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

• ClinicalTrials.gov Identifier: NCT03897127
• Recruitment Status: Recruiting
• First Posted: April 1, 2019
• Last Update Posted: September 10, 2019
• Sponsor: University of Ulm
• Collaborator: Jazz Pharmaceuticals
• Information provided by (Responsible Party): Peter Paschka, University of Ulm

Study Description

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).

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

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 593 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: June 2023
• Estimated Study Completion Date: June 2023

Arms and Interventions

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: Patients age 18-60 years o CPX-351 55 mg/m2 daunorubicin / 125 mg/m2 cytarabine [125 U/m²] i.v. (90 min) d1,3,5; Patients age >60 years o CPX-351 44 mg/m2 daunorubicin / 100 mg/m2 cytarabine [100 U/m²] i.v. (90 min) d1,3,5 Induction 2: • Patients age 18-60 years; CPX-351 55 mg/m2 daunorubicin / 125 mg/m2 cytarabine [125 U/m²] i.v. (90 min) d1,3 • Patients age >60 years; 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

Primary Outcome Measures :

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

Secondary Outcome Measures :

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

Other Outcome Measures:

1. Analysis of rate of response according to cytogenetic and molecular genetic changes [ Time Frame: 2 years ]
   Exploratory endpoint
2. Analysis of Overall survival according to cytogenetic and molecular genetic changes [ Time Frame: 2 years ]
   Exploratory endpoint
3. Analysis of Relapse-free survival according to cytogenetic and molecular genetic changes [ Time Frame: 2 years ]
   Exploratory endpoint
4. Analysis of Event-free survival according to cytogenetic and molecular genetic changes [ Time Frame: 2 years ]
   Exploratory endpoint
5. Analysis of Overall Survival according to Minimal Residual Disease results during and after treatment [ Time Frame: 2 years ]
   Exploratory endpoint
6. Analysis of Event-free Survival according to Minimal Residual Disease results during and after treatment [ Time Frame: 2 years ]
   Exploratory endpoint
7. 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.
8. 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.
9. 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.
10. Rate of hospitalization including admissions at intensive care unit (ICU) [ Time Frame: 8 months ]
    Exploratory endpoint
11. Reasons for hospitalization [ Time Frame: 8 months ]
    Exploratory endpoint
12. days of hospitalization by treatment setting [ Time Frame: 8 months ]
    Exploratory endpoint
13. rate of use of anti-infectives and other medications, e.g. against nausea or vomiting [ Time Frame: 8 months ]
    Exploratory endpoint
14. additional therapies administered [ Time Frame: 8 months ]
    Exploratory endpoint
15. place of chemotherapy administration (inpatient vs outpatient setting) [ Time Frame: 8 months ]
    Exploratory endpoint
16. duration of administration [ Time Frame: 8 months ]
    Exploratory endpoint
17. number of outpatient visits [ Time Frame: 8 months ]
    Exploratory endpoint
18. Frequency of salvage therapies [ Time Frame: 8 months ]
    Exploratory endpoint

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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 (for younger patients [18-60 years of age] ≤ 1)
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 Trial Coordinator
   • 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 Trial Coordinator
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. Known history of positive test for hepatitis B surface Antigen (HBSAg) or hepatitis C antibody or history of positive test for Human Immunodeficiency Virus (HIV)

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.
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).

Contacts and Locations

Contacts

Contact: Peter Paschka, MD; 0049-731-500 ext 45521; peter.paschka@uniklinik-ulm.de

Locations

Germany

Klinikum Aschaffenburg; Not yet recruiting

Aschaffenburg, Germany, 63739

Contact: Manfred Welslau, MD

Contact: Simone Liebler, MD

Vivantes Klinikum Am Urban; Not yet recruiting

Berlin, Germany, 10967

Contact: Christian Scholz, MD

Contact: Annette Dieing, MD

Vivantes Klinikum Neukölln; Not yet recruiting

Berlin, Germany, 12351

Contact: Maike de Witt, MD

Contact: Lore Marretta, MD

Charité Berlin ‐ Campus Virchow‐Klinikum; Not yet recruiting

Berlin, Germany, 13353

Contact: Jörg Westermann, MD

Contact: Anne Flörcken, MD

Knappschaftskrankenhaus Bochum‐Langendreer; Not yet recruiting

Bochum, Germany, 44892

Contact: Roland Schroers, MD

Contact: Alexander Baraniskin, MD

Universitätsklinikum Bonn; Not yet recruiting

Bonn, Germany, 53105

Contact: Georg Feldmann, MD

Contact: Juliane Klein, MD

Städtisches Klinikum Braunschweig gGmbH; Not yet recruiting

Braunschweig, Germany, 38114

Contact: Jürgen Krauter, MD

Contact: Arne Trummer, MD

Klinikum Bremen‐Mitte; Not yet recruiting

Bremen, Germany, 28177

Contact: Bernd Hertenstein, MD

Contact: Stephan Kaun, MD

Klinikum Darmstadt; Not yet recruiting

Darmstadt, Germany, 64283

Contact: Helga Bernhard, MD

Contact: Stephan Schäfer, MD

St.‐Johannes‐Hospital; Not yet recruiting

Dortmund, Germany, 44137

Contact: Darina Kodzhabasheva, MD

Contact: Ralf Georg Meyer, MD

Universitätsklinikum Düsseldorf; Not yet recruiting

Düsseldorf, Germany, 40225

Contact: Thomas Schroeder, MD

Contact: Ulrich Germing, MD

Kliniken Essen Süd, Ev. Krankenhaus Essen‐ Werden gGmbH; Not yet recruiting

Essen, Germany, 45239

Contact: Mohammed Wattad, MD

Contact: Peter Reimer, MD

Klinikum Esslingen; Not yet recruiting

Esslingen, Germany, 73730

Contact: Swen Wessendorf, MD

Contact: Rebekka Mannal, MD

Malteser Krankenhaus St. Franziskus‐Hospital; Not yet recruiting

Flensburg, Germany, 24939

Contact: Nadezda Basara, MD

Contact: Helge Menzel, MD

Universitätsklinikum Gießen; Not yet recruiting

Gießen, Germany, 35392

Contact: Matthias Rummel, MD

Contact: Alexander Burchardt, MD

Katholisches Karl‐Leisner‐Klinikum gGmbH, Wilhelm‐Anton‐Hospital gGmbH Goch; Not yet recruiting

Goch, Germany, 47574

Contact: Volker Runde, MD

Contact: Jörn Westheider, MD

Universitätsklinikum Hamburg‐Eppendorf; Not yet recruiting

Hamburg, Germany, 20246

Contact: Walter Fiedler, MD

Contact: Melanie Janning, MD

Asklepios Klinik Altona; Not yet recruiting

Hamburg, Germany, 22763

Contact: Hans Salwender, MD

Contact: Cord Beeger, MD

Evangelisches Krankenhaus Hamm gGmbH; Not yet recruiting

Hamm, Germany, 59063

Contact: Elisabeth Lange, MD

Contact: Thomas Wehler, MD

Sub-Investigator: Andrea Stoltefuß, MD

Klinikum Region Hannover ‐ Klinikum Siloah; Not yet recruiting

Hannover, Germany, 30459

Contact: Martin Müller, MD

Contact: Kim Marienhagen, MD

Sub-Investigator: Daniela Dörfel, MD

Medizinische Hochschule Hannover; Not yet recruiting

Hannover, Germany, 30625

Contact: Felicitas Thol, MD

Contact: Michael Heuser, MD

Westküstenklinikum Heide; Not yet recruiting

Heide, Germany, 25746

Contact: Karen Rußwurm, MD

Contact: Georg Rußwurm, MD

SLK‐Kliniken GmbH Heilbronn; Not yet recruiting

Heilbronn, Germany, 74078

Contact: Markus Lindauer, MD

Contact: Uwe Martens, MD

Marienhospital Herne, Klinikum der Ruhr; Not yet recruiting

Herne, Germany, 44625

Contact: Beate Schultheis, MD

Contact: Dirk Strumberg, MD

Kaiserslautern, Westpfalz‐Klinikum; Not yet recruiting

Kaiserslautern, Germany, 67655

Contact: Gerhard Held, MD

Contact: Milena Pfeifer, MD

Städtisches Klinikum Karlsruhe gGmbH; Not yet recruiting

Karlsruhe, Germany, 76133

Contact: Mark Ringhoffer, MD

Contact: Lukas Kündgen, MD

Caritas‐Krankenhaus Lebach; Not yet recruiting

Lebach, Germany, 66822

Contact: Stephan Kremers, MD

Contact: Gero Leonhard-Helmschmidt, MD

Klinikum Lippe‐Lemgo; Not yet recruiting

Lemgo, Germany, 32657

Contact: Hesse Tanja, MD

Contact: Frank Hartmann, MD

Klinikum Lüdenscheid; Not yet recruiting

Lüdenscheid, Germany, 58515

Contact: Gerhard Heil, MD

Contact: Christiane Maria Hempel-Overhage, MD

Universitätsklinikum Magdeburg; Not yet recruiting

Magdeburg, Germany, 39120

Contact: Martin Mikusko, MD

Contact: Vanja Zeremski, MD

Klinikum der Johannes Gutenberg Universität; Not yet recruiting

Mainz, Germany, 55131

Contact: Michael Kühn, MD

Contact: Markus Radsak, MD

Johannes Wesling Klinikum Minden; Not yet recruiting

Minden, Germany, 32429

Contact: Hans Joachim Tischler, MD

Contact: Kai Wille, MD

Klinikum rechts der Isar München; Not yet recruiting

München, Germany, 81675

Contact: Katharina Götze, MD

Contact: Isabella Miller, MD

Ortenau Klinikum, Offenburg‐Gengenbach; Not yet recruiting

Offenburg, Germany, 77654

Contact: Carsten Schwänen, MD

Contact: Irmgard Dresel, MD

Sub-Investigator: Jochen Reutschel, MD

Pius Hospital Oldenburg; Not yet recruiting

Oldenburg, Germany, 26121

Contact: Imme Conradi, MD

Contact: Frank Griesinger, MD

Klinikum Passau; Not yet recruiting

Passau, Germany, 94032

Contact: Thomas Südhoff, MD

Contact: Thorsten Nitsch, MD

Universitätsklinikum Regensburg; Not yet recruiting

Regensburg, Germany, 93053

Contact: Daniel Heudobler, MD

Contact: Simone Thomas, MD

Klinikum Stuttgart; Not yet recruiting

Stuttgart, Germany, 70174

Contact: Jan Schleicher, MD

Contact: Alf Jörg Zerzweck, MD

Marienhospital Stuttgart; Not yet recruiting

Stuttgart, Germany, 70199

Contact: Claudio Denzlinger, MD

Contact: Lale Kaylkci, MD

Klinikum Traunstein; Not yet recruiting

Traunstein, Germany, 83278

Contact: Elisabeth Dietl, MD

Contact: Thomas Kubin, MD

Mutterhaus der Borromäerinnen; Not yet recruiting

Trier, Germany, 54290

Contact: Rolf Mahlberg, MD

Contact: Stefan Hebel, MD

Krankenhaus der Barmherzigen Brüder Trier; Not yet recruiting

Trier, Germany, 54292

Contact: Heinz Kirchen, MD

Contact: Monika Lankeshofer-Loch, MD

Universitätsklinikum Tübingen; Not yet recruiting

Tübingen, Germany, 72076

Contact: Marcus Schittenhelm, MD

Contact: Dominik Schneidawind, MD

Universitätsklinikum Ulm; Recruiting

Ulm, Germany, 89081

Contact: Peter Paschka, MD

Contact: Verena Gaidzik, MD

Schwarzwald‐Baar Klinikum Villingen‐ Schwenningen GmbH; Not yet recruiting

Villingen-Schwenningen, Germany, 78052

Contact: Paul Graf La Rosée, MD

Contact: Martin Henkes, MD

Helios Klinikum Wuppertal; Not yet recruiting

Wuppertal, Germany, 42283

Contact: Silke Schostock, MD

Contact: Blasius Liss, MD

Sponsors and Collaborators

University of Ulm

Jazz Pharmaceuticals

More Information

• Responsible Party: Peter Paschka, Principal Investigator, University of Ulm
• ClinicalTrials.gov Identifier: NCT03897127 History of Changes
• Other Study ID Numbers: AMLSG 30-18
• First Posted: April 1, 2019
• Last Update Posted: September 10, 2019
• Last Verified: September 2019

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Peter Paschka, University of Ulm:

CPX-351; Acute Myeloid Leukemia

Additional relevant MeSH terms:

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