FDA Places Full Clinical Hold on Magrolimab Trials in AML, MDS

The FDA previously placed a partial clinical hold on trials evaluating magrolimab in AML in August 2023.

The FDA has placed a full clinical hold on all studies evaluating magrolimab in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), and investigators have discontinued their assessment of the agent in those with AML as part of the phase 3 ENHANCE-3 study (NCT05079230), according to a press release from Gilead Sciences, Inc.¹

The ENHANCE-3 study’s discontinuation follows an independent data monitoring committee’s assessment of topline overall survival (OS) results. Analysis indicated that magrolimab plus azacitidine and venetoclax (Venclexta) resulted in futility and an increased risk of death, which was primarily attributed to respiratory failure and infections.

Findings from other clinical trials, including the phase 3 ENHANCE trial (NCT04313881) assessing magrolimab plus azacitidine in higher-risk MDS and the phase 3 ENHANCE-2 trial (NCT04778397) evaluating the combination in TP53-mutated AML, also highlighted an increased risk of death with magrolimab-based treatment. Investigators discontinued the ENHANCE trial following reports of futility in a planned analysis in July 2023.²

Those enrolled on the ENHANCE-3 trial will discontinue study treatment, and developers are collaborating with investigators to determine suitable next steps for these patients. Investigators are also currently conducting efficacy and safety sub-analyses and plan to share their findings with regulatory authorities. Additionally, data from these analyses will be submitted for presentation at a future medical meeting and/or publication in a medical journal.

Developers plan to share an integrated summary of findings related to magrolimab across all ENHANCE trials. A review of magrolimab’s safety in solid tumor trials is also ongoing.

“The complexity of treating blood cancer is highlighted in these results. We are incredibly grateful to all the patients and investigators for their participation in the ENHANCE studies,” Merdad Parsey, MD, PhD, chief medical officer at Gilead Sciences, said in the press release.¹

In the ENHANCE-3 trial, patients were randomly assigned to receive magrolimab at 1 mg/kg on days 1 and 4 followed by 15 mg/kg on day 8 and 30 mg/kg on days 11, 15, and then every week for 5 doses and every 2 weeks thereafter or matched placebo in combination with venetoclax and azacitidine. Investigators administered venetoclax at 100 mg on day 1, 200 mg on day 2, and 400 mg on day 3 and every day thereafter plus azacitidine at 75 mg/m² on days 1 to 7 or days 1 to 5 and 8 to 9 of each cycle.

The trial’s primary end point was OS. Secondary end points included the complete remission (CR) rate, event-free survival, duration of CR, quality of life, and treatment-emergent adverse effects (TEAEs).

Patients 18 years and older with previously untreated, histologically confirmed AML based on World Health Organization criteria were able to enroll on the trial. Those 18 to 74 years old needed to have an ECOG performance status of 0 to 3 to enroll, while patients 75 years and older were required to have an ECOG performance status of 0 to 2.

Those who received prior antileukemic therapy for AML or active central nervous system involvement were ineligible to enroll on the trial. Patients were also unsuitable for enrollment if they had acute promyelocytic leukemia.

The FDA previously placed a partial clinical hold on trials evaluating magrolimab in AML in August 2023.³

Magrolimab previously earned breakthrough therapy designation from the FDA for the management of newly diagnosed MDS in September 2020.⁴ Supporting data for the designation came from a phase 1b study in which magrolimab elicited an objective response rate of 91% among 33 evaluable patients.

References

1. Gilead statement on discontinuation of phase 3 ENHANCE-3 study in AML. News release. Gilead Sciences, Inc. February 7, 2024. Accessed February 9, 2024. http://tinyurl.com/347tjc2h
2. Gilead to discontinue phase 3 ENHANCE study of magrolimab plus azacitidine in higher-risk MDS. News release. Gilead Sciences, Inc. July 21, 2023. Accessed February 9, 2024. bit.ly/3Qd0xzk
3. Gilead announces partial clinical hold for magrolimab studies in AML. News release. Gilead Sciences, Inc. August 21, 2023. Accessed February 9, 2024. http://tinyurl.com/3t8xjz58
4. Gilead’s magrolimab, an investigational anti-CD47 monoclonal antibody, receives FDA breakthrough therapy designation for treatment of myelodysplastic syndrome. News release. Gilead Sciences, Inc. September 15, 2020. Accessed February 9, 2024. bit.ly/43C2EQs