M3814 + Chemotherapy for Acute Myeloid Leukemia

Recruiting at14 trial locations

Overseen by Brian Jonas, MD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: National Cancer Institute (NCI)

Must not be taking: CYP inhibitors, CYP inducers

Disqualifiers: CNS involvement, Cardiopulmonary disease, others

No Placebo Group

Trial Summary

What is the purpose of this trial?

This trial is testing a new drug called M3814 combined with three chemotherapy drugs to treat patients with a difficult type of leukemia. The new drug blocks cancer cell growth, and the chemotherapy drugs kill or stop the cancer cells.

Do I need to stop taking my current medications for the trial?

Yes, you may need to stop taking certain medications. The trial requires that you discontinue medications that strongly affect specific liver enzymes (CYP3A4/5, CYP2C9, CYP2C19) and those that affect the heart's electrical activity. You should discuss with the study doctor to see if alternative medications can be used.

What data supports the effectiveness of the drug combination M3814, Cytarabine, Etoposide, and Mitoxantrone for treating acute myeloid leukemia?

Research shows that combinations of mitoxantrone, etoposide, and cytarabine have been used successfully in patients with acute myeloid leukemia who did not respond to initial treatments, achieving complete remission in some cases. These studies suggest that this drug combination can be effective for patients with relapsed or refractory acute myeloid leukemia. ^{1 2 3 4 5}

Is the combination of M3814 and chemotherapy generally safe for humans?

The combination of mitoxantrone, etoposide, and cytarabine has been studied in patients with acute myeloid leukemia, showing that while it can be effective, it also comes with significant side effects like severe myelosuppression (a decrease in bone marrow activity), nausea, infections, and mild heart issues. These treatments are considered to have acceptable toxicity levels for further trials, but they do carry risks of serious side effects. ^{1 2 6 7 8}

What makes the drug M3814 combined with chemotherapy unique for treating acute myeloid leukemia?

The combination of M3814 with chemotherapy for acute myeloid leukemia is unique because it includes mitoxantrone, etoposide, and cytarabine, which have shown effectiveness in patients who are resistant to standard treatments. This regimen is particularly notable for its potential to achieve complete remission in difficult-to-treat cases, offering a new option for patients who have not responded to other therapies. ^{1 3 9 10 11}

Research Team

Brian Jonas, MD

Principal Investigator

City of Hope Comprehensive Cancer Center LAO

Eligibility Criteria

Adults (18+) with acute myeloid leukemia that's relapsed or hasn't responded to treatment, without severe allergies or conditions. They must have acceptable organ function and performance status, no active central nervous system involvement by leukemia, not be on certain medications affecting enzyme CYP3A4/5, and agree to use contraception.

Inclusion Criteria

My cancer did not fully respond to initial treatment cycles aimed at remission.

Serum bilirubin =< 1.5 institutional upper limit of normal (ULN) (For patients with hemolysis, Gilbert's syndrome or liver infiltration with leukemia, serum bilirubin =< 3 x institutional ULN)

My heart is strong enough for treatment, and I haven't had too much of a certain cancer drug.

Exclusion Criteria

I am on blood thinners but my platelet count is above 30,000.

Patients should not have severe and/or uncontrolled medical conditions or other conditions that, in the opinion of the investigator, could affect their participation in the study

I do not have leukemia affecting my brain.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive peposertib orally twice daily on days 2-21, and mitoxantrone, etoposide, and cytarabine intravenously on days 1-5

3 weeks

Daily visits for drug administration

Follow-up

Participants are monitored for safety and effectiveness after treatment

5 years

Follow-up at 30 days, every 3 months for 1 year, then every 6 months thereafter

Treatment Details

Interventions

• Cytarabine (Anti-metabolites)
• Etoposide Phosphate (Topoisomerase I inhibitors)
• M3814 (ATR Inhibitor)
• Mitoxantrone Hydrochloride (Anti-tumor antibiotic)

Trial Overview The trial is testing the effectiveness of adding M3814 to standard chemotherapy drugs (mitoxantrone, etoposide phosphate, cytarabine) in patients with relapsed/refractory acute myeloid leukemia. It aims to find the best dose of M3814 and monitor its side effects when combined with these chemotherapies.

Participant Groups

Group I: Treatment (peposertib, mitoxantrone, etoposide, cytarabine) Experimental Treatment 8 Interventions

Patients receive peposertib PO BID on days 2-21, mitoxantrone IV over 15 minutes, etoposide IV over 60 minutes and cytarabine IV over 60 minutes on days 1-5 in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo ECHO and MUGA during baseline, and blood collection and bone marrow biopsy throughout the study.

Cytarabine is already approved in Canada for the following indications:

Approved in Canada as Cytosar-U for:

• Acute myeloid leukemia
• Acute lymphocytic leukemia
• Chronic myeloid leukemia

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Dr. Douglas R. Lowy

National Cancer Institute (NCI)

Chief Executive Officer since 2023

MD from New York University School of Medicine

Dr. Monica Bertagnolli

National Cancer Institute (NCI)

Chief Medical Officer since 2022

MD from Harvard Medical School

Findings from Research

Mitoxantrone and cytarabine induction therapy achieved a high remission rate of 76% in children with relapsed/refractory acute myeloid leukemia (AML) and 77% in those with secondary AML, with a low induction mortality rate of 3%.

The intensification regimen of cytarabine and etoposide was found to be too toxic, exceeding the acceptable death rate, and should be discontinued, while patients with initial remissions longer than 1 year had a significantly better prognosis, with a 2-year survival rate of 75%.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mitoxantrone and cytarabine induction, high-dose cytarabine, and etoposide intensification for pediatric patients with relapsed or refractory acute myeloid leukemia: Children's Cancer Group Study 2951. Wells, RJ., Adams, MT., Alonzo, TA., et al.[2013]

In a study involving 65 patients with primary refractory or relapsed acute myeloid leukemia (AML), the effectiveness of mitoxantrone and etoposide (ME) was compared to a regimen that included intermediate dose cytarabine (MEC).

The research aimed to determine if adding cytarabine to the ME regimen would increase the rate of complete remissions, although the results of this comparison are not detailed in the abstract.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mitoxantrone and etoposide with or without intermediate dose cytarabine for the treatment of primary induction failure or relapsed acute myeloid leukemia. Trifilio, SM., Rademaker, AW., Newman, D., et al.[2013]

In a study of 155 patients with relapsed or refractory acute myeloid leukemia, the Ara-C couplets regimen showed a higher overall response rate (54.4%) compared to the MEC regimen (43.7%), although this difference was not statistically significant (P = 0.10).

Patients receiving Ara-C couplets had significantly better outcomes in terms of overall survival and progression-free survival, were more likely to proceed to allogeneic stem cell transplant (54.4% vs 31%; P = 0.003), and experienced fewer severe toxicities, such as febrile neutropenia and gastrointestinal issues, indicating a safer profile for Ara-C couplets.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A multi-institutional comparison of mitoxantrone, etoposide, and cytarabine vs high-dose cytarabine and mitoxantrone therapy for patients with relapsed or refractory acute myeloid leukemia. Christian, S., Arain, S., Patel, P., et al.[2022]

In a study of 77 patients with relapsed or refractory acute myeloid leukemia (AML), the chemotherapy regimen of mitoxantrone, etoposide, and cytarabine resulted in a complete response rate of 18% and a median overall survival of 6.8 months, indicating limited efficacy.

The study found no significant differences in response rates or survival between patients with relapsed and refractory disease, highlighting the challenges in treating AML and the need for better therapeutic strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Second-line mitoxantrone, etoposide, and cytarabine for acute myeloid leukemia: a single-center experience. Kohrt, HE., Patel, S., Ho, M., et al.[2013]

In a study of 27 patients with acute myelogenous leukemia (AML) receiving a combination of mitoxantrone, etoposide, and cytosine arabinoside (ara-C), there was significant variability in drug concentrations within leukemic blood cells, indicating that individual responses to treatment can differ widely.

The study found no correlation between the drug concentrations achieved and treatment outcomes or hematological toxicity, suggesting that initial drug levels may not be reliable indicators of how well the treatment will work or the side effects experienced.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics of mitoxantrone, etoposide and cytosine arabinoside in leukemic cells during treatment of acute myelogenous leukemia--relationship to treatment outcome and bone marrow toxicity. Gruber, A., Liliemark, E., Tidefelt, U., et al.[2019]

In a study of 36 patients with refractory and relapsed acute myeloid leukemia (AML), the MAV treatment regimen (mitoxantrone, cytosine arabinoside, and etoposide) resulted in a 58.3% complete remission rate, indicating its effectiveness in this challenging patient population.

The treatment was associated with manageable toxicity, with significant side effects including nausea, mucositis, and septicemia, but overall, the regimen showed a promising balance of efficacy and safety, warranting further clinical trials in untreated AML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mitoxantrone, cytosine arabinoside, and VP-16 in 36 patients with relapsed and refractory acute myeloid leukemia. Link, H., Freund, M., Diedrich, H., et al.[2019]

In a phase II study involving 61 patients with refractory and poor-risk acute myelogenous leukemia (AML), the combination of mitoxantrone and etoposide resulted in a 42.6% complete response rate, demonstrating significant antitumor activity.

While the treatment was effective, it also caused severe myelosuppression and other nonhematologic toxicities, such as stomatitis and nausea, but was generally well-tolerated with manageable side effects, indicating a favorable safety profile for this regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination of mitoxantrone and etoposide in refractory acute myelogenous leukemia--an active and well-tolerated regimen. Ho, AD., Lipp, T., Ehninger, G., et al.[2017]

In a study of 32 patients with refractory acute myeloid leukemia (AML), the MEC regimen (mitoxantrone, etoposide, and cytarabine) resulted in a complete remission rate of 66%, demonstrating significant antileukemic activity.

While the treatment was effective, it caused severe myelosuppression in all patients, leading to high rates of fever and infections, but non-hematologic toxicity was minimal, indicating an acceptable safety profile for this salvage therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mitoxantrone, etoposide, and intermediate-dose cytarabine: an effective and tolerable regimen for the treatment of refractory acute myeloid leukemia. Amadori, S., Arcese, W., Isacchi, G., et al.[2017]

In a study involving older patients (over 55) with newly diagnosed acute myelogenous leukemia (AML), the addition of PSC 833 to a mitoxantrone/etoposide regimen was well tolerated, allowing for a maximum tolerated dose (MTD) of mitoxantrone at 6 mg/m² and etoposide at 60 mg/m².

The treatment resulted in a complete response rate of 50%, indicating that while the dosing had to be reduced to manage toxicity, the combination therapy shows promise, especially for patients with de novo AML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I study of induction chemotherapy for older patients with newly diagnosed acute myeloid leukemia (AML) using mitoxantrone, etoposide, and the MDR modulator PSC 833: a southwest oncology group study 9617. Chauncey, TR., Rankin, C., Anderson, JE., et al.[2019]

References

1. England pubmed.ncbi.nlm.nih.gov

Efficacy of etoposide and mitoxantrone in patients with acute myelogenous leukemia refractory to standard induction therapy and intermediate-dose cytarabine with amsidine. Dutch Hematology-Oncology Working Group for Adults (HOVON). [2015]

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

Mitoxantrone and cytarabine induction, high-dose cytarabine, and etoposide intensification for pediatric patients with relapsed or refractory acute myeloid leukemia: Children's Cancer Group Study 2951. [2013]

3. England pubmed.ncbi.nlm.nih.gov

Mitoxantrone and etoposide with or without intermediate dose cytarabine for the treatment of primary induction failure or relapsed acute myeloid leukemia. [2013]

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

A multi-institutional comparison of mitoxantrone, etoposide, and cytarabine vs high-dose cytarabine and mitoxantrone therapy for patients with relapsed or refractory acute myeloid leukemia. [2022]

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

Second-line mitoxantrone, etoposide, and cytarabine for acute myeloid leukemia: a single-center experience. [2013]

6. England pubmed.ncbi.nlm.nih.gov

Pharmacokinetics of mitoxantrone, etoposide and cytosine arabinoside in leukemic cells during treatment of acute myelogenous leukemia--relationship to treatment outcome and bone marrow toxicity. [2019]

7. Germany pubmed.ncbi.nlm.nih.gov

Mitoxantrone, cytosine arabinoside, and VP-16 in 36 patients with relapsed and refractory acute myeloid leukemia. [2019]

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

Combination of mitoxantrone and etoposide in refractory acute myelogenous leukemia--an active and well-tolerated regimen. [2017]

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

Daunorubicin versus mitoxantrone versus idarubicin as induction and consolidation chemotherapy for adults with acute myeloid leukemia: the EORTC and GIMEMA Groups Study AML-10. [2022]

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

Mitoxantrone, etoposide, and intermediate-dose cytarabine: an effective and tolerable regimen for the treatment of refractory acute myeloid leukemia. [2017]

11. England pubmed.ncbi.nlm.nih.gov

A phase I study of induction chemotherapy for older patients with newly diagnosed acute myeloid leukemia (AML) using mitoxantrone, etoposide, and the MDR modulator PSC 833: a southwest oncology group study 9617. [2019]