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Study of Standard Intensive Chemotherapy Versus Intensive Chemotherapy With CPX-351 in Adult Patients With Newly Diagnosed AML and Intermediate- or Adverse Genetics

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ClinicalTrials.gov Identifier: NCT03897127
Recruitment Status : Recruiting
First Posted : April 1, 2019
Last Update Posted : May 7, 2021
Sponsor:
Collaborator:
Jazz Pharmaceuticals
Information provided by (Responsible Party):
Verena Gaidzik, University of Ulm

Tracking Information
First Submitted Date  ICMJE March 19, 2019
First Posted Date  ICMJE April 1, 2019
Last Update Posted Date May 7, 2021
Actual Study Start Date  ICMJE September 4, 2019
Estimated Primary Completion Date March 2024   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 28, 2019)
Event-free survival (EFS) [ Time Frame: 2 years ]
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: March 28, 2019)
  • Overall survival (OS) [ Time Frame: 2 years ]
  • Relapse-free survival (RFS) [ Time Frame: 2 years ]
  • Cumulative incidence of relapse (CIR) [ Time Frame: 2 years ]
  • Cumulative incidence of death (CID) [ Time Frame: 2 years ]
  • Rate of objective response [ Time Frame: 2 months ]
    complete remission [CR], CR with incomplete hematologic recovery [CRi], CR without minimal residual disease [CRMRD-]
  • Adverse events [ Time Frame: 8 months ]
    Incidence and intensity of adverse events (AEs) according to Common Terminology Criteria for Adverse Events (CTCAE) version v5.0
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: April 11, 2019)
  • Analysis of rate of response according to cytogenetic and molecular genetic changes [ Time Frame: 2 years ]
    Exploratory endpoint
  • Analysis of Overall survival according to cytogenetic and molecular genetic changes [ Time Frame: 2 years ]
    Exploratory endpoint
  • Analysis of Relapse-free survival according to cytogenetic and molecular genetic changes [ Time Frame: 2 years ]
    Exploratory endpoint
  • Analysis of Event-free survival according to cytogenetic and molecular genetic changes [ Time Frame: 2 years ]
    Exploratory endpoint
  • Analysis of Overall Survival according to Minimal Residual Disease results during and after treatment [ Time Frame: 2 years ]
    Exploratory endpoint
  • Analysis of Event-free Survival according to Minimal Residual Disease results during and after treatment [ Time Frame: 2 years ]
    Exploratory endpoint
  • QoL NCI PRO-CTCAE (National Cancer Institute) Patient Reported Outcomes Common Terminology Criteria for Adverse Events questionnaire) [ Time Frame: 2 years ]
    PRO-CTCAE responses are scored from 0 to 4, whereas lower values represent a better outcome. For this trial, the burden of symptoms that will be captured by this questionnaire comprises nausea, diarrhea, rash, and alopecia.
  • QoL EORTC QLQ-FA12 [ Time Frame: 2 years ]
    The EORTC QLQ-FA12 module complements the core EORTC QLQ-C30 questionnaire regarding fatigue. . Each item can be scored in four dimension on a scale from 1 to 4 with higher scores indicating worse symptoms.
  • QoL EORTC QLQ-C30 (Core Quality of Life Questionnaire developed by European Organization for Research and Treatment of Cancer ) [ Time Frame: 2 years ]
    The EORTC QLQ-C30 subscale scores are transformed to a 0 to 100 scale, with higher scores on functional scales indicating better function and higher scores on symptom scales indicating worse symptoms.
  • Rate of hospitalization including admissions at intensive care unit (ICU) [ Time Frame: 8 months ]
    Exploratory endpoint
  • Reasons for hospitalization [ Time Frame: 8 months ]
    Exploratory endpoint
  • days of hospitalization by treatment setting [ Time Frame: 8 months ]
    Exploratory endpoint
  • rate of use of anti-infectives and other medications, e.g. against nausea or vomiting [ Time Frame: 8 months ]
    Exploratory endpoint
  • additional therapies administered [ Time Frame: 8 months ]
    Exploratory endpoint
  • place of chemotherapy administration (inpatient vs outpatient setting) [ Time Frame: 8 months ]
    Exploratory endpoint
  • duration of administration [ Time Frame: 8 months ]
    Exploratory endpoint
  • number of outpatient visits [ Time Frame: 8 months ]
    Exploratory endpoint
  • Frequency of salvage therapies [ Time Frame: 8 months ]
    Exploratory endpoint
Original Other Pre-specified Outcome Measures
 (submitted: March 28, 2019)
  • Analysis of rate of response according to cytogenetic and molecular genetic changes [ Time Frame: 2 years ]
    Exploratory endpoint
  • Analysis of Overall survival according to cytogenetic and molecular genetic changes [ Time Frame: 2 years ]
    Exploratory endpoint
  • Analysis of Relapse-free survival according to cytogenetic and molecular genetic changes [ Time Frame: 2 years ]
    Exploratory endpoint
  • Analysis of Event-free survival according to cytogenetic and molecular genetic changes [ Time Frame: 2 years ]
    Exploratory endpoint
  • Analysis of Overall Survival according to Minimal Residual Disease results during and after treatment [ Time Frame: 2 years ]
    Exploratory endpoint
  • Analysis of Event-free Survival according to Minimal Residual Disease results during and after treatment [ Time Frame: 2 years ]
    Exploratory endpoint
  • QoL NCI PRO-CTCAE (National Cancer Institute) Patient Reported Outcomes Common Terminology Criteria for Adverse Events questionnaire) [ Time Frame: 2 years ]
    For this trial, the burden of symptoms captured by the PRO-CTCAE comprises nausea, diarrhea, rash, and alopecia.
  • QoL EORTC QLQ-FA12 [ Time Frame: 2 years ]
    The EORTC QLQ-FA12 module complements the core EORTC QLQ-C30 questionnaire regarding fatigue. . Each item can be scored in four dimension on a scale from 1 to 4 with higher scores indicating worse symptoms.
  • QoL EORTC QLQ-C30 (Core Quality of Life Questionnaire developed by European Organization for Research and Treatment of Cancer ) [ Time Frame: 2 years ]
    The EORTC QLQ-C30 subscale scores are transformed to a 0 to 100 scale, with higher scores on functional scales indicating better function and higher scores on symptom scales indicating worse symptoms.
  • Rate of hospitalization including admissions at intensive care unit (ICU) [ Time Frame: 8 months ]
    Exploratory endpoint
  • Reasons for hospitalization [ Time Frame: 8 months ]
    Exploratory endpoint
  • days of hospitalization by treatment setting [ Time Frame: 8 months ]
    Exploratory endpoint
  • rate of use of anti-infectives and other medications, e.g. against nausea or vomiting [ Time Frame: 8 months ]
    Exploratory endpoint
  • additional therapies administered [ Time Frame: 8 months ]
    Exploratory endpoint
  • place of chemotherapy administration (inpatient vs outpatient setting) [ Time Frame: 8 months ]
    Exploratory endpoint
  • duration of administration [ Time Frame: 8 months ]
    Exploratory endpoint
  • number of outpatient visits [ Time Frame: 8 months ]
    Exploratory endpoint
  • salvage therapies [ Time Frame: 8 months ]
    Exploratory endpoint
 
Descriptive Information
Brief Title  ICMJE Study of Standard Intensive Chemotherapy Versus Intensive Chemotherapy With CPX-351 in Adult Patients With Newly Diagnosed AML and Intermediate- or Adverse Genetics
Official Title  ICMJE Randomized Phase III Study of Standard Intensive Chemotherapy Versus Intensive Chemotherapy With CPX-351 in Adult Patients With Newly Diagnosed AML and Intermediate- or Adverse Genetics
Brief Summary The trial is a randomized, open-label phase III study comparing CPX-351 vs conventional intensive induction and consolidation chemotherapy in patients with newly diagnosed AML and intermediate- or adverse-risk genetics (according to 2017 ELN criteria), including AML with myelodysplasia-related changes (AML-MRC) and therapy-related AML according to the World Health Organization (WHO) classification. Event-free survival (EFS) will be the primary endpoint as defined by standard criteria (Döhner 2017).
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Acute Myeloid Leukemia
Intervention  ICMJE
  • Drug: Cytarabine

    Induction therapy: 200 mg/m2 i.v. (continuously) d1-7

    Consolidation therapy:

    • Patients age 18-60 years

      o Intermediate-dose cytarabine 1500 mg/m2 i.v. q12h (3 hrs) d1-3

    • Patients age >60 years o Intermediate-dose cytarabine 1000 mg/m2 i.v. q12h (3 hrs) d1-3
  • Drug: Daunorubicin
    Induction therapy: 60 mg/m2 i.v. (1 hr) d1-3
  • Drug: CPX-351

    Induction 1:

    o CPX-351 44 mg/m2 daunorubicin / 100 mg/m2 cytarabine [100 U/m²] i.v. (90 min) d1,3,5

    Induction 2:

    o CPX-351 44 mg/m2 daunorubicin / 100 mg/m2 cytarabine [100 U/m²] i.v. (90 min) d1,3

    Consolidation therapy:

    o CPX-351 29 mg/m2 daunorubicin / 65 mg/m2 cytarabine [65 U/m²] i.v. (90 min) d1,3

Study Arms  ICMJE
  • Active Comparator: Standard arm
    Interventions:
    • Drug: Cytarabine
    • Drug: Daunorubicin
  • Experimental: Investigational arm
    Intervention: Drug: CPX-351
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: March 28, 2019)
593
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE March 2024
Estimated Primary Completion Date March 2024   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Patients with newly diagnosed AML and intermediate- or adverse-risk genetics (according to 2017 ELN criteria [Appendix B]), including AML with myelodysplasia-related changes (AML-MRC) and therapy-related AML according to the World Health Organization (WHO) classification
  2. Age ≥ 18 years, no upper age limit
  3. Patient considered eligible for intensive chemotherapy
  4. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 at Screening
  5. Genetic assessment in AMLSG central laboratory
  6. Adequate renal function as evidenced by serum creatinine ≤ 2.0 × ULN or creatinine clearance >40 mL/min based on the Cockcroft-Gault glomerular filtration rate (GFR)
  7. Adequate hepatic function as evidenced by:

    • Serum total bilirubin ≤ 1.5 × upper limit of normal (ULN) unless considered due to Gilbert's disease, or leukemic involvement following approval by the Coordinating Investigator or Co-Coordinating Investigator
    • Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) ≤ 3.0 × ULN, unless considered due to leukemic involvement following approval by the Coordinating Investigator or Co-Coordinating Investigator
  8. No prior chemotherapy for acute leukemia except hydroxyurea for up to 7 days during the diagnostic screening phase for the control of peripheral leukemic blasts in patients with leukocytosis (e.g., white blood cell [WBC] counts >30x109/l); prior treatment of myelo-dysplastic syndrome with hypomethylating agents is allowed
  9. Non-pregnant and non-nursing women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test within a sensitivity of at least 25 mIU/mL within 72 hours prior to randomization ("Women of childbearing potential" is defined as a sexually active mature woman who has not undergone a hysterectomy or bilateral oophorectomy or who has had menses at any time in the preceding 24 consecutive months)
  10. Female patients of childbearing potential must agree to avoid getting pregnant while on therapy and for 6 months after the last dose of CPX-351
  11. Women of childbearing potential must either commit to continued abstinence from heterosexual intercourse or apply one highly effective method of birth control (such as IUD, bilateral tubal ligation, or partner's vasectomy) in combination with one acceptable method of birth control at the same time (such as hormonal contraception or the male partner has to use a latex condom coated with spermicide lubricant or combined with spermicide gel or foam) while on therapy and for 6 months after the last dose of CPX-351. Hormonal contraception is only a highly effective method of birth control in case of combined (estrogen and progestogen containing) associated with inhibition of ovulation or progestogen-only hormonal contraception associated with inhibition of ovulation is used
  12. Men must use a latex condom coated with a spermicide lubricant or combined with spermicide gel or foam during any sexual contact with women of childbearing potential, even if they have undergone a successful vasectomy and must agree to avoid to father a child (while on therapy and for 6 months after the last dose of CPX-351). In addition, their female partners of childbearing potential have to use a highly effective method of birth control
  13. Able to understand and willing to sign an informed consent form (ICF)

Exclusion Criteria:

  1. AML with favorable-risk genetics according to 2017 ELN criteria [Appendix B]:

    • AML with t(8;21)(q22;q22.1), RUNX1-RUNX1T1
    • AML with inv(16)(p13.1q22)/t(16;16)(p13.1;q22), CBFB-MYH11
    • AML with mutated NPM1 without FLT3-ITD or with FLT3-ITDlow
    • AML with biallelic CEBPA mutation
  2. Acute promyelocytic leukemia (APL) with t(15;17)(q22;q12); PML-RARA; or one of the other pathognomonic variant chromosomal translocations/ fusion genes
  3. AML with BCR-ABL1
  4. Prior treatment of myelodysplastic syndrome (MDS) with intensive chemotherapy or bone marrow transplant with a curative intent
  5. Significant active cardiac disease within 6 months prior to the start of study treatment, including New York Heart Association (NYHA) class III or IV congestive heart failure; myocardial infarction, unstable angina and/or stroke; severe cardiac arrhythmias, or left ventricular ejection fraction (LVEF) <50% by ultrasound obtained within 28 days prior to the start of study treatment
  6. Severe obstructive or restrictive ventilation disorder
  7. Uncontrolled infection
  8. Clinical symptoms suggestive of active central nervous system (CNS) leukemia or known CNS leukemia. Evaluation of cerebrospinal fluid (CSF) during screening is only required, if there is a clinical suspicion of CNS involvement by leukemia during screening
  9. Evidence of active hepatitis B or C infection or known Human Immunodeficiency Virus (HIV) infection
  10. Patients with a "currently active" second malignancy. Patients are not considered to have a currently active malignancy, if they have completed therapy and are considered by their physician to be at < 30% risk of relapse within one year. However, subjects with the following history/concurrent conditions are allowed:

    • Basal or squamous cell carcinoma of the skin
    • Carcinoma in situ of the cervix
    • Carcinoma in situ of the breast
    • Incidental histologic finding of prostate cancer
  11. Severe neurological or psychiatric disorder interfering with ability to give an informed consent
  12. No consent for registration, storage and processing of the individual disease characteristics and course as well as information of the family physician about study participation
  13. No consent for biobanking of patient's biological specimens
  14. Current participation in any other interventional clinical study within 30 days before the first administration of the investigational product or at any time during the study
  15. Patients with prior cumulative anthracycline exposure of daunorubicin (or equivalent) can be included but the maximum of daunorubicin (or equivalent) dose of 550 mg/m2 must not be exceeded. In patients who received radiation therapy to the mediastinum the maximum of daunorubicin (or equivalent) dose of 400 mg/m2 must not be exceeded.
  16. Known or suspected hypersensitivity to cytarabine, daunorubicin or liposomal products and/or any excipients
  17. History of Wilson's disease or other copper-metabolism disorder
  18. Receipt of live, attenuated vaccine within 30 days prior to the study inclusion (NOTE: Subjects, if enrolled, should not receive live vaccine during the study and until 6 months after the therapy).
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Verena Gaidzik, MD 0049-731-500 ext 45707 verena.gaidzik@uniklinik-ulm.de
Listed Location Countries  ICMJE Austria,   Germany
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03897127
Other Study ID Numbers  ICMJE AMLSG 30-18
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Verena Gaidzik, University of Ulm
Study Sponsor  ICMJE University of Ulm
Collaborators  ICMJE Jazz Pharmaceuticals
Investigators  ICMJE Not Provided
PRS Account University of Ulm
Verification Date May 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP