Gilead Discontinues Phase 3 ENHANCE-3 Trial of Magrolimab Plus Venetoclax/Azacitidine in AML

The phase 3 ENHANCE-3 study (NCT04313881) evaluating the efficacy of magrolimab plus venetoclax (Venclexta) and azacitidine (Vidaza) vs venetoclax and azacitidine alone in previously untreated patients with acute myeloid leukemia (AML) who are not eligible for chemotherapy has been terminated, according to an announcement from Gilead Sciences.¹

The FDA has also placed full clinical holds on all studies investigating magrolimab in AML and myelodysplastic syndrome (MDS), including associated expanded access programs.

The decisions follow a review of top-line findings from a planned interim analysis of overall survival (OS) conducted by an independent data monitoring committee, which revealed futility with the magrolimab combination and an increased risk of death that was mainly driven by respiratory failure and infections. Patients will now discontinue treatment with magrolimab, and Gilead will connect with study investigators to determine additional next steps.

Previously, in July 2023, the company discontinued the phase 3 ENHANCE trial (NCT04313881) examining frontline magrolimab plus azacitidine vs placebo and azacitidine in patients with higher-risk MDS due to futility with an increased risk of death at a planned analysis.^1,2 In September 2023, the phase 3 ENHANCE-2 trial(NCT04778397) of frontline magrolimab plus azacitidine vs physician’s choice of venetoclax plus azacitidine or intensive chemotherapy in patients with TP53-mutated AML was also discontinued for the same reasons.^1,3

Gilead shared that based on the data from the ENHANCE studies, they will not pursue further development of magrolimab in hematologic malignancies.¹

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

ENHANCE-3: Eligibility, Treatment, Objectives

The randomized, double-blind, placebo-controlled, phase 3 study enrolled patients with treatment-naive, histologically confirmed AML by World Health Organization criteria who were not eligible to receive a standard induction regimen of cytarabine and an anthracycline because of age or cormobidity.⁴

Patients could be 75 years of age or older with an ECOG performance status of 0 to 2, or be at least 18 years of age but no older than 74 years of age and have at least one of the following: an ECOG performance status of 2 or 3, left ventricular ejection fraction of 50% or less, a baseline creatinine clearance of at least 30 mL/min but under 45 mL/min, hepatic disorder with total bilirubin greater than 1.5 x the supper limit of normal, or other comorbidities.

If patients previously received CD47 or SIRPα-targeted agents, antileukemic treatment for their disease with the exception of hydroxyurea (Hydrea), had suspicion of or documented active central nervous system involvement, acute promyelocytic leukemia, or a second malignancy, they were excluded.

All patients received venetoclax at 100 mg on day 1 of cycle 1, 200 mg on day 2 of cycle 1, and 400 mg on day 3 of cycle 1, and daily thereafter plus azacitidine at 75 mg/m2 on days 1 to 7 or days 1 to 5 and days 8 to 9 of each 28-day cycle. Those in the investigative arm were given a 1-mg/kg priming dose of magrolimab on days 1 and 4, followed by 15 mg/kg on day 8, and 30 mg/kg on days 11 and 15, and then every week for 5 doses and every 2 weeks thereafter.

The primary end point of the trial was OS, and secondary end points included complete remission (CR) rate/CR with partial hematologic recovery (CRh) rate, CR rate, and event-free survival, among others.

The company plans to share a summary of data from all 3 magrolimab studies and plans to present the results at future medical meetings.1 Gilead is also examining the safety of the agent across all solid tumor trials and will provide an update on this assessment.

References

1. Gilead statement on discontinuation of phase 3 ENHANCE-3 study in AML. News release. Gilead Sciences, Inc. February 7, 2024. Accessed February 8, 2024. https://www.gilead.com/news-and-press/company-statements/gilead-statement-on-discontinuation-of-phase-3-enhance-3-study-in-aml
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 8, 2024. 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
3. Gilead statement on the discontinuation of magrolimab study in AML with TP53 mutations. News release. September 26, 2023. Accessed February 8, 2024. https://www.gilead.com/news-and-press/company-statements/gilead-statement-on-the-discontinuation-of-magrolimab-study-in-aml-with-tp53-mutations
4. Study of magrolimab versus placebo in combination with venetoclax and azacitidine in participants with acute myeloid leukemia (ENHANCE-3). ClinicalTrials.gov. Updated January 19, 2024. Accessed February 8, 2024. https://classic.clinicaltrials.gov/ct2/show/NCT05079230