GLB-001 for Acute Myeloid Leukemia
Recruiting in Palo Alto (17 mi)
+7 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: GluBio Therapeutics Inc.
Must not be taking: CYP3A4 inhibitors, CYP3A4 inducers
Disqualifiers: APML, CNS involvement, active infections, others
No Placebo Group
Trial Summary
What is the purpose of this trial?This trial tests a new drug, GLB-001, in patients with certain types of blood cancer that haven't responded to other treatments. The goal is to find out how safe the drug is and what dose works best.
Will I have to stop taking my current medications?
You may need to stop taking certain medications before joining the trial, especially if they are strong or moderate inhibitors or inducers of specific enzymes (CYP3A4, CYP2C8) or P-glycoprotein. This should be done within 14 days or 5 half-lives of the medication, whichever is shorter, before starting the study drug.
What data supports the effectiveness of the drug GLB-001 for treating acute myeloid leukemia?
Research shows that inhibiting GLI1, a gene involved in the Hedgehog signaling pathway, can make acute myeloid leukemia cells more sensitive to drugs. This suggests that targeting GLI1, which GLB-001 may do, could be a promising strategy for treating this type of leukemia.
12345What safety data exists for GLB-001 (glasdegib) in humans?
Glasdegib has been studied in combination with low-dose cytarabine for acute myeloid leukemia, and it was generally well-tolerated in clinical trials, leading to its FDA approval for certain patients. However, there are concerns about side effects when combined with other treatments, as it may affect blood-forming cells.
14678How does the drug GLB-001 differ from other treatments for acute myeloid leukemia?
GLB-001 may involve targeting the Hedgehog signaling pathway, similar to glasdegib, which is a known treatment for AML that works by inhibiting this pathway to improve survival in patients unsuitable for intensive chemotherapy. This approach is unique as it focuses on a specific molecular target, potentially offering a novel strategy for enhancing drug sensitivity in AML treatment.
126910Eligibility Criteria
This trial is for adults over 18 with relapsed or refractory acute myeloid leukemia (R/R AML) or higher-risk myelodysplastic syndromes (HR-MDS). They must have failed or be ineligible for other treatments and meet specific health criteria like blood counts, liver and kidney function. Pregnant women are excluded.Inclusion Criteria
My blood tests and health status meet the study's requirements.
I am 18 years or older and can sign the consent form.
You need to understand and agree to sign a document before any study-related tests or procedures are done.
+3 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Dose Escalation
Phase 1a: Evaluate safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of GLB-001 to determine the maximum tolerated dose or maximum administered dose.
Up to 28 days after first dose
Dose Expansion
Phase 1b: Confirm tolerability of selected doses and evaluate efficacy to identify minimally active dose and select recommended dose for phase 2.
Up to 2 years
Follow-up
Participants are monitored for safety and effectiveness after treatment
Up to 2 years
Participant Groups
GLB-001, an oral medication, is being tested in this Phase 1 study on patients with certain types of blood cancers. The study has two parts: dose escalation to assess safety and dosage levels, followed by dose expansion to find the most effective yet tolerable dose for future studies.
2Treatment groups
Experimental Treatment
Group I: Dose Expansion of GLB-001 as a Monotherapy in Participants with R/R AML and R/R HR-MDS-Phase 1bExperimental Treatment1 Intervention
Part 1b (Dose Expansion) will confirm tolerability of the selected doses and schedules and evaluate whether efficacy is in a range that warrants further clinical development for R/R AML and R/R HR-MDS participants.
Group II: Dose Escalation of GLB-001 as a Monotherapy in Participants with R/R AML and R/R HR-MDS-Phase 1aExperimental Treatment1 Intervention
Part 1a (Dose Escalation) of the study will enroll R/R AML and R/R HR-MDS participants and will evaluate the safety, tolerability, PK, PD and preliminary efficacy of GLB-001 administered orally, and determine the maximum tolerated dose/maximum administered dose (MTD/MAD) in R/R AML or R/R HR-MDS patients who are eligible for dose limiting toxicity (DLT) evaluation.
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
City of Hope Medical CenterDuarte, CA
University of Kansas Medical Center Research Institute, Inc.Kansas City, KS
University of California IrvineIrvine, CA
Alliance for Multispecialty Research, LLCMerriam, KS
More Trial Locations
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Who Is Running the Clinical Trial?
GluBio Therapeutics Inc.Lead Sponsor
References
Targeting the PI3K/AKT pathway via GLI1 inhibition enhanced the drug sensitivity of acute myeloid leukemia cells. [2022]Combination targeted therapy is commonly used to treat acute myeloid leukemia (AML) patients, particularly in refractory/relapse (RR) population. However, concerns have been raised regarding the safety and patient tolerance of combination chemotherapy. It is critical to choose the appropriate treatment for precision therapy. We performed genome-wide RNA profiling using RNA-Seq to compare the RR group and the complete remission (CR) group (a total of 42 adult AML patients). The Hedgehog (Hh) and PI3K/AKT pathways were upregulated in the RR population, which was further confirmed by western blot and/or qPCR. Overexpression of GLI1 in AML cells led to increased AKT phosphorylation and decreased drug sensitivity, which was attenuated by GLI1 inhibition. By contrast, neither the expression of GLI1 nor apoptosis in response to Ara-C treatment of AML cells was significantly affected by PI3K inhibition. Furthermore, co-inhibition of GLI1 and PI3K induced apoptosis of hematopoietic stem/progenitor cells (HSPCs), which raised serious concerns about the side effects of this treatment. These results indicated that GLI1 inhibition alone, but not combined inhibition, is sufficient to enhance AML drug sensitivity, which provides a novel therapeutic strategy for AML treatment.
High GLI-1 Expression is a Reliable Indicator of Bad Prognosis in Newly Diagnosed Acute Leukemia Patients. [2023]To explore the expression and prognostic significance of Hedgehog signaling transcription factor GLI-1 in newly diagnosed acute myeloid leukemia (AML) patients.
GLI1 reduces drug sensitivity by regulating cell cycle through PI3K/AKT/GSK3/CDK pathway in acute myeloid leukemia. [2021]Acute myeloid leukemia (AML) is a hematological malignancy with high incidence and recurrence rates. Gene expression profiling has revealed that transcriptional overexpression of glioma-associated oncogene 1 (GLI1), a vital gene in the Hedgehog (Hh) signaling pathway, occurs in poor-prognosis AML, and high levels of phosphoinositide-3-kinase, regulatory subunit 1 (PIK3R1) and AKT3 predict shorter overall survival in AML patients. In this study, we discovered that GLI1 overexpression promotes cell proliferation and reduces chemotherapy sensitivity in AML cells while knocking down GLI1 has the opposite effect. Moreover, GLI1 promoted cell cycle progression and led to elevated protein levels of cyclins and cyclin-dependent kinases (CDKs) in AML cells. By luciferase assays and co-immunoprecipitation, we demonstrated that the PI3K/AKT pathway is directly activated by GLI1. GLI1 overexpression significantly accelerates tumor growth and upregulated p-AKT, CDK4, and cyclinD3 in vivo. Notably, the GLI1 inhibitor GANT61 and the CDK4/6 inhibitor PD 0332991 had synergistic effects in promoting Ara-c sensitivity in AML cell lines and patient samples. Collectively, our data demonstrate that GLI1 reduces drug sensitivity by regulating cell cycle through the PI3K/AKT/GSK3/CDK pathway, providing a new perspective for involving GLI1 and CDK4/6 inhibitors in relapsed/refractory (RR) patient treatment.
Survival outcomes and clinical benefit in patients with acute myeloid leukemia treated with glasdegib and low-dose cytarabine according to response to therapy. [2021]The phase 2 BRIGHT AML 1003 trial evaluated efficacy and safety of glasdegib + low-dose cytarabine (LDAC) in patients with acute myeloid leukemia ineligible for intensive chemotherapy. The multicenter, open-label study randomized patients to receive glasdegib + LDAC (n = 78) or LDAC alone (n = 38). The rate of complete remission (CR) was 19.2% in the glasdegib + LDAC arm versus 2.6% in the LDAC arm (P = 0.015).
Is targeted therapy feasible in acute myelogenous leukemia? [2021]The prognosis for patients with acute myeloid leukemia (AML) is determined to a large degree by the biology of the leukemic cell. In recent years, the identification and characterization of genetic aberrations has vastly improved our understanding of the pathogenesis of AML. In contrast, however, there has been a lack of clinically meaningful therapeutic advances. The same chemotherapeutic strategies have been applied to AML for several decades now, and while these regimens are effective in inducing remission, most patients relapse within months after initial treatment. Hence, there is an urgent need for novel therapies. We review herein a number of lines of laboratory and clinical trial data supporting the clinical value of targeted treatment approaches that will likely result in improved outcomes for patients with AML.
Glasdegib plus intensive/nonintensive chemotherapy in untreated acute myeloid leukemia: BRIGHT AML 1019 Phase III trials. [2020]Glasdegib, an oral Hedgehog pathway inhibitor, has been associated with significantly improved survival when combined with low-dose cytarabine in patients with untreated acute myeloid leukemia (AML) who were unsuitable for intensive chemotherapy, when compared with low-dose cytarabine alone. BRIGHT AML 1019 (NCT03416179) comprises two independently powered Phase III, randomized (1:1), double-blind global trials evaluating oral glasdegib 100 mg once daily or placebo plus one of two standard chemotherapy regimens in adults with untreated AML. The intensive trial combines glasdegib/placebo with cytarabine and daunorubicin (7 + 3), while the nonintensive trial combines glasdegib/placebo with azacitidine. The primary end point of both studies is overall survival. Secondary end points include response, time to and duration of response, event-free survival, safety, patient-reported outcomes and pharmacokinetics. Trial registration number: ClinicalTrials.gov identifier: NCT03416179.
Osteolytic Bone Lesions - A Rare Presentation of AML M6. [2020]Acute myeloid leukemia (AML) M6 is a rare form of AML accounting for
Glasdegib for the treatment of adult patients with newly diagnosed acute myeloid leukemia or high-grade myelodysplastic syndrome who are elderly or otherwise unfit for standard induction chemotherapy. [2019]On November 21, 2018, the U.S. Food and Drug Administration (FDA) approved glasdegib in combination with low-dose cytarabine (LDAC), for the treatment of newly diagnosed acute myeloid leukemia (AML) in patients > 75 years old or who have comorbidities that would be prohibitive of intensive induction chemotherapy. Glasdegib is a small-molecule inhibitor of a component of the hedgehog (HH) pathway, an upregulated pathway in leukemia and leukemia stem cells that is associated with relapse, drug resistance and poor survival. Preclinical studies suggested that glasdegib could sensitize AML cells to chemotherapy. FDA approval was based on a randomized, placebo-controlled, phase II trial in elderly or infirmed adults with new AML, unable to receive intensive induction chemotherapy, in whom the addition of glasdegib to LDAC nearly doubled the median overall survival compared with LDAC alone. In this report, we examine the preclinical development of glasdegib, its pharmacology and the clinical investigation that demonstrated its safety and efficacy, resulting in its approval. Additionally, we highlight ongoing investigation and future applications of this therapy.
An evaluation of glasdegib for the treatment of acute myelogenous leukemia. [2020]Introduction: Despite recent advances in the treatment of adult acute myelogenous leukemia (AML), the overall outcome remains dismal especially in high-risk AML patients, including the elderly and the relapsed/refractory populations. In this setting, various clinical trials have recently explored novel therapeutic agents either used alone or in combination with intensive chemotherapy or low-intensity treatments.Areas covered: The current paper reviews the clinical development of glasdegib, a selective inhibitor of the Hedgehog signaling pathway through binding to its target SMO, for the treatment of AML.Expert opinion: Glasdegib confirmed its efficacy and showed an acceptable tolerability, especially when used in combination either with '3 + 7' chemotherapy or with low-intensity therapies. In 2018, glasdegib was approved by the Food and Drug Administration (FDA) in combination with low-dose cytarabine for the treatment of newly diagnosed AML in patients older than 75 years or presenting with severe comorbidities.
Interpreting data in AML. [2013]Steady progress has been made in the treatment of acute myeloid leukemia since the discovery of daunorubicin in the 1960s. Advances in new drug activity have contributed greatly to that and are responsible for curing about 20 percent of patients diagnosed today. Progress in supportive care has been equally important; broad-spectrum antibiotics are now allowing patients to survive long enough to receive an adequate course of chemotherapy, to which most patients respond with a complete remission. More recently, the development of colony-stimulating factors and their safe use during induction therapy in high-risk patients has allowed greater numbers of patients to be adequately treated during the initial phase of therapy. The most significant recent advance in treatment for acute leukemia is the demonstration that certain leukemic syndromes respond dramatically to specific interventions that are substantially less active in other leukemic syndromes. The challenge for the near future is to understand the mechanisms behind these empiric observations and, for the long-term, to learn to use such information to design molecularly targeted therapy for specific leukemic syndromes that are characterized by unique molecular features. Antisense oligonucleotide therapeutic research is one first step in that direction.