Precision Medicine Informs Treatment in Acute Myeloid Leukemia Trial

Collaborative Effort Across Leading Centers Strives to Accelerate Improved Treatments for AML

Physician researchers at the University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center (UMGCCC) are among an initial group of 14 U.S. academic cancer centers participating in a Leukemia and Lymphoma Association–sponsored trial to explore the feasibility and efficacy of guiding treatment decisions with prospective genetic profiling of acute myeloid leukemia (AML) in older patients. Results from the first cohort of patients enrolled in the Study of Biomarker-Based Treatment of Acute Myeloid Leukemia trial (NCT03013998), also known as the Beat AML^® Master Clinical Trial, were published in December 2020 in Nature Medicine.¹

"We now know more about the genetic structure of AML than just about any other cancer, and yet the standard of care had remained the same for about 50 years. We hope this trial will lay the groundwork for better treatments that exploit the ability to target some AML mutations," says Maria R. Baer, MD, Professor of Medicine at the University of Maryland School of Medicine, Director of Hematologic Malignancies and Co-leader of the Experimental Therapeutics Program at UMGCCC, and one of the study's authors.

There are only a few FDA-approved targeted treatments available for AML, but pharmaceutical companies are developing additional agents that show promise for specific AML mutations. The Beat AML trial is the first prospective trial for AML to explore whether it is feasible to match patients with approved and experimental targeted treatments based on cytogenetic and molecular data, while also looking at the safety of this approach given that it delays first-line treatment.

"Precision medicine is very sophisticated, and the Beat AML trial is helping us refine the coordination among our teams to ensure that laboratory and clinical protocols are promptly and meticulously executed," Dr. Baer says. "This novel approach appears to be beneficial because patients enrolled in the trial's sub-studies are experiencing significantly longer survival compared to those receiving the standard of care," she continues.

Modestly Delaying AML Treatment to Assess Genetic Mutations Is Safe for Most Patients

The Beat AML trial's primary endpoints involve assessing if it is feasible to receive cytogenetic and mutational data from AML samples and assign study participants into corresponding targeted treatment sub-studies in a timely manner. With local cytogenetic data, but all trial centers using the same central molecular laboratory, researchers found it feasible to receive these data and assign patients to an appropriate treatment arm within seven days of diagnostic testing.^1(p1856) For most patients in the Beat AML study, this delay in treatment had no adverse effect, confirming previous retrospective research showing that delaying AML treatment for up to 8 days has very little impact on survival.²

While postponing chemotherapy to first procure genomic data-driven treatment is appropriate for most patients with AML, the study's authors determined there were some rare situations in which intensive treatment should begin immediately because patients' rapidly progressing disease put them at increased mortality risk before being assigned to a treatment arm.^1(p1856)

Most Patients with AML Would Have a Targeted Therapy Option

The trial currently has 11 treatment arms, but it opened initially with only three. This precluded some early trial enrollees from being matched with a targeted treatment arm.^1(p1856) However, the researchers noted that had all arms been available at the onset, all but 75 of the initial cohort of 395 patients would have received targeted treatment.^1(p1856) In other words, current knowledge of AML genomics and available potential treatments permits about 4 of every 5 patients to be assigned a targeted treatment.

However, rather than being a hindrance, the trial's dynamic and adaptive design with various arms opening and closing throughout its duration has proven to be an efficient way to test new agents as they show promise in targeting certain AML mutations. To accommodate these numerous and changing treatment arms, the trial is well on its way towards enrolling 2,000 patients across participating centers.

Targeted Treatment for AML Might Prove to Be a Game-Changer for Older Adults

The prevailing treatment strategy for AML has involved intensive chemotherapy started immediately upon diagnosis. However, as Dr. Baer says, "The biology of the disease in older adults is such that it often doesn't respond well to intensive treatment."

The study's authors observed that in the first cohort of Beat AML enrollees, there were generally differences in the specific AML chromosome changes and mutations between older and younger patients.^1(p1856) Older patients pose a greater treatment challenge, reflected by SEER data showing that fewer than 1 in 10 adults over age 65 with AML reaches 5-year survival³. Finding agents that target the mutations that are common in older adults with AML may improve these survival rates, of particular importance given that the median age at AML diagnosis is 68 years.⁴

Targeted Treatment Might Result in Improved Survival

The trial is not designed to measure overall survival as a primary endpoint, and within the initial cohort it was not determined how much patients assigned to targeted treatment arms benefited merely by participating in a clinical trial and/or being treated at an academic medical center. However, the overall survival of patients enrolled in one of the 11 initial experimental Beat AML treatment arms (n=224) was significantly longer than those who received the current standard of care (n=77). Overall survival for patients in the study receiving palliative care (n=38) was 0.6 months, 3.9 months for patients receiving the standard of care and 12.8 months for patients in one of the targeted treatment study arms.^1(p1856)

University of Maryland Involvement in the Beat AML Trial

To date, UMGCCC has screened 61 patients for the trial and enrolled 48 of them. Of the 395 study participants whose results appear in the December publication, the University of Maryland was among the top four centers contributing the most patients and enrolled 80 percent of its eligible patients.^1(p1853) UMGCCC was invited to participate in the trial because of its decades-long leadership in AML research, stemming back to when the center was part of the National Institutes of Health as the Baltimore Cancer Research Center; more recently, UMGCCC was among the centers instrumental in discovering that gilteritinib (Xospata) effectively targets the FLT3 mutation in relapsed/refractory AML.⁵

Beat AML Clinical Trial Arms Currently Open at UMGCCC:

A Phase 2 Study of Entospletinib in NPM1 Mutant/FLT3 ITD Wild Type AML Patients Age >/= 18 Years (1718GCCC-S6) | The study is an open-label phase 2 study of entospletinib in younger and older AML patients with NPM1+/FLT3ITD-AML. It includes patients age ≥18 years who are able and willing to receive 7 + 3 intensive chemotherapy. Entospletinib is administered daily with IV daunorubicin (days 1-3 for Cycle 1) and cytarabine (days 1-7 for Cycle 1). If a second induction is required, it is given with IV daunorubicin (days 1-2 for Cycle 2) and cytarabine (days 1-5 for Cycle 2).⁶
A Phase1b/2 study of Gilteritinib Monotherapy or in Combination with Decitabine in Elderly Untreated FLT3 mutated Acute Myeloid Leukemia (Group 1) or Gilteritinib in combination with Decitabine and Venetoclax (Group 2) in Untreated FLT3 mutated AML patients Age >/= 18 Years (1718GCCC-S8) | The study is an open-label phase 1b/2 of gilteritinib as a single agent stratified into two cohorts based on dominant versus non-dominant FLT 2 mutation status in AML patients ≥ 60 years old. The combination arm of Group 1 is a small Phase 1b testing gilteritinib with decitabine using standard 3+3 design to test the safety of this combination in patients who progress on gilteritinib or fail to obtain a CR/CRi while on treatment. The trial was amended to study the combination of gilteritinib in combination with decitabine and venetoclax to be evaluated using standard 3+3 design. The phase 1b will consist of induction cycles 1, 2 (if needed) consolidation and maintenance.
A Phase 1b/2 Study of TP-0903 and Decitabine Targeting Mutant TP53 and/or Complex Karyotype in Patients with Untreated Acute Myeloid Leukemia (1718GCCC-S14) | The study is an open-label Phase 1b/2 clinical study of TP-0903 given in addition to decitabine in patients ≥ 60 years with newly diagnosed, previously untreated AML with TP53 mutations and/or complex karyotype. The Phase 1b portion of this study will use a standard 3 + 3 design with dose escalation based upon dose limiting toxicities. The maximum tolerated dose will be defined as the highest dose where at most 1 patient in 6 experiences dose-limiting toxicity, and this is generally the recommended Phase 2 dose (RP2D). Once the RP2D is determined from Phase 1b, patients will be enrolled at this dose level to initiate the Phase 2 portion of the study.⁶

Opening Soon:

A Phase 1b Study of AZD5991 + Azacitidine (AZA) in Previously Untreated Patients ≥60 Years with Hypermethylation and Marker Negative AML >/= 18 Years (1718GCCC-S18) | The study is an open-label clinical study of AZD5991 in combination with AZA in newly diagnosed, untreated hypermethylated and marker negative AMLpatients ≥ 60 years old. The study will adopt the standard 3+3 design, and incorporate two escalation dose levels and one dose level for possible dose de-escalation. The RP2D in the study is defined as the highest dose level where less than 2 dose limiting toxicities (DLT) are observed out of 6 patients. The study will consist of induction, consolidation and maintenance.