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

Acute Myeloid Leukemia Clinical Trial

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03897127
• Other study ID #: AMLSG 30-18
• Status: Recruiting
• Phase: Phase 3
• Start date: September 4, 2019
• Est. completion date: March 2024

Study information

• Verified date: November 2023
• Source: University of Ulm
• Contact: Verena Gaidzik, MD
• Phone: 0049-731-500
• Email: verena.gaidzik[@]uniklinik-ulm.de
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 882
• Est. completion date: March 2024
• Est. primary completion date: March 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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 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 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 study within 30 days before the first administration of the investigational product or at any time during the study

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 study inclusion (NOTE:

Subjects, if enrolled, should not receive live vaccine during the study and until 6 months after the therapy).

Related Conditions & MeSH terms

• Acute Myeloid Leukemia
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute

Intervention

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
• 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

Locations

Country	Name	City	State
Austria	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
Germany	Klinikum Aschaffenburg	Aschaffenburg
Germany	Helios Klinikum Bad Saarow	Bad Saarow
Germany	Berlin Charite - Campus Benjamin Franklin	Berlin
Germany	Berlin Charite - Campus Charite Mitte	Berlin
Germany	Charité Berlin	Berlin
Germany	Vivantes Klinikum Am Urban	Berlin
Germany	Vivantes Klinikum Neukölln	Berlin
Germany	Bochum, Augusta-Kranken-Anstalt	Bochum
Germany	Knappschaftskrankenhaus Bochum-Langendreer	Bochum
Germany	Universitätsklinikum Bonn	Bonn
Germany	Städtisches Klinikum Braunschweig gGmbH	Braunschweig
Germany	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 Klinik Altona	Hamburg
Germany	Asklepios Kliniken Hamburg GmbH St. Georg	Hamburg
Germany	Universitätsklinikum Hamburg-Eppendorf	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	Universitätsklinikum Schleswig-Holstein	Lübeck
Germany	Klinikum Lüdenscheid	Lüdenscheid
Germany	Klinikum der Stadt Ludwigshafen am Rhein gGmbH	Ludwigshafen
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	Klinikum Oldenburg gGmbH	Oldenburg
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	Krankenhaus der Barmherzigen Brüder Trier	Trier
Germany	Mutterhaus der Borromäerinnen	Trier
Germany	Universitätsklinikum Tübingen	Tübingen
Germany	Universitätsklinikum Ulm	Ulm
Germany	Schwarzwald-Baar Klinikum Villingen- Schwenningen GmbH	Villingen-Schwenningen
Germany	Helios Klinikum Wuppertal	Wuppertal

Sponsors (2)

Lead Sponsor	Collaborator
University of Ulm	Jazz Pharmaceuticals

Countries where clinical trial is conducted

Austria,  Germany, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	EFS with CRi considered as failure of induction therapy in the extended set of patients	Exploratory endpoint	2 years
Other	Response rates (CR/CRi/CRMRD-/CRiMRD-) in the extended set of patients	Exploratory endpoint	2 years
Other	Relapse-free survival (RFS) in patients who achieved CR/CRi during induction chemotherapy	Exploratory endpoint	2 years
Other	Relapse-free survival (RFS) in patients who achieved CR during induction chemotherapy	Exploratory endpoint	2 years
Other	Cumulative incidence of relapse (CIR) in patients who achieved CR/CRi during induction chemotherapy	Exploratory endpoint	2 years
Other	Cumulative incidence of relapse (CIR) in patients who achieved CR during induction chemotherapy	Exploratory endpoint	2 years
Other	Cumulative incidence of death (CID) in patients who achieved CR/CRi during induction chemotherapy	Exploratory endpoint	2 years
Other	Cumulative incidence of death (CID) in patients who achieved CR during induction chemotherapy	Exploratory endpoint	2 years
Other	EFS with allogeneic HCT considered as competing event	Exploratory endpoint	2 years
Other	RFS with allogeneic HCT considered as competing event	Exploratory endpoint	2 years
Other	CIR with allogeneic HCT considered as competing event	Exploratory endpoint	2 years
Other	CID with allogeneic HCT considered as competing event	Exploratory endpoint	2 years
Other	OS with allogeneic HCT considered as competing event	Exploratory endpoint	2 years
Other	QoL NCI PRO-CTCAE (National Cancer Institute) Patient Reported Outcomes Common Terminology Criteria for Adverse Events questionnaire)	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.	2 years
Other	QoL EORTC QLQ-FA12	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.	2 years
Other	QoL EORTC QLQ-C30 (Core Quality of Life Questionnaire developed by European Organization for Research and Treatment of Cancer)	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.	2 years
Other	Rate of hospitalization including admissions at intensive care unit (ICU)	Exploratory endpoint	8 months
Other	Reasons for hospitalization	Exploratory endpoint	8 months
Other	days of hospitalization by treatment setting	Exploratory endpoint	8 months
Other	rate of use of anti-infectives and other medications, e.g. against nausea or vomiting	Exploratory endpoint	8 months
Other	additional therapies administered	Exploratory endpoint	8 months
Other	place of chemotherapy administration (inpatient vs outpatient setting)	Exploratory endpoint	8 months
Other	duration of administration	Exploratory endpoint	8 months
Other	number of outpatient visits	Exploratory endpoint	8 months
Other	Frequency of salvage therapies	Exploratory endpoint	8 months
Other	Incidence and intensity of adverse events (AEs) according to Common Terminology Criteria for Adverse Events (CTCAE) version v5.0		2 years
Primary	Overall survival (OS) in the restricted set of de novo patients		2 years
Secondary	Overall survival (OS) in the extended set of patients		2 years
Secondary	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
Secondary	Event-free survival (EFS) with CRi considered as failure of induction therapy in the restricted set of de novo patients		2 years
Secondary	Rate of objective response in the restricted set of de novo patients	complete remission [CR], CR with incomplete hematologic recovery [CRi], CRi without measurable residual disease [CRiMRD-], CR without measurable residual disease [CRMRD-])	2 months