This is a Phase Ib/II, open-label, multi-center study evaluating the safety, tolerability, efficacy, and PK/ Pharmacodynamics of APG-2575 in combination with Pd/DRd in patients with relapsed/refractory (RR) multiple myeloma (MM).
This trial is currently open and accepting patients.
This is a Phase Ib/II, open-label, multi-center study evaluating the safety, tolerability, efficacy, and PK/ Pharmacodynamics of APG-2575 in combination with Pd/DRd in patients with relapsed/refractory (RR) multiple myeloma (MM). The study consists of dose escalation and dose expansion phases. The study consists of will start with 2 arms noted below, both arms are independent.
Arm A: APG-2575 will be administered in combination with Pd to determine the MTD and /RP2D of APG-2575 in subjects with R/R MM.
3+3 design will be utilized in dose escalation phase of APG-2575 in combination with Pd. The starting target dose of APG-2575 is 400 mg (dose level; DL1) and will be escalated in subsequent cohorts to 600 mg (DL2), 800 mg (DL3) accordingly. Dose reduction to 200 mg (DL-1) is acceptable if APG-2575 at dose of 400 mg cannot be tolerated. This rule-based design proceeds with cohorts of three patients. If none of the three patients enrolled in DL1 experiences a DLT, another three patients will be treated at DL2, and so on. However, if one patient experiences a DLT, three more patients will be treated at the same dose level. The dose escalation continues until at least two patients among a cohort of three to six patients experience DLT. MTD is conventionally defined as the highest dose level at which ≤ 33% of patients experience DLT. Higher dose level would be considered after a comprehensive analyses of safety data in the context of 800 mg can be well tolerated, otherwise, 800 mg (DL3) should be considered as MTD (Arm A). RP2D (Arm A) will be determined based on efficacy and safety profile of APG-2575 in combination with Pd.
Patients will receive APG-2575 at target dose once daily for 28 days plus pomalidomide (4 mg ) on Days 1 through 21 and dexamethasone (40 mg for patients ≤ 75 years old or 20 mg for patients > 75 years old) on Days 1, 8, 15, and 22 of a repeated 28-day cycle
The following criteria is a partial list of reasons why patients may be eligible to participate in this clinical trial. Further evaluation with a medical professional is required.
Exclusion Criteria:
Phase 1/2
Enrollment: 108 patients (estimated)
View MoreDecember 09, 2024
Results: As of May 29, 2024, 52 pts were enrolled, including 42 with R/R MM and 10 with AL amyloidosis. In Arm A (n = 35), lisaftoclax was administered orally at dose assigned: 400 mg (n = 3), 600 mg (n = 4), 800 mg (n = 15), 1,000 mg (n = 7), and 1,200 mg (n = 6). In Arm B (n = 7), all pts were treated with lisaftoclax 600 mg. In Arm C (n = 10), lisaftoclax was administered at 400 mg (n = 1), 600 mg (n = 4), 800 mg (n = 3), and 1,000 mg (n = 2). The median (range) age of all patients was 69.5 (24-88) years, of whom 63.5% were male and 63.5% were ≥ 65 years of age. The enrolled patients were heavily treated, with a median (range) number of treatment cycles of 4 (1-26), and a median (range) number of prior therapy lines of 3 (1-19). In Arm A, out of 31 evaluable patients, 3 (9.7%) achieved complete remission (CR), 7 (22.6%) reached very good partial remission (VGPR), and 9 (29.0%) achieved partial response (PR). The overall response rate (ORR) was 19 (61.3%), and the ≥ VGPR rate was 10 (32.3%). In Arm B, of 4 evaluable patients, 2 (50%) achieved CR and 2 (50%) ≥ VGPR. In Arm C, of 7 assessed patients, 1 (14.3%) achieved CR, 4 (57.1%) VGPR, 1 (14.3%) PR, and 5 (71.4%) ≥ VGPR, for an ORR of 6 (85.7%); 2 pts had cardiac response.
Among 49 pts in the safety population, 34 (69.4%) reported any-grade lisaftoclax treatment-related AEs (TRAEs; ≥ 5% incidence), including neutropenia (20.4%), thrombocytopenia (6.1%), leukopenia (10.2%), nausea (16.3%), abdominal distension (10.2%), diarrhea (12.2%), and constipation (8.2%). A total of 11 pts experienced grade ≥ 3 TRAEs, including neutropenia (14.3%) and febrile neutropenia (2%), and 3 pts experienced lisaftoclax-related serious AEs (1 each): febrile neutropenia, acute kidney injury, and diarrhea with electrolyte imbalance. In Arm B, 1 pt experienced a dose-limiting toxicity (prolonged QT interval). Pharmacokinetic analyses showed no drug-drug interaction (DDI) in all pts treated with lisaftoclax at all doses in combination with other therapeutic agents used in 3 arms.
Conclusions: Our findings suggest that lisaftoclax improves the depth of response in pts with R/R MM or AL amyloidosis when combined with Pd or DRd. These combination therapies demonstrated a favorable safety profile with no drug-drug interactions, particularly in hematologic side effects. ClinicalTrials.gov registration: NCT04942067; internal study identifier: APG2575MU101.
December 09, 2023
As of July 3, 2023, a total of 30 patients were enrolled: 22 in Arm A at dose levels of 400 (n = 3), 600 (n = 4), 800 (n = 3), 1,000 (n = 6), and 1,200 mg (n = 6); 3 in Arm B at 600 mg; and 5 in Arm C at 400 (n = 1) and 600 mg (n = 4). A total of 66.7% of patients were male, and the median (range) age was 70.5 (24-88) years, with 66.7% of patients above the age of 65. The median (range) lines of prior therapies was 4 (1-19), and median (range) time from diagnosis to first dose was 5.2 (1-29) years. The median (range) number of treatment cycles was 4 (1-19). A total of 18 patients were triple-class-exposed, 7 had received pomalidomide, and 3 harbored t(11;14) at baseline. A total of 19 patients reported experiencing any-grade lisaftoclax treatment-related adverse events (TRAEs), including neutropenia or nausea (16.7% each); and thrombocytopenia, leukopenia, abdominal distension, constipation, or diarrhea (6.7% each). Seven patients experienced grade ≥ 3 TRAEs, including neutropenia (10%) and febrile neutropenia, iron deficiency anemia, thrombocytopenia, prolonged electrocardiogram QT interval, and acute kidney injury (3.3% each). Two patients experienced lisaftoclax-related serious AEs, of which 1 was febrile neutropenia and 1 acute kidney injury. In Arm B, 1 patient experienced a dose-limiting toxicity (prolonged QT interval). A total of 12 patients discontinued treatment because of disease progression (n = 8), an AE (n = 1), noncompliance (n = 1), and investigator/patient decision (n = 2). In Arm A, 21 patients with R/R MM were evaluable, of whom 9 experienced a partial response (PR) and 5 a very good PR (VGPR). The overall response rate (ORR [PR or better]) was 66.7%, with a median (range) time to response of 1.2
(1-3) months. After a median (range) time to response of 1.4 (1-2) months, 2 patients with R/R MM in Arm B achieved a PR (n = 1) or VGPR (n = 1). In Arm C, 3 patients with R/R amyloidosis achieved a hematologic VGPR; the ORR was 60%; the median (range) time to response was 0.9 (1-1) month; and 1 patient experienced organ function improvement.
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