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

50 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase II trial studies the side effects and how well liposome-encapsulated daunorubicin-cytarabine and gemtuzumab ozogamicin work in treating patients with acute myeloid leukemia that has come back (relapsed) or that does not respond to treatment (refractory) or high risk myelodysplastic syndrome. Drugs used in chemotherapy, such as liposome-encapsulated daunorubicin-cytarabine, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Gemtuzumab ozogamicin is a monoclonal antibody, called gemtuzumab, linked to a toxic agent called calicheamicin. Gemtuzumab ozogamicin attached to CD33 positive cancer cells in a targeted way and delivers calicheamicin to kill them. Giving liposome-encapsulated daunorubicin-cytarabine and gemtuzumab ozogamicin together may be an effective treatment for relapsed or refractory acute myeloid leukemia or high risk myelodysplastic syndrome.

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).

What data supports the effectiveness of the drug Daunorubicin-Cytarabine + Gemtuzumab for Acute Myeloid Leukemia?

Research shows that CPX-351, a combination of daunorubicin and cytarabine, has improved outcomes in patients with acute myeloid leukemia (AML) compared to traditional treatments. Additionally, Gemtuzumab ozogamicin has shown promising results in early trials for AML, particularly in targeting specific leukemia cells. ^{1 2 3 4 5}

Is the treatment Daunorubicin-Cytarabine + Gemtuzumab safe for humans?

Gemtuzumab ozogamicin (Mylotarg) has been studied in various trials and is generally well tolerated, but it can cause serious side effects like liver damage (hepatotoxicity) and veno-occlusive disease (a liver condition). It has an acceptable safety profile when used alone, but combining it with other chemotherapy drugs may increase the risk of these side effects. ^{5 6 7 8 9}

What makes the drug Daunorubicin-Cytarabine + Gemtuzumab unique for treating acute myeloid leukemia?

This drug combines a liposomal formulation of daunorubicin and cytarabine, which maintains a specific ratio to enhance effectiveness, with gemtuzumab ozogamicin, offering a novel approach that improves survival rates and remission compared to traditional chemotherapy. ^{2 3 4 10 11}

Research Team

Yesid Alvarado-Valero, MD

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

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.

I can take care of myself but might not be able to do heavy physical work.

Exclusion Criteria

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.

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

Timeline

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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 (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]

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]

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, 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 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]

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 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]

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. England 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. [2018]

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

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

3. 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]

4. United States 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. [2021]

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

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

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

Pharmacokinetic/Pharmacodynamic Modeling to Support the Re-approval of Gemtuzumab Ozogamicin. [2020]

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

Gemtuzumab ozogamicin: a review of its use in acute myeloid leukaemia. [2022]

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

Approval summary: gemtuzumab ozogamicin in relapsed acute myeloid leukemia. [2022]

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

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

10. England 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. [2021]

11. 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]