Daunorubicin-Cytarabine + Gemtuzumab for Acute Myeloid Leukemia

Overseen By Yesid Alvarado-Valero, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: CPX-351, Gemtuzumab

Disqualifiers: Uncontrolled CNS pathology, Active infections, 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: Unknown

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the effectiveness of combining two treatments: liposome-encapsulated daunorubicin-cytarabine (a chemotherapy drug) and gemtuzumab ozogamicin (also known as Mylotarg, an antibody-drug conjugate), for certain blood cancers. It targets patients with acute myeloid leukemia (AML) that has relapsed or is refractory, and those with high-risk myelodysplastic syndrome (MDS), a pre-cancerous blood condition. The trial examines the side effects and effectiveness of these drugs, which kill cancer cells in different ways. This trial may suit those with relapsed or refractory AML or high-risk MDS who have a specific marker on their cancer cells called CD33. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

The trial protocol does not specify whether you need to stop taking your current medications. However, it mentions that prior chemotherapy, radiotherapy, or investigational therapy should not have been received within 2 weeks before starting the study drugs, except for certain medications like cytarabine or hydroxyurea, which do not require a washout period (time without taking certain medications).

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

Research has shown that gemtuzumab ozogamicin is generally safe for patients with acute myeloid leukemia (AML). Studies indicate it does not significantly increase the risk of serious issues like liver problems or treatment-related death when used correctly. One study found that it effectively targets and kills cancer cells without causing severe side effects.

For liposome-encapsulated daunorubicin-cytarabine, research has shown it to be well-tolerated. It has been associated with better survival rates compared to traditional treatments in older patients with AML. Patients typically handle the treatment without experiencing severe or unexpected side effects.

Both treatments have shown promise in previous research, suggesting they are relatively safe for patients to consider in clinical trials. However, as with any medical treatment, risks may exist, so discussing these with a healthcare provider is essential. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of gemtuzumab ozogamicin with liposome-encapsulated daunorubicin-cytarabine for treating Acute Myeloid Leukemia (AML) because it introduces unique features not seen in traditional treatments like standard chemotherapy. This treatment combines a targeted therapy, gemtuzumab ozogamicin, which directly targets leukemia cells using an antibody-drug conjugate, with a liposome-encapsulated formulation of daunorubicin and cytarabine, enhancing delivery and potentially reducing side effects. Unlike conventional chemotherapy that affects both healthy and cancerous cells, this approach aims to increase efficacy by concentrating the attack on cancer cells while minimizing collateral damage to healthy cells. This innovative delivery method and targeted action are what make this treatment stand out and offer hope for improved outcomes in AML therapy.

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

In this trial, participants will receive a combination of gemtuzumab ozogamicin and CPX-351 (liposome-encapsulated daunorubicin-cytarabine). Research has shown that gemtuzumab ozogamicin effectively treats acute myeloid leukemia (AML), particularly when the disease recurs after treatment, with about 31.6% of patients responding. This treatment targets cancer cells directly and delivers a substance that kills them. Studies indicate that CPX-351, a combination of two chemotherapy drugs in a special form, helps older patients with AML live longer compared to traditional treatments. Both treatments have shown promise in managing AML, offering hope for patients with difficult-to-treat forms of the disease. ^{2 3 4 5 6}

Who Is on the Research Team?

Yesid Alvarado-Valero, MD

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults with relapsed or refractory acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome, who are CD33 positive and have an ECOG performance status of <=2. They must not be pregnant, agree to use contraception, and have acceptable liver and kidney function. Excluded are those with significant CNS issues, uncontrolled infections, recent transplants with GvHD, prior extensive anthracycline treatment (>200 mg/m^2), active hepatitis B/C or HIV.

Inclusion Criteria

My high-risk MDS worsened after hypomethylating treatment.

I have AML that developed after treatment for MDS or CMML.

Total serum bilirubin =< 2 x upper limit of normal (ULN). Patients with known Gilbert's syndrome may have a total bilirubin up to =< 3 x ULN

Exclusion Criteria

Other severe, uncontrolled acute or chronic medical or psychiatric condition or laboratory abnormality that in the opinion of the investigator may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and/or would make the patient inappropriate for enrollment into this study

I haven't had cancer treatment in the last 2 weeks, except for specific emergency treatments.

I have recovered from the side effects of my previous treatments.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction Cycle

Patients receive liposome-encapsulated daunorubicin-cytarabine and gemtuzumab ozogamicin. Treatment repeats every 28 days for up to 2 cycles.

8 weeks

Consolidation Cycle

Patients receive liposome-encapsulated daunorubicin-cytarabine and gemtuzumab ozogamicin. Treatment repeats every 28 days for up to 2 cycles.

8 weeks

Maintenance Cycle

Patients receive gemtuzumab ozogamicin. Treatment repeats every 6 weeks for up to 6 cycles.

36 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

14 months

What Are the Treatments Tested in This Trial?

Interventions

• Gemtuzumab Ozogamicin
• Liposome-encapsulated Daunorubicin-Cytarabine

Trial Overview

The trial tests a combination of liposome-encapsulated daunorubicin-cytarabine (a chemotherapy drug) and gemtuzumab ozogamicin (an antibody linked to a toxin targeting cancer cells). It aims to see how well these drugs treat patients whose AML has returned after treatment or doesn't respond at all.

How Is the Trial Designed?

Group I: Treatment (CPX-351, gemtuzumab ozogamicin) Experimental Treatment 3 Interventions

INDUCTION CYCLE: Patients receive liposome-encapsulated daunorubicin-cytarabine IV over 90 minutes on days 1, 3, and 5 of cycle 1 and days 1 and 3 of cycle 2 and gemtuzumab ozogamicin IV over 120 minutes on day 1. Treatment repeats every 28 days for up to 2 cycles in the absence of unacceptable toxicity. CONSOLIDATION CYCLE: Patients receive liposome-encapsulated daunorubicin-cytarabine IV over 90 minutes on days 1 and 3 and gemtuzumab ozogamicin over 120 minutes on day 1. Treatment repeats every 28 days for up to 2 cycles in the absence of unacceptable toxicity. MAINTENANCE CYCLE: Patients receive gemtuzumab ozogamicin IV over 120 minutes on day 1. Treatment repeats every 6 weeks for up to 6 cycles in the absence of disease progression or unacceptable toxicity.

Gemtuzumab Ozogamicin is already approved in United States, European Union for the following indications:

Approved in United States as Mylotarg for:

• Acute myeloid leukemia (AML)

Approved in European Union as Mylotarg for:

• Acute myeloid leukemia (AML)

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

CPX-351, a liposomal formulation of cytarabine and daunorubicin, showed high efficacy in treating childhood acute lymphoblastic leukemia (ALL) xenograft models, achieving complete responses in four B-lineage models and a partial response in one T-lineage model.

The drug was administered at a dose that resulted in plasma drug exposures similar to those seen in patients with acute myeloid leukemia (AML), indicating its potential effectiveness and safety for use in pediatric leukemia treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of CPX-351, (cytarabine:daunorubicin) liposome injection, against acute lymphoblastic leukemia (ALL) xenograft models of the Pediatric Preclinical Testing Program. Carol, H., Fan, MM., Harasym, TO., et al.[2021]

In a phase II trial involving 82 patients with high-risk relapsed acute myeloid leukaemia (AML), none of the treatment regimens achieved the target of a 40% complete remission rate, with response rates of only 12% for Arm A, 7% for Arm B, and 4% for Arm C.

Despite the lack of efficacy, the treatments did not result in unexpected toxicities, indicating that while the regimens were safe, they were not effective enough to justify further research.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Failure of three novel regimens to improve outcome for patients with relapsed or refractory acute myeloid leukaemia: a report from the Eastern Cooperative Oncology Group. Litzow, MR., Othus, M., Cripe, LD., et al.[2021]

Gemtuzumab ozogamicin is an effective treatment for patients with CD33 positive acute myeloid leukemia (AML) in first relapse, showing an overall response rate of 30% in Phase 2 trials involving 142 patients, with a complete response rate of 16%.

While it offers a potentially better tolerability profile compared to conventional chemotherapy, it carries risks of significant side effects, including myelosuppression, hepatotoxicity, and severe allergic reactions, necessitating careful patient monitoring and management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Approval summary: gemtuzumab ozogamicin in relapsed acute myeloid leukemia. Bross, PF., Beitz, J., Chen, G., 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]

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]

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]

Gemtuzumab ozogamicin, the first antibody-drug conjugate approved for CD33-positive acute myeloid leukemia (AML), was initially withdrawn from the market due to lack of clinical benefit, but later studies with new dosing regimens demonstrated its efficacy.

Pharmacokinetic modeling revealed significant relationships between drug exposure and clinical outcomes, leading to its full FDA approval in 2017 for both newly diagnosed and relapsed AML in adults and children aged 2-17 years.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetic/Pharmacodynamic Modeling to Support the Re-approval of Gemtuzumab Ozogamicin. Fostvedt, LK., Hibma, JE., Masters, JC., et al.[2020]

Gemtuzumab ozogamicin is an effective treatment for older patients (≥60 years) with CD33-positive acute myeloid leukaemia (AML) in first relapse, achieving complete remission in about 25% of cases.

While it has a tolerability profile that is generally acceptable, serious side effects like hepatotoxicity can occur, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gemtuzumab ozogamicin: a review of its use in acute myeloid leukaemia. Fenton, C., Perry, CM.[2022]

Gemtuzumab ozogamicin (Mylotarg) is an effective treatment for relapsed acute myeloid leukemia (AML), targeting CD33 on leukemic cells and using a potent cytotoxic agent to induce cell death, with promising results from early phase I/II studies.

While it shows significant efficacy, there are concerns about potential adverse effects, including veno-occlusive disease and increased liver toxicity, which are important considerations as it is being tested in new patient populations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Early phase I/II trials with gemtuzumab ozogamicin (Mylotarg) in acute myeloid leukemia. Nabhan, C., Tallman, MS.[2019]

Gemtuzumab ozogamicin (Mylotarg) is being studied in ongoing trials for its safety and efficacy in treating acute myeloid leukemia (AML) patients, both newly diagnosed and those with relapsed or refractory disease.

While gemtuzumab ozogamicin shows an acceptable toxicity profile as a standalone treatment, there is a notable risk of veno-occlusive disease when used in combination with chemotherapy, highlighting the need for careful monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trials with gemtuzumab ozogamicin (Mylotarg) combined with chemotherapy regimens in acute myeloid leukemia. Stadtmauer, EA.[2019]

In a study involving 53 AML patients, CPX-351 demonstrated significant cytotoxic activity, particularly in cases with the FLT3-ITD mutation, which were five times more sensitive to the treatment.

The effectiveness of CPX-351 was consistent across various leukemia types, with its cellular uptake correlating with its cytotoxic potency, suggesting that ex vivo testing could help identify AML patients who would benefit most from this therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CPX-351 exhibits potent and direct ex vivo cytotoxicity against AML blasts with enhanced efficacy for cells harboring the FLT3-ITD mutation. Gordon, MJ., Tardi, P., Loriaux, MM., et al.[2018]

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