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

Sponsor
University of Ulm (Other)
Overall Status
Recruiting
CT.gov ID
NCT03897127
Collaborator
Jazz Pharmaceuticals (Industry)
882
63
2
53.9
14
0.3

Study Details

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

Condition or Disease Intervention/Treatment Phase
Phase 3

Study Design

Study Type:
Interventional
Anticipated 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 :
Sep 4, 2019
Anticipated Primary Completion Date :
Mar 1, 2024
Anticipated Study Completion Date :
Mar 1, 2024

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: 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

Primary Outcome Measures

  1. Overall survival (OS) in the restricted set of de novo patients [2 years]

Secondary Outcome Measures

  1. Overall survival (OS) in the extended set of patients [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 [2 years]

  3. Event-free survival (EFS) with CRi considered as failure of induction therapy in the restricted set of de novo patients [2 years]

  4. 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-])

Other Outcome Measures

  1. EFS with CRi considered as failure of induction therapy in the extended set of patients [2 years]

    Exploratory endpoint

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

    Exploratory endpoint

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

    Exploratory endpoint

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

    Exploratory endpoint

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

    Exploratory endpoint

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

    Exploratory endpoint

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

    Exploratory endpoint

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

    Exploratory endpoint

  9. EFS with allogeneic HCT considered as competing event [2 years]

    Exploratory endpoint

  10. RFS with allogeneic HCT considered as competing event [2 years]

    Exploratory endpoint

  11. CIR with allogeneic HCT considered as competing event [2 years]

    Exploratory endpoint

  12. CID with allogeneic HCT considered as competing event [2 years]

    Exploratory endpoint

  13. OS with allogeneic HCT considered as competing event [2 years]

    Exploratory endpoint

  14. QoL NCI PRO-CTCAE (National Cancer Institute) Patient Reported Outcomes Common Terminology Criteria for Adverse Events questionnaire) [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 [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) [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) [8 months]

    Exploratory endpoint

  18. Reasons for hospitalization [8 months]

    Exploratory endpoint

  19. days of hospitalization by treatment setting [8 months]

    Exploratory endpoint

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

    Exploratory endpoint

  21. additional therapies administered [8 months]

    Exploratory endpoint

  22. place of chemotherapy administration (inpatient vs outpatient setting) [8 months]

    Exploratory endpoint

  23. duration of administration [8 months]

    Exploratory endpoint

  24. number of outpatient visits [8 months]

    Exploratory endpoint

  25. Frequency of salvage therapies [8 months]

    Exploratory endpoint

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

Eligibility Criteria

Criteria

Ages Eligible for Study:
18 Years and Older
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
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

  1. 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

  2. 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)

  3. 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

  4. 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

  5. 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

  6. 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

  1. 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%).

  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. 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

  1. Severe neurological or psychiatric disorder interfering with ability to give an informed consent

  2. 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

  3. No consent for biobanking of patient's biological specimens

  4. 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

  5. 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.

  6. Known or suspected hypersensitivity to cytarabine, daunorubicin or liposomal products and/or any excipients

  7. History of Wilson's disease or other copper-metabolism disorder

  8. 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

Locations

Site City State Country Postal Code
1 Medizinische Universität Graz Graz Austria 8036
2 Tirol Kliniken GmbH Innsbruck Innsbruck Austria 6020
3 Ordensklinikum Linz GmbH, Elisabethinen Linz Austria 4020
4 Feldkirch, Landeskrankenhaus Rankweil Austria 6830
5 Landeskrankenhaus Salzburg Salzburg Austria 5020
6 Hanuschkrankenhaus Wien Wien Austria 1140
7 Klinikum Aschaffenburg Aschaffenburg Germany 63739
8 Helios Klinikum Bad Saarow Bad Saarow Germany 15526
9 Berlin Charite - Campus Charite Mitte Berlin Germany 10117
10 Vivantes Klinikum Am Urban Berlin Germany 10967
11 Berlin Charite - Campus Benjamin Franklin Berlin Germany 12200
12 Vivantes Klinikum Neukölln Berlin Germany 12351
13 Charité Berlin Berlin Germany 13353
14 Bochum, Augusta-Kranken-Anstalt Bochum Germany 44791
15 Knappschaftskrankenhaus Bochum-Langendreer Bochum Germany 44892
16 Universitätsklinikum Bonn Bonn Germany 53105
17 Städtisches Klinikum Braunschweig gGmbH Braunschweig Germany 38114
18 Klinikum Bremen-Mitte Bremen Germany 28177
19 Klinikum Darmstadt Darmstadt Germany 64283
20 St.-Johannes-Hospital Dortmund Germany 44137
21 Universitätsklinikum Düsseldorf Düsseldorf Germany 40225
22 Kliniken Essen Süd, Ev. Krankenhaus Essen- Werden gGmbH Essen Germany 45239
23 Klinikum Esslingen Esslingen Germany 73730
24 Malteser Krankenhaus St. Franziskus-Hospital Flensburg Germany 24939
25 Universitätsklinikum Freiburg Freiburg Germany 79106
26 Universitätsklinikum Gießen Gießen Germany 35392
27 Katholisches Karl-Leisner-Klinikum gGmbH, Wilhelm-Anton-Hospital gGmbH Goch Goch Germany 47574
28 Universitätsmedizin Greifswald Greifswald Germany 17475
29 Asklepios Kliniken Hamburg GmbH St. Georg Hamburg Germany 20099
30 Universitätsklinikum Hamburg-Eppendorf Hamburg Germany 20246
31 Asklepios Klinik Altona Hamburg Germany 22763
32 Evangelisches Krankenhaus Hamm gGmbH Hamm Germany 59063
33 Klinikum Region Hannover - Klinikum Siloah Hannover Germany 30459
34 Medizinische Hochschule Hannover Hannover Germany 30625
35 SLK-Kliniken GmbH Heilbronn Heilbronn Germany 74078
36 Marienhospital Herne, Klinikum der Ruhr Herne Germany 44625
37 Kaiserslautern, Westpfalz-Klinikum Kaiserslautern Germany 67655
38 Städtisches Klinikum Karlsruhe gGmbH Karlsruhe Germany 76133
39 Klinikum Lippe-Lemgo Lemgo Germany 32657
40 Klinikum der Stadt Ludwigshafen am Rhein gGmbH Ludwigshafen Germany 67063
41 Universitätsklinikum Schleswig-Holstein Lübeck Germany 23538
42 Klinikum Lüdenscheid Lüdenscheid Germany 58515
43 Universitätsklinikum Magdeburg Magdeburg Germany 39120
44 Klinikum der Johannes Gutenberg Universität Mainz Germany 55131
45 Klniikum Hochsauerland GmbH Meschede Germany 59872
46 Johannes Wesling Klinikum Minden Minden Germany 32429
47 Klinikum rechts der Isar München München Germany 81675
48 Sana Klinikum Offenbach Offenbach Germany 63069
49 Ortenau Klinikum, Offenburg-Gengenbach Offenburg Germany 77654
50 Pius Hospital Oldenburg Oldenburg Germany 26121
51 Klinikum Oldenburg gGmbH Oldenburg Germany 26133
52 Klinikum Passau Passau Germany 94032
53 Universitätsklinikum Regensburg Regensburg Germany 93053
54 Sande, Nordwest-Krankenhaus Sanderbusch Sande Germany 26453
55 Klinikum Stuttgart Stuttgart Germany 70174
56 Stuttgart, Diakonie-Klinikum Stuttgart Germany 70176
57 Klinikum Traunstein Traunstein Germany 83278
58 Mutterhaus der Borromäerinnen Trier Germany 54290
59 Krankenhaus der Barmherzigen Brüder Trier Trier Germany 54292
60 Universitätsklinikum Tübingen Tübingen Germany 72076
61 Universitätsklinikum Ulm Ulm Germany 89081
62 Schwarzwald-Baar Klinikum Villingen- Schwenningen GmbH Villingen-Schwenningen Germany 78052
63 Helios Klinikum Wuppertal Wuppertal Germany 42283

Sponsors and Collaborators

  • University of Ulm
  • Jazz Pharmaceuticals

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.
Responsible Party:
Verena Gaidzik, Principal Investigator, University of Ulm
ClinicalTrials.gov Identifier:
NCT03897127
Other Study ID Numbers:
  • AMLSG 30-18
First Posted:
Apr 1, 2019
Last Update Posted:
Jun 24, 2022
Last Verified:
Jun 1, 2022
Studies a U.S. FDA-regulated Drug Product:
Yes
Studies a U.S. FDA-regulated Device Product:
No
Keywords provided by Verena Gaidzik, Principal Investigator, University of Ulm
Additional relevant MeSH terms:

Study Results

No Results Posted as of Jun 24, 2022