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
Conditions
Interventions
Trade Name: Vyxeos
Product Name: Vyxeos
Product Code: CPX-351
Pharmaceutical Form: Powder for concentrate for solution for infusion
CAS Number: 20830-81-3
Other descriptive name: DAUNORUBICIN HYDROCHL
Sponsors
University Hospital Ulm
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. 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 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: o 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 o 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 AML 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 >30x10^9/L); prior treatment of myelodysplastic 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 child-bearing 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) Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for
Exclusion criteria
Exclusion criteria: 1. AML with favorable-risk genetics according to 2017 ELN criteria: o AML with t(8;21)(q22;q22.1), RUNX1-RUNX1T1 o AML with inv(16)(p13.1q22)/t(16;16)(p13.1;q22), CBFB-MYH11 o AML with mutated NPM1 without FLT3-ITD or with FLT3-ITD low o 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: o Basal or squamous cell carcinoma of the skin o Carcinoma in situ of the cervix o Carcinoma in situ of the breast o 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 inc
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To evaluate the impact of CPX-351 vs standard intensive chemotherapy on overall survival (OS) in the restricted set of de novo patients ;Secondary Objective: -To evaluate the impact of CPX-351 vs standard intensive chemotherapy on EFS with CRi considered as response to induction therapy in the restricted set of de novo patients -To evaluate the impact of CPX-351 vs standard intensive chemotherapy on OS in the extended set of pat. -To evaluate the impact of CPX-351 vs standard intensive chemotherapy on EFS with CRi considered as response to induction therapy in the extended set of patients -To evaluate the impact of CPX-351 vs standard intensive chemotherapy on EFS with CRi considered as failure of induction therapy in the restricted set of de novo patients -To evaluate the impact of CPX-351 vs standard intensive chemotherapy on response rate (CR or CRi after induction therapy) in the restricted set of de novo patients -To evaluate the impact of CPX-351 vs standard intensive chemotherapy on response rate (CR or CRi without measurable residual disease (CRMRD-/CRiMRD-) after induction therapy) in the restricted set of de novo patients;Primary end point(s): Overall survival (OS) in the restricted set of de novo patients;Timepoint(s) of evaluation of this end point: Endpoint will be evaluated when the data of all eligible patients are available | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Secondary Efficacy Endpoints - Overall survival (OS) in the extended set of patients - 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 - Event-free survival (EFS) with CRi considered as failure of induction therapy in the restricted set of de novo patients - Rate of objective responses (complete remission [CR], CR with incomplete hematologic recovery [CRi], CRi without measurable residual disease [CRiMRD-], CR without measurable residual disease [CRMRD-]) in the restricted set of de novo patients Exploratory Endpoints - EFS with CRi considered as failure of induction therapy in the extended set of patients - Response rates (CR/CRi/CRiMRD-/CRMRD-) in the extended set of patients - Relapse-free survival (RFS), cumulative incidence of relapse (CIR) and death (CID) with CRi considered (a) as response to induction therapy and (b) as failure of induction therapy - EFS, RFS, CIR/CID, and OS with allogeneic HCT considered as competing event - Resource utilization assessed by the number of days of hospitals stays -QoL assessment via o the Core Quality of Life Questionnaire developed by European Organization for Research and Treatment of Cancer (EORTC QLQ-C30) o EORTC QLQ-FA-12 module o NCI (National Cancer Institute) Patient Reported Outcomes Common Terminology Criteria for Adverse Events questionnaire [(CTCAE)-PRO] Safety Endpoint - Incidence and intensity of adverse events (AEs) according to Common Terminology Criteria for Adverse Events (CTCAE) version v5.0 ;Timepoint(s) of evaluation of this end point: Secondary efficacy endpoints will be analyzed using the corresponding ITT analysis set (for the restricted and extended set of patients). | — |
Countries
Austria, Germany, Spain
Contacts
Public ContactVerena Gaidzik
University Hospital Ulm
Outcome results
None listed