Liposome-encapsulated Daunorubicin-Cytarabine for Leukemia

Overseen By Guillermo M Bravo

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Investigational agents, Chemotherapy

Disqualifiers: Heart failure, Myocardial infarction, Infection, Pregnancy, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

38 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase I trial studies best dose and side effects of liposome-encapsulated daunorubicin-cytarabine (CPX-351) and how well it works in treating patients with high risk myelodysplastic syndrome or chronic myelomonocytic leukemia that has come back or has not responded to treatment. Drugs used in chemotherapy, such as liposome-encapsulated daunorubicin-cytarabine, 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.

Do I need to stop my current medications for the trial?

The trial does not specify if you need to stop your current medications. However, you cannot be on any other investigational agents or chemotherapy, radiotherapy, or immunotherapy within 14 days of starting the study treatment.

What data supports the effectiveness of the drug Liposome-encapsulated Daunorubicin-Cytarabine (CPX-351) for leukemia?

Research shows that CPX-351, a combination of two drugs in a special delivery system, significantly improved survival rates and remission in patients with certain types of acute myeloid leukemia compared to traditional chemotherapy. This drug is designed to deliver the drugs directly to leukemia cells, making it more effective and potentially safer. ^{1 2 3 4 5}

Is Liposome-encapsulated Daunorubicin-Cytarabine (CPX-351) safe for humans?

Liposome-encapsulated Daunorubicin-Cytarabine, also known as CPX-351 or Vyxeos, has been shown to have an acceptable safety profile in clinical trials for older adults with certain types of leukemia. The types and severities of side effects were generally similar to those of conventional chemotherapy, making it a viable treatment option for these patients. ^{2 4 6 7 8}

What makes the drug CPX-351 unique for treating leukemia?

CPX-351 is unique because it combines two drugs, cytarabine and daunorubicin, in a special liposome (a tiny bubble-like structure) that maintains a specific 5:1 ratio, enhancing their effectiveness against leukemia. This formulation allows the drugs to be released slowly and taken up preferentially by leukemia cells, improving treatment outcomes compared to traditional chemotherapy. ^{1 2 3 4 5}

Research Team

Guillermo M Bravo

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

This trial is for adults with high-risk myelodysplastic syndrome or chronic myelomonocytic leukemia that's relapsed or resistant to treatment. They should not be candidates for a stem cell transplant, have certain levels of bone marrow blasts, and adequate kidney and liver function. Pregnant women, those with recent heart issues, uncontrolled infections, or who are on other treatments are excluded.

Inclusion Criteria

Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) =< 3 x ULN

Patient (or patient's legally authorized representative) must have signed an informed consent document indicating that the patient understands the purpose of and procedures required for the study and is willing to participate in the study

Total bilirubin < 3 mg/dL (will allow less than 5 x upper limit of normal [ULN] if Gilbert's at investigator's discretion)

Exclusion Criteria

I have had a high dose of certain chemotherapy drugs, or less if I also had chest radiation.

I am currently pregnant or breastfeeding.

I have an infection that isn't getting better with antibiotics.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction Therapy

Patients receive liposome-encapsulated daunorubicin-cytarabine IV over 90 minutes on days 1, 3, and 5. After 2-5 weeks, patients may receive additional treatment if criteria are met.

2-5 weeks

Consolidation Therapy

Patients who achieve at least a hematological improvement response receive treatment every 28 days for up to 12 cycles.

Up to 12 months

Follow-up

Participants are monitored for safety and effectiveness after treatment completion.

30 days and then every 6 months

Treatment Details

Interventions

• Liposome-encapsulated Daunorubicin-Cytarabine

Trial Overview The study tests CPX-351 (liposome-encapsulated daunorubicin-cytarabine), aiming to find the best dose and assess side effects. It's designed for patients whose cancer has returned or didn't respond to prior therapies. The drug aims to stop cancer cells by killing them or preventing their growth and spread.

Participant Groups

Group I: Treatment (liposome-encapsulated daunorubicin-cytarabine) Experimental Treatment 1 Intervention

INDUCTION THERAPY: Patients receive liposome-encapsulated daunorubicin-cytarabine IV over 90 minutes on days 1, 3, and 5 in the absence of disease progression or unacceptable toxicity. After 2-5 weeks, patients who do not achieve a CR/CRi/CRp, have acceptable or no toxicity, and have stable disease and no disease progression may receive liposome-encapsulated daunorubicin-cytarabine IV over 90 minutes on days 1 and 3 in the absence of disease progression or unacceptable toxicity. CONSOLIDATION THERAPY: Patients who achieve at least a HI response, receive liposome-encapsulated daunorubicin-cytarabine IV over 90 minutes on days 1 and 3. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. After 5-8 weeks, patients who do not show clinically significant disease progression or unacceptable toxicity may receive liposome-encapsulated daunorubicin-cytarabine for up to 12 additional cycles.

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)

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

In a phase II study involving 125 patients with acute myeloid leukemia (AML) in first relapse, CPX-351 showed improved response rates and lower 60-day mortality in patients classified as poor-risk according to the European Prognostic Index.

While CPX-351 did not meet the overall statistical criteria for 1-year survival improvement compared to standard salvage chemotherapy, it demonstrated significant benefits in event-free survival and overall survival for the poor-risk subgroup, suggesting it may be a more effective treatment option for these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II, multicenter, randomized trial of CPX-351 (cytarabine:daunorubicin) liposome injection versus intensive salvage therapy in adults with first relapse AML. Cortes, JE., Goldberg, SL., Feldman, EJ., et al.[2021]

VYXEOS™, a liposomal formulation of daunorubicin and cytarabine, has been shown to significantly improve overall survival and event-free survival in older patients with newly diagnosed high-risk acute myeloid leukaemia (AML) compared to conventional chemotherapy (7+3).

The treatment also resulted in higher rates of complete remission and was well-tolerated, with a safety profile similar to that of the standard chemotherapy regimen, making it a valuable option for patients with therapy-related AML or AML with myelodysplasia-related changes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Daunorubicin/Cytarabine Liposome: A Review in Acute Myeloid Leukaemia. Blair, HA.[2020]

CPX-351 (Vyxeos®) is a dual-drug liposomal formulation of cytarabine and daunorubicin designed to improve efficacy in treating acute myeloid leukemia (AML) by maintaining a synergistic 5:1 drug ratio, which enhances its effectiveness compared to traditional chemotherapy regimens.

The liposomal encapsulation allows for controlled release and preferential uptake by malignant cells, which helps to protect the drugs from metabolism and reduces exposure to off-target tissues, contributing to a favorable safety profile while effectively targeting leukemia cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CPX-351: a nanoscale liposomal co-formulation of daunorubicin and cytarabine with unique biodistribution and tumor cell uptake properties. Mayer, LD., Tardi, P., Louie, AC.[2020]

CPX-351 is a liposomal formulation that combines cytarabine and daunorubicin in a 5:1 ratio, which has shown synergistic effects in laboratory and animal studies for treating blood cancers.

The study developed a pharmacokinetic model to understand how CPX-351 behaves in the body, including how the drugs are released from the liposome and their concentrations in plasma and bone marrow, which is crucial for predicting its therapeutic effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics of CPX-351 (cytarabine/daunorubicin HCl) liposome injection in the mouse. Bayne, WF., Mayer, LD., Swenson, CE.[2013]

CPX-351, a liposome formulation of cytarabine and daunorubicin, demonstrated potent anti-leukemic activity in a mouse model, effectively reducing leukemia cells in bone marrow to undetectable levels for weeks, unlike the free-drug cocktail which only provided temporary suppression.

The enhanced efficacy of CPX-351 is attributed to its ability to deliver higher concentrations of the drugs directly to leukemia cells, leading to prolonged exposure and selective killing of these cells, while causing similar levels of myelosuppression as the free-drug cocktail.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Leukemia-selective uptake and cytotoxicity of CPX-351, a synergistic fixed-ratio cytarabine:daunorubicin formulation, in bone marrow xenografts. Lim, WS., Tardi, PG., Dos Santos, N., et al.[2022]

CPX-351, a liposomal formulation of cytarabine and daunorubicin, shows improved safety and efficacy in treating acute myeloid leukemia by providing prolonged tissue exposure and altered distribution compared to traditional non-liposomal combinations.

Preclinical studies indicate that CPX-351 maintains similar drug release and metabolism patterns as the standard treatment but results in lower unbound plasma concentrations, which may contribute to its enhanced therapeutic effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics, drug metabolism, and tissue distribution of CPX-351 in animals. Wang, Q., Tardi, P., Sadowski, N., et al.[2021]

CPX-351, a liposome-encapsulated combination of cytarabine and daunorubicin, demonstrated consistent pharmacokinetics across 48 patients, with a stable 5:1 drug ratio maintained in circulation, indicating effective delivery of the medication.

The treatment showed dose-dependent effects on blood cell counts, with significant antileukemic responses achieved at higher doses, suggesting CPX-351 can be tailored for both intensive chemotherapy and for patients at higher risk of complications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics of CPX-351; a nano-scale liposomal fixed molar ratio formulation of cytarabine:daunorubicin, in patients with advanced leukemia. Feldman, EJ., Kolitz, JE., Trang, JM., et al.[2013]

In a phase 3 trial involving 309 patients aged 60-75 with high-risk acute myeloid leukaemia, CPX-351 demonstrated a median overall survival of 9.33 months compared to 5.95 months for standard chemotherapy (7+3), indicating a significant improvement in survival rates.

After 5 years, the overall survival rate was 18% for the CPX-351 group versus 8% for the 7+3 group, suggesting that CPX-351 may lead to long-term remission and better outcomes for patients with this type of leukemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CPX-351 versus 7+3 cytarabine and daunorubicin chemotherapy in older adults with newly diagnosed high-risk or secondary acute myeloid leukaemia: 5-year results of a randomised, open-label, multicentre, phase 3 trial. Lancet, JE., Uy, GL., Newell, LF., et al.[2021]

References

1. United States pubmed.ncbi.nlm.nih.gov

Phase II, multicenter, randomized trial of CPX-351 (cytarabine:daunorubicin) liposome injection versus intensive salvage therapy in adults with first relapse AML. [2021]

2. New Zealand pubmed.ncbi.nlm.nih.gov

Daunorubicin/Cytarabine Liposome: A Review in Acute Myeloid Leukaemia. [2020]

3. New Zealand pubmed.ncbi.nlm.nih.gov

CPX-351: a nanoscale liposomal co-formulation of daunorubicin and cytarabine with unique biodistribution and tumor cell uptake properties. [2020]

4. United States pubmed.ncbi.nlm.nih.gov

Pharmacokinetics of CPX-351 (cytarabine/daunorubicin HCl) liposome injection in the mouse. [2013]

5. England pubmed.ncbi.nlm.nih.gov

Leukemia-selective uptake and cytotoxicity of CPX-351, a synergistic fixed-ratio cytarabine:daunorubicin formulation, in bone marrow xenografts. [2022]

6. United States pubmed.ncbi.nlm.nih.gov

Pharmacokinetics, drug metabolism, and tissue distribution of CPX-351 in animals. [2021]

7. England pubmed.ncbi.nlm.nih.gov

Pharmacokinetics of CPX-351; a nano-scale liposomal fixed molar ratio formulation of cytarabine:daunorubicin, in patients with advanced leukemia. [2013]

8. England pubmed.ncbi.nlm.nih.gov

CPX-351 versus 7+3 cytarabine and daunorubicin chemotherapy in older adults with newly diagnosed high-risk or secondary acute myeloid leukaemia: 5-year results of a randomised, open-label, multicentre, phase 3 trial. [2021]