M3814 + Chemotherapy for Acute Myeloid Leukemia

Not currently recruiting at 15 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: National Cancer Institute (NCI)

Must not be taking: CYP inhibitors, CYP inducers

Disqualifiers: CNS involvement, Cardiopulmonary disease, others

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

Compensation: Varies

Number of Visits: 30

Duration: 3 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine the best dose and understand the side effects of a new drug, M3814 (also known as Peposertib, an experimental treatment), when combined with a chemotherapy mix for acute myeloid leukemia (AML) that has returned or isn't responding to treatment. M3814 stops cancer cells from growing, while the chemotherapy drugs aim to kill the cancer cells or prevent their spread. People with AML that has returned after treatment or does not respond to standard treatments could be suitable candidates. As a Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new treatment.

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.

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

Earlier studies have shown that M3814, also known as peposertib, works with chemotherapy drugs to inhibit the growth of leukemia cells. Researchers have found that M3814 can enhance cancer treatments by aiding in the destruction of cancer cells. Although these studies have focused on M3814's efficacy, information on its side effects remains limited.

This trial is in its early stages, so researchers are primarily focused on assessing the treatment's safety and determining the optimal dose. As an early phase trial, there may be limited safety data, but the design ensures careful monitoring for any side effects.

The chemotherapy drugs used in the trial—mitoxantrone, etoposide, and cytarabine—are well-established in cancer treatments. These drugs can cause side effects, and the trial will evaluate how adding M3814 influences these effects.

Prospective participants should note that the trial's main goal is to ensure safety and identify the correct dose of M3814. The research team will closely monitor participants for any adverse effects. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this treatment for acute myeloid leukemia (AML) because it introduces peposertib, a new player in the battle against cancer. Unlike standard treatments that focus on killing rapidly dividing cells, peposertib works by inhibiting DNA repair mechanisms in cancer cells, making them more vulnerable to chemotherapy. This unique mechanism could enhance the effectiveness of traditional drugs like cytarabine, etoposide, and mitoxantrone. By targeting the cancer cells' ability to repair, this combination might offer a more powerful punch against AML than existing therapies.

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

Research has shown that M3814, also known as peposertib, might inhibit cancer cell growth in acute myeloid leukemia (AML) by blocking essential enzymes. In this trial, participants will receive M3814 combined with chemotherapy drugs such as mitoxantrone, etoposide, and cytarabine. Studies have found that this combination can reduce the likelihood of leukemia cells growing or spreading. In animal studies of AML, this combination performed better than chemotherapy alone. This suggests that M3814 could enhance current AML treatments, potentially offering improved outcomes for patients with difficult-to-treat forms of the disease. ^{1 2 3 6 7}

Who Is on the Research Team?

Brian Jonas, MD

Principal Investigator

City of Hope Comprehensive Cancer Center LAO

Are You a Good Fit for This Trial?

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.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• Cytarabine
• Etoposide Phosphate
• M3814
• Mitoxantrone Hydrochloride

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.

How Is the Trial Designed?

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 United States, European Union, Canada for the following indications:

Approved in United States as Cytosar-U for:

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

Approved in European Union as Depocyt for:

• Lymphomatous meningitis

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+

Published Research Related to This Trial

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]

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 2,157 adult patients with newly diagnosed acute myeloid leukemia (AML), the overall complete remission (CR) rate was similar (69%) across three different anthracyclines: daunorubicin, idarubicin, and mitoxantrone.

However, patients treated with daunorubicin had significantly shorter disease-free survival (DFS) rates compared to those treated with idarubicin or mitoxantrone, suggesting that using either idarubicin or mitoxantrone may enhance long-term chemotherapy efficacy for AML.

NCBI (Pubmed)

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. Mandelli, F., Vignetti, M., Suciu, S., et al.[2022]

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 of 37 newly diagnosed acute myeloid leukemia (AML) patients who did not achieve complete remission after initial chemotherapy, 32.4% attained complete remission after treatment with mitoxantrone and etoposide, particularly those who showed some responsiveness to prior therapies.

The median duration of remission for responders was over 15 months, indicating that even patients with a poor prognosis can achieve durable remission with this treatment, although the therapy was associated with significant hematologic toxicity.

NCBI (Pubmed)

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). Daenen, S., Löwenberg, B., Sonneveld, P., et al.[2015]

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 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 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 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 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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8190296/

DNA-PK inhibitor peposertib enhances p53-dependent ... Results. M3814 enhances ATM/p53 signaling in response to radiation in acute leukemia cells. M3814 intervenes in the response of cancer cells to ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT03983824

Testing the Addition of an Anti-cancer Drug, M3814, to ... Giving M3814 in combination with mitoxantrone, etoposide, and cytarabine may lower the chance of the acute myeloid leukemia growing or spreading. Detailed ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7031257/

DNA-PK Inhibitor, M3814, as a New Combination Partner of ... Combination of M3814 with Mylotarg in two AML xenograft models, MV4-11 and HL-60, demonstrated increased efficacy and significantly improved ...

4. withpower.com withpower.com/trial/phase-1-leukemia-myeloid-9-2019-4c156

M3814 + Chemotherapy for Acute Myeloid Leukemia This trial is testing a new drug called M3814 combined with three chemotherapy drugs to treat patients with a difficult type of leukemia.

5. trialx.com trialx.com/clinical-trials/listings/269557/testing-the-addition-of-an-anti-cancer-drug-m3814-to-the-usual-treatment-mitoxantrone-etoposide-and-cytarabine-for-relapsed-or-refractory-acute-myeloid-leukemia/

Testing the Addition of an Anti-cancer Drug, M3814, to ... Giving M3814 in combination with mitoxantrone, etoposide, and cytarabine may lower the chance of the acute myeloid leukemia growing or spreading ...

6. sciencedirect.com sciencedirect.com/science/article/pii/S2211383521002781

DNA-PK inhibition by M3814 enhances chemosensitivity in ... The present study aims to systematically evaluate the efficacy and safety of a novel DNA-PK inhibitor M3814 in synergy with chemotherapies on NSCLC. We ...

7. mdpi.com mdpi.com/2072-6694/16/1/189

DNA-Dependent Protein Kinase Inhibitor Peposertib ... This study focuses on finding improved treatment strategies for advanced or metastatic synovial sarcoma, which is a rare and aggressive type ...