CPX-351 and Glasdegib for the Treatment of Therapy-Related Acute Myeloid Leukemia
- Previously untreated therapy-related AML or AML with myelodysplastic related changes as described by World Health Organization (WHO) * AML arising in MDS (including chronic myelomonocytic leukemia [CMML]) or MDS/myeloproliferative neoplasm (MPN) syndrome * AML with MDS-related cytogenetic abnormalities (metaphase fluorescence in situ hybridization [FISH] allowable as surrogate for cytogenetics) * AML with multi-lineage dysplasia involving the presence of 50% or more dysplastic cells in at least two cell lines and in the absence of mutation in NPM1 or biallelic CEBPA (as per WHO 2016)
- Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2
- Left ventricular ejection fraction (LVEF) > 50%
- Serum total bilirubin < 2.0 mg/dL, unless considered due to Gilbert's disease or leukemic involvement
- Aspartate aminotransferase (AST) < 3 times the upper limit of normal, unless considered due to leukemic involvement
- Alanine aminotransferase (ALT) < 3 times the upper limit of normal, unless considered due to leukemic involvement
- Alkaline phosphatase < 3 times the upper limit of normal, unless considered due to leukemic involvement
- Serum creatinine < 2.0 mg/dL, or creatinine clearance > 40 mL/min based on Cockcroft-Gault glomerular filtration rate (GFR)
- Absence of unstable cardiac disease defined as myocardial infarction within 6 months, uncontrolled heart failure, or uncontrolled cardiac arrhythmia
- Ability to understand and the willingness to sign a written informed consent or subject’s legally authorized representative (LAR) has provided informed consent prior to any study-specific activities/procedures being initiated when the subject has any kind of condition that, in the opinion of the investigator, may compromise the ability of the subject to give written informed consent
- Women of child-bearing potential and men with partners of child-bearing potential must agree to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication * A woman of child-bearing potential is any female (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria: ** Has not undergone a hysterectomy or bilateral oophorectomy; or ** Has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months) * Women of child-bearing potential has negative pregnancy test within 72 hours of initiating study drug dosing
- Male subjects must agree to use a latex condom during sexual contact with females of childbearing potential even if they have had a successful vasectomy starting with the first dose of study therapy through 120 days after the last dose of study therapy
- Leukapheresis, corticosteroids and hydroxyurea are permitted after screening bone marrow biopsy is performed for up to 7 days prior to starting study therapy as management of hyperleukocytosis at the investigator's discretion. Hyperleukocytosis is defined as greater than 30k white blood cells (WBC)
- Prior treatment with glasdegib or CPX-351
- Previously treated AML except for initial management of hyperleukocytosis. Treatment with hypomethylating therapy for MDS is allowable but not since their diagnosis of AML. No prior treatment with cytarabine or daunorubicin are allowed
- Concurrent FLT3 mutation that the treating physician deems necessary to treat with midostaurin, whereas patients with FLT3-mutated AML not treated with midostaurin can be enrolled
- Active central nervous system (CNS) or testicular involvement by leukemia
- History of neurologic disorder including but not limited to: prior seizure, epilepsy, structural brain abnormality, benign brain tumor, stroke, brain injuries, dementia, movement disorder or other significant CNS abnormalities
- Baseline QT corrected interval based on Fridericia’s formula (QTcF) interval > 450 ms
- Acute coronary syndrome in the past 12 months, New York Heart Association (NYHA) class III or VI
- Known history of Wilson’s disease or other copper handling disorder
- History of gastrointestinal (GI) malabsorptive disease
- Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy
- Known human immunodeficiency virus (HIV) infection
- Active hepatitis B or hepatitis C infection (patients who successfully completed curative hepatitis C therapy can be enrolled)
- Any uncontrolled infection, active bacterial or viral infection manifesting as fevers or hemodynamic instability within the past 72 hours
- Proven active invasive fungal infection
- Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment
- Severe or uncontrolled medical disorder that would, in the investigator’s opinion, impair ability to receive study treatment (i.e., uncontrolled diabetes, chronic renal disease, chronic pulmonary disease or active, uncontrolled infection, psychiatric illness/social situations that would limit compliance with study requirements
- Current or anticipated use of other investigational agents
I. To determine the efficacy when using the combination of liposome-encapsulated daunorubicin-cytarabine (CPX-351) and glasdegib maleate (glasdegib) to treat patients with newly diagnosed acute myeloid leukemia (AML) with myelodysplastic syndrome (MDS)-related changes or treatment related AML.
I. To evaluate any toxicities associated with the combination.
II. To evaluate the rate of response.
III. To evaluate the durability of response.
IV. To evaluate survival and the length of survival.
V. To evaluate the time to return of normal hematopoiesis.
VI. To evaluate the proportion of subjects who go on to receive allogenic hematopoietic stem cell transplantation (HSCT).
I. To determine if minimal residual disease (MRD) status can be used as a surrogate marker for survival.
II. To determine if gene expression profiling can be biomarkers of response.
INDUCTION: Patients receive liposome-encapsulated daunorubicin-cytarabine intravenously (IV) on days 1, 3, and 5 over 90 minutes and glasdegib maleate orally (PO) daily on days 6-28 in the absence of disease progression or unacceptable toxicity.
RE-INDUCTION: Patients responding to the initial induction but not yet less than 5% blasts receive liposome-encapsulated daunorubicin-cytarabine IV on days 1 and 3 over 90 minutes and glasdegib maleate PO daily on days 4-28 in the absence of disease progression or unacceptable toxicity.
CONSOLIDATION: Patients who achieve complete remission (CR) and complete remission with incomplete count recovery (CRi) receive liposome-encapsulated daunorubicin-cytarabine IV on days 1 and 3 over 90 minutes and glasdegib maleate PO daily on days 4-28. Treatment repeats every 28-55 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients may then undergo HSCT.
MAINTENANCE: Patients who do not undergo HSCT, receive glasdegib maleate PO daily on days 1-28. Cycles repeat every 28 days for up to 1 year in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 3 months for 1 year.
Trial Phase Phase II
Trial Type Treatment
UC Irvine Health / Chao Family Comprehensive Cancer Center
- Primary ID UCI 18-105
- Secondary IDs NCI-2020-00407, UCHMC1913, 2019-5533
- Clinicaltrials.gov ID NCT04231851