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A Study of PLX2853 in Relapsed or Refractory Acute Myeloid Leukemia or High Risk Myelodysplastic Syndrome

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ClinicalTrials.gov Identifier: NCT03787498
Recruitment Status : Recruiting
First Posted : December 25, 2018
Last Update Posted : July 19, 2019
Sponsor:
Information provided by (Responsible Party):
Plexxikon

Brief Summary:
The purpose of this research study is to evaluate safety, pharmacokinetics, pharmacodynamics and preliminary efficacy of the investigational drug PLX2853 in subjects with Relapsed or Refractory Acute Myeloid Leukemia or High-risk Myelodysplastic Syndrome

Condition or disease Intervention/treatment Phase
Relapsed Acute Myeloid Leukemia (AML) Refractory Acute Myeloid Leukemia (AML) High-risk Myelodysplastic Syndrome (MDS) Drug: PLX2853 Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 36 participants
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1b Dose-escalation Study to Assess the Safety, Pharmacokinetics, Pharmacodynamics, and Preliminary Efficacy of PLX2853 in Subjects With Relapsed or Refractory Acute Myeloid Leukemia or High-risk Myelodysplastic Syndrome
Actual Study Start Date : March 19, 2019
Estimated Primary Completion Date : January 2020
Estimated Study Completion Date : June 26, 2020


Arm Intervention/treatment
Experimental: PLX2853
Approximately 30 subjects will be enrolled as part of dose escalation to identify the MTD/RP2D of PLX2853. Up to 6 additional subjects may be enrolled at the MTD/RP2D to further characterize the PK and PDy of PLX2853.
Drug: PLX2853
Tablets




Primary Outcome Measures :
  1. Number of participants with treatment-related adverse events as assessed by CTCAE v5.0 [ Time Frame: First dose of study drug through at least 30 days after end of treatment ]
  2. Area under the concentration-time curve (AUC) of PLX2853 [ Time Frame: From first dose of PLX2853 up to 30 days after end of treatment ]
  3. Maximum observed concentration (Cmax) of PLX2853 [ Time Frame: From first dose of PLX2853 up to 30 days after end of treatment ]
  4. Time to peak concentration (Tmax) of PLX2853 [ Time Frame: From first dose of PLX2853 up to 30 days after end of treatment ]
  5. Half life (t1/2) of PLX2853 [ Time Frame: From first dose of PLX2853 up to 30 days after end of treatment ]
  6. Terminal elimination rate constant (Kel) [ Time Frame: From first dose of PLX2853 up to 30 days after end of treatment ]
  7. Number of participants who experience dose limiting toxicity as defined in the protocol [ Time Frame: up to 18 months ]
    Dose escalation will be guided by a modified continuous reassessment method (mCRM) using a Bayesian logistic regression model that follows the escalation with overdose control (EWOC) principle. In this method, a decision to escalate to the next dose level is based on a review of all subjects who have completed the DLT observation period.


Secondary Outcome Measures :
  1. Overall complete remission (OCR) rate [ Time Frame: From the first dose of study drug until the date of documented best response to treatment, assessed up to 18 months ]
    AML — CR + CRi; MDS — CR

  2. Overall response rate (ORR) [ Time Frame: From the first dose of study drug until the date of documented response to treatment, assessed up to 18 months ]
    AML — Complete response (CR) + CR with incomplete hematologic recovery (CRi) + partial response (PR); MDS — CR + PR

  3. Duration of response (DOR) [ Time Frame: DOR defined as the time from the initial objective response to disease progression or death, whichever occurs first, assessed up to 18 months ]
  4. Event-free survival (EFS) [ Time Frame: EFS time is defined as the time from the first dose of PLX2853 to treatment failure, relapse after initial response or death from any cause, assessed up to 18 months. ]
  5. Progression-free survival (PFS) [ Time Frame: PFS time is defined as the time from the first dose of PLX2853 to disease progression or death, whichever occurs first, assessed up to 18 months. ]
  6. Overall survival (OS) [ Time Frame: From the first dose of study drug until the date of death from any cause, assessed up to 18 months. ]


Information from the National Library of Medicine

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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:

  1. Confirmed diagnosis of one of the following myeloid malignancies, based on the 2016 revision of the World Health Organization classification:

    A. Relapsed or refractory AML.

    I. Subjects must have received no more than 3 prior induction therapies and have no standard therapeutic option that is expected to result in a clinical benefit.

    B. Relapsed or refractory MDS.

    I. Subjects must have high-risk disease (intermediate or greater disease according to the revised International Prognostic Scoring System [IPSS-R]).

    II. Subjects must have received no more than 3 prior therapies, 1 of which must have included a hypomethylating agent such as azacytidine or decitabine.

    III. Subjects must have no standard therapeutic option that is expected to result in a clinical benefit.

  2. Age ≥18 years.
  3. Eastern Cooperative Oncology Group (ECOG) performance status of ≤2.
  4. Life expectancy of ≥3 months in the judgment of the investigator.
  5. Adequate renal, hepatic, and coagulation parameters:

    A. Measured or calculated (Cockcroft-Gault formula) creatinine clearance (CrCl) ≥60 mL/min.

    B. Total bilirubin ≤1.5 × ULN unless due to Gilbert's syndrome. C. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 × ULN.

    D. Prothrombin time or international normalized ratio ≤1.5 × ULN. E. Activated partial thromboplastin time ≤1.5 × ULN.

  6. Women of child-bearing potential must have a negative pregnancy test at Screening and must agree to use an effective form of contraception from the time of the negative pregnancy test to 90 days after the last dose of study drug. Effective forms of contraception include abstinence, hormonal contraception in conjunction with a barrier method, or a double barrier method. Women of non-child-bearing potential may be included if they are either surgically sterile or have been postmenopausal for ≥ 1 year.
  7. Fertile men must agree to use an effective method of birth control during the study and for 90 days after the last dose of study drug.
  8. Resolution (to ≤Grade 1 or baseline) of all significant toxicity associated with prior cancer therapy prior to study drug initiation. (Grade 2 alopecia is allowed.)
  9. Willingness and ability to provide written informed consent prior to any study-related procedures and to comply with all study requirements.

Exclusion Criteria:

  1. Prior treatment with a bromodomain inhibitor.
  2. Any one of the following therapies:

    A. Stem cell transplantation within 90 days of study drug initiation;

    B. Active immunosuppressive therapy for graft-versus-host disease (GVHD);

    C. GVHD prophylaxis within 2 weeks of study drug initiation.

  3. Known uncontrolled fungal, bacterial, and/or viral infection ≥Grade 2.
  4. Uncontrolled autoimmune hemolytic anemia or immune thrombocytopenia.
  5. Active symptomatic central nervous system involvement of AML. (Individuals who have had leptomeningeal disease that was effectively treated are eligible.)
  6. A diagnosis of acute promyelocytic leukemia or chronic myeloid leukemia in blast crisis.
  7. Known or suspected allergy to the study drug or any agent given in association with this trial.
  8. Women who are either pregnant or breast feeding.
  9. Clinically significant cardiac disease.
  10. Inability to take oral medication or significant nausea and vomiting, malabsorption, or significant small bowel resection that, in the opinion of the Investigator, would preclude adequate absorption.
  11. Individuals who are known to be infected with HIV, hepatitis B virus (HBV), or hepatitis C virus (HCV) or are known carriers of HBV or HCV. Individuals who are positive for HCV antibody must be negative for HCV RNA by polymerase chain reaction (PCR) to be eligible. Individuals with occult or prior HBV infection (defined as being seropositive for total hepatitis B core antibody and seronegative for hepatitis B surface antigen) may be included if HBV DNA is undetectable. These individuals must be willing to undergo additional testing per local standard of care.
  12. Active secondary malignancy that confounds interpretation of the study results or limits the subject's survival to <2 years in the judgement of the investigator.
  13. Major surgery or significant injury within the 14-day period prior to study drug initiation.
  14. Anti-cancer therapy in the period immediately preceding study drug initiation.
  15. Any other medical, psychological, familial, sociologic, or geographic condition that, in the judgement of the investigator, would potentially hamper compliance with the study protocol or interfere with the study endpoints or the subject's ability to participate in the study.
  16. Participation in any other therapeutic clinical study. (Participation in observational or registry trials is allowed.)
  17. Individuals who are on active anticoagulation therapy (e.g., warfarin, factor Xa inhibitors, thrombin inhibitors, heparin).

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): NCT03787498


Contacts
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Contact: Paul Watkins 510-647-4151 PWatkins@plexxikon.com

Locations
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United States, Georgia
Northside Hospital Recruiting
Atlanta, Georgia, United States, 30342
Contact: Stacy Brown    404-780-7965    stacey.brown@northside.com   
United States, Maryland
Sidney Kimmel Comprehensive Cancer At Johns Hopkins Recruiting
Baltimore, Maryland, United States, 27287
Contact: Amy Dezern, MD    410-502-7208    adezern1@jhmi.edu   
United States, Ohio
Ohio State University Medical Center Recruiting
Columbus, Ohio, United States, 43210
Contact    614-293-3316      
United States, Oregon
Oregon Health and Sciences University Recruiting
Portland, Oregon, United States, 97239
Contact    503-494-1080    Trials@ohsu.edu   
United States, Texas
University of Texas MD Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: Naveen Pemmaraju    713-792-4956    npemmaraju@mdanderson.org   
Sponsors and Collaborators
Plexxikon

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Responsible Party: Plexxikon
ClinicalTrials.gov Identifier: NCT03787498     History of Changes
Other Study ID Numbers: PLX124-02
First Posted: December 25, 2018    Key Record Dates
Last Update Posted: July 19, 2019
Last Verified: July 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Plexxikon:
PLX2853
Acute Myeloid Leukemia
AML
Myelodysplastic Syndrome
MDS
Hematologic Malignancy
Blood Cancer

Additional relevant MeSH terms:
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Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Preleukemia
Myelodysplastic Syndromes
Syndrome
Disease
Pathologic Processes
Neoplasms by Histologic Type
Neoplasms
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions