FDA Pauses Magrolimab Studies in Acute Myeloid Leukemia

• No new patients with acute myeloid leukemia (AML) can be screened or enrolled in a magrolimab clinical trial at this time due to a partial clinical hold.

• The partial clinical hold impacts the newly-launched phase 3 ENHANCE-2 clinical trial (NCT04778397).

• Gilead Sciences is working with the FDA to have the partial clinical hold lifted.

A partial clinical hold has been placed by the FDA on the initiation of new patients in studies of magrolimab for the treatment of AML.¹

This FDA action impacts screening and enrollment for studies under a specific investigational new drug application (IND 147229) as well as a US Expanded Access Program. The action does not impact treatment of patients who were already receiving the drug, nor does it affect trials of magrolimab in patients with solid tumors.

This partial clinical hold is a second for magrolimab. In January 2022, development of magrolimab in combination with azacitidine (Vidaza) was halted for patients with AML and myelodysplastic syndrome due to an imbalance of investigator-reported unexpected adverse events in the study.² The hold was lifted in April 2022,³ but the company then discontinued the phase 3 ENHANCE study (NCT04313881) of magrolimab plus azacitidine vs placebo plus azacitidine due to futility.

Before the pause, Gilead Sciences was exploring the use of magrolimab in combination with azacitidine vs physician’s choice of venetoclax (Venclexta) in combination with azacitidine or intensive chemotherapy in previously untreated patients with TP53-mutant AML (ENHANCE-2). The phase 3, randomized, open-label study was aiming to enroll 346 patients with TP53-mutant AML who would receive an escalating dose of intravenous (IV) magrolimab with azacitidine 75 mg/m² on days 1 through 7 or days 1 through 5, 8, and 9 of a 28-day cycle in the experimental arm.⁴

Those randomly assigned to the venetoclax plus azacitidine control arm were going to receive venetoclax 100 mg on day 1, 200 mg on day 2, 400 mg on days 3 through 28 during cycle 1, followed by 400 mg on days 1 to 28 of every cycle with matching azacitidine. In the 7 + 3 chemotherapy control arm, patients were to be treated with IV cytarabine at 100 or 200 mg/m² on days 1 to 7 with IV daunorubicin 60 mg/m² on days 1 to 3, IV idarubicin 12 mg/m² on days 1 to 3, and steroidal eye drops.

The primary end point of the ENHANCE-2 study is overall survival in patients eligible for non-intensive therapy. Secondary efficacy end points to be explored if the study resumes are OS in all patients, event-free survival, transfusion independence conversion rate, rate of complete remission (CR) in all patients, rate of CR in without minimal residual disease, quality of life measures, rate of CR and CR with partial hematologic recovery (CR+CRh), and duration of CR+CRh.

For safety, the study will evaluate the percentage of patients with grade 3 or higher treatment-emergent adverse events, the percentage of patients who experience grade 3 or higher treatment-emergent laboratory abnormalities, serum concentration of magrolimab, and the rate of anti-magrolimab antibody indigence.

Patients who will be eligible to enroll once the partial clinical hold is lifted are those with confirmed AML, an ECOG performance status of 0 to 2 if under 75 years of age, and 0 to 3 if 75 years or older. In addition, patients are required to have adequate cardiac function and laboratory values at baseline to be eligible for inclusion in the study. A pretreatment blood cross-match must be completed in all patients, and they must all agree to use contraception while on the study treatment.

Gilead Sciences plans to work with the FDA to take the needed steps to have the partial clinical hold lifted from trials of magrolimab for the treatment of patients with AML.

_REFERENCES:

_{1. Gilead announces partial clinical hold for magrolimab studies in AML. News release. Gilead Sciences. August 21, 2023. Accessed August 21, 2023. https://www.gilead.com/news-and-press/press-room/press-releases/2023/8/gilead-announces-partial-clinical-hold-for-magrolimab-studies-in-aml}

_{2. Gilead announces partial clinical hold for studies evaluating magrolimab in combination with azacitidine. News release. January 25, 2022. Accessed August 21, 2023. https://bit.ly/3KIX0nb}

_{3. FDA lifts partial clinical hold on MDS and AML magrolimab studies. News release. Gilead Sciences, Inc. April 11, 2022. Accessed August 21, 2022. https://bit.ly/3v8QIXb}

_{4. 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 21, 2023. Accessed August 21, 2023. https://classic.clinicaltrials.gov/ct2/show/NCT04778397}