FDA Lifts Partial Clinical Hold Placed on Studies Evaluating Magrolimab in MDS and AML

Merdad Parsey, MD, PhD

The FDA has lifted a partial clinical hold that had been placed on studies examining magrolimab in combination with azacitidine following a review of comprehensive safety data collected from each trial, according to an announcement from Gilead Sciences, Inc.¹

The partial hold was put into place in January 2022, after an apparent imbalance in investigator-reported, suspected unexpected serious adverse reactions (SUSARs) that had been noted between study arms.² Although no clear trend in toxicities or new safety signals had been observed by the company at the time, the hold was placed on all ongoing studies that were evaluating the combination on a global scale.

The following trials were impacted by the hold: phase 3 ENHANCE trial (NCT04313881) in myelodysplastic syndrome (MDS), phase 3 ENHANCE-2 trial (NCT04778397) in acute myeloid leukemia (AML) and TP53 mutations, phase 3 ENHANCE-3 trial (NCT05079230) in unfit AML, phase 1b trial (NCT03248479) in MDS, and the phase 2 GS-4721 trial (NCT04778410) in myeloid malignancies (only the cohorts examining azacitidine combinations).

With the decision to lift the hold, trials examining the doublet in MDS and AML within the United States are permitted to resume enrollment.

The biopharmaceutical company is working with regulatory authorities to re-open enrollment to the studies that are evaluating magrolimab and were placed on voluntary hold outside of the United States. The company is also working with the FDA to address the remaining partial clinical hold on studies examining the agent in diffuse large B-cell lymphoma and multiple myeloma.

“Our confidence in the risk-benefit profile of magrolimab has been unwavering, and we continue to believe in the potential for this treatment to address the unmet medical needs faced by people living with MDS and AML,” Merdad Parsey, MD, PhD, chief medical officer of Gilead Sciences, stated in a press release. “This is a significant milestone for Gilead and, more importantly, for patients diagnosed with these cancers. We look forward to continuing our work developing magrolimab and advancing this potential cancer treatment option.”

Magrolimab was developed to block CD47 and the binding of the agent to the signal that results in strong macrophage-mediated phagocytosis of tumor cells, and azacitidine is known to synergize with the agent by boosting the expression of prophagocytic “eat me” signals.^3-5

In a phase 1b trial, the doublet was examined in patients with hematologic malignancies; this trial had been impacted by the partial hold.⁶ A total of 39 patients received the regimen on the trial, and they were of a median age of 70 years (range, 47-80). Thirteen percent of these patients had TP53-mutated disease.

Magrolimab was given in a priming/intrapatient dose-escalation regimen of 1 mg/kg up to 30 mg/kg once weekly for the first 2 cycles of treatment. The agent was then administered once every 2 weeks for cycles 3 and beyond. Patients received azacitidine at a dose of 75 mg/m² on days 1 and 7.

Data from the early-phase trial indicated that the doublet produced an objective response rate (ORR) of 91% in evaluable patients (n = 33); notably, 42% of those who responded to the doublet experienced a complete remission (CR). Several responses were noted to deepen with time. Those with at least 6 months of follow-up achieved a 56% CR rate. Moreover, the median overall survival (OS) had not yet been reached with the regimen (95% CI, 1.4-18.3), and the estimated OS rate at 6 months was 100%.

Of the 33 evaluable patients, 35% had cytogenetic CRs with the doublet, and the majority of responders (91%) still responded to treatment at 6 months. The median time to initial response was 1.9 months. Twenty-two percent of patients who achieved a CR, CR with incomplete hematologic recovery (CRi), or marrow CR also had minimal residual disease (MRD) negativity.

Patients who received the doublet experienced anemia (44%), fatigue (18%), infusion reaction (18%), and neutropenia (8%). Notably no patients in the MDS cohort stopped treatment due to an adverse effect. Moreover, no incidents of treatment-related febrile neutropenia were observed.

The open-label, phase 2 GS-4721 trial, another trial that had been impacted by the hold, was launched to examine the addition of magrolimab to other antileukemia therapies as potential therapeutic options for those with AML who require treatment in the first-line, relapsed/refractory, or maintenance settings.⁷

The trial is comprised of 3 safety run-ins that will be performed with a corresponding phase 2 trial. Cohort 1 will include patients with newly diagnosed, previously untreated AML who are not eligible to receive chemoimmunotherapy. These patients will be given magrolimab in combination with both azacitidine and venetoclax (Venclexta). A total of 6 patients will comprise the safety-run in, and 40 patients will be included in the phase 2 portion of the research.

Cohort 2 will include those with AML who are relapsed/refractory to induction chemoimmunotherapy. Those in this cohort will be given magrolimab for up to 1 year, in combination with mitoxantrone, etoposide, and cytarabine (MEC) for 2 to 3 cycles. The safety-run in will include 6 patients and 30 patients will comprise the phase 2 cohort.

Lastly, cohort 3 of the trial will include patients with AML who are either in CR or CRi after chemoimmunotherapy and who have MRD-positive disease. In these patients, magrolimab will be combined with CC-486. Six patients will be included in the safety run-in and 40 patients will comprise the phase 2 cohort.

Primary end points for GS-4721 include CR rate, MRD, percentage of those experiencing dose-limiting toxicities, percentage of patients experiencing treatment-emergent toxicities, and percentage of those with laboratory abnormalities.

Secondary end points include ORR, CR, duration of response (DOR), duration of CR, event-free survival, relapse-free survival, MRD, duration of MRD negativity, OS, red blood cell transfusion independence rate, platelet transfusion independence rate, and immunogenicity of the combinations.

Another trial impacted by the hold, the phase 3 ENHANCE trial, was launched to compare the effectiveness of magrolimab plus azacitidine compared with that of azacitidine alone in previously untreated patients with intermediate-, high-, or very high–risk MDS.⁸

ENHANCE will include patients with acceptable performance status and adequate hematologic, liver, and kidney function.⁹ Exclusion criteria include active hepatitis B, C, and/or human immunodeficiency virus, and those who received prior anti-CD47 or signal-regulatory protein α-targeting agents or those with clinical suspicion of active central nervous system involvement, among others.

Those on the investigative arm will receive magrolimab at 1 mg/kg on days 1 and 4 of cycle 1, followed by 15 mg/kg on day 8, and 30 mg/kg on days 11, 15, and 22. In cycle 2, participants will be administered 30 mg/kg of magrolimab on days 1, 8, 15, and 22. In cycle 3 and subsequent cycles, magrolimab will be given at 30 mg/kg every 2 weeks on days 1 and 15. Those in the control arm will be given matching placebo. Azacitidine was given in both treatment arms at 75 mg/m² on days 1 through 8, or days 1 through 5 and 8 to 9 of each cycle.

The primary end points of the trial are CR rate and OS, and key secondary end points are duration of CR, ORR, DOR, and progression-free survival.

Before the hold was put into place, the company had met the prespecified enrollment threshold required for the first interim analysis of ENHANCE. With the decision to lift the hold, Gilead shared that the readout for the first interim analysis is likely to remain on schedule for 2023.

References

1. FDA lifts partial clinical hold on MDS and AML magrolimab studies. News release. Gilead Sciences, Inc.; April 11, 2022. Accessed April 12, 2022. https://bit.ly/3vaf0jn
2. Gilead announces partial clinical hold for studies evaluating magrolimab in combination with azacitidine. News release. Gilead Sciences, Inc.; January 25, 2022. Accessed January 27, 2022. https://bit.ly/3rXlT6c
3. Bewersdorf JP, Carraway H, Prebet T. Emerging treatment options for patients with high-risk myelodysplastic syndrome. Ther Adv Hematol. 2020;11:2040620720955006. doi:10.1177/2040620720955006
4. Liu J, Wang L, Zhao F, et al. Pre-clinical development of a humanized anti-cd47 antibody with anti-cancer therapeutic potential. PLOS One. 2015;10(9):e0137345. doi:10.1371/journal.pone. e0137345
5. Sallman D, Malki MA, Asch A, et al. The first-in-class anti-CD47 antibody magrolimab combined with azacitidine is well-tolerated and effective in MDS patients: phase 1b results. Paper presented at: European Hematology Association 25 Virtual Congress. June 11-October 15, 2020. Accessed April 12, 2022. https://bit.ly/3CrsgSX
6. Sallman D, Malki MA, Asch A, et al. The first-in-class anti-CD47 antibody magrolimab combined with azacitidine is well-tolerated and effective in MDS patients: phase 1b results. Paper presented at: European Hematology Association 25 Virtual Congress. June 11-October 15, 2020. Accessed April 12, 2022. https://bit.ly/3CrsgSX
7. Vyas P, Daver N, Chao M, et al. A phase 2, open-label, multiarm, multicenter study to evaluate magrolimab combined with antileukemia therapies for first-line, relapsed/refractory, or maintenance treatment of acute myeloid leukemia. Blood. 2021;138(suppl 1):3424. doi:10.1182/blood-2021-145584
8. Garcia-Manero G, Daver NG, Xu J, et al. Magrolimab + azacitidine versus azacitidine + placebo in untreated higher risk (HR) myelodysplastic syndrome (MDS): the phase 3, randomized, ENHANCE study. J Clin Oncol. 2021;39(suppl 15):TPS7055. doi:10.1200/JCO.2021.39.15_suppl.TPS7055
9. Magrolimab + azacitidine versus azacitidine + placebo in untreated participants with myelodysplastic syndrome (MDS) (ENHANCE). ClinicalTrials.gov. Updated August 23, 2021. Accessed April 12, 2022. https://clinicaltrials.gov/ct2/show/NCT0431388