FDA Places Partial Clinical Hold on Trials Examining Magrolimab Plus Azacitidine in MDS, AML, and Myeloid Malignancies

Merdad Parsey, MD, PhD

The FDA has placed a partial clinical hold on clinical trials evaluating the combination of magrolimab and azacitidine after an apparent imbalance in investigator-reported, suspected unexpected serious adverse reactions (SUSARs) observed between study arms.¹

Gilead Sciences Inc. reported that although no clear trend in adverse effects or new safety signals have been observed by the company at this time, the hold is being implemented across all ongoing studies evaluating the doublet on a global scale, as it is in the best interests of patients.

The following trials will be impacted by the hold:

• Phase 3 ENHANCE trial (NCT04313881) in myelodysplastic syndromes (MDS)
• Phase 3 ENHANCE-2 trial (NCT04778397) in acute myeloid leukemia (AML) harboring TP53 mutations
• Phase 3 ENHANCE-3 trial (NCT05079230) in unfit AML
• Phase 1b trial (NCT03248479) in MDS
• Phase 2 GS-4721 trial (NCT04778410) in myeloid malignancies (only the cohorts exploring azacitidine combinations)

These trials examining the combination will pause the screening and enrollment of new study participants, but those who are already enrolled can continue to receive the combination. They will be closely monitored per the current study protocol.

The company is in the process of informing both clinical investigators and global regulatory authorities about the partial clinical hold.

The phase 2 trials being done in diffuse large B-cell lymphoma (NCT02853509), multiple myeloma (NCT04892446), head and neck squamous cell carcinoma (NCT04854499), solid tumors (NCT04827576), triple-negative breast cancer (NCT04958785), and colorectal cancer (planned, not currently recruiting), are not impacted by the decision; as such, they will continue as planned.

During this time, additional data are being collected and evaluated to address the concerns raised by the regulatory agency. Gilead is working with regulatory authorities to identify next steps to release the hold for new enrollment in the studies that are affected by the decision.

“The safety and wellbeing of people enrolled in our studies is our top priority. We will share more information with the medical and patient community as soon as we can,” Merdad Parsey, MD, PhD, chief medical officer at Gilead Sciences, stated in a press release. “Considering the high unmet need for new medicines in MDS and AML, we will work closely with regulatory authorities worldwide to continue the magrolimab development program appropriately. We remain confident in the potential of magrolimab across a broad range of tumors, including the other, ongoing magrolimab studies.”

Magrolimab is designed to block CD47, and the binding of the agent to that signal produces potent macrophage-mediated phagocytosis of tumor cells. Azacitidine synergizes with magrolimab by increasing the expression of prophagocytic “eat me” signals.^2-4

Investigators evaluated magrolimab and azacitidine in patients with hematologic malignancies as part of a phase 1b trial, which is impacted by the partial clinical hold. Here, 39 patients were treated with the combination. The median age of participants in this cohort was 70 years (range, 47-80). Notably, 13% of patients had tumors that harbored a TP53 mutation.⁵

Participants received magrolimab in a priming/intrapatient dose-escalation regimen of 1 mg/kg to 30 mg/kg once weekly for the first 2 treatment cycles, then once every 2 weeks in cycles 3 and beyond. Azacitidine was given at 75 mg/m² on days 1 and 7.

The combination elicited an objective response rate (ORR) of 91% among 33 evaluable patients, with 42% of responders experiencing a complete remission (CR). Moreover, several responses were observed to deepen over time, and those with at least 6 months of follow-up were reported to achieve a CR rate of 56%. The median overall survival (OS) with the combination had not yet been reached (95% CI, 1.4-18.3), and the estimated 6-month OS rate was 100%.

Thirty-five percent of evaluable patients experienced cytogenetic CRs, and 91% of responders were still in response at 6 months. The median time to initial response was 1.9 months. Notably, 22% of patients with a CR, CR with incomplete hematologic recovery, or marrow CR achieved minimal residual disease (MRD) negativity.

The most common toxicities experienced by those who received the treatment included anemia (44%), fatigue (18%), infusion reaction (18%), and neutropenia (8%). None of the patients in the MDS cohort discontinued treatment because of toxicity, and no treatment-related febrile neutropenia was observed.

Magrolimab in combination with several antileukemia therapies are under investigation for efficacy as options for frontline, relapsed/refractory, or maintenance treatment of patients with AML as part of the phase 2 GS-4721 trial, although this research is also impacted by the hold.⁶

The open-label study will have 3 safety run-ins will be conducted with a corresponding phase 2 trial. Cohort 1 of the trial will comprise patients with newly diagnosed, previously untreated AML who are not candidates for chemoimmunotherapy. They will receive magrolimab plus venetoclax (Venclexta) and azacitidine. Six patients will be included in the safety run-in and the phase 2 arm will comprise 40 patients.

Cohort 2 will include patients with AML who are relapsed/refractory to induction chemoimmunotherapy. These patients will receive magrolimab up to 12 months in combination with mitoxantrone, etoposide, and cytarabine (MEC) for 2 to 3 cycles. Six patients will be included in the safety run-in and 30 patients will be included in the phase 2 cohort.

Cohort 3 will comprise those with AML who are in CR or CRi following chemoimmunotherapy and who have MRD positivity. Magrolimab will be administered in combination with CC-486. Again, the safety run-in will include 6 patients and the phase 2 arm will comprise 40 patients.

The primary end points of the trial include CR rate, MRD, percentage of those experiencing dose-limiting toxicities, percentage of patients experiencing treatment-emergent toxicities, and the percentage of those experiencing laboratory abnormalities. Secondary end points comprise 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 combination regimens.

Additionally, the phase 3 ENHANCE trial, which is also impacted by the hold, was recently launched to examine the efficacy of magrolimab plus azacitidine vs azacitidine plus placebo in previously untreated patients with intermediate-, high-, or very high–risk MDS.⁷

To be eligible for enrollment, patients must have acceptable performance status and hematologic, liver, and kidney function.⁸ Those with active hepatitis B, C, and/or human immunodeficiency virus after testing at screening or in their medical history, will be excluded, as will those who previously received an anti-CD47 or signal-regulatory protein α-targeting agents or those with clinical suspicion of active central nervous system involvement.

Other exclusion criteria include having previously undergone antileukemic therapy for treatment of intermediate-, high-, or very high–risk MDS, having contraindications to azacitidine, and those who are immediately eligible for allogenic stem cell transplant with an available donor.

Patients on the investigative arm will be given intravenous magrolimab at a dose of 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, patients will be given 30 mg/kg of magrolimab on days 1, 8, 15, and 22. In cycle 3 and thereafter, magrolimab will be given at 30 mg/kg every 2 weeks on days 1 and 15. Those on the control arm were given placebo to match magrolimab. Azacitidine was administered in both arms at a dose of 75 mg/m² on days 1 to 7, or days 1 to 5 and 8 to 9 of each treatment cycle.

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

References

1. 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
2. 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
3. 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
4. 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 January 27, 2022. https://bit.ly/3CrsgSX
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 January 27, 2022. https://bit.ly/3CrsgSX
6. 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
7. 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
8. Magrolimab + azacitidine versus azacitidine + placebo in untreated participants with myelodysplastic syndrome (MDS) (ENHANCE). ClinicalTrials.gov. Updated August 23, 2021. Accessed January 27, 2022. https://clinicaltrials.gov/ct2/show/NCT0431388