Trial Explores New Drug for AML

Researchers report on the BRIGHT AML 1019 Phase III trial.

Consisting of many cytogenetic and molecular alterations that influence clinical outcomes, such as response to therapy and overall survival, acute myeloid leukemia (AML) is a heterogeneous malignancy.  Current treatments for AML, including the ‘7+3’ regimen of cytarabine plus an anthracycline, as well as newer targeted first line treatments, lead to complete remission in between 50 and 80% of patients. However after initial response, between 60 and 80% of patients become refractory to treatment or relapse. Better alternative treatments are needed.

In a clinical trial protocol published in Future Oncology, an outline for the BRIGHT AML 1019 Phase III trial was detailed. In this clinical trial, glasdegib will be used to treat adult AML to elucidate its effects alone or in combination with chemotherapy.

More about glasdegib
Glasdegib is a transmembrane protein smoothened (SMO) inhibitor that in vivo has important antitumor effects and in vitro potently and selectively inhibits hedgehog (Hh) signaling.

Targeting leukemia stem cells (LSCs) in AML has long been a goal of researchers. Inhibition of SMOs can result in LSCs to enter the cell cycle once again. Notably, LSCs continuously divide and trigger AML development. They also contribute to chemotherapy resistance and disease relapse.

Epigenetic silencing of the pathway suppressor GLI3 can result in aberrant Hh signaling. Furthermore, hypomethylating agents can re-induce GLI3 expression and modulation of Hh singaling interference. Administering a hypomethalating agent and glasdegib can result in synergism in the treatment of AML.

In Phase I and Ib/II clinical trials, glasdegib plus low-dose cytarabine (LDAC) (N = 78) lengthened OS vs low-dose cytarabine (LDAC) alone (N = 38) (median 8.3 vs 4.3 months; hazard ratio [HR] 0.46; 80% CI: 0.35–0.62, 95% CI: 0.30–0.72; p = 0.0002) among patients with untreated AML who were not candidates for chemotherapy. Furthermore, complete remission (CR) rates were higher in those receiving LDAC monotherapy. In light of these and other findings, glasdegib plus LDAC is approved for AML patients ≥75 years with comorbidities that rule out chemotherapy.

In a 2018 press release, Mace Rothenberg, M.D., chief development officer, Oncology, Pfizer Global Product Development, had the following to say about the drug. “Patients with acute myeloid leukemia who are ineligible for intensive chemotherapy are in critical need of new treatment options to improve their overall survival,” he stated.
Study design

BRIGHT AML 1019 will comprise two independent global studies in adult AML patients; one study is “intensive” and the other is “non-intensive.”

“This is an innovative, patient-centric design allowing treating physicians and patients to determine goals of care and enroll on either arm,” wrote investigators, led by Jorge E Cortes, Georgia Cancer Center, Augusta University, Augusta.
In total, 400 patients in the intensive study will, along with standard chemotherapy, be randomly assigned (1:1) to take either glasdegib or placebo. In the non-intensive study, 320 patients will be randomly assigned to take glasdegib or placebo, plus azacitidine. Patients enrolled in either the intensive or non-intensive study was determined by the researchers.

The primary outcome for the study is whether glasdegib outperforms placebo plus cytarabine and daunorubicin (intensive trial) or azacitidine (non-intensive trial) in terms of extending OS.
“Upon completion, these studies will provide substantial evidence which may be useful to support expanding the current registration of glasdegib to include treatment of patients with AML in combination with ‘7 + 3’ or azacitidine, in addition to the current approved indication in combination with LDAC for patients aged 75 years or older or who have comorbidities that preclude use of intensive chemotherapy,” concluded the authors.

Cortes JE et al. “Glasdegib plus intensive/non-intensive chemotherapy in untreated acute myeloid leukemia: BRIGHT AML 1019 Phase III trials.” Future Oncol. 2019 Sep 13. doi: 10.2217/fon-2019-0373.