FDA Halts Studies of Magrolimab Plus Azacitidine Amid Safety Discrepancy

The FDA has placed a partial clinical hold on studies evaluating the combination of magrolimab plus azacitidine (Vidaza) as a result of an imbalance in the investigator-reported serious adverse reaction between treatment arms, announced Gilead Sciences Inc, in a press release.¹

There has been no clear adverse event profile established from studies of magrolimab plus azacitidine so far, and no new safety signals have been observed. The partial clinical hold will include all clinical trials of magrolimab/azacitidine worldwide. The FDA’s action will halt screening and enrollment, but patients already enrolled in any study may continue treatment. The FDA suggests that these patients be closely monitored while on treatment.

"The safety and well-being 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,” said Merdad Parsey, MD, PhD, chief medical officer, Gilead Sciences, in a press release.

One clinical trial of note is the ENHANCE-2 study of magrolimab plus azacitidine versus venetoclax (Venclexta) in adult patients with previously untreated tp53-mutant acute myeloid leukemia (AML).² The study follows a phase 1b study of patients with AML and myelodysplastic syndrome (MDS) in which the magrolimab/azacitidine achieved an objective response rate (ORR) of 92% in a population of 24 patients with MDS. Response to magrolimab and azacitidine included the achievement of a complete response (CR), in 50% of patients a marrow CR in 33%, and hematologic improvement in 8%. Eight percent of patients had stable disease (SD).³

In the AML population of 22 patients, treatment with magrolimab plus azacitidine led to an ORR of 64%, which included CRs in 41% of patients, CR with complete blood count recovery in 14%, a morphologic leukemia-free state in 5%. In addition, 32% of patients had SD and 5% had progressive disease.

The median time to response in the overall study population was 1.9 months.

In terms of survival, the median overall survival was not reached in either cohort with a median follow-up of 6.4 months (range, 2.0-14.4) in the MDS cohort and 8.8 months (range, 1.9-16.9 months) in the AML cohort.

In ENHANCE-2, a phase 3, randomized, open-label study of magrolimab plus azacitidine in patients with tp53-mutant AML was recruiting roughly 346 patients to continue to evaluate the efficacy and safety of the combination. In the experimental arm, patients will be treated with intravenous magrolimab in combination with azacitidine 75 mg/m² on days 1-7 or days 1-5, 8, and 9 during every cycle. The study includes 2 comparator arms.²

In 1 comparator arm, patients will be treated with venetoclax 100 mg on day 1, 200 mg on Day 2, 400 mg on days 3-28 during cycle 1, followed by 400 mg on days 1-28 during every cycle in combination with azacitidine. In the second comparator arm, patients will receive 7 + 3 chemotherapy.

In the chemotherapy arm, cytarabine will be administered at 100 or 200 mg/m² on days 1-7. Patients will also receive cytarabine consolidation administered IV at 3000 mg/m2 on days 1, 3, and 5 once every 12 hours for up to 4 cycles. Daunorubicin will be administered at 60 mg/m² on days 1-3. Patients may be treated with idarubicin 2 mg/m² on days 1-3 in place of the other chemotherapy agents.

The primary end point of ENHANCE-2 is OS among patients appropriate for non-intensive therapy. The secondary end points of the study include OS in the overall population, event-free survival, red blood cell and platelet transfusion independence, complete remission rate, and quality of life.

Patients are eligible to enroll given they have a diagnosis of AML by World Health Organization criteria, an ECOG performance status of 0 to 2, as well as adequate cardiac function, liver function, and laboratory values at screening.

In addition to ENHANCE-2, the combination of magrolimab and azacitidine is being assessed in 10 other clinical trials that span AML, MDS, and other hematologic malignancies as well as in solid tumors.

“Considering the high unmet need for new medicines in myelodysplastic syndrome and acute myeloid leukemia, 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, said Parsey, in a press release.¹

Gilead is working closely with the FDA to determine what is needed to lift the partial clinical hold from studies of magrolimab plus azacitidine.

_References:

_{1. Gilead announces partial clinical hold for studies evaluating magrolimab in combination with azacitidine. News release. January 25, 2022. Accessed January 26, 2022. https://bit.ly/3KIX0nb}

_{2. Study to Evaluate the safety and efficacy of magrolimab in combination with azacitidine versus physician's choice of venetoclax in combination with azacitidine or intensive chemotherapy in previously untreated adults with tp53 mutant acute myeloid leukemia (ENHANCE-2). Clinicaltrials.gov. Accessed January 26, 2022. https://bit.ly/3o357Bv}

_{3. Forty Seven, Inc. announces updated data from ongoing clinical trial of magrolimab showing robust, durable activity in patients with myelodysplastic syndrome and acute myeloid leukemia. News release. December 9, 2019. Accessed January 26, 2022. https://bit.ly/3fWKJxk}