Trial Summary
What is the purpose of this trial?This phase II trial studies how well liposome-encapsulated daunorubicin-cytarabine and venetoclax work in treating participants with acute myeloid leukemia that has come back (relapsed), does not respond to treatment (refractory), or has not been treated (untreated). Drugs used in chemotherapy, such as liposome-encapsulated daunorubicin-cytarabine and venetoclax, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading.
Is the drug Liposome-encapsulated Daunorubicin-Cytarabine, Venetoclax a promising treatment for Acute Myeloid Leukemia?Yes, the drug Liposome-encapsulated Daunorubicin-Cytarabine, Venetoclax is promising for treating Acute Myeloid Leukemia. It has shown to improve survival rates and increase the chances of complete remission compared to traditional chemotherapy. The drug is designed to deliver its components more effectively to leukemia cells, which helps in better targeting the cancer while maintaining a manageable safety profile.13457
What safety data is available for the treatment of Liposomal Daunorubicin-Cytarabine + Venetoclax in AML?The safety data for Liposomal Daunorubicin-Cytarabine, also known as CPX-351 or Vyxeos, indicates that it has an acceptable tolerability profile in older patients with newly diagnosed high-risk or secondary acute myeloid leukemia (AML). The safety profile, including types and severities of adverse events, is generally similar to that of the conventional 7+3 chemotherapy regimen. CPX-351 has been shown to significantly improve overall survival and event-free survival compared to 7+3, with a comparable safety profile. Preclinical studies also suggest that CPX-351 has a different tissue distribution and lower unbound plasma and tissue concentrations compared to non-liposomal combinations, which may contribute to its safety and efficacy. However, specific safety data for the combination with Venetoclax is not detailed in the provided research.23567
What data supports the idea that Liposomal Daunorubicin-Cytarabine + Venetoclax for Acute Myeloid Leukemia is an effective treatment?The available research shows that Liposomal Daunorubicin-Cytarabine, also known as CPX-351, is effective for treating Acute Myeloid Leukemia (AML) in older adults. In a study comparing CPX-351 to a traditional chemotherapy treatment called 7+3, CPX-351 significantly improved the time patients lived without the disease getting worse. It also increased the chances of complete recovery from the disease. Additionally, CPX-351 had a similar safety profile to the traditional treatment, meaning it was not more harmful. These findings suggest that CPX-351 is a strong option for treating AML, especially in older patients.34567
Do I need to stop my current medications for this trial?The trial protocol does not specify if you need to stop taking your current medications. However, prior therapy with hydroxyurea, hematopoietic growth factors, or tretinoin (ATRA) is allowed without a washout period. It's best to discuss your specific medications with the trial team.
Eligibility Criteria
Adults diagnosed with Acute Myeloid Leukemia that's untreated, not responding to treatment, or has returned after treatment. Participants must be over 18 (up to 69 for certain groups), have acceptable organ function and performance status, and women of childbearing age must test negative for pregnancy. Those with CNS leukemia, prior CPX-351 or venetoclax use (except specific cases), uncontrolled illnesses, known hypersensitivity to the drugs used, or unwillingness to use contraception are excluded.Inclusion Criteria
I am 18 or older with AML that has come back or didn’t respond to treatment.
I am between 18 and 69 years old and have not received any treatment for AML.
I can take care of myself but might not be able to do heavy physical work.
Exclusion Criteria
I am not pregnant or breastfeeding.
I do not have any severe illnesses that could interfere with the study.
My leukemia is either acute promyelocytic (M3) or core-binding factor.
I do not have active leukemia in my brain or spinal cord.
Treatment Details
The trial is testing a combination of chemotherapy agents: liposome-encapsulated daunorubicin-cytarabine and venetoclax in patients with Acute Myeloid Leukemia. It aims to see how well these drugs work together in different scenarios such as relapsed/refractory AML or newly diagnosed patients.
1Treatment groups
Experimental Treatment
Group I: Treatment (CPX-351, venetoclax)Experimental Treatment2 Interventions
INDUCTION: Participants receive liposome-encapsulated daunorubicin-cytarabine IV over 90 minutes on days 1, 3, and 5 of cycle 1 and on days 1 and 3 of cycle 2. Participants also receive venetoclax PO QD on days 2-21. Treatment repeats every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity.
CONSOLIDATION: Participants receive liposome-encapsulated daunorubicin-cytarabine IV over 90 minutes on days 1 and 3 and venetoclax PO QD on days 2-21. Treatment repeats every 28 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity.
Liposome-encapsulated Daunorubicin-Cytarabine is already approved in United States for the following indications:
🇺🇸 Approved in United States as Vyxeos for:
- Acute Myeloid Leukemia with myelodysplasia-related changes (AML-MRC)
- Therapy-related AML (t-AML)
Find a clinic near you
Research locations nearbySelect from list below to view details:
M D Anderson Cancer CenterHouston, TX
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Who is running the clinical trial?
M.D. Anderson Cancer CenterLead Sponsor
References
Leukemia-selective uptake and cytotoxicity of CPX-351, a synergistic fixed-ratio cytarabine:daunorubicin formulation, in bone marrow xenografts. [2022]The objective of this study was to examine the pharmacodynamic basis for the potent preclinical and clinical anti-leukemic activity of CPX-351, a nano-scale liposome formulation of cytarabine and daunorubicin co-encapsulated at a synergistic 5:1 molar ratio. A bone marrow-engrafting CCRF-CEM leukemia model in Rag2-M mice was utilized to correlate the therapeutic and myelosuppressive properties of CPX-351 with bone marrow delivery and drug uptake in leukemia cells relative to normal bone marrow cell populations. When administered to mice bearing CCRF-CEM human leukemia xenografts, CPX-351 ablated bone marrow (BM) leukemic cells to below detectable levels for multiple weeks, whereas the free-drug cocktail only transiently suppressed leukemia growth. In contrast to the activity against leukemia cells, CPX-351 and free-drug cocktail induced similar myelosuppression in non-tumor-bearing BM. In leukemia-laden BM, drug concentrations were markedly elevated for CPX-351 over free-drug cocktail and the first dose of CPX-351, but not free-drug cocktail, potentiated BM drug accumulation for subsequent doses. Confocal fluorescence microscopy revealed that CPX-351 liposomes are taken up by CCRF-CEM cells and subsequently release drugs intracellularly. The improved in vivo efficacy of CPX-351 appears related to increased and prolonged exposure of synergistic cytarabine:daunorubicin ratios in BM, and the selective killing of leukemia may arise from direct liposome-leukemia cell interactions. These features may also have broader applicability in the treatment of other haematological malignancies.
CPX-351 exhibits hENT-independent uptake and can be potentiated by fludarabine in leukaemic cells lines and primary refractory AML. [2022]CPX-351, a liposomal formulation co-encapsulating cytarabine and daunorubicin (DNR) in a synergistic 5:1 M ratio, has shown favourable response in newly diagnosed elderly high-risk AML. This study assessed intracellular ara-CTP levels following in vitro exposure of human immortalised leukaemic cell lines and primary AML blasts to CPX-351, and investigated fludarabine potentiation of intracellular ara-CTP formation from CPX-351. Comparison of intracellular handling of CPX-351 to cytarabine in HL-60 cells indicated slower conversion to ara-CTP for CPX-351, but equivalent cytotoxicity to cytarabine and combined DNR/cytarabine (DA) at 48 h, mostly likely reflecting the need for intracellular liposome processing to release encapsulated drugs. Further assessment demonstrated cytotoxicity of CPX-351 to be superior to DA at 48 and 72 h in cytarabine-resistant THP-1 cells (p
Daunorubicin/Cytarabine Liposome: A Review in Acute Myeloid Leukaemia. [2020]VYXEOS™ is a liposomal-encapsulated formulation of daunorubicin and cytarabine delivering a fixed, synergistic 1:5 molar ratio (hereafter referred to as daunorubicin/cytarabine liposome). Daunorubicin/cytarabine liposome is approved in several countries worldwide for the treatment of adults with therapy-related acute myeloid leukaemia (tAML) and AML with myelodysplasia-related changes (MRC). Approval was based on its clinical benefit in older patients with newly diagnosed high-risk/secondary AML in a pivotal phase III trial. In this study, daunorubicin/cytarabine liposome significantly prolonged overall survival (OS) and event-free survival (EFS) relative to conventional chemotherapy with cytarabine plus daunorubicin (hereafter referred to as 7 + 3). Daunorubicin/cytarabine liposome was also associated with significantly higher rates of complete remission (CR) and CR with incomplete haematological recovery (CRi) compared with 7 + 3. Daunorubicin/cytarabine liposome had an acceptable tolerability profile in older patients with newly diagnosed high-risk/secondary AML. The safety profile of daunorubicin/cytarabine liposome, including types and severities of adverse events, was generally similar to that of 7 + 3. Therefore, daunorubicin/cytarabine liposome is an important treatment option for adults with newly diagnosed tAML or AML-MRC.
CPX-351: a nanoscale liposomal co-formulation of daunorubicin and cytarabine with unique biodistribution and tumor cell uptake properties. [2020]Combination regimens are a standard of care for many cancers. However, components of such regimens are typically first developed individually and subsequently combined using strategies to minimize toxicity. Little or no consideration is given to strategies that potentially maximize efficacy. In contrast, CPX-351 (Vyxeos®) is a dual-drug liposomal encapsulation of cytarabine and daunorubicin that was rationally designed to improve efficacy over the traditional 7+3 cytarabine/daunorubicin chemotherapy regimen for patients with acute myeloid leukemia (AML). The notable clinical efficacy of CPX-351 is achieved through maintenance of a synergistic 5:1 molar ratio of cytarabine and daunorubicin within the liposome after intravenous injection. The CPX-351 liposome, which is formulated to contain bilayers of distearoylphosphatidylcholine, distearoylphosphatidylglycerol, and cholesterol at a 7:2:1 molar ratio and remains in a gel phase at body temperature, provides stability without polyethylene glycol, controlled release of cytarabine and daunorubicin, limited systemic drug distribution, and preferential internalization within malignant myeloblasts in the bone marrow via active uptake of liposomes into cytoplasmic vacuoles. Thus, the CPX-351 liposome protects cytarabine and daunorubicin from metabolism and elimination, while overcoming pharmacokinetic differences between the two agents. In clinical studies, these liposome properties markedly increased the elimination half-life of CPX-351 versus free cytarabine and daunorubicin and maintained a synergistic drug ratio for over 24 hrs after administration. Preferential uptake of liposomes by leukemia cells suggests that relatively large amounts of cytarabine and daunorubicin enter malignant cells via liposomes, potentially bypassing P-glycoprotein-based efflux pumps, which are important mediators of chemotherapy resistance, and contribute to the rapid clearance of leukemia cells from the circulation and bone marrow. These pharmacologic advantages, a direct consequence of properties of the encapsulating liposome, may explain the efficacy of CPX-351 in patients with newly diagnosed high-risk/secondary AML and the reduced drug exposure in off-target tissues that contribute to a manageable safety profile.
Pharmacokinetics, drug metabolism, and tissue distribution of CPX-351 in animals. [2021]CPX-351, a liposomal encapsulation of cytarabine and daunorubicin at a synergistic 5:1 molar ratio, is indicated for adults with newly diagnosed, therapy-related acute myeloid leukemia or acute myeloid leukemia with myelodysplasia-related changes. In preclinical species, this article demonstrated (1) similar release of cytarabine and daunorubicin by CPX-351 in plasma; (2) similar patterns of metabolism of cytarabine and daunorubicin following administration of CPX-351 versus non-liposomal cytarabine/daunorubicin combination; (3) prolonged tissue exposure to CPX-351; (4) dramatically different tissue distribution of cytarabine and daunorubicin following administration of CPX-351 versus non-liposomal combination (tissue:plasma ratios generally 1, respectively); and (5) dramatically lower unbound plasma and tissue concentrations of cytarabine and daunorubicin following administration of CPX-351 versus non-liposomal combination. Together, these results provide insight into the safety profile of CPX-351, as well as mechanisms that drive the improved efficacy observed for CPX-351 versus the conventional 7 + 3 cytarabine/daunorubicin regimen in clinical studies.
Quality-adjusted Time Without Symptoms of disease or Toxicity (Q-TWiST) analysis of CPX-351 versus 7 + 3 in older adults with newly diagnosed high-risk/secondary AML. [2021]Label="BACKGROUND">CPX-351 (United States: Vyxeos®; Europe: Vyxeos® Liposomal), a dual-drug liposomal encapsulation of daunorubicin and cytarabine in a synergistic 1:5 molar ratio, is approved by the US FDA and the EMA for the treatment of adults with newly diagnosed therapy-related acute myeloid leukemia or acute myeloid leukemia with myelodysplasia-related changes. In a pivotal phase 3 study that evaluated 309 patients aged 60 to 75 years with newly diagnosed high-risk/secondary acute myeloid leukemia, CPX-351 significantly improved median overall survival versus conventional 7 + 3 chemotherapy (cytarabine continuous infusion for 7 days plus daunorubicin for 3 days), with a comparable safety profile. A Quality-adjusted Time Without Symptoms of disease or Toxicity (Q-TWiST) analysis of the phase 3 study was performed to compare survival quality between patients receiving CPX-351 versus conventional 7 + 3 after 5 years of follow-up.
Comparison of Hospital Length of Stay and Supportive Care Utilization Between Patients Treated with CPX-351 and 7+3 for Therapy-Related Acute Myeloid Leukemia or Acute Myeloid Leukemia with Myelodysplasia-Related Changes. [2022]CPX-351 is dual-drug liposomal encapsulation of daunorubicin and cytarabine at a fixed synergistic 1:5 molar ratio. This study determined current real-world use of CPX-351 versus conventional 7+3 (cytarabine+daunorubicin) therapy and evaluated hospital length of stay (LOS) and supportive care utilization in t-AML and AML-MRC.