The initiation of the phase 3 ENHANCE trial looks to build on the generally early response to azacitidine with the addition of magrolimab, a first-in-class monoclonal antibody, for patients with intermediate-, high-, and very highrisk myelodysplastic syndrome.
Standard-of-care options for patients with intermediate-, high-, and very highrisk myelodysplastic syndrome (MDS) have plateaued in their efficacy, leading investigators to seek alternative novel therapies. The initiation of the phase 3 ENHANCE trial (NCT04313881) looks to build on the generally early response to azacitidine with the addition of magrolimab, a first-in-class monoclonal antibody.1
There are only 2 treatments available [for these patients], said Eytan M. Stein, MD, a hematologic oncologist at Memorial Sloan Kettering Cancer Center in New York, New York, in an interview with OncologyLive. These options are essentially 2 sides of the same coin. They are both hypomethylating agents; one is azacitidine [Vidaza] and the other is decitabine [Dacogen].
Azacitidine was approved for all types of MDS in May 2004 based on results of the phase 3 Cancer and Leukemia Group B 9221 study in which the agent elicited a 16.2% response (n = 16/99) compared with no response with placebo (n = 0/92); response rates in similar single-arm studies ranged from 11.8% to 18.8%.2 Similar results were observed to support the FDA approval of decitabine in 2006; the response rate was 21% among 56 evaluable patients treated with the agent vs 0% in the supportive care arm (n = 89).3
We know from clinical studies that were done about a decade ago that theyre better than doing nothing, which is what we had before these treatments, Stein said. But theyre certainly not good enough. The remission rate is in the range of 30% to 40%, [and] survival is somewhat limited. For this patient population, another key factor is that even in the patients who do respond to these drugs, they typically stop working after a year or two. The duration of response [DOR] is not particularly long. Theres a real need for new agents for MDS.
ENHANCE will evaluate the efficacy of magrolimab in combination with azacitidine, compared with azacitidine plus placebo in previously untreated participants with intermediate-, high-, or very highrisk MDS.1 Preclinical models have shown synergistic effects of combining hypomethylating agents with immune checkpoint inhibitors, and investigators have hypothesized that the combination may overcome resistance mechanisms that arise with hypomethylating agents alone.4
Magrolimab blocks CD47, a key do not eat me signal that is often overexpressed on tumor cells. The binding of magrolimab to CD47 induces potent macrophage- mediated phagocytosis of tumor cells. Azacitidine synergizes with magrolimab by increasing expression of prophagocytic eat me signals.5-7
There was a lot of good preclinical science that was done primarily in laboratory work by Ravi Majeti MD, PhD, at Stanford [University in California], Stein noted. This [preclinical work] showed that by giving an anti-CD47 antibody, you can get this immunologic approach where you can eradicate the MDS cells, the bad cells, that are causing the problem. The [inhibition of the] do not eat me signal allows macrophages to basically recognize the malignant MDS cells, which then allows them to be eradicated through phagocytosis.
Investigators examined the combination of magrolimab and azacitidine in patients with hematological malignancies in a phase 1b trial (NCT03248479). A total of 39 patients with MDS have been treated with the combination. The median age of this cohort was 70 years (range, 47-80) and 13% of patients harbored a TP53 mutation.7
Magrolimab was given via a priming/intrapatient dose-escalation regimen of 1 to 30 mg/kg once a week for the first 2 cycles, then once every 2 weeks in cycles 3 and beyond. Azacitidine was administered at a dose of 75 mg/m2 on days 1 to 7.
Among 33 patients evaluable for efficacy, the objective response rate (ORR) was 91% with 42% of responders achieving complete remission (CR). Several responses deepened over time; patients with at least a 6-month follow-up achieved a CR rate of 56%. The median overall survival (OS) has not been reached (95% CI, 1.4-18.3), and the 6-month estimated OS rate is 100%.7
Cytogenetic CRs were observed in 35% of efficacy-evaluable patients, with 91% of responding patients having a continuing response at 6 months. The median time to initial response was 1.9 months. Minimal residual disease negativity by multi- parameter flow cytometry was reported in 22% of patients with CR, CR with incomplete hematologic recovery, or marrow CR.7
Regarding safety, the most common adverse effects (AEs) of any grade were anemia (44%), fatigue (18%), infusion reaction (18%), and neutropenia (8%). No patients in the MDS cohort discontinued treatment because of an AE, and no treatment-related febrile neutropenia was seen by investigators.7
The median decrease in hemoglobin with the first dose of magrolimab plus azacitidine was 0.4 g/dL. Investigators noted that the combination had a similar safety profile compared with azacitidine monotherapy.7
Magrolimab actually possesses a fairly good toxicity profile; it doesnt have many significant AEs, Stein said. The most significant AE is that patients can experience an on-target anemia, which can be pretty dramatic at the onset. Also, in some patients, you can see the hemoglobin dropped by 2 to 3 grams.
The phase 3 trial will enroll approximately 520 previously untreated adult patients with intermediate-, high-, very highrisk MDS by Revised International Prognostic Scoring System in the United States, Europe, Asia, and Australia [Figure8]. To be eligible for the study, patients must have adequate performance status and hematological, liver, and kidney function. Patients will be evenly randomized to receive either magrolimab plus azacitidine or placebo plus azacitidine.1,8
Ineligible patients include those with active hepatitis B, C, and/or HIV after testing at screening or in their medical history. Patients previously treated with anti-CD47 or signal-regulatory protein -targeting agents are not eligible for the trial. Patients with clinical suspicion of active central nervous system involvement or those who are pregnant or actively breastfeeding also will be excluded.8
Patients in the trial cannot have undergone any prior antileukemic therapy for treatment of intermediate-, high-, or very highrisk MDS. Patients with contraindications to azacitidine will be excluded, as well as those who have immediate eligibility for allogenic stem cell transplant with an available donor, as determined by the investigators.8
Patients in the experimental arm will receive a 1 mg/kg dose of magrolimab intravenously 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 beyond, 30 mg/kg of magrolimab will be administered every 2 weeks on days 1 and 15.1,8
Stein said that a change in the trial designtreating patients frequently with smaller doses at the starthelped to curb some of the common AEs. As a result of [this dosing schedule], we believe that is going to help prevent this anemia that you may see, he said.
In the control arm, placebo to match magrolimab will be administered intravenously. In both arms, azacitidine will be given at 75 mg/m2 on days 1 to 7, or days 1 to 5 and 8 to 9 of each cycle, either subcutaneously or intravenously according to region-specific drug labeling.8
The primary end points of the trial are CR rate and overall survival. Key secondary end points include duration of CR, ORR, DOR, and progression-free survival. The trial is estimated to be completed by February 2025.8
I believe magrolimab with azacitidine will become the standard of care, Stein concluded. If [the data] pan out in this phase 3 trial, it would be the first real immunotherapy/checkpoint inhibitor treatment for a myeloid malignancy. People talk about PD-L1 and PD-1 inhibitors in solid tumors [but] we havent had something that really works like that in patients with MDS or acute myeloid leukemia. If this [regimen] does work in the phase 3 setting, its a proof of concept that there is an immunologic therapy that you can give that can make outcomes in patients better in this class of diseases.
Visit link:
Investigators Aim to Fill Unmet Need of Intermediate- to High-Risk MDS With ENHANCE Trial - OncLive
- Botox could be used as new treatment for stomach cancer, experts say [Last Updated On: August 22nd, 2014] [Originally Added On: August 22nd, 2014]
- Botox Injections Could Be Used To Treat Stomach Cancer, Experts Say [Last Updated On: August 22nd, 2014] [Originally Added On: August 22nd, 2014]
- Botox 'could be used to treat stomach cancer' [Last Updated On: August 22nd, 2014] [Originally Added On: August 22nd, 2014]
- New York Stem Cell | Regenerative Disk Therapy for Spine NY [Last Updated On: August 22nd, 2014] [Originally Added On: August 22nd, 2014]
- Stem Cell Research in New York State | NYSTEM [Last Updated On: August 22nd, 2014] [Originally Added On: August 22nd, 2014]
- NYU researchers ID process producing neuronal diversity in fruit flies' visual system [Last Updated On: August 29th, 2014] [Originally Added On: August 29th, 2014]
- Novogen Announces Presentation at Rodman & Renshaw 16th Annual Healthcare Conference [Last Updated On: September 4th, 2014] [Originally Added On: September 4th, 2014]
- Stem Cells - The New York Times [Last Updated On: September 4th, 2014] [Originally Added On: September 4th, 2014]
- Donate blood and join in on the fight against cancer [Last Updated On: September 6th, 2014] [Originally Added On: September 6th, 2014]
- New Drug Study Offers Promise of Brain Cell Regeneration for Alzheimers Patients [Last Updated On: September 11th, 2014] [Originally Added On: September 11th, 2014]
- TiGenix: TiGenix to participate or present at key conferences in the second half of 2014 [Last Updated On: September 16th, 2014] [Originally Added On: September 16th, 2014]
- New Treatment May Prevent Diabetes After Pancreatitis Surgery [Last Updated On: September 22nd, 2014] [Originally Added On: September 22nd, 2014]
- Americord Backs Another Cord Blood Clinical Trial [Last Updated On: September 25th, 2014] [Originally Added On: September 25th, 2014]
- Harvard makes diabetes breakthrough [Last Updated On: October 13th, 2014] [Originally Added On: October 13th, 2014]
- Analysis of the Global Stem Cell Market [Last Updated On: October 13th, 2014] [Originally Added On: October 13th, 2014]
- Cell Discovery Challenges Dogma on How Fetus Develops; Holds Insights for Liver Cancer and Regeneration [Last Updated On: October 15th, 2014] [Originally Added On: October 15th, 2014]
- Scientists at New York Stem Cell Foundation, Columbia U ... [Last Updated On: October 29th, 2014] [Originally Added On: October 29th, 2014]
- New York Stem Cell [Last Updated On: November 11th, 2014] [Originally Added On: November 11th, 2014]
- Mount Sinai Researchers Awarded $1 Million Grant to Find New Stem Cell Therapies for Vision Recovery [Last Updated On: November 20th, 2014] [Originally Added On: November 20th, 2014]
- Stranger Donates Stem Cells In Hopes Of Curing New York Woman With Leukemia [Last Updated On: November 28th, 2014] [Originally Added On: November 28th, 2014]
- "Breakthrough" drug tested for Hodgkin lymphoma [Last Updated On: December 9th, 2014] [Originally Added On: December 9th, 2014]
- Hodgkin Lymphoma Treatment Shows Promise in Small Trial [Last Updated On: December 9th, 2014] [Originally Added On: December 9th, 2014]
- "Breakthrough" drug shows promise for Hodgkin lymphoma [Last Updated On: December 9th, 2014] [Originally Added On: December 9th, 2014]
- Human primordial cells created in the lab [Last Updated On: December 24th, 2014] [Originally Added On: December 24th, 2014]
- BrainStorm Announces Final Analysis of Phase 2a ALS Study Showing Nearly All Subjects Experienced Clinical Benefit ... [Last Updated On: January 5th, 2015] [Originally Added On: January 5th, 2015]
- Major grant rewards Roswell Park for innovative research into immunotherapy [Last Updated On: January 16th, 2015] [Originally Added On: January 16th, 2015]
- IntelliCell BioSciences Announces Collaboration to Develop Closed Processing System for Cell Therapy Manufacturing [Last Updated On: January 21st, 2015] [Originally Added On: January 21st, 2015]
- Girl aged just EIGHT helps scientist dad make cancer breakthrough after chat round dinner table [Last Updated On: January 29th, 2015] [Originally Added On: January 29th, 2015]
- Master Switch Found to Stop Tumor Cell Growth by Inducing Dormancy [Last Updated On: January 31st, 2015] [Originally Added On: January 31st, 2015]
- Mount Sinai Health System Names Director of Newly Established Ronald M. Loeb Center for Alzheimer's Disease [Last Updated On: February 19th, 2015] [Originally Added On: February 19th, 2015]
- New York City Pain Specialists Introduce New Treatment for Knee Pain; First Physicians in Northeast to Offer iovera ... [Last Updated On: February 23rd, 2015] [Originally Added On: February 23rd, 2015]
- Study affirms role of specialized protein in assuring normal cell development [Last Updated On: February 27th, 2015] [Originally Added On: February 27th, 2015]
- Asterias Biotherapeutics to Ring Opening Bell at New York Stock Exchange [Last Updated On: March 8th, 2015] [Originally Added On: March 8th, 2015]
- Faulty gene may cut short male fertility [Last Updated On: March 8th, 2015] [Originally Added On: March 8th, 2015]
- New York Blood Center's New Mobile App Helps Save Lives On the Go [Last Updated On: March 8th, 2015] [Originally Added On: March 8th, 2015]
- New ALS gene and signaling pathways identified [Last Updated On: March 10th, 2015] [Originally Added On: March 10th, 2015]
- Stanley Center at the Broad Institute and NYSCF partner to study psychiatric diseases [Last Updated On: March 10th, 2015] [Originally Added On: March 10th, 2015]
- Key mechanism identified in tumor-cell proliferation in pediatric bone cancers [Last Updated On: April 2nd, 2015] [Originally Added On: April 2nd, 2015]
- Key Mechanism Identified In Pediatric Bone Cancers That Allows Proliferation Of Tumor-Forming Stem Cells [Last Updated On: April 2nd, 2015] [Originally Added On: April 2nd, 2015]
- Research in the News: Tiny hair follicle offers big clues about the life and death of stem cells [Last Updated On: April 7th, 2015] [Originally Added On: April 7th, 2015]
- New York State Stem Cell Science Consortia | Memorial ... [Last Updated On: April 18th, 2015] [Originally Added On: April 18th, 2015]
- Stem Cell Rejuvenation New York - Norman Rowe MD [Last Updated On: May 4th, 2015] [Originally Added On: May 4th, 2015]
- New York Stem Cell Treatment Center [Last Updated On: July 2nd, 2015] [Originally Added On: July 2nd, 2015]
- Center for Stem Cell Biology | Memorial Sloan Kettering ... [Last Updated On: September 29th, 2016] [Originally Added On: September 29th, 2016]
- Stem Cell Therapy New York City | Regenerative Medicine ... [Last Updated On: November 29th, 2016] [Originally Added On: November 29th, 2016]
- These Scientists Have a Plan To Cheat Death. Will It Work? - NBCNews.com [Last Updated On: July 6th, 2017] [Originally Added On: July 6th, 2017]
- Sex For Reproduction May Be Obsolete Within 30 Years Thanks To New Technology, Professor Predicts - Medical Daily [Last Updated On: July 6th, 2017] [Originally Added On: July 6th, 2017]
- A New Method for Making Stem Cells - Live Science [Last Updated On: July 6th, 2017] [Originally Added On: July 6th, 2017]
- Do Stem Cells have the ability to reverse aging process? - Fox Weekly [Last Updated On: August 3rd, 2017] [Originally Added On: August 3rd, 2017]
- Chop Off This Worm's Head and It Can Still Detect Light - New York Times [Last Updated On: August 3rd, 2017] [Originally Added On: August 3rd, 2017]
- Researchers find how to reprogramme cells in immune system - India.com [Last Updated On: August 3rd, 2017] [Originally Added On: August 3rd, 2017]
- Good cellular neighbors combat incipient cancers - Medical Xpress - Medical Xpress [Last Updated On: August 3rd, 2017] [Originally Added On: August 3rd, 2017]
- Scientists Repair Gene in Human Embryos for First Time - NBC New York [Last Updated On: August 3rd, 2017] [Originally Added On: August 3rd, 2017]
- Scientists Successfully Slow Aging in Mice Using Stem Cells - Futurism [Last Updated On: August 3rd, 2017] [Originally Added On: August 3rd, 2017]
- Gene Editing for 'Designer Babies'? Highly Unlikely, Scientists Say - New York Times [Last Updated On: August 5th, 2017] [Originally Added On: August 5th, 2017]
- Penn Engineers Identify Protein Implicated in 3-D Epigenetics of Brain Development - Penn Current [Last Updated On: August 5th, 2017] [Originally Added On: August 5th, 2017]
- Gene therapy via skin may treat diabetes, obesity - Economic Times [Last Updated On: August 5th, 2017] [Originally Added On: August 5th, 2017]
- How New York Post readers helped save a toddler's life - New York Post [Last Updated On: August 7th, 2017] [Originally Added On: August 7th, 2017]
- Blood Donations needed pre and post Labor Day Holiday! - TAPinto.net [Last Updated On: August 27th, 2017] [Originally Added On: August 27th, 2017]
- 'Mini-organs' help personalize treatments for cystic fibrosis patients - New York Post [Last Updated On: August 27th, 2017] [Originally Added On: August 27th, 2017]
- Are stems cells really the fountain of youth? - Star2.com - Star2.com [Last Updated On: August 27th, 2017] [Originally Added On: August 27th, 2017]
- The organoid architect - Science Magazine [Last Updated On: August 27th, 2017] [Originally Added On: August 27th, 2017]
- 5. Hematopoietic Stem Cells | stemcells.nih.gov [Last Updated On: September 19th, 2017] [Originally Added On: September 19th, 2017]
- Are Stem Cells the Future of Hip Replacement? | Plancher ... [Last Updated On: October 18th, 2017] [Originally Added On: October 18th, 2017]
- Stem Cell Transplant - New York - Park Avenue Stem Cell ... [Last Updated On: August 9th, 2018] [Originally Added On: August 9th, 2018]
- Stem Cell Therapy New York | NYC Stem Cells | (212) 262-2412 [Last Updated On: September 5th, 2018] [Originally Added On: September 5th, 2018]
- Stem Cell Therapy for Heart Disease | Stem Cell Therapy in ... [Last Updated On: December 26th, 2018] [Originally Added On: December 26th, 2018]
- Stem Cell Therapy | New York - Park Avenue Stem Cell [Last Updated On: January 8th, 2019] [Originally Added On: January 8th, 2019]
- Stem Cell Investigator Awards - New York Stem Cell Foundation [Last Updated On: January 23rd, 2019] [Originally Added On: January 23rd, 2019]
- Stem Cells New York | Stem Cell Recovery | Oral Surgery [Last Updated On: February 18th, 2019] [Originally Added On: February 18th, 2019]
- NYC Stem Cells Treatment Institute - Call Us (646) 480-1259 [Last Updated On: February 18th, 2019] [Originally Added On: February 18th, 2019]
- Rethink Stem Cells? Science Already Has - The New York Times [Last Updated On: February 22nd, 2019] [Originally Added On: February 22nd, 2019]
- Stem Cell Therapy Doctor in New York, NYC Dr. Reyfman [Last Updated On: February 25th, 2019] [Originally Added On: February 25th, 2019]
- Neuroscience Investigator Awards - New York Stem Cell ... [Last Updated On: March 8th, 2019] [Originally Added On: March 8th, 2019]
- Banking Menstrual Stem Cells | What are Menstrual Stem ... [Last Updated On: April 15th, 2019] [Originally Added On: April 15th, 2019]
- Stem Cell Therapy in New York | National Stem Cell Centers [Last Updated On: April 17th, 2019] [Originally Added On: April 17th, 2019]
- Stem cells for tendinopathy - Dr. Marc Darrow is a Stem ... [Last Updated On: April 20th, 2019] [Originally Added On: April 20th, 2019]
- Stem Cell Therapy New York | Stem Cell Treatment ... [Last Updated On: April 28th, 2019] [Originally Added On: April 28th, 2019]
- Attorney General James Announces Lawsuit Against New York ... [Last Updated On: April 28th, 2019] [Originally Added On: April 28th, 2019]
- In Mice and Men, Prostate Drug Reportedly Treats Parkinson's Disease? - Alzforum [Last Updated On: September 21st, 2019] [Originally Added On: September 21st, 2019]