Pevonedistat for Myelodysplastic Syndromes

Phase-Based Estimates
1
Effectiveness
1
Safety
University of Minnesota/Masonic Cancer Center, Minneapolis, MN
Myelodysplastic Syndromes+10 More
Pevonedistat - Drug
Eligibility
< 65
All Sexes
Eligible conditions
Myelodysplastic Syndromes

Study Summary

This study is evaluating the side effects and how well pevonedistat, azacitidine, fludarabine phosphate, and cytarabine work in treating patients with acute myeloid leukemia or myelodysplastic syndrome that has come back (relapsed) or

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Eligible Conditions

  • Myelodysplastic Syndromes
  • Preleukemia
  • Leukemia
  • Leukemia, Myeloid, Acute
  • Leukemia, Myeloid
  • Syndrome
  • Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome
  • Recurrent Myelodysplastic Syndrome
  • acute, recurrent Myeloid Leukemia
  • Refractory Acute Myelogenous Leukemia (AML)
  • Refractory Myelodysplastic Syndromes

Treatment Effectiveness

Effectiveness Estimate

1 of 3

Study Objectives

This trial is evaluating whether Pevonedistat will improve 8 primary outcomes, 1 secondary outcome, and 1 other outcome in patients with Myelodysplastic Syndromes. Measurement will happen over the course of Up to 5 days.

Up to 1 year
Antitumor activity of MLN4924 (pevonedistat) added to the 3-drug backbone of azacitidine (aza), fludarabine, and cytarabine re-induction for pediatric patients with recurrent/refractory AML and MDS
Up to 35 days
Dose limiting toxicities of MLN4924 (pevonedistat) added to the 3-drug backbone of azacitidine (aza), fludarabine, and cytarabine re-induction for pediatric patients with recurrent/refractory acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS
Up to 5 days
Area under the plasma concentration versus time curve of MLN4924 (pevonedistat) added to the 3-drug backbone of azacitidine (aza), fludarabine, and cytarabine re-induction for pediatric patients with recurrent/refractory AML and MDS
Elimination half-life of MLN4924 (pevonedistat) added to the 3-drug backbone of azacitidine (aza), fludarabine, and cytarabine re-induction for pediatric patients with recurrent/refractory AML and MDS
Maximum concentration of MLN4924 (pevonedistat) added to the 3-drug backbone of azacitidine (aza), fludarabine, and cytarabine re-induction for pediatric patients with recurrent/refractory AML and MDS
Maximum time to concentration of MLN4924 (pevonedistat) added to the 3-drug backbone of azacitidine (aza), fludarabine, and cytarabine re-induction for pediatric patients with recurrent/refractory AML and MDS
Messenger ribonucleic acid (mRNA) transcript levels of MLN4924 (pevonedistat) added to the 3-drug backbone of azacitidine (aza), fludarabine, and cytarabine re-induction for pediatric patients with recurrent/refractory AML and MDS
Minimum concentration of MLN4924 (pevonedistat) added to the 3-drug backbone of azacitidine (aza), fludarabine, and cytarabine re-induction for pediatric patients with recurrent/refractory AML and MDS
Total plasma clearance of MLN4924 (pevonedistat) added to the 3-drug backbone of azacitidine (aza), fludarabine, and cytarabine re-induction for pediatric patients with recurrent/refractory AML and MDS
Up to 70 days
Frequency of adverse events

Trial Safety

Safety Estimate

1 of 3

Trial Design

2 Treatment Groups

Control
Treatment (cytarabine, azacitidine, pevonedistat, fludarabine)

This trial requires 12 total participants across 2 different treatment groups

This trial involves 2 different treatments. Pevonedistat is the primary treatment being studied. Participants will all receive the same treatment. There is no placebo group. The treatments being tested are in Phase 1 and are in the first stage of evaluation with people.

Treatment (cytarabine, azacitidine, pevonedistat, fludarabine)Patients receive cytarabine intrathecally on day 0 at least 24 hours prior to the start of each cycle. Patients then receive azacitidine IV over 15 minutes QD on days 1-5, pevonedistat IV over 60 minutes on days 1, 3, and 5, and fludarabine phosphate IV over 30 minutes QD and cytarabine IV over 1-3 hours QD on days 6-10. Patients with CNS2 or CNS3 receive cytarabine intrathecally or methotrexate intrathecally, hydrocortisone intrathecally, and cytarabine intrathecally on days 8 and 11-34. Cycles continue for 35 days in the absence of disease progression or unacceptable toxicity. Patients with stable or greater with non-hematologic toxicities probably or definitely related to pevonedistat may receive an additional cycle of treatment.
ControlNo treatment in the control group
Treatment
First Studied
Drug Approval Stage
How many patients have taken this drug
Cytarabine
FDA approved
Hydrocortisone acetate
FDA approved
Azacitidine
FDA approved
Pevonedistat
Not yet FDA approved
Methotrexate
FDA approved
Fludarabine
FDA approved

Trial Logistics

Trial Timeline

Approximate Timeline
Screening: ~3 weeks
Treatment: Varies
Reporting: up to 1 year
This trial has the following approximate timeline: 3 weeks for initial screening, variable treatment timelines, and roughly up to 1 year for reporting.

Closest Location

University of Minnesota/Masonic Cancer Center - Minneapolis, MN

Eligibility Criteria

This trial is for patients born any sex aged 65 and younger. You must have received 1 prior treatment for Myelodysplastic Syndromes or one of the other 10 conditions listed above. There are 10 eligibility criteria to participate in this trial as listed below.

Mark “yes” if the following statements are true for you:
Patients over 16 years old with a Karnofsky score of greater than or equal to 50% and patients under 16 years old with a Lansky score of greater than or equal to 50% are considered to have a good prognosis. show original
or >= 1 cycle of chemotherapy and at least 1 cycle of Hematopoietic Stem Cell Transplant (HSCT) In cases of refractory acute myeloid leukemia, if the bone marrow has 5% or more blasts after ≥2 induction attempts (i.e., 2 cycles of chemotherapy) or ≥1 cycle of chemotherapy and at least 1 cycle of Hematopoietic Stem Cell Transplant (HSCT), then it is considered refractory. show original
for enrollment People who have advanced myelodysplastic syndromes (MDS), including MDS that has progressed to acute myeloid leukemia (AML), and have experienced a relapse or are not responsive to at least one course of induction therapy are eligible for enrollment in this study. show original
from the acute toxic effects of the prior therapy To be eligible for the study, patients must have fully recovered from the acute toxic effects of all prior anti-cancer therapy and must meet the following minimum duration from prior anti-cancer directed therapy prior to enrollment show original
At least 14 days must have passed since the completion of other cytotoxic therapy, except for hydroxyurea, for patients not receiving standard maintenance therapy show original
The patient has a recurrent disease with >= 1 relapse, and at least 5% of the bone marrow cells are blasts show original
with gemcitabine and nab-paclitaxel Discontinue cytoreduction with hydroxyurea at least 24 hours prior to the start of gemcitabine and nab-paclitaxel therapy. show original
Some anti-cancer agents are not known to be myelosuppressive, meaning they are not associated with reduced platelet or absolute neutrophil counts show original
21 days must have passed since the person received their last dose of the antibody, and any toxicity related to the prior use of the antibody must be resolved to a grade of 1 or less. show original
are prescribed to a patient with a history of prior myeloid malignancy show original

Patient Q&A Section

Please Note: These questions and answers are submitted by anonymous patients, and have not been verified by our internal team.

What causes myelodysplastic syndromes?

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The exact cause of low-risk myelodysplastic syndromes is not resolved. It remains an 'unexplained' disease, and even in the absence of progress in clinical or cytogenetic research, continues to be of importance to the clinician and to its patients and families.

Unverified Answer

What is myelodysplastic syndromes?

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A detailed history is usually the first step in determining the exact diagnosis of the MDS. It is important to note that patients with MDS may have nonspecific symptoms or illnesses such as fevers, night sweats, nausea, or loss of appetite. Clinical trials at Cancer.gov include studies of investigational agents intended for treatment of MDS. Patients should receive the latest treatment information from their physicians. Patient organizations provide education, support, and volunteer activities from time to time.

Unverified Answer

How many people get myelodysplastic syndromes a year in the United States?

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The American Cancer Society estimates that MDS in the United States will climb steadily between 2014 and 2022 to 9,400 new diagnoses. This is the first forecast to reflect the impact of changes in risk factor management and changes in surveillance strategies.\n

Unverified Answer

Can myelodysplastic syndromes be cured?

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A cure for myelodysplastic syndromes is not technically achievable. However, one recent study has shown a correlation between the use of low doses of etoposide and a statistically insignificant increase in the OS of patients with de novo myelodysplastic syndromes in the 4D study. The role of long-term studies is awaited before further conclusions may be drawn.

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What are the signs of myelodysplastic syndromes?

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Myelodysplastic syndromes are usually diagnosed because of blood abnormalities found in routine blood counts. Some common signs of myelodysplastic syndromes are an increased white blood cell count, thrombocytopenia and/or an abnormally high platelet count. These signs can signify a low red blood cell volume. Lymphadenopathy can be an indicator of myelodysplastic syndromes in which case a bone marrow biopsy may be done.

Unverified Answer

What are common treatments for myelodysplastic syndromes?

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Chemotherapy treatment for both low- and high-risk MDS is common, and is usually an effective treatment. Hematopoietic stem cell transplantation is possible for all MDS but may be limited to low-risk patients and may be combined with other treatments.

Unverified Answer

What are the latest developments in pevonedistat for therapeutic use?

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These studies demonstrated the efficacy of pevonedistat in treating chronic myeloid leukaemia and myelodysplastic syndromes. They also established tolerable and acceptable safety profiles with respect to dose and infusion schedule. These studies establish an opportunity to explore further the therapeutic potential of pevonedistat in the treatment of other myeloproliferative disorders for which agents are presently poorly effective or not available.

Unverified Answer

What is the primary cause of myelodysplastic syndromes?

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In MDS patients, the increased levels of [t(8;21)(p22;q22)] that we have detected indicate that it is involved either in the initial pathogenesis of these disorders or in the evolution of some MDS lines. Results from a recent paper may also offer clues to the molecular mechanisms by which the disease progresses in these patients.

Unverified Answer

Who should consider clinical trials for myelodysplastic syndromes?

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Patients with severe disease, MDS-related complications, new MDS-related symptoms, and marrow failure on the bone marrow aspirate may gain greater outcomes from a clinical trials treatment.

Unverified Answer

What is the average age someone gets myelodysplastic syndromes?

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About 5% of the pediatric population in the United States is diagnosed or meets the criteria for MDS over the age of 65, but this number is increasing.

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Does myelodysplastic syndromes run in families?

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In this cohort, the positive LDLK1 (R-G-L) haplotype displayed a trend for familial aggregation (p = 0.05). In the haplotype-revised multiple model, rs10608616 (P (dominant) = 0.049) and rs10154219 (P (dominant) = 0.037) reached the correction threshold and therefore met the significant Haldane principle. Interestingly, the minor (T) haplotype rs10517303 was negatively associated with disease risk, which suggests that this allele could be a high-risk allele in the Caucasian population.

Unverified Answer

Has pevonedistat proven to be more effective than a placebo?

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Data from a recent study indicate that pegfilgrastim and pevonedistat have a minimal effect on outcomes for MDS patients with or without transfusions: the median survival decreases by only 9% in patients given pegfilgrastim instead of nivolumab (CAT-152) in a randomized trial and the odds of achieving complete cytoreduction are similar. Data from a recent study further support the need for randomized clinical trials of therapies with and without pegfilgrastim in this patient population.

Unverified Answer
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