Vyxeos + Gilteritinib for Acute Myeloid Leukemia

Overseen By Jhada-Kai Hunter

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: H. Lee Moffitt Cancer Center and Research Institute

Must not be taking: Investigational agents

Disqualifiers: CNS involvement, GI abnormalities, others

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

Compensation: Varies

Number of Visits: Unknown

22 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new combination of two treatments: Vyxeos (a chemotherapy drug) and Gilteritinib (also known as Xospata, a targeted therapy), for individuals with FLT3-mutated acute myeloid leukemia that has returned or not responded to previous treatments. The goal is to determine if this combination can help patients achieve remission, where the cancer shrinks or disappears. Individuals who have experienced a relapse of this leukemia and have undergone at least one prior treatment might be suitable candidates. As a Phase 1 trial, the 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.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot be on other investigational drugs. If you are using hydroxyurea to control white blood cell counts, you can continue it until the study treatment starts.

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

Research has shown that the combination of Vyxeos and gilteritinib is generally well-tolerated. In earlier studies, Vyxeos, which combines daunorubicin and cytarabine in a special form, had mostly mild side effects that doctors could manage. Gilteritinib has been used successfully in patients with a specific type of leukemia and is approved for that use due to its effectiveness and safety.

When used together, these treatments have shown promising results in other combinations, with no unexpected safety issues reported so far. This suggests that the combination of Vyxeos and gilteritinib in this study might be safe for most people, although side effects can vary. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about Vyxeos combined with Gilteritinib for treating Acute Myeloid Leukemia (AML) because this combination targets AML in a unique way. Vyxeos contains a fixed-dose combination of daunorubicin and cytarabine, two chemotherapy agents, delivered in a liposomal formulation that allows for better drug delivery to cancer cells. Gilteritinib is a targeted therapy that inhibits FLT3, a mutation found in some AML cases that drives cancer growth. This combo of chemotherapy with a targeted FLT3 inhibitor could potentially enhance treatment effectiveness compared to standard chemotherapy regimens alone, offering hope for better outcomes in AML patients.

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

Research shows that Vyxeos, a combination of daunorubicin and cytarabine, can extend the lives of patients with certain types of leukemia. Studies indicate that this treatment helps patients achieve remission and has manageable side effects. Gilteritinib targets a specific mutation called FLT3, common in some leukemia patients, and has effectively treated acute myeloid leukemia that has returned or is difficult to treat. In this trial, participants will receive a combination of Vyxeos and Gilteritinib to more effectively attack leukemia cells. Although researchers are still studying the efficacy of this combination, early results suggest it could benefit patients with FLT3-mutated acute myeloid leukemia. ^{1 3 4 5 6}

Who Is on the Research Team?

Onyee Chan, MD

Principal Investigator

Moffitt Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults with a specific mutation in their leukemia cells (FLT3) who have seen their disease return or not respond to treatment. They must be able to perform daily activities with some limitations, take oral meds, and use effective birth control if applicable. People can't join if they've had certain complications like severe graft versus host disease after a stem cell transplant or AML progression on gilteritinib.

Inclusion Criteria

Provision of signed and dated informed consent form

I had a stem cell transplant and my graft-versus-host disease is under control.

Breastfeeding mothers must agree to discontinue nursing

Exclusion Criteria

My digestive system can properly absorb medications.

Patients may not be receiving any other investigational agents

My body cannot handle the usual strong cancer drugs.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction Therapy

Participants receive Vyxeos on days 1, 3, and 5, and Gilteritinib on days 6-19

3 weeks

Consolidation Therapy

Participants in complete remission proceed to consolidation therapy with Vyxeos and Gilteritinib

Variable, based on remission status

Maintenance Therapy

Participants not proceeding to stem cell transplant enter maintenance phase with daily Gilteritinib

Up to 18 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 5 years

What Are the Treatments Tested in This Trial?

Interventions

• Gilteritinib
• Vyxeos

Trial Overview The study tests combining Vyxeos (chemotherapy) and Gilteritinib (targeted therapy) in patients whose acute myeloid leukemia has returned or resisted treatment. It involves initial intense therapy followed by maintenance using Gilteritinib alone for those ineligible for stem cell transplant.

How Is the Trial Designed?

Group I: Dose Expansion Arm Experimental Treatment 2 Interventions

Participants will receive intravenous Vyxeos on days 1, 3 and 5 and Gilteritinib will be given on days 6-19 of induction therapy in the dose determined in the dose escalation arm.

Group II: Dose Escalation Arm Experimental Treatment 2 Interventions

Participants will receive intravenous Vyxeos on days 1, 3 and 5 and Gilteritinib will be given on days 6-19 of induction therapy. The induction and reinduction dose of Vyxeos is 44mg/m2 daunorubicin and 100mg/m2 of cytarabine with each infusion. Dose level 1: Vyxeos + 120 mg Gilertinib In the event of a dose-limiting toxicity (DLT) at the initial dose level, a dose level minus (-) 1 is permitted Dose Level -1: Vyxeos + 80 mg Gilertinib

Gilteritinib is already approved in United States, European Union, Japan for the following indications:

Approved in United States as Xospata for:

• Acute myeloid leukemia (AML) with FLT3 mutation

Approved in European Union as Xospata for:

• Acute myeloid leukemia (AML) with FLT3 mutation

Approved in Japan as Xospata for:

• Acute myeloid leukemia (AML) with FLT3 mutation

Who Is Running the Clinical Trial?

H. Lee Moffitt Cancer Center and Research Institute

Lead Sponsor

Trials

576

Recruited

145,000+

Jazz Pharmaceuticals

Industry Sponsor

Trials

252

Recruited

35,100+

Bruce C. Cozadd

Jazz Pharmaceuticals

Chief Executive Officer since 2009

BA in Economics from Yale University, MBA from Stanford University

Dr. Austin

Jazz Pharmaceuticals

Chief Medical Officer since 2023

MD from the Royal College of Surgeons in Ireland

Published Research Related to This Trial

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]

Vyxeos, a liposomal formulation combining daunorubicin and cytarabine, significantly improves overall survival in patients aged 60-75 with untreated high-risk acute myeloid leukemia (AML), showing a median survival of 9.56 months compared to 5.95 months with standard chemotherapy.

The study demonstrated that Vyxeos not only enhances survival rates but also increases the likelihood of patients undergoing hematopoietic stem cell transplantation, which is crucial for potentially curing AML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

EMA Review of Daunorubicin and Cytarabine Encapsulated in Liposomes (Vyxeos, CPX-351) for the Treatment of Adults with Newly Diagnosed, Therapy-Related Acute Myeloid Leukemia or Acute Myeloid Leukemia with Myelodysplasia-Related Changes. Tzogani, K., Penttilä, K., Lapveteläinen, T., et al.[2022]

CPX-351, a liposomal formulation of daunorubicin and cytarabine, significantly improves overall survival in older adults (ages 60-75) with newly diagnosed high-risk or secondary acute myeloid leukemia (AML), showing a median survival of 9.56 months compared to 5.95 months with standard chemotherapy.

Preliminary evidence suggests that combining CPX-351 with FLT3 inhibitors may offer a promising treatment strategy for patients with FLT3 mutation-positive AML, which is associated with poorer outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CPX-351 in FLT3-mutated acute myeloid leukemia. Andrews, C., Pullarkat, V., Recher, C.[2023]

Gilteritinib significantly improves overall survival and response rates in adults with relapsed or refractory acute myeloid leukaemia (AML) with FLT3 mutations, as demonstrated in the phase III ADMIRAL trial.

While gilteritinib is effective, it can cause serious side effects like anaemia and febrile neutropenia, but these are generally manageable with dose adjustments, highlighting the importance of monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gilteritinib: A Review in Relapsed or Refractory FLT3-Mutated Acute Myeloid Leukaemia. Kang, C., Blair, HA.[2021]

CPX-351 (vyxeos) is the first FDA-approved treatment specifically for adults with newly diagnosed acute myeloid leukemia (AML) with myelodysplasia-related changes or therapy-related AML, representing a significant advancement in targeted therapy for this subgroup.

In a phase III study involving patients aged 60-75, CPX-351 demonstrated a higher median overall survival (9.56 months) compared to the traditional 7+3 regimen (5.95 months), indicating its superior efficacy in treating this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CPX-351 (vyxeos) in AML. Alfayez, M., Kantarjian, H., Kadia, T., et al.[2021]

Gilteritinib has been approved in the EU as a monotherapy for adult patients with relapsed or refractory acute myeloid leukemia (AML) with a FLT3 mutation, showing a significant improvement in overall survival (9.3 months) compared to salvage chemotherapy (5.6 months) in a phase III study with 371 participants.

The safety profile of gilteritinib is considered manageable, with common side effects including increases in liver enzymes and creatine phosphokinase, as well as gastrointestinal and general symptoms like fatigue and nausea.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The European Medicines Agency Review of Gilteritinib (Xospata) for the Treatment of Adult Patients with Relapsed or Refractory Acute Myeloid Leukemia with an FLT3 Mutation. Tzogani, K., Røshol, H., Olsen, HH., et al.[2021]

CPX-351, a liposomal-encapsulated combination of daunorubicin and cytarabine, has been approved for treating therapy-related acute myeloid leukemia (tAML) and AML with myelodysplasia-related changes (AML-MRCs), showing improved overall survival and remission rates in older patients compared to the traditional '7 + 3' treatment.

In a Phase III trial involving patients aged 60-75, CPX-351 demonstrated higher rates of complete remission and event-free survival, suggesting that its fixed 5:1 drug ratio may enhance efficacy in these challenging subgroups of AML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reformulating acute myeloid leukemia: liposomal cytarabine and daunorubicin (CPX-351) as an emerging therapy for secondary AML. Chen, EC., Fathi, AT., Brunner, AM.[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]

Gilteritinib fumarate is a highly selective oral FLT3 inhibitor that has shown significant efficacy in treating relapsed or refractory FLT3-mutated acute myeloid leukemia (AML), with clinical trials indicating higher response rates and longer overall survival compared to traditional salvage chemotherapy.

The drug was well tolerated in clinical trials, with dose-proportional plasma concentrations observed at doses ranging from 20 to 450 mg/day, supporting its safety profile for patients in Japan.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Pharmacological and clinical profile of gilteritinib (Xospata® tablets 40 mg), a therapeutic agent for relapsed or refractory FLT3-mutated acute myeloid leukemia]. Mori, M., Hidaka, K.[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]

Citations

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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 ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8931513/

Cost-effectiveness of liposomal cytarabine/daunorubicin in ... The liposomal formulation of cytarabine/daunorubicin (CPX-351) has been shown to improve overall survival (OS) in older (60-75 years of age) patients with newly ...

3. ascopubs.org ascopubs.org/doi/10.1200/JCO.2022.40.16_suppl.7043

V-FAST master trial: Preliminary results of treatment with ... Preliminary results from the V-FAST trial suggest CPX-351 + MID is feasible, with a manageable safety profile and promising remission rates in adults with ...

4. cda-amc.ca cda-amc.ca/sites/default/files/DRR/2021/PC0237-combined-report-final.pdf

Daunorubicin and Cytarabine Liposome (Vyxeos) Liposomal daunorubicin and cytarabine statistically significantly improved overall survival versus 7 + 3 in a single randomized controlled trial of adult ...

5. sciencedirect.com sciencedirect.com/science/article/pii/S2950328025000585

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 ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10691756/

CPX-351 in FLT3-mutated acute myeloid leukemia - PMC Phase III trial data have shown CPX-351 to be significantly more effective than standard-of-care 7 + 3 chemotherapy (7 days cytarabine; 3 days ...