Gilead Discontinues Phase 3 ENHANCE-2 Trial of Magrolimab Plus Azacitidine in TP53-Mutant AML

The phase 3 ENHANCE-2 trial (NCT04778397) examining the frontline combination of magrolimab and azacitidine (Vidaza) vs physician’s choice of venetoclax (Venclexta) with azacitidine or intensive chemotherapy in patients with acute myeloid leukemia and TP53 mutations has been discontinued, according to an announcement from Gilead Sciences.¹

The decision followed a review conducted by an independent data monitoring committee and was based on data from an ad-hoc analysis. It was concluded that magrolimab is not likely to provide a survival benefit compared with standard of care in this population.

“Gilead is deeply grateful to the patients, families, investigators, and the advocacy community who participated in this trial and contributed greatly to this research. Investigators have been notified and Gilead is working with them on appropriate next steps for patients enrolled in the study,” according to the press release.

The randomized, open-label trial enrolled patients with treatment-naïve AML whose tumors harbored at least 1 TP53 mutation.² To participate, they needed to have an ECOG performance status ranging from 0 to 2 and have acceptable renal and cardiac function. Moreover, they were required to have a white blood cell count of up to 20 x 103/μL before randomization and a hemoglobin level of at least 9 g/dL.

Those who were candidates for intensive treatment but who had previously received maximum cumulative doses of idarubicin and/or other anthracyclines and anthracenediones were excluded, as were those who previously received SIRPα-targeted drugs or antileukemic therapy for their disease, a hypomethylating agent, low-dose cytarabine, and/or venetoclax. Those with suspected active central nervous system involvement or those with acute promyelocytic leukemia were also not permitted.

In the study, patients received an escalating dose of magrolimab and a fixed dose of azacitidine, which was given subcutaneously or intravenously (IV) at 75 mg/m2 on days 1 to 7 or days 1 to 5, as well as days 8 and 9 of every 28-day treatment cycle.

Those in the control arm of venetoclax plus azacitidine received venetoclax at 100 mg on day 1, 200 mg on day 2, and 400 mg on days 3 to 28 in cycle 1 followed by a dose of 400 mg on days 1 to 28 thereafter. Those in the intensive chemotherapy arm received induction and consolidation treatment, with daunorubicin given IV peripherally at 60 mg/m2 on days 1 to 3 and if needed on days 1 to 2 during a treatment cycle of up to 42 days and IV idarubicin given at 12 m/m2 on days 1 to 3 and if needed on days 1 to 2 during a treatment cycle of up to 42 days. Steroidal eye drops were given during consolidation in accordance with institutional standards.

Overall survival (OS) in patients who were candidates for non-intensive therapy represented the primary end point of the trial. Key secondary end points included OS in all patients, event-free survival in all patients, transfusion independence conversion rate in all patients, complete remission (CR) rate in all patients, and CR rate without minimal residual disease in all patients, among others.

In January 2022, the FDA placed a partial clinicalhold on all clinical trials examining magrolimab plus azacitidine after an apparent imbalance in investigator-reported, suspected unexpected serious adverse reactions observed between study arms.³ At the time, no clear trend in toxicities or new safety signals were reported. The partial hold impacted ENHANCE-2, the phase 3 ENHANCE trial (NCT04313881) in those with myelodysplastic syndrome, the phase 3 ENHANCE-3 trial (NCT05079230) in unfit patients with AML, a phase 1b trial (NCT03248479) in those with MDS, and the azacitidine cohorts of the phase 2 GS-4721 trial (NCT04778410) in those with myeloid malignancies. In April 2022, the partial hold was lifted after a comprehensive safety data review was performed.⁴

In July 2023, the ENHANCE trial was discontinued due to futility.⁵ A month later, in August 2023, the regulatory agency again placed a partial clinical hold on the initiation of new patients in US studies evaluating magrolimab in AML.⁶

References

1. Gilead statement on the discontinuation of magrolimab study in AML with TP53 mutations. News release. September 26, 2023. Accessed September 27, 2023. https://www.gilead.com/news-and-press/company-statements/gilead-statement-on-the-discontinuation-of-magrolimab-study-in-aml-with-tp53-mutations
2. Study of magrolimab in combination with azacitidine versus physician’s choice of venetoclax in combination with azacitidine or intensive chemotherapy in patients with TP53 mutant acute myeloid leukemia that have not been treated (ENHANCE-2). ClinicalTrials.gov. Updated August 31, 2023. Accessed September 27, 2023. https://classic.clinicaltrials.gov/ct2/show/NCT04778397
3. Gilead announces partial clinical hold for studies evaluating magrolimab in combination with azacitidine. News release. Gilead Sciences, Inc. January 25, 2022. Accessed September 27, 2023. https://www.gilead.com/news-and-press/press-room/press-releases/2022/1/gilead-announces-partial-clinical-hold-for-studies-evaluating-magrolimab-in-combination-with-azacitidine
4. FDA lifts partial clinical hold on MDS and AML magrolimab studies. News release. Gilead Sciences, Inc. April 11, 2022. Accessed September 27, 2023. https://www.gilead.com/news-and-press/press-room/press-releases/2022/4/fda-lifts-partial-clinical-hold-on-mds-and-aml-magrolimab-studies
5. Gilead to discontinue phase 3 ENHANCE study of magrolimab plus azacitidine in higher-risk MDS. News release. Gilead Sciences, Inc. July 21, 2023. Accessed September 27, 2023. https://www.gilead.com/news-and-press/press-room/press-releases/2023/7/gilead-to-discontinue-phase-3-enhance-study-of-magrolimab-plus-azacitidine-in-higher-risk-mds
6. Gilead announces partial clinical hold for magrolimab studies in AML. News release. Gilead Sciences, Inc. August 21, 2023. Accessed September 27, 2023. https://www.gilead.com/news-and-press/press-room/press-releases/2023/8/gilead-announces-partial-clinical-hold-for-magrolimab-studies-in-aml