Phase III Randomized Study of CPX-351 Versus Standard Chemotherapy in Adults with Newly Diagnosed AML and Intermediate or Adverse Genetic Risk
- Trial ID
- 2023-503670-21-00
- Protocol
- AMLSG 30-18
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this randomized Phase III study is to evaluate the impact of **CPX-351** compared to standard intensive chemotherapy on overall survival (OS) in a restricted set of de novo patients with newly diagnosed acute myeloid leukemia (AML) and intermediate- or adverse-risk genetics. This objective is clinically relevant as it aims to determine whether CPX-351 can improve survival outcomes in this specific patient population, which is characterized by a poor prognosis due to genetic risk factors.
Secondary objectives include evaluating the impact of CPX-351 versus standard intensive chemotherapy on several outcomes:
- Event-free survival (EFS) with complete remission with incomplete hematologic recovery (CRi) considered as a response to induction therapy in the restricted set of de novo patients.
- Overall survival (OS) in the extended set of patients.
- Event-free survival (EFS) with CRi considered as a response to induction therapy in 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.
- Response rate (complete remission (CR) or CRi after induction therapy) in the restricted set of de novo patients.
- Response rate (CR or CRi without measurable residual disease (CRMRD-/CRiMRD-) after induction therapy) in the restricted set of de novo patients.
Participants
The clinical trial involves participants diagnosed with **acute myeloid leukemia (AML)**, specifically those with newly diagnosed AML and intermediate- or adverse-risk genetics, including AML with myelodysplasia-related changes and therapy-related AML as per the World Health Organization classification. The study population includes both male and female subjects aged 18 years and older, with no upper age limit specified. Participants are required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less at screening, indicating they are ambulatory and capable of all self-care but unable to carry out any work activities. The trial does not include a vulnerable population. Participants must have adequate renal and hepatic function, as evidenced by specific laboratory criteria, and must not have received prior chemotherapy for acute leukemia, except for hydroxyurea under certain conditions. The sponsor has not provided information regarding the total number of participants or specific lifestyle considerations such as diet or physical activity. The selection criteria ensure that participants are eligible for intensive chemotherapy and have undergone a genetic assessment in a central laboratory. The trial does not include pregnant or nursing women, and women of childbearing potential must adhere to strict contraceptive measures during and after the study period.
Plans and Procedures
The clinical trial is a **randomized**, **double-blind**, **controlled** Phase III study designed to evaluate the impact of CPX-351 compared to standard intensive chemotherapy on overall survival in adult patients with newly diagnosed acute myeloid leukemia (AML) and intermediate- or adverse-risk genetics. The trial will involve the administration of **cytarabine** and **daunorubicin** as part of the treatment regimen. The study is expected to run from October 2019 to June 2027, with participant involvement lasting up to 19 weeks, depending on the treatment arm and response to therapy.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, performance status, and organ function. Following randomization, participants will receive treatment according to their assigned group, with regular follow-up visits to monitor safety, efficacy, and any adverse events. The end-of-study visit will occur after the completion of the treatment period or upon early termination, which may be due to disease progression, unacceptable toxicity, or withdrawal of consent.
The trial will include several follow-up visits to assess primary and secondary endpoints, such as overall survival and event-free survival. Participants will be closely monitored for compliance with the study protocol, and any deviations may result in early termination from the study. The trial aims to provide valuable insights into the efficacy of CPX-351 in improving outcomes for patients with AML, contributing to the advancement of treatment strategies for this challenging condition.
Treatment
The clinical trial involves the administration of **CYTARABINE**, a **concentrate for solution for infusion**. This experimental medication is administered **intravenously**. The dosage is calculated based on body surface area, with a maximum daily dose of **1500 mg/m²** and a total maximum dose of **17900 mg/m²** over a treatment period of up to **19 days**. The active substance, cytarabine, is of chemical origin. Participant compliance with the dosing schedule will be monitored throughout the trial.
**DAUNORUBICIN** is used as a comparator treatment in this study. It is provided in the form of a **powder for solution for infusion** and is also administered **intravenously**. The dosage is determined by body surface area, with a maximum daily dose of **60 mg/m²** and a total maximum dose of **330 mg/m²** over a treatment period of up to **6 days**. The active substance, daunorubicin, is chemically derived. Compliance with the administration schedule will be closely monitored.
The experimental treatment, **Vyxeos Liposomal**, is a combination of **cytarabine** and **daunorubicin** in a **powder for concentrate for solution for infusion** form. This formulation is administered **intravenously**. The maximum daily dose is **100 units**, with a total maximum dose of **990 units** over a treatment period of up to **12 days**. The active substances are of chemical origin, and the product is manufactured by Jazz Pharmaceuticals Ireland Ltd. Participant adherence to the dosing regimen will be assessed throughout the study.
Efficacy
Efficacy in this clinical trial will be assessed primarily through the measurement of **Overall Survival (OS)** in the restricted set of de novo patients with newly diagnosed acute myeloid leukemia (AML) and intermediate- or adverse-risk genetics. Secondary endpoints include OS in the extended set of patients, **Event-Free Survival (EFS)** with complete remission with incomplete hematologic recovery (CRi) considered as both response and failure of induction therapy, and the rate of objective responses, including complete remission (CR), CRi, CRi without measurable residual disease (CRiMRD-), and CR without measurable residual disease (CRMRD-).
The trial will employ a randomized Phase III design to compare standard intensive chemotherapy with CPX-351. Efficacy parameters will be collected and analyzed at various timepoints throughout the study, although specific timepoints are not detailed in the provided data. The trial aims to evaluate the impact of CPX-351 versus standard intensive chemotherapy on the aforementioned efficacy endpoints, with the primary focus on improving overall survival rates in the targeted patient population.
Inclusion and Exclusion Criteria
Inclusion Criteria
- 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
- Age ≥ 18 years, no upper age limit
- Patient considered eligible for intensive chemotherapy
- Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 at screening
- Genetic assessment in AMLSG central laboratory
- 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)
- 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
- 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 >30x10^9/l); prior treatment of myelo-dysplastic syndrome with hypomethylating agents is allowed
- 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)
- 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
- 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
- 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
- Able to understand and willing to sign an informed consent form (ICF)
Exclusion Criteria
- 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
- 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%).
- Acute promyelocytic leukemia (APL) with t(15;17)(q22;q12); PML-RARA; or one of the other pathognomonic variant chromosomal translocations/ fusion genes
- AML with BCR-ABL1
- Prior treatment of myelodysplastic syndrome (MDS) with intensive chemotherapy or bone marrow transplant with a curative intent
- 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
- Severe obstructive or restrictive ventilation disorder
- Uncontrolled infection
- 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
- Evidence of active hepatitis B or C infection or known Human Immunodeficiency Virus (HIV) infection
- 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
- Severe neurological or psychiatric disorder interfering with ability to give an informed consent
- 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
- No consent for biobanking of patient’s biological specimens
- 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
- 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.
- Known or suspected hypersensitivity to cytarabine, daunorubicin or liposomal products and/or any excipients
- History of Wilson’s disease or other copper-metabolism disorder
- 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).
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Austria | Not Recruiting | 01 Oct 2019 | 41 |
 Germany | Not Recruiting | 01 Oct 2019 | 842 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
CYTARABINE | Comparator | — | INTRAVENOUS | 1500 | 19 | SUB06880MIG |
Vyxeos Liposomal 44 mg/100 mg powder for concentrate for solution for infusion. | Test | POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS | 100 | 12 | PRD6605639 |
DAUNORUBICIN | Comparator | — | INTRAVENOUS | 60 | 6 | SUB06917MIG |