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CPX-351 and Glasdegib for Newly Diagnosed Acute Myelogenous Leukemia With MDS Related Changes or Therapy-related Acute Myeloid Leukemia

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ClinicalTrials.gov Identifier: NCT04231851
Recruitment Status : Recruiting
First Posted : January 18, 2020
Last Update Posted : August 11, 2020
Sponsor:
Collaborators:
Jazz Pharmaceuticals
Pfizer
Information provided by (Responsible Party):
Deepa Jeyakumar, University of California, Irvine

Brief Summary:
This is a phase 2 single-arm, open-label clinical trial determining efficacy of CPX-351 in combination with Glasdegib in subjects with Acute Myelogenous Leukemia with myelodysplastic syndrome related changes or therapy-related acute myeloid leukemia.

Condition or disease Intervention/treatment Phase
Acute Myelogenous Leukemia (AML) Due to Therapy Acute Myeloid Leukemia With Myelodysplasia-Related Changes Drug: Glasdegib Drug: CPX-351 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase II Study of the Combination of CPX-351 and Glasdegib in Previously Untreated Patients With Acute Myelogenous Leukemia With MDS Related Changes or Therapy-related Acute Myeloid Leukemia
Actual Study Start Date : February 19, 2020
Estimated Primary Completion Date : December 31, 2020
Estimated Study Completion Date : December 31, 2021


Arm Intervention/treatment
Experimental: CPX-351 and Glasdegib

In Induction, subjects receive 44mg/m2/100mg/m2 IV on days 1, 3 and 5 and Glasdegib 100mg PO daily on days 6 to 28.

If re-induction is needed: Subjects receive 29mg/m2/65mg/m2 IV on days 1 and 3 and Glasdegib 100mg PO daily on days 4 to 28.

In consolidation: Subjects receive 29mg/m2/65mg/m2 IV on days 1 and 3 and Glasdegib 100mg PO daily on days 4 to 28.

If maintenance is required, Subjects receive Glasdegib 100mg PO daily for up to one year

Drug: Glasdegib
Given PO
Other Name: DAURISMO™

Drug: CPX-351
Given IV
Other Names:
  • Daunorubicin and cytarabine
  • VYXEOS®




Primary Outcome Measures :
  1. Percentage of Participants with Event-Free Survival at 6 months [ Time Frame: 6 months ]
    This is defined as the percentage of subjects with event-free survival (EFS) at 6 months. EFS is defined as the number of months where patients are in a remission state.


Secondary Outcome Measures :
  1. Percentage of Grade 3-5 Adverse Events [ Time Frame: From the start date of treatment until 4 weeks after removal of treatment due to disease progression, toxicity, delay of treatment, or withdrawal of treatment, whichever came first, an average of 1 year. ]
    To evaluate the tolerability of administering CPX-351 in combination with glasdegib in patients with newly diagnosed with Acute Myeloid Leukemia (AML) with Myelodysplastic Syndrome (MDS) related changes or treatment-related AML from the start of treatment, duration of treatment and up to 4 weeks after completion of study treatment. Toxicity and adverse events are based on the CTCAE (NCI Common Terminology Criteria for Adverse Events) Version 5.0.

  2. Overall Response Rate [ Time Frame: From the start date of treatment until first date of CR/CRi or an average of 1 year. ]
    To assess the overall response rate to the combination of CPX-351 and glasdegib. The overall response rate (ORR) is defined as the rate of complete remissions (CR) and complete remission with incomplete count recovery (CRi). ORR = CR + CRi

  3. Durability of Response [ Time Frame: From the start date of treatment until first date of CR/CRi or an average of 1 year. ]
    Durability of response is measured by relapse-free survival (RFS). RFS is defined as the amount of time a patient remains in remission after having achieved a CR or CRi

  4. Overall Survival of Patients who received the combination of CPX-351 and glasdegib [ Time Frame: Time from screening biopsy for up to 12 months after the last patient is enrolled or until death from any cause, whichever came first. ]
    To evaluate the overall survival of patients with newly diagnosed with Acute Myeloid Leukemia (AML) with Myelodysplastic Syndrome (MDS) related changes or treatment-related AML.

  5. Time to normal hematopoiesis as assessed by laboratory studies [ Time Frame: From the start date of treatment until laboratory studies confirmation of normal hematopoiesis or an average of 1 year ]
    To evaluate the time to normal hematopoiesis, process by which blood cells are formed, as determined by laboratory studies inclusive of complete blood counts (CBCs)

  6. Number of participants who go on to receive an allogenic hematopoietic stem cell transplant [ Time Frame: Up to 3 years ]
    This is defined as the number of participants who continue on to receive an allogenic hematopoietic stem cell transplant after induction, re-induction, or consolidation.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Previously untreated therapy-related AML or AML with myelodysplastic related changes as described by World Health Organization (WHO)

    1. AML arising in MDS (including CMML) or MDS/MPN syndrome
    2. AML with MDS-related cytogenetic abnormalities (Appendix A, metaphase FISH allowable as surrogate for cytogenetics)
    3. 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 CEBPA (as per WHO 2016)
  • Adults 18 years of age or older
  • ECOG performance status 0 to 2
  • Adequate organ function as defined as:

    1. Left Ventricular Ejection Fraction (LVEF) > 50%
    2. Serum total bilirubin < 2.0 mg/dL, unless considered due to Gilbert's disease or leukemic involvement
    3. AST, ALT and alkaline phosphatase < 3 times the upper limit of normal, unless considered due to leukemic involvement
    4. Serum creatinine < 2.0 mg/dL, or creatinine clearance > 40 mL/min based on Cockcroft-Gault 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
  • 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

    1. 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:

      1. Has not undergone a hysterectomy or bilateral oophorectomy; or
      2. 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)
    2. Women of child-bearing potential has negative pregnancy test within 72 hours of initiating study drug dosing
    3. 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 WBC

Exclusion Criteria:

  • 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
  • Active 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, NYHA class III or VI
  • Known history of Wilson's disease or other copper handling disorder
  • History of 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 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04231851


Contacts
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Contact: Chao Family Comprehensive Cancer Center University of California, Irvine 1-877-827-7883 ucstudy@uci.edu
Contact: University of California Irvine Medical

Locations
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United States, California
Chao Family Comprehensive Cancer Center, University of California, Irvine Recruiting
Orange, California, United States, 92868
Contact: Deepa Jeyakumar, MD    877-827-8839    ucstudy@uci.edu   
Sponsors and Collaborators
University of California, Irvine
Jazz Pharmaceuticals
Pfizer
Investigators
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Principal Investigator: Deepa Jeyakumar, MD Chao Family Comprehensive Cancer Center
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Responsible Party: Deepa Jeyakumar, HS Associate Clinical Professor, University of California, Irvine
ClinicalTrials.gov Identifier: NCT04231851    
Other Study ID Numbers: UCI 18-105
2019-5533 ( Other Identifier: University of California, Irvine )
UCHMC1913 ( Other Identifier: University of California Hematologic Malignancies Consortium )
First Posted: January 18, 2020    Key Record Dates
Last Update Posted: August 11, 2020
Last Verified: August 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Deepa Jeyakumar, University of California, Irvine:
Therapy-Related AML
AML with MDS related changes
Additional relevant MeSH terms:
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Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Preleukemia
Myelodysplastic Syndromes
Neoplasms by Histologic Type
Neoplasms
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Cytarabine
Daunorubicin
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antibiotics, Antineoplastic
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors