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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 : January 14, 2022
Sponsor:
Collaborator:
Jazz Pharmaceuticals
Information provided by (Responsible Party):
Verena Gaidzik, University of Ulm

Study Description
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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. Overall survival (OS) in the restricted set of de novo patients will be the primary endpoint.

Condition or disease Intervention/treatment Phase
Acute Myeloid Leukemia Drug: Cytarabine Drug: Daunorubicin Drug: CPX-351 Phase 3

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 882 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : September 4, 2019
Estimated Primary Completion Date : March 2024
Estimated Study Completion Date : March 2024

Resource links provided by the National Library of Medicine

Drug Information available for: Cytarabine

Arms and Interventions
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Arm Intervention/treatment
Active Comparator: Standard arm 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
Experimental: Investigational arm 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


Outcome Measures
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Primary Outcome Measures :
  1. Overall survival (OS) in the restricted set of de novo patients [ Time Frame: 2 years ]

Secondary Outcome Measures :
  1. Overall survival (OS) in the extended set of patients [ Time Frame: 2 years ]
  2. Event-free survival (EFS) with CRi considered as response to induction therapy in both, the restricted set of de novo patients and the extended set of patients [ Time Frame: 2 years ]
  3. Event-free survival (EFS) with CRi considered as failure of induction therapy in the restricted set of de novo patients [ Time Frame: 2 years ]
  4. Rate of objective response in the restricted set of de novo patients [ Time Frame: 2 months ]
    complete remission [CR], CR with incomplete hematologic recovery [CRi], CRi without measurable residual disease [CRiMRD-], CR without measurable residual disease [CRMRD-])


Other Outcome Measures:
  1. EFS with CRi considered as failure of induction therapy in the extended set of patients [ Time Frame: 2 years ]
    Exploratory endpoint

  2. Response rates (CR/CRi/CRMRD-/CRiMRD-) in the extended set of patients [ Time Frame: 2 years ]
    Exploratory endpoint

  3. Relapse-free survival (RFS) in patients who achieved CR/CRi during induction chemotherapy [ Time Frame: 2 years ]
    Exploratory endpoint

  4. Relapse-free survival (RFS) in patients who achieved CR during induction chemotherapy [ Time Frame: 2 years ]
    Exploratory endpoint

  5. Cumulative incidence of relapse (CIR) in patients who achieved CR/CRi during induction chemotherapy [ Time Frame: 2 years ]
    Exploratory endpoint

  6. Cumulative incidence of relapse (CIR) in patients who achieved CR during induction chemotherapy [ Time Frame: 2 years ]
    Exploratory endpoint

  7. Cumulative incidence of death (CID) in patients who achieved CR/CRi during induction chemotherapy [ Time Frame: 2 years ]
    Exploratory endpoint

  8. Cumulative incidence of death (CID) in patients who achieved CR during induction chemotherapy [ Time Frame: 2 years ]
    Exploratory endpoint

  9. EFS with allogeneic HCT considered as competing event [ Time Frame: 2 years ]
    Exploratory endpoint

  10. RFS with allogeneic HCT considered as competing event [ Time Frame: 2 years ]
    Exploratory endpoint

  11. CIR with allogeneic HCT considered as competing event [ Time Frame: 2 years ]
    Exploratory endpoint

  12. CID with allogeneic HCT considered as competing event [ Time Frame: 2 years ]
    Exploratory endpoint

  13. OS with allogeneic HCT considered as competing event [ Time Frame: 2 years ]
    Exploratory endpoint

  14. 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.

  15. 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.

  16. 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.

  17. Rate of hospitalization including admissions at intensive care unit (ICU) [ Time Frame: 8 months ]
    Exploratory endpoint

  18. Reasons for hospitalization [ Time Frame: 8 months ]
    Exploratory endpoint

  19. days of hospitalization by treatment setting [ Time Frame: 8 months ]
    Exploratory endpoint

  20. rate of use of anti-infectives and other medications, e.g. against nausea or vomiting [ Time Frame: 8 months ]
    Exploratory endpoint

  21. additional therapies administered [ Time Frame: 8 months ]
    Exploratory endpoint

  22. place of chemotherapy administration (inpatient vs outpatient setting) [ Time Frame: 8 months ]
    Exploratory endpoint

  23. duration of administration [ Time Frame: 8 months ]
    Exploratory endpoint

  24. number of outpatient visits [ Time Frame: 8 months ]
    Exploratory endpoint

  25. Frequency of salvage therapies [ Time Frame: 8 months ]
    Exploratory endpoint

  26. Incidence and intensity of adverse events (AEs) according to Common Terminology Criteria for Adverse Events (CTCAE) version v5.0 [ Time Frame: 2 years ]

Eligibility Criteria
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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

Patient 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 27 weeks after the last dose of study drug
  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 27 weeks after the last dose of study drug. 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 study drug). 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)

Patient 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. AML with FLT3 mutation as assessed by DNA fragment analysis PCR for FLT3-ITD and FLT3-TKD mutation. Positivity is defined as a FLT3-ITD or FLT3-TKD / FLT3-WT ratio of ≥ 0.05 (5%).
  3. Acute promyelocytic leukemia (APL) with t(15;17)(q22;q12); PML-RARA; or one of the other pathognomonic variant chromosomal translocations/ fusion genes
  4. AML with BCR-ABL1
  5. Prior treatment of myelodysplastic syndrome (MDS) with intensive chemotherapy or bone marrow transplant with a curative intent
  6. 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
  7. Severe obstructive or restrictive ventilation disorder
  8. Uncontrolled infection
  9. 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
  10. Evidence of active hepatitis B or C infection or known Human Immunodeficiency Virus (HIV) infection

  11. 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
  12. Severe neurological or psychiatric disorder interfering with ability to give an informed consent
  13. 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
  14. No consent for biobanking of patient's biological specimens
  15. 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
  16. 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. Anthracycline-based therapy should be avoided until exposure to the previous cardiotoxic agents is negligible. If this is not possible, the patient's cardiac function should be carefully monitored and an absolute cumulative dose of 400 mg/m² in adults can be exceeded only with great caution. In patients who received radiation therapy to the mediastinum the maximum of daunorubicin (or equivalent) dose of 400 mg/m2 must not be exceeded.
  17. Known or suspected hypersensitivity to cytarabine, daunorubicin or liposomal products and/or any excipients
  18. History of Wilson's disease or other copper-metabolism disorder
  19. 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).
Contacts and Locations
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Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

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): NCT03897127


Contacts
Layout table for location contacts
Contact: Verena Gaidzik, MD 0049-731-500 ext 45707 verena.gaidzik@uniklinik-ulm.de

Locations
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Sponsors and Collaborators
University of Ulm
Jazz Pharmaceuticals
More Information
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Responsible Party: Verena Gaidzik, Principal Investigator, University of Ulm
ClinicalTrials.gov Identifier: NCT03897127    
Other Study ID Numbers: AMLSG 30-18
First Posted: April 1, 2019    Key Record Dates
Last Update Posted: January 14, 2022
Last Verified: December 2021

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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 Verena Gaidzik, University of Ulm:
CPX-351
Acute Myeloid Leukemia
Additional relevant MeSH terms:
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Leukemia, Myeloid
Leukemia, Myeloid, Acute
Leukemia
Neoplasms by Histologic Type
Neoplasms
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