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Clinical Trial
. 2024 Dec 24;8(24):6248-6256.
doi: 10.1182/bloodadvances.2024013687.

Lower-intensity CPX-351 plus venetoclax induction for adults with newly diagnosed AML unfit for intensive chemotherapy

Geoffrey L Uy  1 , Vinod Pullarkat  2 , Praneeth Baratam  3 , Robert K Stuart  3 , Roland B Walter  4 , Eric S Winer  5 , Qi Wang  6 , Stefan Faderl  7 , Divya Chakravarthy  7 , Diane Menno  6 , Ronald S Cheung  7 , Tara L Lin  8
Affiliations
Clinical Trial

Lower-intensity CPX-351 plus venetoclax induction for adults with newly diagnosed AML unfit for intensive chemotherapy

Geoffrey L Uy et al. Blood Adv. .

Abstract

Preclinical data suggest a rationale for combining CPX-351, a dual-drug liposomal encapsulation of daunorubicin and cytarabine, with venetoclax, a B-cell lymphoma-2 inhibitor. This phase 1b study evaluated lower-intensity CPX-351 combined with venetoclax in adults with acute myeloid leukemia (AML) considered unfit/ineligible for intensive chemotherapy. In a dose-exploration phase using a 3+3 design, patients received stepwise dosing of CPX-351 IV on days 1 and 3 plus venetoclax 400 mg orally on days 2 to 21 per cycle to determine the recommended phase 2 dose (RP2D) for this combination. During the expansion phase, additional patients received CPX-351 plus venetoclax at the identified RP2D. The primary end points were the RP2D and safety of CPX-351 combined with venetoclax. Secondary end points included preliminary efficacy and pharmacokinetics. Overall, 35 patients were enrolled in the study. A RP2D of CPX-351 30 units/m2 (daunorubicin 13.2 mg/m2 and cytarabine 30 mg/m2) plus venetoclax 400 mg was established. The safety profile of the combination was consistent with the known safety profiles of CPX-351 and venetoclax. Complete remission (CR)/CR with incomplete hematologic recovery (CRi) was achieved by 17 of 35 patients (49%), all after cycle 1; of these, 14 were negative for measurable residual disease. CR was achieved by 1 of 8 patients (13%) with a mutation in TP53, and CR/CRi was achieved by 15 of 26 patients (58%) with wild-type TP53. This study highlights that lower-intensity therapy of CPX-351 plus venetoclax as induction therapy provides a well-tolerated treatment option in adults with AML deemed unfit for intensive chemotherapy. This trial was registered at www.ClinicalTrials.gov as #NCT04038437.

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Conflict of interest statement

Conflict-of-interest disclosure: G.L.U. has received consulting fees from and has participated on a data safety monitoring board or advisory board for Jazz Pharmaceuticals. V.P. has received consulting fees and payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from AbbVie and Jazz Pharmaceuticals; and has participated on a data safety monitoring board or advisory board for AbbVie. P.B. has received payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Bristol Myers Squibb and Rigel Pharma; and participated on a data safety monitoring board or advisory board for Kite Pharma, ONO Pharma, and Protagonist Therapeutics. R.K.S. declares no competing financial interests. R.B.W. received clinical trial support from Jazz Pharmaceuticals. E.S.W. has participated on a data safety monitoring board or advisory board for Curis and Takeda. Q.W. was an employee of Jazz Pharmaceuticals at the time of the study and holds stock ownership in Jazz Pharmaceuticals. S.F. is an employee of and holds stock ownership/options in and participated on a data safety monitoring board for Jazz Pharmaceuticals. D.C. and R.S.C. are employees of, hold stock ownership/options in, received support for meetings/conferences and travel from, and participated on a data safety monitoring board for Jazz Pharmaceuticals. D.M. was an employee of Jazz Pharmaceuticals at the time of the study and received stock options in Jazz Pharmaceuticals. T.L.L. has received funding (with payments made directly to her institution) from Jazz Pharmaceuticals; grants or contracts (with payments made directly to her institution) from Aptevo, Astellas Pharma, Biopath Holdings, Ciclomed, Cleave, Kura Oncology, Leukemia & Lymphoma Society, and Trovagene; and has participated in an advisory board with Servier.

The current affiliation for Q.W. is Enliven Therapeutics, Boulder, CO.

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References

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