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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores how two chemotherapy drugs, liposome-encapsulated daunorubicin-cytarabine (also known as CPX-351 or Vyxeos) and venetoclax, can combat acute myeloid leukemia (AML). The focus is on individuals whose AML has returned, isn't responding to treatment, or hasn't been treated yet. The goal is to determine if these drugs can stop cancer cells from growing and spreading. Individuals with relapsed AML or those whose AML isn't responding to other treatments might be suitable for this trial. As a Phase 2 trial, this research measures how well the treatment works in an initial, smaller group of people.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that the combination of liposome-encapsulated daunorubicin-cytarabine and venetoclax is generally safe and manageable. Earlier studies found that most participants tolerated this combination, experiencing manageable side effects. The treatment also demonstrated promising effectiveness.

Liposome-encapsulated daunorubicin-cytarabine is a type of chemotherapy that uses tiny fat bubbles (liposomes) to deliver the drugs more effectively. Venetoclax helps stop cancer cells from growing. Previous research indicates that these treatments can be used safely, with controllable side effects. This suggests that the combination could be a potential option for people with acute myeloid leukemia (AML), especially if the cancer has returned or hasn't responded to other treatments.

The ongoing research in this trial aims to confirm these findings and further evaluate the safety of this treatment combination. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the treatment combining liposome-encapsulated daunorubicin-cytarabine and venetoclax for acute myeloid leukemia because it offers a unique approach compared to standard chemotherapy regimens. Unlike traditional treatments, this therapy uses a liposomal delivery system for daunorubicin-cytarabine, which helps the drugs stay in the bloodstream longer and target cancer cells more effectively. Additionally, venetoclax works by inhibiting a protein that cancer cells need to survive, potentially leading to better outcomes. This combination aims to enhance the effectiveness of treatment while minimizing side effects, providing new hope for patients with this aggressive form of leukemia.

What evidence suggests that this trial's treatments could be effective for acute myeloid leukemia?

Studies have shown that CPX-351, a special form of chemotherapy, effectively treats acute myeloid leukemia (AML). It has been linked to longer survival compared to traditional chemotherapy, particularly in older adults. This treatment helps more patients reach remission, meaning their cancer is reduced or gone.

In this trial, participants will receive CPX-351 combined with venetoclax. Research indicates that venetoclax can improve results when used with other drugs. One study showed a 15.5% response rate in patients with AML, with some achieving a complete response, meaning no signs of cancer. These findings suggest both treatments have potential in effectively targeting AML. ^{5 6 7 8 9}

Who Is on the Research Team?

Tapan Kadia, MD

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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, 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 (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]

Citations

1.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC12185649/

The Role of CPX-351 in the Acute Myeloid Leukemia ...

These protective effects and confirmed effectiveness in everyday practice mean CPX-351 is a safe and effective treatment option for people with ...

2.

ascopubs.org

ascopubs.org/doi/10.1200/JCO.2017.77.6112

CPX-351 (cytarabine and daunorubicin) Liposome for ...

CPX-351 treatment is associated with significantly longer survival compared with conventional 7+3 in older adults with newly diagnosed sAML.

3.

ashpublications.org

ashpublications.org/blood/article/138/Supplement%201/4415/482221/Liposome-Encapsulated-Cytarabine-and-Daunorubicin

Liposome-Encapsulated Cytarabine and Daunorubicin (CPX ...

Liposome-Encapsulated Cytarabine and Daunorubicin (CPX-351) Induces Remission in Newly Diagnosed Pediatric Secondary Myeloid Malignancies ...

4.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC7485353/

EMA Review of Daunorubicin and Cytarabine ...

Secondary endpoints support the primary outcome, in particular an increased rate of hematopoietic stem cell transplantation, which is potentially the only ...

5.

sciencedirect.com

sciencedirect.com/science/article/pii/S2152265023002124

Real-World Experience With CPX-351 Treatment for Acute ...

This study provides real-world survival outcomes data suggesting that CPX-351 is an effective treatment for both younger (<60 years) and older (≥60 years) ...

6.

pubmed.ncbi.nlm.nih.gov

pubmed.ncbi.nlm.nih.gov/39418644

Lower-intensity CPX-351 plus venetoclax induction for ...

This phase 1b study evaluated lower-intensity CPX-351 combined with venetoclax in adults with acute myeloid leukemia (AML) considered unfit/ ...

7.

ashpublications.org

ashpublications.org/bloodneoplasia/article/2/4/100123/537598/V-FAST-a-phase-1b-master-trial-to-investigate-CPX

V-FAST: a phase 1b master trial to investigate CPX-351 ...

CPX-351 combined with venetoclax or midostaurin demonstrated a manageable safety profile and promising remission rates. These results support further ...

8.

mycancergenome.org

mycancergenome.org/content/clinical_trials/NCT03629171/

Clinical Trial: NCT03629171

This phase II trial studies how well liposome-encapsulated daunorubicin-cytarabine and venetoclax work in treating participants with acute ...

9.

mdanderson.org

mdanderson.org/patients-family/diagnosis-treatment/clinical-trials/clinical-trials-index/clinical-trials-detail.ID2017-1055.html

Phase II Study of CPX-351 in Combination with Venetoclax ...

This phase II trial studies how well liposome-encapsulated daunorubicin-cytarabine and venetoclax work in treating participants with acute myeloid leukemia.