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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



September 2019

Letztes Update:

Cytarabine, Daunorubicin, CPX-351

Indikation (Clinical Trials):
Leukemia, Myeloid, Leukemia, Myeloid, Acute


Erwachsene (18+)

Phase 3

University of Ulm

Jazz Pharmaceuticals


Verena Gaidzik, MD
Phone: 0049-731-500
Phone (ext.): 45707
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Interdisziplinäres Brustzentrum am Klinikum Esslingen
Hirschlandstraße 97
73730 Esslingen am Neckar
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Swen Wessendorf, MD

Guido Hausner, MD
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Katholisches Karl-Leisner-Klinikum gGmbH, Wilhelm-Anton-Hospital gGmbH Goch
47574 Goch
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Volker Runde, MD

Jörn Westheider, MD
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Darmkrebszentrum am Universitätsklinikum Schleswig-Holstein, Campus Lübeck
Ratzeburger Allee 160
23562 Lübeck
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Maxim Kebenko, MD

Tobias Bartscht
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Pankreaskarzinomzentrum Universitätsklinikum Regensburg
Franz-Josef-Strauß-Allee 11
93053 Regensburg
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Daniel Heudobler, MD

Hendrik Poeck, MD
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Gynäkologisches Krebszentrum Marienhospital Stuttgart
Böheimstraße 37
70199 Stuttgart
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Claudio Denzlinger, MD

Lale Kaylkci, MD
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Viszeralonkologisches Zentrum Universitätsklinikum Tübingen
Hoppe-Seyler-Straße 3
72076 Tübingen
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Maximilian Christopeit, MD

Dominik Schneidawind, MD
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Schwarzwald-Baar Klinikum Villingen- Schwenningen GmbH
78052 Villingen-Schwenningen
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Paul Graf La Rosée, MD

Martin Henkes, MD
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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. Event-free survival (EFS) will be the primary

endpoint as defined by standard criteria (Döhner 2017).


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


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


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


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


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).


Primary outcome:

1. Event-free survival (EFS) (Time Frame - 2 years)

Secondary outcome:

1. Overall survival (OS) (Time Frame - 2 years)

2. Relapse-free survival (RFS) (Time Frame - 2 years)

3. Cumulative incidence of relapse (CIR) (Time Frame - 2 years)

4. Cumulative incidence of death (CID) (Time Frame - 2 years)

5. Rate of objective response (Time Frame - 2 months):
complete remission [CR], CR with incomplete hematologic recovery [CRi], CR without minimal residual disease [CRMRD-]

6. 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


  • Active Comparator: Standard arm
  • Experimental: Investigational arm

Geprüfte Regime

  • 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
  • Daunorubicin:
    Induction therapy: 60 mg/m2 i.v. (1 hr) d1-3
  • 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


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