Clinical trial NCT03897127: 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: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Acute Myeloid Leukemia
Keywords: CPX-351
Acute Myeloid Leukemia
Lead sponsor: University of Ulm
Sponsor class: OTHER
Collaborators: name: Jazz Pharmaceuticals
First posted: 2019-04-01
Enrollment: 882
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility 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 14 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 trial within 30 days before the first administration of the investigational product or at any time during the trial
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 inclusion in the clinical trial (NOTE: Subjects, if enrolled, should not receive live vaccine during the trial and until 6 months after the therapy).

Primary outcomes:
measure: Overall survival (OS) in the restricted set of de novo patients
timeFrame: 2 years
Secondary outcomes:
measure: Overall survival (OS) in the extended set of patients
timeFrame: 2 years
measure: 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
timeFrame: 2 years
measure: Event-free survival (EFS) with CRi considered as failure of induction therapy in the restricted set of de novo patients
timeFrame: 2 years
measure: Rate of objective response in the restricted set of de novo patients
timeFrame: 2 months
Other outcomes:
measure: EFS with CRi considered as failure of induction therapy in the extended set of patients
timeFrame: 2 years
measure: Response rates (CR/CRi/CRMRD-/CRiMRD-) in the extended set of patients
timeFrame: 2 years
measure: Relapse-free survival (RFS) in patients who achieved CR/CRi during induction chemotherapy
timeFrame: 2 years
measure: Relapse-free survival (RFS) in patients who achieved CR during induction chemotherapy
timeFrame: 2 years
measure: Cumulative incidence of relapse (CIR) in patients who achieved CR/CRi during induction chemotherapy
timeFrame: 2 years
measure: Cumulative incidence of relapse (CIR) in patients who achieved CR during induction chemotherapy
timeFrame: 2 years
measure: Cumulative incidence of death (CID) in patients who achieved CR/CRi during induction chemotherapy
timeFrame: 2 years
measure: Cumulative incidence of death (CID) in patients who achieved CR during induction chemotherapy
timeFrame: 2 years
measure: EFS with allogeneic HCT considered as competing event
timeFrame: 2 years
measure: RFS with allogeneic HCT considered as competing event
timeFrame: 2 years
measure: CIR with allogeneic HCT considered as competing event
timeFrame: 2 years
measure: CID with allogeneic HCT considered as competing event
timeFrame: 2 years
measure: OS with allogeneic HCT considered as competing event
timeFrame: 2 years
measure: QoL NCI PRO-CTCAE (National Cancer Institute) Patient Reported Outcomes Common Terminology Criteria for Adverse Events questionnaire)
timeFrame: 2 years
measure: QoL EORTC QLQ-FA12
timeFrame: 2 years
measure: QoL EORTC QLQ-C30 (Core Quality of Life Questionnaire developed by European Organization for Research and Treatment of Cancer)
timeFrame: 2 years
measure: Rate of hospitalization including admissions at intensive care unit (ICU)
timeFrame: 8 months
measure: Reasons for hospitalization
timeFrame: 8 months
measure: days of hospitalization by treatment setting
timeFrame: 8 months
measure: rate of use of anti-infectives and other medications, e.g. against nausea or vomiting
timeFrame: 8 months
measure: additional therapies administered
timeFrame: 8 months
measure: place of chemotherapy administration (inpatient vs outpatient setting)
timeFrame: 8 months
measure: duration of administration
timeFrame: 8 months
measure: number of outpatient visits
timeFrame: 8 months
measure: Frequency of salvage therapies
timeFrame: 8 months
measure: Incidence and intensity of adverse events (AEs) according to Common Terminology Criteria for Adverse Events (CTCAE) version v5.0
timeFrame: 2 years
Locations:
city: Graz
country: Austria
facility: Medizinische Universität Graz
city: Innsbruck
country: Austria
facility: Tirol Kliniken GmbH Innsbruck
city: Linz
country: Austria
facility: Ordensklinikum Linz GmbH, Elisabethinen
city: Rankweil
country: Austria
facility: Feldkirch, Landeskrankenhaus
city: Salzburg
country: Austria
facility: Landeskrankenhaus Salzburg
city: Wien
country: Austria
facility: Hanuschkrankenhaus Wien
city: Aschaffenburg
country: Germany
facility: Klinikum Aschaffenburg
city: Bad Saarow
country: Germany
facility: Helios Klinikum Bad Saarow
city: Berlin
country: Germany
facility: Berlin Charite - Campus Charite Mitte
city: Berlin
country: Germany
facility: Vivantes Klinikum Am Urban
city: Berlin
country: Germany
facility: Berlin Charite - Campus Benjamin Franklin
city: Berlin
country: Germany
facility: Vivantes Klinikum Neukölln
city: Berlin
country: Germany
facility: Charité Berlin
city: Bochum
country: Germany
facility: Bochum, Augusta-Kranken-Anstalt
city: Bochum
country: Germany
facility: Knappschaftskrankenhaus Bochum-Langendreer
city: Bonn
country: Germany
facility: Universitätsklinikum Bonn
city: Braunschweig
country: Germany
facility: Städtisches Klinikum Braunschweig gGmbH
city: Bremen
country: Germany
facility: Klinikum Bremen-Mitte
city: Darmstadt
country: Germany
facility: Klinikum Darmstadt
city: Dortmund
country: Germany
facility: St.-Johannes-Hospital
city: Düsseldorf
country: Germany
facility: Universitätsklinikum Düsseldorf
city: Essen
country: Germany
facility: Kliniken Essen Süd, Ev. Krankenhaus Essen- Werden gGmbH
city: Esslingen
country: Germany
facility: Klinikum Esslingen
city: Flensburg
country: Germany
facility: Malteser Krankenhaus St. Franziskus-Hospital
city: Freiburg
country: Germany
facility: Universitätsklinikum Freiburg
city: Gießen
country: Germany
facility: Universitätsklinikum Gießen
city: Goch
country: Germany
facility: Katholisches Karl-Leisner-Klinikum gGmbH, Wilhelm-Anton-Hospital gGmbH Goch
city: Greifswald
country: Germany
facility: Universitätsmedizin Greifswald
city: Hamburg
country: Germany
facility: Asklepios Kliniken Hamburg GmbH St. Georg
city: Hamburg
country: Germany
facility: Universitätsklinikum Hamburg-Eppendorf
city: Hamburg
country: Germany
facility: Asklepios Klinik Altona
city: Hamm
country: Germany
facility: Evangelisches Krankenhaus Hamm gGmbH
city: Hannover
country: Germany
facility: Klinikum Region Hannover - Klinikum Siloah
city: Hannover
country: Germany
facility: Medizinische Hochschule Hannover
city: Heilbronn
country: Germany
facility: SLK-Kliniken GmbH Heilbronn
city: Herne
country: Germany
facility: Marienhospital Herne, Klinikum der Ruhr
city: Kaiserslautern
country: Germany
facility: Kaiserslautern, Westpfalz-Klinikum
city: Karlsruhe
country: Germany
facility: Städtisches Klinikum Karlsruhe gGmbH
city: Lemgo
country: Germany
facility: Klinikum Lippe-Lemgo
city: Ludwigshafen
country: Germany
facility: Klinikum der Stadt Ludwigshafen am Rhein gGmbH
city: Lübeck
country: Germany
facility: Universitätsklinikum Schleswig-Holstein
city: Lüdenscheid
country: Germany
facility: Klinikum Lüdenscheid
city: Magdeburg
country: Germany
facility: Universitätsklinikum Magdeburg
city: Mainz
country: Germany
facility: Klinikum der Johannes Gutenberg Universität
city: Meschede
country: Germany
facility: Klniikum Hochsauerland GmbH
city: Minden
country: Germany
facility: Johannes Wesling Klinikum Minden
city: München
country: Germany
facility: Klinikum rechts der Isar München
city: Offenbach
country: Germany
facility: Sana Klinikum Offenbach
city: Offenburg
country: Germany
facility: Ortenau Klinikum, Offenburg-Gengenbach
city: Oldenburg
country: Germany
facility: Pius Hospital Oldenburg
city: Oldenburg
country: Germany
facility: Klinikum Oldenburg AöR
city: Passau
country: Germany
facility: Klinikum Passau
city: Regensburg
country: Germany
facility: Universitätsklinikum Regensburg
city: Saarlouis
country: Germany
facility: Marienhaus Klinikum St. Elisabeth Saarlouis
city: Sande
country: Germany
facility: Sande, Nordwest-Krankenhaus Sanderbusch
city: Stuttgart
country: Germany
facility: Klinikum Stuttgart
city: Stuttgart
country: Germany
facility: Stuttgart, Diakonie-Klinikum
city: Traunstein
country: Germany
facility: Klinikum Traunstein
city: Trier
country: Germany
facility: Mutterhaus der Borromäerinnen
city: Trier
country: Germany
facility: Krankenhaus der Barmherzigen Brüder Trier
city: Tübingen
country: Germany
facility: Universitätsklinikum Tübingen
city: Ulm
country: Germany
facility: Universitätsklinikum Ulm
city: Villingen-Schwenningen
country: Germany
facility: Schwarzwald-Baar Klinikum Villingen- Schwenningen GmbH
city: Wuppertal
country: Germany
facility: Helios Klinikum Wuppertal
Study officials:
References: