Preliminary Safety and Efficacy of Bgb-11417, a Novel Bcl-2 Inhibitor, in Combination with Azacitidine in Patients with Acute Myeloid Leukemia (AML)
As of June 1, 2022, 51 pts with AML were treated (16 in cohort 1; 17 in cohort 2; 14 in cohort 3; 4 in cohort 4). Median age was 77 yrs (TN, n=28) and 64 yrs (R/R, n=23) (Table 1). At baseline, 23 pts (45.1%) had adverse-risk cytogenetics, 37 (72.5%) had grade ≥3 neutropenia, and 27 (52.9%) had grade ≥3 thrombocytopenia.
At a median follow-up of 2.8 mo (range 0.1-12.3) and median duration of treatment of 1.9 mo (range 0.0-12.3), 2 of 41 evaluable pts experienced DLTs (grade 4 neutropenia and grade 4 thrombocytopenia at 80 mg) (Table 2), which did not meet the safety stopping protocol criteria. Laboratory tumor lysis syndrome (TLS; Howard criteria) was observed in 1 pt (160 mg x 10 days) with a known history of chronic kidney disease; TLS resolved within 4 days.
Twenty-one (41%) pts discontinued study drugs: 7 (13.7%) due to AEs, 5 (9.8%) due to disease progression, 4 (7.8%) proceeded to transplant, 3 (5.9%) withdrew consent, 1 (2.0%) per investigator decision, and 1 (2.0%) started new anti-cancer treatment.
The most common TEAEs were neutropenia (58.8%), thrombocytopenia (45.1%), anemia (43.1%), febrile neutropenia (33.3%), nausea (39.2%), and constipation (37.3%). Neutropenia was the most common grade ≥3 TEAE observed in 30 (58.8%) pts; most cases did not require dose modification. Grade ≥3 infections occurred in 23 (45.1%) pts, mostly in cycle 1. The general incidence of febrile neutropenia and infections decreased with subsequent cycles. Four (7.8%) pts died due to unrelated TEAEs: bronchopulmonary aspergillosis, pneumonia, pulmonary sepsis, and possible intracranial hemorrhage after a fall. TEAEs leading to dose reduction (5.9%) or dose interruption (11.8%) were infrequent.
In TN AML, complete remission (CR)/CR with partial hematologic recovery (CRh) was achieved in 16 (59.3%) and CR in 13 (48.1%) evaluable pts (Table 1). Of the 13 pts in CR, 7 (53.8 %) reached CR by end of cycle 1. In cohort 2 with the longest follow-up, CR was achieved in 8 (72.7%) pts with TN AML. Notably, 7 of these pts are continuing study treatment (median of 5 cycles, range 1-12) without progression. In R/R AML, CR/CRh was seen in 50% of evaluable pts, with a CR rate of 25%. Nine (50.0%; 6 TN, 3 R/R) of 18 evaluable pts with CR/CRh achieved MRD negativity (<0.1% per ELN 2018).
In pts with AML treated with 40, 80, and 160 mg, PK increased in a dose-dependent manner at steady state with no drug-drug interaction observed with aza.