Mitoxantrone for Acute Myeloid Leukemia

Overseen By Derek Schatz

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: University of Colorado, Denver

Must be taking: Venetoclax, HMA

Must not be taking: Anthracyclines, Anthracenediones

Disqualifiers: Active CNS AML, Cardiac disease, others

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

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 28

30 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests mitoxantrone, a drug that could help treat individuals with acute myeloid leukemia (AML) who have not responded to initial treatments or have experienced a recurrence. The study aims to determine the optimal dose of mitoxantrone when combined with other drugs like venetoclax and azacitidine. Participants will be divided into groups to evaluate the drug's efficacy and safety. This trial targets individuals with AML who have previously tried venetoclax and HMA treatments but still show signs of the disease. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this potentially groundbreaking therapy.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. It's best to discuss this with the trial team or your doctor.

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

Research has shown that mitoxantrone, a treatment tested for acute myeloid leukemia (AML), presents some known safety concerns. Studies have found that many patients experience significant blood-related side effects. For instance, about 95% of patients had serious issues like anemia (low red blood cell count) and thrombocytopenia (low platelet count), which can increase the risk of bleeding. Additionally, reports indicate a small risk of developing another type of blood cancer, called secondary leukemia, after using mitoxantrone, especially in those treated for multiple sclerosis or other cancers.

While mitoxantrone has demonstrated strong effects against leukemia, these safety considerations are important for potential clinical trial participants. Discussing potential risks and benefits with a healthcare provider is crucial before making a decision. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatment?

Mitoxantrone is unique because it is being explored in combination with venetoclax and azacitidine to determine its maximum tolerated dose for treating acute myeloid leukemia (AML), offering a potentially new approach for patients who have limited options after relapse. Unlike the standard treatments like chemotherapy or standalone venetoclax and hypomethylating agents, this combination aims to enhance the effectiveness of existing therapies by possibly achieving a deeper remission. Researchers are excited about mitoxantrone because it could lead to more effective treatment cycles that target cancer cells more aggressively, which might result in better outcomes for patients who are resistant to first-line therapies.

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

Research has shown that mitoxantrone may help treat acute myeloid leukemia (AML). In studies, patients with newly diagnosed AML had a 67% chance of living for two years without disease progression and a 77.8% chance of overall survival. This trial will explore different cohorts using mitoxantrone in combination with venetoclax and azacitidine. Cohort 1 will determine the maximum tolerated dose (MTD) of mitoxantrone. Subsequent cohorts will use this MTD or a lower dose to assess effectiveness in various patient scenarios. The treatment has also succeeded when adjusted to fit individual needs, leading to remission in many cases, although the disease can return. Overall, mitoxantrone seems to offer a good chance of improving outcomes for AML patients. ^{5 6 7 8 9}

Who Is on the Research Team?

Andrew Kent, MD, PhD

Principal Investigator

University of Colorado, Denver

Are You a Good Fit for This Trial?

This trial is for adults with Acute Myeloid Leukemia (AML) who didn't respond to initial treatment with Venetoclax+HMA or those in remission but still have detectable disease. Key eligibility details are not provided, so interested individuals should inquire further.

Inclusion Criteria

My liver functions are within normal limits, except for Gilbert's syndrome.

I have AML (not APL type) and was treated with venetoclax and HMA.

My condition did not improve after at least one full treatment cycle with venetoclax/HMA.

Exclusion Criteria

Known or suspected hypersensitivity to azacitidine or mannitol.

I have been treated with anthracycline or anthracenedione before.

I do not have any major health issues that could interfere with the study.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose-Escalation

Cohort 1 will undergo a 3+3 dose-escalation study to determine the maximum tolerated dose (MTD) of mitoxantrone with venetoclax+azacitidine.

Up to 5 cycles (28 days each)

Regular visits for dose escalation and monitoring

Expansion Cohorts

After determining the MTD, expansion cohorts will receive treatment with the established dose of mitoxantrone and venetoclax+azacitidine.

Up to 3 cycles (28 days each)

Bone marrow biopsy on day 28 +/- 7 days of each cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment, with bone marrow biopsies every 6 months.

Until disease progression or administration of other therapies

What Are the Treatments Tested in This Trial?

Interventions

• Mitoxantrone

Trial Overview The study tests Mitoxantrone's effectiveness on AML that's resistant to Venetoclax. It starts with dose-finding and then expands into three groups to assess safety and efficacy more broadly.

How Is the Trial Designed?

Group I: Cohort 4 Experimental Treatment 3 Interventions

Subjects in a morphologic remission w/ MRD+ after \>3 cyc of soc ven/HMA will enroll 28-50 days after the previous ven/HMA cyc. Subjects will receive mitox IV days 1-4 at a dose tbd below the MTD from cohort 1; on day 14, the subject will start ven+aza at the dose \& schedule per the soc. On day 42, a BMBX, w/ MRD assessment, will be repeated. If MRD- occurs, subseq cyc will cont to admin ven+aza, at the dose \& schedule per the soc, with the tbd dose of IV mitox on days 1-4, for a max of 3 cyc of mitox. If MRD- does not occur, the next cyc will retain the same schedule \& may escalate the mitox to a dose level tbd \& not exceeding the MTD. If MRD- occurs, 1 add'l cyc of mitox at this dose, w/ ven+aza at the dose \& schedule per the soc, will be given. If MRD- does not occur, the next cyc will retain the same schedule \& may escalate the mitox to a level tbd \& not exceeding the MTD.

Group II: Cohort 3 Experimental Treatment 3 Interventions

Subjects in a morph remission w/ MRD+ after ≤3 cycles of soc ven+HMA will enroll \& receive mitox on days 1-4 at dose tbd that is below the MTD from cohort 1, concurrently w/ven+aza, at the dose \& schedule being soc admin, over a 28-day cycle. A BMBX w/ MRD assessment will be done day 28. If MRD- occurs, subseq treatment cycles will continue to admin ven+aza, at the dose \& schedule being soc admin, w/ the tbd dose of mitox on days 1-4, for max of 3 cycles. If MRD- does not occur, the next cycle may escalate the mitox dose to a level tbd \& not exceeding the MTD, w/ ven+aza at the dose \& schedule being soc admin. If MRD- occurs, subseq treatment cycles will continue to admin ven+aza, at the dose \& schedule being soc admin, with the tbd dose of IV mitox on days 1-4, for a max of 3 cycles. If MRD- does not occur, the next cycle may escalate the mitox to a level tbd \& not exceeding the MTD, w/ ven+aza at the dose \& schedule being admin per the soc. Subjects will not receive \>3 cycles.

Group III: Cohort 2 Experimental Treatment 3 Interventions

After establishing the MTD of mitoxantrone, an expansion cohort will open. 10 subjects refractory to first-line therapy w/venetoclax+HMA, or respond then relapse after first-line therapy w/venetoclax+HMA, will enroll in the study \& receive a subsequent cycle of venetoclax+azacitidine at the dose \& schedule being administered per the standard of care, w/the determined MTD/recommended dose of IV mitoxantrone given days 1-4. Day 28 +/- 7 days of this cycle, a bone marrow biopsy will be repeated. In the absence of a ≥50% blast reduction from baseline, the subject will discontinue the study. If a CR, CRi, MLFS or blast reduction from baseline of ≥50% occurs, the subject can continue sequential cycles of venetoclax+azacitidine at the dose \& schedule being administered per the standard of care, with the MTD/recommended dose of mitoxantrone on days 1-4, up to 3 cycles. No subject will receive \>3 cycles of mitoxantrone.

Group IV: Cohort 1 Experimental Treatment 3 Interventions

Cohort 1 will be a conventional 3+3 dose-escalation study to determine maximum tolerated (MTD) or recommended dose of mitoxantrone when used with venetoclax+azacitidine.

Mitoxantrone is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Novantrone for:

• Acute myeloid leukemia
• Prostate cancer
• Multiple sclerosis

Approved in European Union as Mitoxantrone for:

• Acute myeloid leukemia
• Non-Hodgkin's lymphoma
• Prostate cancer
• Multiple sclerosis

Approved in Canada as Mitoxantrone for:

• Acute myeloid leukemia
• Non-Hodgkin's lymphoma
• Prostate cancer
• Multiple sclerosis

Who Is Running the Clinical Trial?

University of Colorado, Denver

Lead Sponsor

Trials

1,842

Recruited

3,028,000+

The Leukemia and Lymphoma Society

Collaborator

Trials

87

Recruited

26,200+

Published Research Related to This Trial

Mitoxantrone, a synthetic drug used in treating acute leukemia, showed a 48% overall response rate and a 25% complete remission rate in a five-day treatment regimen, indicating its potential effectiveness.

The drug demonstrated limited toxicity compared to traditional anthracycline antibiotics, with only mild side effects like alopecia and nausea, although the short duration of trials did not allow for assessment of cardiac toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mitoxantrone in relapsed and refractory acute leukemia. Prentice, HG., Robbins, G., Ma, DD., et al.[2018]

Mitoxantrone, combined with other chemical agents, showed a complete response rate of 44.7% in untreated adult acute myeloid leukemia patients and 27.5% in those who were relapsing or resistant, indicating its effectiveness as a first-line treatment.

While mitoxantrone is effective, it can cause significant side effects, particularly bone marrow depression leading to fever and bleeding in 40.4% and 24.3% of patients, respectively, along with liver damage occurring in 31.8% of cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[A study of mitoxantrone with other chemical agents in treating 126 cases of adult acute myeloid leukemia]. Chen, Y., Fu, J., Du, X., et al.[2014]

In a phase II study involving 35 patients with acute leukemia, mitoxantrone demonstrated significant efficacy, achieving a 46.2% complete remission rate in untreated patients and a 18.2% rate in previously treated patients.

While 73% of patients experienced mild and reversible gastrointestinal side effects, the overall safety profile was acceptable, suggesting that mitoxantrone is a promising treatment option for acute leukemia, warranting further investigation in a phase III study.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase II study of mitoxantrone in acute leukemia. Masaoka, T., Shibata, H., Oguma, S., et al.[2019]

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]

Mitoxantrone has shown complete remission rates of 14-44% in refractory acute myelogenous leukemia (AML) and 46-79% in relapsed patients, indicating its efficacy in treating this type of cancer.

The drug is well-tolerated, offering a better quality of life compared to standard treatments, and is now considered a valuable option in first-line therapy for AML, despite not being clearly superior to anthracyclines in newly diagnosed cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mitoxantrone in the treatment of acute myelogenous leukemia: a review. Thomas, X., Archimbaud, E.[2019]

In a trial involving 49 patients with refractory or relapsed acute myelocytic leukemia (AML), the combination of mitoxantrone and cytosine arabinoside (ara-C) resulted in a 62.5% response rate in patients experiencing their first relapse, indicating significant efficacy for this treatment.

The treatment was well tolerated with minimal side effects, and no cardiac toxicity was observed, although transient hepatic dysfunction occurred in over 50% of treatment courses, suggesting a favorable safety profile for mitoxantrone plus ara-C in previously untreated AML patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mitoxantrone and ara-C in previously treated patients with acute myelogenous leukemia. Paciucci, PA., Dutcher, JP., Cuttner, J., et al.[2013]

Mitoxantrone is an effective and well-tolerated treatment for acute leukemia, achieving remission in conditions like acute myelogenous leukemia (AML) and acute lymphoblastic leukemia (ALL) at doses of 50-60 mg/m².

The drug's manageable toxicity allows it to be combined with other therapies, and future trials will explore high-dose mitoxantrone in combination with cytarabine to enhance treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Current status of mitoxantrone combination chemotherapy programs: a personal view. Arlin, ZA.[2019]

In a study of 24 patients with acute leukemia or blast crisis of chronic myelocytic leukemia, mitoxantrone treatment led to complete remission in 5 out of 20 evaluable patients, indicating its potential efficacy in this challenging patient population.

While mitoxantrone caused moderate to severe side effects like bone marrow suppression and mucositis, it did not result in cardiotoxicity, suggesting a relatively safe profile for further investigation in combination therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mitoxantrone in the treatment of relapsed and refractory acute leukemia. Meyer, P., Ho, AD., Ehninger, G., et al.[2019]

In a phase II trial involving 167 patients with relapsed or refractory acute myeloid leukemia (AML), the combination of diaziquone and mitoxantrone showed the highest complete remission (CR) rate of 30%, particularly in patients experiencing their first relapse, who had a CR rate of 40%.

The trial also noted significant non-hematologic toxicity, with 24% of patients on diaziquone experiencing severe stomatitis, highlighting the need for careful monitoring of side effects in future studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An evaluation of combinations of diaziquone, etoposide and mitoxantrone in the treatment of adults with relapsed or refractory acute myeloid leukemia: results of 8722, a randomized phase II study conducted by Cancer and Leukemia Group B. Lee, EJ., George, SL., Amrein, PC., et al.[2019]

Mitoxantrone significantly improved the complete remission (CR) rate and disease-free survival (DFS) in patients with acute myeloid leukemia (AML) compared to daunorubicin, based on a review of 12 randomized controlled trials involving 4583 patients.

There was no significant difference in death during induction therapy or overall survival (OS) between mitoxantrone and daunorubicin, suggesting that while mitoxantrone may enhance remission rates, it does not increase the risk of mortality during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of Dose Ratio on Mitoxantrone and Daunorubicin in Acute Myeloid Leukemia: A Systematic Review and Meta-analysis of Randomized Controlled Trials. Deng, L., Zhang, C., Ying, S., et al.[2021]

In a study of 74 patients with newly diagnosed acute myeloid leukemia (AML) who did not achieve complete remission after initial treatment, a second course of therapy with mitoxantrone and etoposide resulted in a 39% complete remission rate.

The treatment was associated with manageable toxicity, as only 14% of patients experienced infectious complications and no severe hepatic toxicities were reported, indicating that this regimen is a viable option for patients who do not respond to first-line therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mitoxantrone and etoposide in patients with newly diagnosed acute myeloid leukemia with persistent leukemia after a course of therapy with cytarabine and idarubicin. McHayleh, W., Sehgal, R., Redner, RL., et al.[2019]

Citations

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Real-world effectiveness of mitoxantrone hydrochloride ... This study evaluated the real-world efficacy and safety of Lipo-MIT-containing regimens in the treatment of acute myeloid leukemia (AML).

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NOVANTRONE mitoXANTRONE for injection concentrate Secondary acute myelogenous leukemia (AML) has been reported in multiple sclerosis and cancer patients treated with mitoxantrone. In a cohort of mitoxantrone ...

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Efficacy and safety of mitoxantrone hydrochloride liposome ... Moreover, 95% patients experienced grade 3/4 hematologic treatment-related adverse events (TRAEs), including anemia (60.0%), thrombocytopenia ( ...

8. ashpublications.org ashpublications.org/blood/article/144/Supplement%201/7318/528707/The-Efficacy-and-Safety-of-the-Addition-of

The Efficacy and Safety of the Addition of Mitoxantrone ... Mitoxantrone, a synthetic anthracycline agent, has demonstrated superior anti-leukemic efficacy in acute myelogenous leukemia (AML).

9. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0145212624000341

Efficacy and safety of mitoxantrone, etoposide, and ... Research paper. Efficacy and safety of mitoxantrone, etoposide, and cytarabine for treatment of relapsed or refractory acute myeloid leukemia.