Liposomal Daunorubicin-Cytarabine + Venetoclax for Acute Myeloid Leukemia

Overseen By Tapan Kadia

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: M.D. Anderson Cancer Center

Disqualifiers: Pregnancy, Uncontrolled illness, CNS leukemia, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 30

52 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, prior therapy with certain drugs like hydroxyurea, hematopoietic growth factors, or tretinoin is allowed without a break, and a specific dose of ara-C is allowed if given more than 48 hours before joining the trial.

What data supports the effectiveness of the drug Liposomal Daunorubicin-Cytarabine (CPX-351) for treating Acute Myeloid Leukemia?

Research shows that CPX-351 significantly improved survival rates in older adults with high-risk acute myeloid leukemia compared to traditional chemotherapy. It also had higher rates of complete remission and a similar safety profile, making it an important treatment option for this condition. ^{1 2 3 4 5}

Is the treatment Liposomal Daunorubicin-Cytarabine + Venetoclax safe for humans?

The treatment using Liposomal Daunorubicin-Cytarabine, also known as CPX-351 or Vyxeos, has been shown to have an acceptable safety profile in older adults with certain types of acute myeloid leukemia, with side effects similar to traditional chemotherapy. It is approved for use in several countries and has been studied in clinical trials, indicating it is generally safe for human use in the conditions tested. ^{1 2 3 4 6}

What makes the drug Liposomal Daunorubicin-Cytarabine + Venetoclax unique for treating acute myeloid leukemia?

This drug is unique because it uses a liposomal formulation to deliver a fixed, synergistic ratio of daunorubicin and cytarabine, which enhances its effectiveness and prolongs survival compared to traditional chemotherapy. The liposome helps protect the drugs from being broken down too quickly, allowing for better targeting of leukemia cells and potentially reducing side effects. ^{2 3 4 5 7}

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.

Research Team

Tapan Kadia, MD

Principal Investigator

M.D. Anderson Cancer Center

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

Creatinine =< 1.5 x ULN

I am 18 or older with AML that has come back or didn’t respond to treatment, including prior venetoclax treatment.

Known cardiac ejection fraction of > or = 45% within the past 3 months

Exclusion Criteria

Patient with documented hypersensitivity to any of the components of the chemotherapy program

I am not pregnant or breastfeeding.

I do not have any severe illnesses that could interfere with the study.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction

Participants receive liposome-encapsulated daunorubicin-cytarabine IV and venetoclax PO. Treatment repeats every 28 days for up to 2 cycles.

8 weeks

Multiple visits for IV administration and monitoring

Consolidation

Participants receive liposome-encapsulated daunorubicin-cytarabine IV and venetoclax PO. Treatment repeats every 28 days for up to 4 cycles.

16 weeks

Multiple visits for IV administration and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

3 years

Follow-up at 30 days, then every 3 months

Treatment Details

Interventions

• Liposome-encapsulated Daunorubicin-Cytarabine
• Venetoclax

Trial Overview 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.

Participant Groups

Group I: Treatment (CPX-351, venetoclax) Experimental Treatment 2 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)

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

Findings from Research

In a phase 3 study involving 309 patients aged 60 to 75 with high-risk acute myeloid leukemia, CPX-351 significantly improved median overall survival compared to conventional 7+3 chemotherapy, while maintaining a similar safety profile.

The Quality-adjusted Time Without Symptoms of disease or Toxicity (Q-TWiST) analysis showed that CPX-351 provided a relative gain of 53.6% in quality-adjusted survival compared to 7+3, indicating a substantial clinical benefit for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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. Cortes, JE., Lin, TL., Uy, GL., et al.[2021]

In a study of 195 patients treated with CPX-351 and 160 patients treated with the conventional 7+3 therapy, CPX-351 was associated with a significantly shorter hospital length of stay (LOS), averaging 183.7 days compared to 197.1 days for 7+3 (p<0.001).

Despite the shorter LOS with CPX-351, the use of supportive care, such as blood products and anti-infectives, was similar between the two treatment groups, indicating that CPX-351 may offer resource advantages without compromising care.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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. Price, K., Cao, Z., Lipkin, C., et al.[2022]

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, 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 (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, a liposomal formulation of cytarabine and daunorubicin, shows superior cytotoxicity compared to standard daunorubicin and cytarabine combinations in cytarabine-resistant leukemia cells, indicating its potential effectiveness in treating high-risk acute myeloid leukemia (AML).

In primary AML patient samples, CPX-351 demonstrated a rapid increase in intracellular ara-CTP levels, particularly in patients who later experienced treatment failure, suggesting that Flu-CPX may improve patient outcomes by enhancing drug activation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CPX-351 exhibits hENT-independent uptake and can be potentiated by fludarabine in leukaemic cells lines and primary refractory AML. Anderson, E., Mehta, P., Heywood, J., et al.[2022]

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]

References

1. England pubmed.ncbi.nlm.nih.gov

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]

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

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]

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

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

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

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

5. 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]

6. England pubmed.ncbi.nlm.nih.gov

CPX-351 exhibits hENT-independent uptake and can be potentiated by fludarabine in leukaemic cells lines and primary refractory AML. [2022]

7. 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]