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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial examines the safety and effectiveness of combining chemotherapy with enzyme inhibitors, which block enzymes necessary for cancer cell growth, in treating acute myeloid leukemia (AML) that has returned or is resistant to treatment. The study tests two enzyme inhibitors, palbociclib and tazemetostat, alongside a standard chemotherapy treatment called CPX-351 (also known as Vyxeos or Liposome-encapsulated Daunorubicin-Cytarabine). Patients with AML who have tried at least one unsuccessful treatment might be suitable for this study. Participants must be able to take oral medication and should not have other active cancers or severe heart issues. As a Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants a chance to be among the first to receive this new combination therapy.

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.

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

Research has shown that the combination of palbociclib and tazemetostat with CPX-351 is being tested for safety in patients with acute myeloid leukemia (AML) that has returned or is not responding to treatment. CPX-351, a mix of daunorubicin and cytarabine, is already used to treat certain types of AML. The FDA approved it because it improves survival chances compared to standard chemotherapy while maintaining a similar safety profile.

Palbociclib and tazemetostat are enzyme inhibitors approved for treating other types of cancer, but not yet for AML. They have been proven safe for humans in some situations. However, since this is an early-stage study of their use with CPX-351, complete safety data for this specific combination is not yet available. The trial aims to ensure that when these drugs are used together, they are well-tolerated and any side effects are manageable. As this is the first time this combination is being tested, understanding patient responses is crucial to ensuring its safety for wider use. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard chemotherapy treatments for acute myeloid leukemia that use free-form drugs, this new approach utilizes a liposome-encapsulated form of daunorubicin and cytarabine called CPX-351. This innovative delivery system allows the drugs to stay in the body longer and target cancer cells more precisely, potentially increasing effectiveness while reducing side effects. Additionally, researchers are excited about incorporating enzyme inhibitors like palbociclib and tazemetostat, which target specific pathways in cancer cell growth, offering a new mechanism of action that could enhance treatment outcomes. These distinct features provide hope for a more efficient and targeted attack on leukemia cells compared to conventional options.

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

Research has shown that CPX-351, a combination of daunorubicin and cytarabine, significantly improves survival rates for patients with acute myeloid leukemia (AML) compared to traditional chemotherapy. Specifically, studies have found that CPX-351 more than doubles the five-year survival rate compared to the older 7+3 treatment. In this trial, participants will receive CPX-351 combined with either Tazemetostat or Palbociclib, drugs that block certain enzymes cancer cells need to grow. Although these drugs are approved for other types of cancer, this trial tests their potential to enhance CPX-351's effectiveness for AML. While their success in AML is still under investigation, they have shown promise in treating other cancers. ^{1 2 4 6 7}

Who Is on the Research Team?

Gina Keiffer, MD

Principal Investigator

Thomas Jefferson University

Are You a Good Fit for This Trial?

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.

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

I can do most of my daily activities on my own.

Exclusion Criteria

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

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

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

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

Group I: Part II: palbociclib Pre-Treatment Followed by Tazemetostat + CPX-351 Experimental Treatment 5 Interventions

Patients receive palbociclib PO QD on days -3 to -1, then tazemetostat PO twice daily (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.

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+

Pennsylvania Department of Health

Collaborator

Trials

42

Recruited

999,000+

Published Research Related to This Trial

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]

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]

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 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]

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 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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05627232

Palbociclib or Tazemetostat in Combination With CPX-351 ... 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 ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12063066/

The Clinical Safety and Efficacy of Cytarabine ... This review presents strong evidence supporting CPX‐351 as a therapeutic alternative with superior efficacy and comparable safety to standard chemotherapy ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9221356/

CPX-351: An Old Scheme with a New Formulation in the ... The FDA approved CPX-351, a liposomal formulation of cytarabine and daunorubicin at a fixed 5:1 molar ratio, for the treatment of adults with newly diagnosed t ...

4. vyxeospro.com vyxeospro.com/clinical-data/efficacy

The only choice for more than double the 5-year OS vs 7+3 1 VYXEOS is the only FDA-approved treatment for sAML demonstrating superior overall survival a in a Phase 3 study.

5. bloodcancerunited.org bloodcancerunited.org/resources/newsroom/publication-cpx-351-clinical-data-blood-advances-phase-3-post-hoc-analyses

Publication of CPX-351 Clinical Data in 'Blood Advances' CPX-351 was designed to improve efficacy versus conventional chemotherapy through the coencapsulation of daunorubicin and cytarabine at a synergistic 1:5 molar ...

6. ash.confex.com ash.confex.com/ash/2020/webprogram/Paper139494.html

1962 A Phase I/II Trial of CPX-351 + Palbociclib in Patients ... Preclinical studies have shown that the administration of palbociclib to AML cells in vitro for 48 hours can arrest 91% of the cells in the G0/G1 phase. When ...

7. vyxeospro.com vyxeospro.com/

VYXEOS® | A Treatment for sAML VYXEOS is indicated for the treatment of newly-diagnosed therapy-related acute myeloid leukemia (t‐AML) or AML with myelodysplasia-related changes (AML-MRC)