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 Clinical Trial)
The study we are conducting here is a randomized phase 3 international study of Azacitidine Magrolimab (Hu5F9-G4), versus investigator choice therapy of either Azacitidine Venetoclax or intensive three plus seven, specifically in a molecular subset of TP53-mutated (TP53m), acute myeloid leukemia. The goal of this study is to see whether the combination treatment of Azacitidine with CD47 immune therapy Magrolimab (Hu5F9-G4) could improve overall survival compared to investigative choice therapy, whether it’s lower intensity, such as Azacitidine Venetoclax, or even higher intensity, such as the 3 plus seven treatment, and the studies based on Phase 1B2 data that we have presented showing that the combination of Azacitidine and CD47 antibody Magrolimab (Hu5F9-G4).
Magrolimab highly effective, both at generating responses, including true CRs, as well as very encouraging median overall survival greater than 12 months. These compare very favorably to previously published datasets with either Azacitidine Venetoclax or 3 Plus 7 and is now led to this randomized registration, frontline studying TB53 mutated, acute myeloid leukemia.
The most common questions I get about these Magrolimab studies is what do we assume will be the response rates as an overall survival with the citing micro and whether this will be sufficient to beat the standard of care arm. We can only base this based on the data we have already presented from the phase 1B study.
This was last presented at the ASH 2020 meeting by Dr. David Solomon, one of my colleagues that was the last author on that presentation. And we basically showed that the combination of Azacitidine Magrolimab (Hu5F9-G4) in the TP53-mutated (TP53m) acute myeloid leukemia, we had 29 patients presented at that time shows a overall response rate of about 65%.
With a true CR rate of about 45%. And this is very encouraging because with Azacitidine Venetoclax, which is the current frontline standard of care for over on 50 P 50 mutated acute myeloid leukemia, the overall response rate is about 50% with a true CR rate of 20%. So numerically, these look better and more importantly, the median survival in the TP53 acute myeloid leukemia was greater than 12 months and historically Azacitidine Venetoclax the median survival in 3 different subsets that have been presented has been between 5 and 7 months. So, this looks like it’s so far among the treatments, we have seen the best combination for TP53-mutated (TP53m) AML. And that’s why we’re evaluating it in this randomized study.
The other question I often get is whether. A triple combination of Azacitidine and Venetoclax with Magrolimab (Hu5F9-G4) could be the best way in TP53-mutated (TP53m) acute myeloid leukemia, rather than just to double it either Azacitidine Magrolimab (Hu5F9-G4) or Azacitidine Venetoclax. That’s a great question. Biologically we do see that there is a increased synergy when we add Venetoclax, Azacitidine, Magrolimab (Hu5F9-G4), in fact, Dr. Marina Konopleva who runs the translational lab here at MD Anderson also had an oral presentation at the ASH 2021 meeting where her team shows that combining Azacitidine, Magrolimab (Hu5F9-G4), and Venetoclax together gives us the highest synergy and synthetic laity, bone TP50 mutated and TP50 wild type AML. And so, to look at this, we now have ongoing studies evaluating Magrolimab at MD Anderson.
That is looking at the frontline, newly diagnosed AML, both TP53-mutated (TP53m). And TP50 wild type where we’re combining Azacitidine, Venetoclax, and Magrolimab (Hu5F9-G4). And I think we’ll have to look at both the data sets over time to see whether the triple combination of Azacitidine, Venetoclax, and Magrolimab (Hu5F9-G4) add or is better than just Azacitidine or Magrolimab (Hu5F9-G4) in TP50 AML.
But we don’t know the answer to that question at this time. The, the results of this study, if positive, meaning if Azacitidine Magrolimab (Hu5F9-G4) does show superior overall survival compared to the investigational investigative choice arm of either Azacitidine, Venetoclax, or three plus 7, this will have an important. Change in frontline treatment of TP53-mutant (TP53m) AML, it would then basically establish the frontline treatment of all TP53-mutated (TP53m) AML to be the combination of Azacitidine and Magrolimab (Hu5F9-G4).
And this would actually be the first time we have a any drug approved for a TP53 mutation target that I’m aware of, not just in AML, but actually across hematological malignancies. This would also then of course, open the door. To build novel combinations on top of Azacitidine Magrolimab (Hu5F9-G4) because there are other drugs that are showing some signals of activity in TP53-mutated (TP53m) AML drugs, like APR, Sabatolimab.
And so the next step would be, can we now use Azacitidine Magrolimab (Hu5F9-G4) as a background, but then add to it either (inaudible) 3 antibodies like Sabatolimab or APR map or APR or other TP53 directed therapies. And this would be very important because historically, TP53-mutated (TP53m) AML is one of the worst leukemias and one of the worst cancers in general, with median survival of only 5 to 7 months.
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So, any progress in that group, even if it’s incremental, would be an important step forward.
The next steps are to look at other combinations with macro map we have actually 3 randomized studies that are ongoing. One is a myelodysplastic syndrome (MDS) where we’re looking at Azacitidine Magrolimab (Hu5F9-G4) versus Azacitidine in the higher-risk myelodysplastic syndrome (MDS) populations. The other study is the one we’ve discussed Azacitidine Magrolimab (Hu5F9-G4) versus investigator choice of either the 3 plus 7 or Venetoclax specifically in the TP53-mutated (TP53m) AML. And the most recent is to look at the triple combination. Azacitidine Venetoclax, which is the standard, but adding to that micro versus the Azacitidine Venetoclax, and this would be specifically in the older unfit acute myeloid leukemia AML to see if we could improve the outcomes of all older unfit, AML, both TP53 and mutated.
And TP53 wild type with a triple therapy beyond that. We’re also looking at novel combinations, intensive chemotherapy in combination Magrolimab (Hu5F9-G4) maintenance with Magrolimab (Hu5F9-G4). I think it will be important to look at, and we are proposing post-transplant approaches with maintenance with Magrolimab (Hu5F9-G4). And in the future maybe ways that we can synergize the innate immune system activation such as NK-cell therapies or gamma Delta T-cell therapies in combination with Magrolimab (Hu5F9-G4). So, I think if we can get the positive results, so hopefully from one of these phase threes and get the CD47 antibody, which will be the first CD47 antibody to approve.
There will be a lot of further directions for development. In fact, even outside of leukemia, there is encouraging data using the CD47 antibodies, including Magrolimab (Hu5F9-G4) in follicular and diffuse large B-cell lymphoma and potential biological rationale in myeloma as well as some of the solid tumors. So just like PD1, PDL1 inhibitors, 15 years ago.
Emerge as a completely new class of therapy that activated the immune system. We’re hoping that the CD47 could similarly have activity in multiple different tumor side sites and tumor types by activating the innate immune system. So, it’s quite exciting and we’re looking forward to the data in the near future.
One of the things that I think it’s important to note is that although macro in general has been very well tolerated. There is one side effect that is on target that we do see, this is anemia because the CD47 is expressed on the tumor cell, but it’s also expressed on older red cells. And it is a part of the RBC exoskeleton.
Where is bound to the RH protein. And so, we do see an initial clearance of the older RBCs by splenic and extravascular sequestration. And this can sometimes have larger drops in hemoglobin in general. The drop in hemoglobin is in the range of 0.5 to 1.5, but we have seen in about 10 to 15% of patients that there could be a greater than 2 or 2.5 gram drop in hemoglobin.
This is important because a lot of patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) Have a starting hemoglobin of 8 or 7 and of course, if you dropped by 2, to 2, and a half, that could bring it down. So usually transfuse RBCs to get the hemoglobin above 9. And we usually monitor the hemoglobin daily very closely for that first 7-day period.
It’s very interesting that the anemia seems to occur almost all of it within that first, quite a 7-day period. And then usually after the first week, we don’t see much anemia. I think just something for the colleagues who will be treating a number of these patients on clinical trials, because these are now open across the us and internationally to be aware of and to manage if they see such anemia, but otherwise Magrolimab actually has been a very well tolerated drug.
We don’t see neutropenia, thrombocytopenia, and that’s one of the reasons I think that the combinations with micro map have been reasonably well tolerated.
Authors and Affiliates:
Naval Daver, MD from The University of Texas MD Anderson Cancer Center speaks about the ASH 2021 Abstract – 3426 A Phase 3, Randomized, Open-Label Study Evaluating the Safety and Efficacy of Magrolimab in Combination with Azacitidine in Previously Untreated Adults with TP53-Mutant Acute Myeloid Leukemia.
Background:
Magrolimab (Hu5F9-G4) is an antibody that kills leukemia stem cells by encouraging tumor phagocytosis by inhibiting CD47, a macrophage immune checkpoint and “don’t eat me” signal on cancer cells. Hypomethylating drugs work along with magrolimab to increase phagocytosis by eliciting “eat me” signals on leukemic blasts. In frontline acute myeloid leukemia (AML) enrolling patients who are not candidates for heavy chemotherapy or who have higher risk myelodysplastic syndrome, magrolimab plus azacitidine (AZA) has shown promising results. It showed an objective response rate of 69 percent, a complete response rate of 45 percent, and a median overall survival (OS) of 12.9 months in TP53-mutant (TP53m) AML. The TP53 gene mutation is found in 10-15% of newly diagnosed AML patients and is linked to a poor prognosis. Regardless of whether patients are treated with intensive chemotherapy or non-intensive methods, such as a hypomethylating drug with venetoclax, the documented first-line median OS in TP53m AML is 5-7 months (VEN). Patients diagnosed with AML who have a TP53 gene mutation have a huge unmet medical need. Aims: To compare the effectiveness, comprehensive safety data, and tolerability of magrolimab+AZA versus VEN+AZA or “7+3” chemotherapy as prescribed by the physician in patients with previously untreated patients with TP53m AML.
Methods and Design:
This is a multicenter, phase 3 randomized, open-label clinical trial. Based on patient fitness, approximately 346 patients will be randomized (1:1) to Magrolimab + AZA (investigational arm) or physician’s choice of VEN+AZA or 7+3 chemotherapy (NCT04778397). Randomization will be stratified by age (75 vs 75 years), geographic region (US vs non-US sites), and appropriateness for non-intensive vs intensive therapy. Patients must be at least 18 years old, have histologically proven acute myeloid leukemia AML, and have at least one TP53 gene mutation that is not benign or likely benign (confirmed by central laboratory), or biallelic 17p deletions (based on a locally reviewed karyotype/fluorescence in situ hybridization report). Patients assigned to magrolimab+AZA will be given magrolimab intravenously (IV) at initial priming dose of 1 mg/kg on Days 1 and 4, 15 mg/kg on Day 8, and 30 mg/kg on Days 11, 15, and 22 during the first 28-day cycle. After that, Magrolimab 30 mg/kg will be given weekly during cycle 2 and every other week from cycle 3 onward. VEN and AZA will be given to patients in the VEN+AZA arm according to the labeled indications. Patients receiving 7+3 chemotherapy will have 1-2 induction cycles with IV daunorubicin or idarubicin on Days 1-3 and cytarabine 100 mg/m2 or 200 mg/m2 on Days 1-7, followed by up to four consolidation cycles with high-dose cytarabine (3,000 mg/m2) on Days 1-7. Patients who receive Magrolimab + AZA or VEN+AZA will be treated until disease progression, relapse, clinical benefit loss, intolerable toxicities, or stem cell transplant. Patients may receive stem cell transplants if the investigator so chooses. The primary aim is OS in patients who are candidates for non-intensive therapy, with OS in all patients as a crucial secondary endpoint.
From Gilead Sciences:
The FDA has placed a partial clinical hold on trials testing the combination of magrolimab plus azacitidine due to an apparent imbalance in investigator-reported suspected unexpected severe adverse reactions (SUSARs) between study arms, according to Gilead Sciences Inc. (Nasdaq: GILD). While Gilead Sciences has not identified a clear trend in adverse reactions or a new comprehensive safety data, signal at this time, a partial clinical hold is being implemented across all ongoing magrolimab and azacitidine combination studies worldwide in the best interests of patients while additional data is gathered and analyzed to address the FDA concerns.
During the partial clinical hold, any research exploring the combination of magrolimab and azacitidine will halt screening and recruitment of new study participants. Patients who are already engaged in these clinical trials may continue to receive magrolimab and azacitidine, or a placebo, and will be continuously followed in accordance with the current study protocol. The partial clinical pause is now being communicated to clinical investigators and global regulatory agencies by Gilead Sciences. Other magrolimab studies or cohorts that are not investigating the combination of magrolimab and azacitidine will be unaffected by the partial clinical hold.
“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.
Also quoted “Considering the high unmet need for new medicines in higher risk 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. We are grateful to those participating in our studies, their families, and the investigators for their continued contributions to the clinical program for Magrolimab.”said Merdad Parsey, MD, PhD, Chief Medical Officer, Gilead Sciences.
Gilead Sciences is collaborating with regulatory authorities to determine the next steps in lifting the partial clinical hold on fresh patient enrollment in the impacted studies.
About Gilead Sciences Inc
Gilead Sciences, Inc. is a biopharmaceutical business that has spent more than three decades pursuing and achieving medical innovations with the objective of creating a better world for all people. The company is dedicated to developing new medicines to prevent and treat life-threatening diseases such as HIV, viral hepatitis, and cancer. Gilead works in over 35 countries throughout the world, with its headquarters in Foster City, California.
What is Magrolimab used for?
Magrolimab is a potential, first-in-class investigational monoclonal antibody against CD47 and a macrophage checkpoint inhibitor that is designed to interfere with recognition of CD47 by the SIRPα receptor on macrophages, with the goal of blocking the “don’t eat me” signal used by cancer cells to avoid being ingested by macrophages. Magrolimab is being developed in several hematologic cancers, including myelodysplastic syndrome (MDS), as well as solid tumor malignancies.
More information about this clinical trial with magrolimab is available at www.clinicaltrials.gov.
Patients will be enrolled in about 140 clinics around the world. Accumulation is still going on.
Reference
Gilead Sciences Inc – Gilead Announces Partial Clinical Hold for Studies Evaluating Magrolimab in Combination With Azacitidine. Gilead Sciences Press Release, January 25, 2022