Mitoxantrone for Acute Myeloid Leukemia
Recruiting in Palo Alto (17 mi)
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
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
Breakthrough Therapy
Approved in 3 Jurisdictions
Trial Summary
What is the purpose of this trial?This is an open label, phase 1 study for AML subjects with relapsed or refractory disease or subjects in morphologic remission with MRD+ after first line therapy with venetoclax+HMA. A preliminary dose-finding cohort will be followed by 3 expansion cohorts.
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.
What data supports the effectiveness of the drug Mitoxantrone for treating Acute Myeloid Leukemia?
Research shows that Mitoxantrone, when combined with other drugs like etoposide, can help some patients with acute myeloid leukemia achieve complete remission, especially those who have not responded to initial treatments. In one study, 39% of patients achieved complete remission with this combination, suggesting it can be an effective second-line treatment.
12345Is mitoxantrone safe for treating acute myeloid leukemia?
Mitoxantrone has been used in treating acute leukemia and is generally considered to have manageable side effects, such as nausea, hair loss, and mild gastrointestinal issues. Some studies noted no heart-related side effects, but others were too short to fully assess this risk. Overall, it is seen as a relatively safe option compared to similar drugs.
16789How is the drug Mitoxantrone unique in treating acute myeloid leukemia?
Mitoxantrone is unique because it is an intravenous drug that is structurally related to anthracycline antibiotics but offers better tolerance and incomplete cross-resistance with other similar drugs. It is effective in inducing remission in relapsed or refractory acute myeloid leukemia (AML) and can be combined with other agents like cytarabine for enhanced effectiveness, with a tolerable side effect profile.
4691011Eligibility Criteria
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.
+8 more
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.
+6 more
Trial Timeline
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
Participant Groups
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.
4Treatment groups
Experimental Treatment
Group I: Cohort 4Experimental Treatment3 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 3Experimental Treatment3 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 2Experimental Treatment3 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 1Experimental Treatment3 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
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
University of Colorado HospitalAurora, CO
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Who Is Running the Clinical Trial?
University of Colorado, DenverLead Sponsor
The Leukemia and Lymphoma SocietyCollaborator
References
[A study of mitoxantrone with other chemical agents in treating 126 cases of adult acute myeloid leukemia]. [2014]To estimate the effect of mitoxantrone with other chemical agents in treating adult acute myeloid leukemia.
Effect of Dose Ratio on Mitoxantrone and Daunorubicin in Acute Myeloid Leukemia: A Systematic Review and Meta-analysis of Randomized Controlled Trials. [2021]To investigate the effects of mitoxantrone and daunorubicin in induced chemotherapy on complete remission (CR), death during induction therapy, overall survival (OS), disease-free survival (DFS), and relapse in patients of all ages with acute myeloid leukemia (AML).
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]Thirty-seven newly diagnosed patients with acute myeloid leukemia (AML) who were not in complete remission (CR) after induction chemotherapy with cytarabine and daunorubicin followed by intermediate-dose cytarabine and amsacrine, were treated with mitoxantrone and etoposide in a prospective, open multicenter study. The aim was to examine the efficacy and the toxicity of mitoxantrone and etoposide in a patient population with bad prognosis because of refractoriness to two standardized induction courses. Twelve patients attained CR (32.4%). Responders were found only among the patients with documented susceptibility (i.e. partial remission) to the previous therapy. In responding patients the median remission duration and disease-free survival was 15+ months (range 3-52+). Toxicity was mainly hematologic and characterized by prolonged hypoplasia; one patient died in aplasia. Granulocytes and platelets recovered unexpectedly early in six of 22 non-responders. This study suggests that AML patients refractory to two standardized chemotherapy courses can still attain a durable CR after an additional course, here with mitoxantrone and etoposide, provided they show some responsiveness to the previously given cytostatic drugs.
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. [2019]A phase II trial was conducted to determine which of the three possible two-drug combinations of diaziquone, etoposide and mitoxantrone was associated with the highest response rate in patients with relapsed or refractory acute myeloid leukemia (AML). Of the 167 patients (median age 55) with AML who entered the trial, 123 were in first relapse, 22 were in second relapse and 22 had failed to achieve complete remission (CR). CR rates were 30% for diaziquone and mitoxantrone, and 23% for the other two combinations (mitoxantrone/etoposide and diaziquone/etoposide), NS. Patients in first relapse had higher CR rates (40%) than other patients. Of the 166 patients who actually received treatment, 43 died before having either a CR or persistent leukemia. Non-hematologic toxicity was primarily mucosal with 24% of patients experiencing grade 3 or greater stomatitis on the two diaziquone arms, and 43% on the mitoxantrone/etoposide arm. The combination of diaziquone and mitoxantrone was selected for further testing in patients with AML.
Mitoxantrone and etoposide in patients with newly diagnosed acute myeloid leukemia with persistent leukemia after a course of therapy with cytarabine and idarubicin. [2019]The most effective regimen for patients with acute myeloid leukemia (AML) who do not achieve complete remission (CR) after one course of cytarabine and an anthracycline has not been extensively studied. We evaluated retrospectively the efficacy, toxicity, and prognostic factors for the achievement of CR following mitoxantrone and etoposide in 74 patients with newly diagnosed AML who did not respond to one course of therapy with cytarabine and idarubicin. CR was achieved in 39% of patients; 14% died of infectious complications; no grade 3 or 4 hepatic toxicities were observed. Median duration of overall survival was 9.0 months (95% CI 5.8-14.9 months). The median duration of relapse-free survival was 11.0 months (95% CI: 9.0-19.3 months). A lower CR rate was associated with unfavorable risk status at diagnosis and higher percent blasts. Our data suggest that the combination of etoposide and mitoxantrone is an effective second-course therapy in patients with newly diagnosed AML.
Mitoxantrone in the treatment of relapsed and refractory acute leukemia. [2019]Twenty-four patients with acute leukemia or blast crisis (BC) of chronic myelocytic leukemia (CML) in relapse or refractory to standard chemotherapy, were eligible for treatment with mitoxantrone. Mitoxantrone (Novantrone; dihydroxyanthracenedione) was administered in a dose of 8-13 mg/m2 on five consecutive days. Five of 20 evaluable patients were induced into complete remission, one patient achieved a partial remission. Side-effects included moderate to severe bone marrow suppression, moderate mucositis and hair loss. No cardiotoxicity was observed. We believe that mitoxantrone is an active agent in the treatment of acute leukemia and suggest further studies in combination chemotherapy.
Mitoxantrone in relapsed and refractory acute leukemia. [2018]Mitoxantrone is a relatively new synthetic anthracenedione derivative with intercalating properties. An in vitro study with established leukemia cell lines indicated that DNA strand breaks were caused by mitoxantrone; when these were progressive after the initial insult, the cell line was sensitive to the drug. Clinical trials involved patients with relapsed and/or refractory acute leukemia. None of the patients receiving a single slow infusion of mitoxantrone achieved a complete remission. A five day treatment regimen produced an overall response rate of 48% with a complete remission rate of 25%. Toxicity in these preliminary studies was limited compared to that expected with the anthracycline antibiotics. Alopecia and nausea were the only commonly observed side effects. The trials were too short, however, to evaluate possible cardiac toxicity. Mitoxantrone is an acute and relatively nontoxic agent that merits further study to identify its role in the first line therapy of acute leukemia; such studies are underway.
A phase II study of mitoxantrone in acute leukemia. [2019]A phase II study of mitoxantrone (Novantrone; dihydroxyanthracenedione) was conducted in 35 patients (22 male: 13 female) with acute leukemia. There were 35 evaluable cases with a mean age of 34 (range 8-61). Twenty-eight patients had acute non-lymphocytic leukemia (ANLL) and seven had acute lymphocytic leukemia (ALL). Mitoxantrone was administered intravenously 2-4 mg/m2 daily for five days and after the nadir a further 2-3 doses were added if necessary. All previously treated cases (22 patients) had been treated with anthracyclines; 13 had no previous treatment. Out of the 13 untreated cases there were six complete remissions (CRs) (46.2%) and five partial remissions (PRs) (38.5%), while out of 22 pretreated cases, four CRs (18.2%) and five PRs (22.7%) were obtained. In seven of the untreated cases the decrease of leukemic cells and neutrophil leukocytes were analysed. Mitoxantrone showed a longer duration of decrease and higher log decrease of leukemic cells in the bone marrow than daunorubicin or cytosine arabinoside. Seventy-three percent of patients showed gastrointestinal disturbances such as nausea or loss of appetite. In 38.1% SGPT elevation and in 8.8% abnormal ECG findings were observed. All side-effects were mild and reversible. From this data mitoxantrone seems a very promising agent in the treatment of acute leukemia and a phase III study is now being carried out.
Mitoxantrone in the treatment of acute myelogenous leukemia: a review. [2019]Mitoxantrone is an intravenous anthracenedione structurally related to the anthracycline antibiotics. This drug has been used for several years in the treatment of acute myelogenous leukemia (AML). Its use has been based on its pharmacological properties, its incomplete cross-resistance with other intercalating agents, and its better tolerance as predicted by preclinical studies. Various treatment schedules, using mitoxantrone alone and in combination with other antileukemic agents, have been used in clinical trials. Complete remission (CR) rates ranged from 14 to 44% in refractory AML and from 46 to 79% in relapsed patients. Although a superiority of mitoxantrone over anthracyclines has not been clearly demonstrated in newly diagnosed patients, mitoxantrone is now recognized as a useful drug in first line therapy. The tolerability profile of mitoxantrone indicates that it offers patients an acceptable quality of life compared with standard treatment regimens, and could be a good alternative to the anthracyclines. The development of new therapeutic concepts aiming at an optimization of its use is now in process and first results are promising.
Mitoxantrone and ara-C in previously treated patients with acute myelogenous leukemia. [2013]Mitoxantrone is a synthetic aminoanthraquinone we have previously reported to be effective for patients with acute leukemia in relapse. We presently report the results of a trial of mitoxantrone in combination with cytosine arabinoside (ara-C) in patients with refractory or relapsed acute myelocytic leukemia (AML). Forty-nine patients, 24 males and 25 females, with a median age of 56, of whom 32 were in first relapse, four were in second relapse, and 13 had primarily refractory AML, were treated with mitoxantrone 10 mg/m2 daily for 3 days and ara-C 100 mg/m2 daily by continuous infusion for 7 days. Twenty patients (62.5%) with first relapse AML achieved M1 marrow, whereas only two of 13 patients with refractory AML did; none of four patients with more than one prior remission responded. Marrow recovery was observed in a median of 32 days. Remissions were maintained with monthly ara-C plus mitoxantrone alternating with ara-C plus 6-TG; median duration of remission was 8 months and two patients are in continuing remission at 8 and 16 months. Treatment was well tolerated, with minimal nausea and vomiting, diarrhea, drug-induced mucositis. Treatment-related cardiac toxicity was not observed. Transient hepatic dysfunction was observed in greater than 50% of courses. Mitoxantrone plus ara-C is an active combination with great promise for the therapy of previously untreated patients with AML.
Current status of mitoxantrone combination chemotherapy programs: a personal view. [2019]Mitoxantrone is effective therapy in acute leukemia. As a single agent it is well tolerated and at doses of 50-60 mg/m(2) induces remission in acute myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL) and blastic transformation of chronic myelogenous leukemia (CML). Its toxicity profile suggested that it could be combined readily with other agents, and over the last five years effective combinations incorporating mitoxantrone have been developed. Future trials will be designed to take advantage of our ability to deliver high doses of mitoxantrone without appreciable toxicity and to combine it with the more effective doses of cytarabine.