Clinical trial NCT06146257: A Study of GLB-001 in Patients With Relapsed or Refractory Acute Myeloid Leukemia or Relapsed or Refractory Higher Risk Myelodysplastic Syndromes
Official title: A First-in-human, Phase 1, Dose Escalation and Expansion Study to Evaluate the Safety, Pharmacokinetics, Pharmacodynamics and Preliminary Efficacy of GLB-001 in Patients With Relapsed or Refractory Acute Myeloid Leukemia or Relapsed or Refractory Higher-risk Myelodysplastic Syndromes
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: Acute Myeloid Leukemia
Myelodysplastic Syndromes
Lead sponsor: GluBio Therapeutics Inc.
Sponsor class: INDUSTRY
First posted: 2023-11-24
Enrollment: 48
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: Study GLB-001-01 is a first-in-human (FIH), Phase 1, open-label, dose escalation and expansion clinical study of GLB-001 in participants with relapsed or refractory acute myeloid leukemia (R/R AML) or in participants with relapsed or refractory higher-risk myelodysplastic syndromes (R/R HR-MDS). The dose escalation part (Phase 1a) of the study will evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary efficacy of GLB-001 administered orally. Approximately 24 participants (up to 42 participants) may be enrolled in Phase 1a of the study.

The dose expansion part (Phase 1b) will be followed to understand the relationships among dose, exposure, toxicity, tolerability and clinical activity, to identify minimally active dose, and to select the recommended dose(s) for phase 2 study. Up to 24 participants (12 participants per dose level) may be enrolled in Phase 1b of the study.

Detailed description: A standard 3+3 dose-escalation design will be applied to evaluate a set of several dose levels to determine the maximum tolerated dose (MTD) or maximum administered dose (MAD) of GLB-001 in R/R AML or R/R HR-MDS patients who are eligible for DLT evaluation. The actual dose-escalation magnitude or dosing frequency may be adjusted based on the available PK and safety data in human.

After the MTD or MAD of GLB-001 is defined in Phase 1a, 1 or 2 dose levels will be selected for expansion per safety review committee (SRC) recommendation, approximately 12 patients will be enrolled per dose level. Recommended phase 2 dose (RP2D) will be selected based on the results of PK, PD, safety and efficacy in the dose escalation and expansion study.

Eligibility criteria: Inclusion Criteria:

* Participants is ≥ 18 years of age at the time of signing the Informed Consent Form (ICF).
* Participants must understand and voluntarily sign an ICF prior to any study-related assessments/procedures being conducted.
* Participants are willing and able to adhere to the study visit schedule and other protocol requirements.
* Participants with histologically or cytologically confirmed AML including de novo AML or secondary AML transformed from MDS according to 2022 World Health Organization (WHO) criteria classification, or with histologically or cytologically confirmed HR-MDS.
* R/R AML and R/R HR-MDS who have failed or are ineligible for all available therapies which may provide clinical benefit.
* Participants must have the following screening laboratory values:

  * Total white blood cell count (WBC) \< 25 x 10\^9/L prior to the first dose of the study drug.
  * Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3.0 × upper limit of normal (ULN), unless considered due to extensive leukemic liver involvement, in which case AST and ALT can be ≤ 5.0 x ULN.
  * Serum total bilirubin ≤ 1.5 x ULN, unless considered due to Gilbert's syndrome, in which case serum total bilirubin \< 3 x ULN.
  * Estimated serum creatinine clearance of ≥ 60 mL/min using the Cockcroft-Gault equation. Measured creatinine clearance from a 24-hour urine collection is acceptable if clinically indicated.
  * International normalized ratio (INR) ≤ 1.5 x ULN and active partial thromboplastin time (aPTT) ≤ 1.5 x ULN.
* Life expectancy ≥ 12 weeks.
* Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 2.
* Female Participants of child-bearing potential must have a negative serum or urine pregnancy test at screening and at pre-dose on Cycle 1 Day 1 (C1D1).

Exclusion Criteria:

* Participants with acute promyelocytic leukemia (APML).
* Participants with known leukemic involvement in central nervous system (CNS).
* Receipt of anticancer medications/therapies within 5 half-lives or 28 days before the first administration of the study drug.
* Participants with unresolved clinically significant non-hematologic toxicities of ≥ Grade 2 AE from prior therapies with exception of residual alopecia.
* Participants with chronic graft versus host disease (GVHD) requiring systemic immunosuppressive therapy.
* Participants with active malignancies other than AML or MDS.
* Participants who have undergone major surgery ≤ 4 weeks prior to the first dose of the study drug.
* Participants with immediately life-threatening, severe complications of leukemia such as disseminated/uncontrolled infection (bacterial and/or fungal), uncontrolled bleeding, and/or uncontrolled disseminated intravascular coagulation.
* Participants with known chronic, active infection of hepatitis B virus (HBV), hepatitis C virus C (HCV), human immunodeficiency virus (HIV).
* Participants unable to swallow oral medications, or Participants with clinically significant diarrhea, vomiting or malabsorption felt limited absorption of orally administered medications.
* Participants with any other significant medical conditions, any other conditions, laboratory abnormality, or psychiatric illness which place the Participants at unacceptable risk if he/she were to participate in the study or that would hamper the Participants understanding of the study, or would prevent the Participant from complying with the study.
* Medications or supplements that are known to be strong and moderate inhibitors or inducers of CYP450 isozyme 3A4 (CYP3A4) and/or P-glycoprotein (P-gp), or strong inhibitors or inducers of CYP450 isozyme 2C8 (CYP2C8) within 14 days or 5 half-lives, whichever is shorter, before the first dose of study drug.
* Pregnant or lactating women.

Primary outcomes:
measure: Dose-limiting Toxicity (DLT)
timeFrame: Up to 28 days after first dose of study treatment in Phase 1a
measure: Maximum Tolerated Dose (MTD)/Maximum Administered Dose (MAD)
timeFrame: Up to 2 years
measure: Incidence of Adverse Events (AEs)
timeFrame: Up to 2 years
measure: Recommended Phase 2 Dose (RP2D)
timeFrame: Up to 2 years
Secondary outcomes:
measure: GLB-001 Pharmacokinetics-AUC0-last
timeFrame: Up to 2 years
measure: GLB-001 Pharmacokinetics-AUC0-24
timeFrame: Up to 2 years
measure: GLB-001 Pharmacokinetics-AUC0-∞
timeFrame: Up to 2 years
measure: GLB-001 Pharmacokinetics-Cmax
timeFrame: Up to 2 years
measure: GLB-001 Pharmacokinetics-Tmax
timeFrame: Up to 2 years
measure: GLB-001 Pharmacokinetics-T1/2
timeFrame: Up to 2 years
measure: GLB-001 Pharmacokinetics-Vd/F
timeFrame: Up to 2 years
measure: GLB-001 Pharmacokinetics-LI
timeFrame: Up to 2 years
measure: GLB-001 Pharmacokinetics-CL/F
timeFrame: Up to 2 years
measure: GLB-C183-A-2R (Isomer of GLB-001) Pharmacokinetics-AUC0-last
timeFrame: Up to 2 years
measure: GLB-C183-A-2R Pharmacokinetics-AUC0-24
timeFrame: Up to 2 years
measure: GLB-C183-A-2R Pharmacokinetics-AUC0-∞
timeFrame: Up to 2 years
measure: GLB-C183-A-2R Pharmacokinetics-Cmax
timeFrame: Up to 2 years
measure: GLB-C183-A-2R Pharmacokinetics-Tmax
timeFrame: Up to 2 years
measure: GLB-C183-A-2R Pharmacokinetics-T1/2
timeFrame: Up to 2 years
measure: GLB-C183-A-2R Pharmacokinetics-Vd/F
timeFrame: Up to 2 years
measure: GLB-C183-A-2R Pharmacokinetics-LI
timeFrame: Up to 2 years
measure: GLB-C183-A-2R Pharmacokinetics-CL/F
timeFrame: Up to 2 years
measure: Complete Remission Without Minimal Residual Disease (CRMRD-) Rate in Participants with Acute Myeloid Leukemia (AML)
timeFrame: Up to 2 years
measure: Complete Remission (CR) Rate in Participants with AML
timeFrame: Up to 2 years
measure: CR with Incomplete Hematologic Recovery (CRi) Rate in Participants with AML
timeFrame: Up to 2 years
measure: CR with Partial Hematological Recovery (CRh) Rate in Participants with AML
timeFrame: Up to 2 years
measure: Morphologic Leukemia-free State (MLFS) Rate in Participants with AML
timeFrame: Up to 2 years
measure: Partial Remission (PR) Rate in Participants with AML
timeFrame: Up to 2 years
measure: Duration of Remission or Response (DOR) in Participants with AML
timeFrame: Up to 2 years
measure: Time to Remission or Response (TOR) in Participants with AML
timeFrame: Up to 2 years
measure: Stable Disease (SD) Rate in Participants with AML
timeFrame: Up to 2 years
measure: CR Rate in Participants with Higher Risk Myelodysplastic Syndromes (HR-MDS)
timeFrame: Up to 2 years
measure: PR Rate in Participants with HR-MDS
timeFrame: Up to 2 years
measure: SD Rate in Participants with HR-MDS
timeFrame: Up to 2 years
measure: DOR in Participants with HR-MDS
timeFrame: Up to 2 years
measure: TOR in Participants with HR-MDS
timeFrame: Up to 2 years
measure: Progression-free Survival (PFS) in Participants with AML or HR-MDS
timeFrame: Up to 2 years
measure: Overall Survival (OS) in Participants with AML or HR-MDS
timeFrame: Up to 2 years
Other outcomes:
Locations:
city: Duarte
country: United States
facility: City of Hope Medical Center
state: California
city: Irvine
country: United States
facility: University of California Irvine
state: California
city: Kansas City
country: United States
facility: University of Kansas Medical Center Research Institute, Inc.
state: Kansas
city: Merriam
country: United States
facility: Alliance for Multispecialty Research, LLC
state: Kansas
city: Buffalo
country: United States
facility: Roswell Park Comprehensive Cancer Center
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center-David H. Koch Center
state: New York
city: New York
country: United States
facility: Icahn School of Medicine at Mount Sinai
state: New York
city: Houston
country: United States
facility: University of Texas M. D. Anderson Cancer Center
state: Texas
Study officials:
affiliation: GluBio Therapeutics Inc.
name: Gang Lu, Ph.D.
role: STUDY_DIRECTOR
References: