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

Phase 3

Recruiting

• Conditions: Acute Myeloid Leukemia
• Interventions: Drug: CPX-351; Drug: Cytarabine; Drug: Daunorubicin

• Registration Number: NCT03897127
• Lead Sponsor: University of Ulm

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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2019-03-19
• Study First Submitted QC: 2019-03-28
• Study First Posted: 2019-04-01
• Study Start: 2019-09-04
• Status Verified: 2024-11
• Last Update Submitted: 2024-11-04
• Last Update Posted: 2024-11-06
• Primary Completion: 2027-06
• Study Completion: 2027-06

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 882

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).

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Investigational arm	CPX-351	-
Standard arm	Cytarabine	-
Standard arm	Daunorubicin	-

Primary Outcome Measures

Name	Time	Method
Overall survival (OS) in the restricted set of de novo patients	2 years

Secondary Outcome Measures

Name	Time	Method
Overall survival (OS) in the extended set of patients	2 years
Rate of objective response in the restricted set of de novo patients	2 months	complete remission \[CR\], CR with incomplete hematologic recovery \[CRi\], CRi without measurable residual disease \[CRiMRD-\], CR without measurable residual disease \[CRMRD-\])
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	2 years
Event-free survival (EFS) with CRi considered as failure of induction therapy in the restricted set of de novo patients	2 years

Trial Locations

Locations (64)

Klinikum Bremen-Mitte; 🇩🇪 Bremen, Germany

Klinikum Darmstadt; 🇩🇪 Darmstadt, Germany

St.-Johannes-Hospital; 🇩🇪 Dortmund, Germany

Universitätsklinikum Düsseldorf; 🇩🇪 Düsseldorf, Germany

Kliniken Essen Süd, Ev. Krankenhaus Essen- Werden gGmbH; 🇩🇪 Essen, Germany

Klinikum Esslingen; 🇩🇪 Esslingen, Germany

Malteser Krankenhaus St. Franziskus-Hospital; 🇩🇪 Flensburg, Germany

Universitätsklinikum Freiburg; 🇩🇪 Freiburg, Germany

Universitätsklinikum Gießen; 🇩🇪 Gießen, Germany

Katholisches Karl-Leisner-Klinikum gGmbH, Wilhelm-Anton-Hospital gGmbH Goch; 🇩🇪 Goch, Germany

Universitätsmedizin Greifswald; 🇩🇪 Greifswald, Germany

Asklepios Kliniken Hamburg GmbH St. Georg; 🇩🇪 Hamburg, Germany

Universitätsklinikum Hamburg-Eppendorf; 🇩🇪 Hamburg, Germany

Asklepios Klinik Altona; 🇩🇪 Hamburg, Germany

Evangelisches Krankenhaus Hamm gGmbH; 🇩🇪 Hamm, Germany

Klinikum Region Hannover - Klinikum Siloah; 🇩🇪 Hannover, Germany

Medizinische Hochschule Hannover; 🇩🇪 Hannover, Germany

SLK-Kliniken GmbH Heilbronn; 🇩🇪 Heilbronn, Germany

Marienhospital Herne, Klinikum der Ruhr; 🇩🇪 Herne, Germany

Kaiserslautern, Westpfalz-Klinikum; 🇩🇪 Kaiserslautern, Germany

Städtisches Klinikum Karlsruhe gGmbH; 🇩🇪 Karlsruhe, Germany

Klinikum Lippe-Lemgo; 🇩🇪 Lemgo, Germany

Klinikum der Stadt Ludwigshafen am Rhein gGmbH; 🇩🇪 Ludwigshafen, Germany

Klinikum Oldenburg AöR; 🇩🇪 Oldenburg, Germany

Medizinische Universität Graz; 🇦🇹 Graz, Austria

Tirol Kliniken GmbH Innsbruck; 🇦🇹 Innsbruck, Austria

Ordensklinikum Linz GmbH, Elisabethinen; 🇦🇹 Linz, Austria

Feldkirch, Landeskrankenhaus; 🇦🇹 Rankweil, Austria

Landeskrankenhaus Salzburg; 🇦🇹 Salzburg, Austria

Hanuschkrankenhaus Wien; 🇦🇹 Wien, Austria

Klinikum Aschaffenburg; 🇩🇪 Aschaffenburg, Germany

Helios Klinikum Bad Saarow; 🇩🇪 Bad Saarow, Germany

Berlin Charite - Campus Charite Mitte; 🇩🇪 Berlin, Germany

Vivantes Klinikum Am Urban; 🇩🇪 Berlin, Germany

Berlin Charite - Campus Benjamin Franklin; 🇩🇪 Berlin, Germany

Vivantes Klinikum Neukölln; 🇩🇪 Berlin, Germany

Charité Berlin; 🇩🇪 Berlin, Germany

Bochum, Augusta-Kranken-Anstalt; 🇩🇪 Bochum, Germany

Knappschaftskrankenhaus Bochum-Langendreer; 🇩🇪 Bochum, Germany

Universitätsklinikum Bonn; 🇩🇪 Bonn, Germany

Städtisches Klinikum Braunschweig gGmbH; 🇩🇪 Braunschweig, Germany

Universitätsklinikum Schleswig-Holstein; 🇩🇪 Lübeck, Germany

Klinikum Lüdenscheid; 🇩🇪 Lüdenscheid, Germany

Universitätsklinikum Magdeburg; 🇩🇪 Magdeburg, Germany

Klinikum der Johannes Gutenberg Universität; 🇩🇪 Mainz, Germany

Klniikum Hochsauerland GmbH; 🇩🇪 Meschede, Germany

Johannes Wesling Klinikum Minden; 🇩🇪 Minden, Germany

Klinikum rechts der Isar München; 🇩🇪 München, Germany

Sana Klinikum Offenbach; 🇩🇪 Offenbach, Germany

Ortenau Klinikum, Offenburg-Gengenbach; 🇩🇪 Offenburg, Germany

Pius Hospital Oldenburg; 🇩🇪 Oldenburg, Germany

Klinikum Passau; 🇩🇪 Passau, Germany

Universitätsklinikum Regensburg; 🇩🇪 Regensburg, Germany

Marienhaus Klinikum St. Elisabeth Saarlouis; 🇩🇪 Saarlouis, Germany

Sande, Nordwest-Krankenhaus Sanderbusch; 🇩🇪 Sande, Germany

Klinikum Stuttgart; 🇩🇪 Stuttgart, Germany

Stuttgart, Diakonie-Klinikum; 🇩🇪 Stuttgart, Germany

Klinikum Traunstein; 🇩🇪 Traunstein, Germany

Mutterhaus der Borromäerinnen; 🇩🇪 Trier, Germany

Krankenhaus der Barmherzigen Brüder Trier; 🇩🇪 Trier, Germany

Universitätsklinikum Tübingen; 🇩🇪 Tübingen, Germany

Universitätsklinikum Ulm; 🇩🇪 Ulm, Germany

Schwarzwald-Baar Klinikum Villingen- Schwenningen GmbH; 🇩🇪 Villingen-Schwenningen, Germany

Helios Klinikum Wuppertal; 🇩🇪 Wuppertal, Germany