expansion Phase): Following the completion of Part 1, Part 2 will be initiated to further evaluate dose safety. Doses will be determined based on a comprehensive assessment of the pharmacokinetic (PK), pharmacodynamic (PD), safety, and efficacy data of APG-3288 from Part 1. In Part 2, up to 60 patients per chosen indication will be enrolled and randomly assigned in equal proportions to 2 or 3 dose cohorts to evaluate dose safety.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
180
Orally administered daily; 28 days per cycle.
Mayo Clinic
Jacksonville, Florida, United States
Henan Cancer Hospital
Zhengzhou, Henan, China
Incidence of dose-limiting toxicities (DLTs) at each dose level
A DLT is defined as any treatment-related adverse event (TRAE) meeting protocol-specified toxicity criteria occurring during the DLT evaluation period (Cycle 1). DLTs will be assessed in participants receiving escalating dose levels of APG-3288 to evaluate its safety and tolerability.
Time frame: From first dose through the end of Cycle 1 (e.g., Day 1 to Day 28)
Incidence of treatment emergent adverse events (TEAEs)
The incidence of treatment emergent adverse events (TEAEs), including Grade 3-5 TEAEs, serious adverse events (SAEs), TEAEs leading to dose interruption, dose reduction, or treatment discontinuation, and deaths, will be assessed in participants receiving APG-3288 in Part 1 (dose escalation) and Part 2 (dose expansion) of the study.
Time frame: From first dose of study treatment through 30 days after the last dose
Maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of APG 3288
The MTD and/or RP2D of APG-3288 will be determined during the dose escalation phase based on the incidence of DLTs, overall safety, tolerability, and available pharmacokinetic and pharmacodynamic data.
Time frame: During the dose escalation phase (Part 1)
Peak plasma concentration (Cmax) of APG-3288
The assessment of maximum observed plasma concentration (Cmax) following administration of APG-3288.
Time frame: From first dose through 24 hours post-dose
Area Under the Plasma Concentration-Time Curve (AUC) of APG-3288
Area under the plasma concentration vs time curve (AUC0-t and AUC0-inf) of APG-3288 following administration APG-3288 at escalating dose levels.
Time frame: From first dose through last measurable concentration, assessed up to 24 hours post-dose
Pharmacodynamic (PD) profile of APG 3288
The pharmacodynamic effects of APG 3288 will be evaluated by changes in Bruton's tyrosine kinase (BTK) levels from baseline over time during treatment.
Time frame: From baseline of study treatment through 30 days after the last dose
Objective response rate (ORR)
ORR is defined as the proportion of patients who achieve partial response (PR) or better as assessed by the investigator at each efficacy assessment and upon disease progression or at end-of-treatment
Time frame: From first dose until the first documented disease progression or end of treatment, assessed up to 24 months
Duration of response (DoR)
DoR is defined as duration in days from the date of initial documentation of a response (PR or better) to the date of first documented evidence of progressive disease for responders (PR or better) as assessed by the investigator or death due to any cause, whichever occurs first.
Time frame: From the first documented response until disease progression or death, assessed up to 24 months
Time to response (TTR)
TTR is defined as the time interval from date of first dose of study drug to the date of initial documentation of a response (PR or better) as assessed by the investigator.
Time frame: From first dose until the first documented response, assessed up to 24 months
Progression free survival (PFS)
PFS is defined as the time interval from date of first dose of study drug to the date of initial documentation of disease progression or death due to any cause, whichever occurs first, as assessed by the investigator.
Time frame: From first dose until the first documented disease progression or death, whichever occurs first, assessed up to 24 months
Overall survival (OS)
OS is defined as the time interval from date of first dose of study drug to the date of death due to any cause.
Time frame: From first dose until death from any cause, assessed up to 24 months
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