The combination of venetoclax and idasanutlin (ven-idasa) showed manageable safety and encouraging efficacy results in a phase 1b trial including patients with relapsed/refractory (R/R) acute myeloid leukemia (AML). Results for the ven-idasa arm of this trial were reported in the journal Blood.

The trial ( Identifier: NCT02670044) enrolled patients with R/R AML or newly diagnosed secondary AML who were ineligible for treatment with cytotoxic chemotherapy. Patients in the ven-idasa arm received venetoclax each day of a 28-day cycle and idasanutlin on days 1 to 5 of each cycle.

The study involved a 2-dimensional dose escalation and a dose schedule optimization. Primary study objectives focused on safety and determination of the maximum tolerated dose and recommended phase 2 dose (RP2D). Secondary objectives involved preliminary efficacy and pharmacokinetics analyses.

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There were 55 patients in the analysis of the ven-idasa arm, with 49 participating in dose escalation and 6 participating in dose schedule optimization. The median age for patients overall was 72.0 years (range, 41-93), and the overall population had a median of 1 prior therapy (range, 1-4). The AML type was de novo in 55% of patients overall, and secondary in 45%. Eastern Cooperative Oncology Group performance status was 0 in 31% of patients, 1 in 49%, and 2 in 20%.

The median follow-up duration for the total population was 4.0 months (95% CI, 0.0-23.3). The rate of composite complete remission (CRc) was 26.0% when including all doses in dose escalation, with a rate of morphologic leukemia-free state (MLFS) of 12.0% and an antileukemic response rate of 40.0%.

The anticipated RP2D included a venetoclax dose level of 600 mg plus idasanutlin at 150 mg or 200 mg. These doses were associated with a combined CRc rate of 34.3%, a combined MLFS rate of 14.3%, and a combined antileukemic response rate of 48.5%.

Antileukemic response rates were 78.6% in patients with IDH1/2 alterations and 60.0% in patients with RUNX1 alterations. TP53 alterations identified at baseline, with a threshold of 1% variant allele frequency, were associated with an antileukemic response rate of 30.0%. This represented 3 patients, 2 of whom also had an IDH1 or RUNX1 alteration.

The most common treatment-emergent adverse events (AEs) of any grade were diarrhea (87.3%), nausea (74.5%), vomiting (52.7%), hypokalemia (50.9%), and febrile neutropenia (45.5%). Serious AEs occurred in 81.8% of the population. Laboratory tumor lysis syndrome was reported in 3 patients and 1 patient with baseline renal insufficiency had clinical tumor lysis syndrome. Rates of treatment withdrawal due to an AE or a serious AE were 21.8% and 16.4%, respectively.

“In summary, ven-idasa demonstrated manageable safety and encouraging preliminary efficacy in a difficult-to-treat unfit R/R AML population, supporting further evaluation of combined BCL-2 and MDM2 inhibition in AML,” the study investigators wrote in their report.

Disclosures: Some authors have declared affiliations with or received grant support from the pharmaceutical industry. Please refer to the original study for a full list of disclosures.


Daver NG, Dail M, Garcia JS, et al. Venetoclax and idasanutlin in relapsed/refractory AML: a nonrandomized, open-label phase 1b trial. Blood. 2023;141(11):1265-1276. doi:10.1182/blood.2022016362