Chemotherapy + Enzyme Inhibitors for Acute Myeloid Leukemia

Overseen By Gina Keiffer, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Thomas Jefferson University

Must not be taking: Chemotherapy, Growth factors

Disqualifiers: Acute promyelocytic leukemia, CNS leukemia, Active second malignancy, Unstable cardiac disease, others

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

Compensation: Varies

Number of Visits: 10

24 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase I trial tests the safety, side effects, and best dose of palbociclib or tazemetostat in combination with CPX-351 in treating patients with acute myeloid leukemia (AML) that has come back (relapsed) or does not respond to treatment (refractory). CPX-351 is a combination of the chemotherapy drugs, daunorubicin and cytarabine, which is the standard of care for AML. Chemotherapy drugs 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. Palbociclib and tazemetostat are enzyme inhibitor drugs that are approved for treating certain cancers but not AML. These drugs may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving CPX-351 chemotherapy with enzyme inhibitors palbociclib or tazemetostat may kill more cancer cells.

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

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot be on active chemotherapy agents (except hydroxyurea) or growth factors (except erythropoietin). It's best to discuss your specific medications with the trial team.

What data supports the idea that Chemotherapy + Enzyme Inhibitors for Acute Myeloid Leukemia is an effective treatment?

The available research shows that the drug CPX-351, a combination of chemotherapy drugs daunorubicin and cytarabine, is effective for treating Acute Myeloid Leukemia (AML). In studies, CPX-351 improved survival rates compared to the traditional 7+3 chemotherapy regimen. Specifically, it significantly increased the time patients lived without the disease getting worse and had higher rates of complete remission, meaning more patients had no signs of cancer after treatment. These benefits were observed in older adults with high-risk AML, and the safety of CPX-351 was similar to the traditional treatment, making it a strong option for this condition. ^{1 2 3 4 5}

What safety data is available for the treatment of chemotherapy combined with enzyme inhibitors for acute myeloid leukemia?

The treatment, known as Vyxeos or CPX-351, is a liposomal formulation of daunorubicin and cytarabine. It has been approved for adults with therapy-related acute myeloid leukemia (t-AML) or AML with myelodysplasia-related changes (AML-MRC). Clinical trials, including a pivotal phase 3 study, have shown that CPX-351 has a safety profile comparable to the conventional 7+3 chemotherapy regimen, with similar types and severities of adverse events. However, CPX-351 is associated with more prolonged neutropenia and thrombocytopenia. The pharmacokinetics and tissue distribution studies in animals also support its safety profile, showing prolonged tissue exposure and lower unbound plasma concentrations compared to non-liposomal formulations. Overall, CPX-351 is considered to have an acceptable tolerability profile for older patients with high-risk or secondary AML. ^{1 4 6 7 8}

Is the drug Liposome-encapsulated Daunorubicin-Cytarabine, Palbociclib, Tazemetostat a promising treatment for acute myeloid leukemia?

Yes, the drug Liposome-encapsulated Daunorubicin-Cytarabine, also known as CPX-351 or Vyxeos, is a promising treatment for acute myeloid leukemia. It has shown to improve survival rates and achieve higher remission rates compared to traditional chemotherapy. It is designed to deliver the drugs more effectively to cancer cells, which helps in reducing side effects and increasing its effectiveness. ^{1 2 4 5 7}

Research Team

Gina Keiffer, MD

Principal Investigator

Thomas Jefferson University

Eligibility Criteria

This trial is for adults (18+) with acute myeloid leukemia that has relapsed or is refractory, having failed at least one prior therapy. Participants must be able to take oral medication, have a certain level of kidney function (CrCL >= 45), and an ECOG performance status of 2 or less. They should not be pregnant/breastfeeding, have active second cancers except some exceptions, severe diseases, known allergies to study drugs, CNS leukemia involvement, or conditions affecting study compliance.

Inclusion Criteria

I am willing and able to follow all study rules and attend all appointments.

I am 18 years old or older.

Total bilirubin < 2 x upper limit of normal (ULN)

Exclusion Criteria

I have no active cancer except for certain skin, cervical, or low-grade prostate cancers.

Anything that would place the individual at increased risk or preclude the individual's full compliance with or completion of the study

My heart condition is stable and my heartbeat rhythm is controlled.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment Part I

Patients receive tazemetostat orally twice a day on days -1 to 6, and CPX-351 intravenously on days 1, 3, and 5.

1 week

3 visits (in-person)

Treatment Part II

Patients receive palbociclib orally daily on days -3 to -1, and CPX-351 intravenously on days 1, 3, and 5.

1 week

3 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 1 year

Follow-up at 3 months, 6 months, and 1 year

Treatment Details

Interventions

• Liposome-encapsulated Daunorubicin-Cytarabine
• Palbociclib
• Tazemetostat

Trial Overview The trial tests the safety and optimal doses of palbociclib or tazemetostat combined with CPX-351 chemotherapy in AML patients. CPX-351 includes daunorubicin and cytarabine which are standard treatments for AML. Palbociclib and tazemetostat are enzyme inhibitors approved for other cancers but not yet for AML; they may help stop cancer cell growth by blocking necessary enzymes.

Participant Groups

Group I: Part II (palbociclib, CPX-351) Experimental Treatment 4 Interventions

Patients receive palbociclib PO QD on days -3 to -1, and CPX-351 IV over 90 minutes on days 1, 3, and 5. Patients also undergo bone marrow aspiration and biopsy and blood sample collection during screening and on study.

Group II: Part I (tazemetostat, CPX-351) Experimental Treatment 4 Interventions

Patients receive tazemetostat PO BID on days -1 to 6, and CPX-351 IV over 90 minutes on days 1, 3, and 5. Patients also undergo bone marrow aspiration and biopsy and blood sample collection during screening and on study.

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?

Thomas Jefferson University

Lead Sponsor

Trials

475

Recruited

189,000+

Findings from Research

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]

The introduction of CPX-351, a liposomal formulation of daunorubicin and cytarabine, has significantly improved overall survival in patients aged 60-75 with newly diagnosed secondary and therapy-related acute myeloid leukemia (AML) compared to the traditional '7 + 3' regimen.

CPX-351 received FDA approval in August 2017, marking a significant advancement in AML treatment after decades of stagnation in therapy options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Daunorubicin-cytarabine liposome (CPX-351) in the management of newly diagnosed secondary AML: A new twist on an old cocktail. Maakaron, JE., Mims, AS.[2020]

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]

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]

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]

Vyxeos (CPX-351) received FDA approval for treating adults with newly diagnosed therapy-related acute myeloid leukemia (t-AML) or acute myeloid leukemia with myelodysplasia-related changes (AML-MRC), based on a study involving 309 patients aged 60-75 that showed improved overall survival (9.6 months vs. 5.9 months with standard treatment).

The safety profile of Vyxeos was comparable to the standard treatment, but it was associated with longer periods of neutropenia and thrombocytopenia, highlighting the need for careful monitoring and a warning against switching between different formulations of daunorubicin and cytarabine during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: (Daunorubicin and Cytarabine) Liposome for Injection for the Treatment of Adults with High-Risk Acute Myeloid Leukemia. Krauss, AC., Gao, X., Li, L., et al.[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]

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

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

2. Netherlands pubmed.ncbi.nlm.nih.gov

Daunorubicin-cytarabine liposome (CPX-351) in the management of newly diagnosed secondary AML: A new twist on an old cocktail. [2020]

3. 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]

4. 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]

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

FDA Approval Summary: (Daunorubicin and Cytarabine) Liposome for Injection for the Treatment of Adults with High-Risk Acute Myeloid Leukemia. [2020]

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

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

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]