Pevonedistat + Chemotherapy for Acute Myeloid Leukemia

Recruiting at 4 trial locations

Overseen By Christine Duran

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: University of Southern California

Must not be taking: Antineoplastics, Radiotherapy

Disqualifiers: Cardiopulmonary disease, COPD, HIV, others

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

Compensation: Varies

Number of Visits: 3

53 Participants Needed

Trial Summary

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

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot take any investigational or commercial agents intended to treat your cancer within 14 days before starting the study drug, except for hydroxyurea to control white blood cell counts.

What data supports the effectiveness of the drug combination Pevonedistat, Cytarabine, and Idarubicin for treating acute myeloid leukemia?

Research shows that combining idarubicin and cytarabine is effective for treating acute myeloid leukemia, with some studies indicating that idarubicin is better than another drug, daunorubicin, for certain patients. Adding cladribine to this combination has also been shown to improve treatment outcomes. ^{1 2 3 4 5}

What safety data exists for Pevonedistat + Chemotherapy for Acute Myeloid Leukemia?

The combination of idarubicin and cytarabine, used in chemotherapy for acute myeloid leukemia, has been generally well-tolerated, with some patients experiencing nausea, vomiting, mouth sores, diarrhea, and changes in liver and kidney function. These side effects were considered low, and no deaths occurred during the treatment phase in the studies reviewed. ^{1 3 6 7 8}

What makes the drug Pevonedistat + Chemotherapy unique for treating acute myeloid leukemia?

Pevonedistat is a novel drug that works by inhibiting a specific protein involved in cancer cell survival, making it different from standard chemotherapy drugs like cytarabine and idarubicin, which target rapidly dividing cells. This combination aims to enhance the effectiveness of traditional chemotherapy by adding a new mechanism of action. ^{1 6 7 9 10}

What is the purpose of this trial?

This phase Ib/II trial studies the side effects and best dose of pevonedistat and to see how well it works in combination with cytarabine and idarubicin in treating patients with acute myeloid leukemia. Pevonedistat may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as cytarabine and idarubicin, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Given pevonedistat, cytarabine, and idarubicin may work better in treating patients with acute myeloid leukemia.

Research Team

Kevin Kelly, MD

Principal Investigator

University of Southern California

Eligibility Criteria

This trial is for adults with acute myeloid leukemia (AML) who are fit for chemotherapy, have certain genetic features or a history of myelodysplastic syndrome, and haven't had AML treatment. Participants must be able to perform daily activities with minimal assistance (ECOG 0-2), have adequate organ function, agree to use contraception if they can have children, and not expect other serious health issues within the next 3 months.

Inclusion Criteria

Within 3 days before the first dose of study drug: albumin > 2.7 g/dL

Within 3 days before the first dose of study drug: total bilirubin < upper limit of normal (ULN)

Within 3 days before the first dose of study drug: creatinine clearance > 50 mL/min

Exclusion Criteria

I have severe liver problems or cirrhosis.

I haven't had cancer treatment or radiation in the last 14 days.

I haven't taken any strong enzyme inducers in the last 14 days.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction

Patients receive idarubicin IV on days 1-3, cytarabine IV on days 1-7, and pevonedistat IV on days 1, 3, and 5. A second course may be given if residual disease is present.

Up to 14 days

Consolidation

Patients achieving CR receive cytarabine IV every 12 hours on days 1, 3, and 5. Treatment repeats every 28-35 days for 4 courses.

4-5 months

Follow-up

Participants are monitored for safety and effectiveness after treatment completion.

2 years

Every 3 months

Treatment Details

Interventions

• Cytarabine
• Idarubicin
• Pevonedistat

Trial Overview The study tests pevonedistat combined with cytarabine and idarubicin in treating AML. Pevonedistat may block enzymes that cancer cells need to grow. Cytarabine and idarubicin are chemotherapy drugs that kill or stop cancer cells from dividing. The trial aims to find the best dose of pevonedistat and see how well this combination works.

Participant Groups

Group I: Treatment (idarubicin, cytarabine, pevonedistat) Experimental Treatment 5 Interventions

INDUCTION: Patients receive idarubicin IV over 10-15 minutes on days 1-3, cytarabine IV over 1-3 hours on days 1-7, and pevonedistat IV over 60 minutes on days 1, 3, and 5. Patients with gross residual disease on day 14 bone marrow may receive a second course of induction chemotherapy. CONSOLIDATION: Patients who achieve CR and will not undergo bone marrow transplant receive cytarabine IV over 3 hours every 12 hours on days 1, 3, and 5. Treatment repeats every 28-35 days for 4 courses in the absence of disease progression or unaccepted toxicity.

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?

University of Southern California

Lead Sponsor

Trials

956

Recruited

1,609,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

In a study of 125 patients with de novo acute myeloid leukemia, idarubicin combined with cytarabine resulted in a significantly higher complete remission rate (82.1%) compared to daunorubicin (41.2%) in patients with high MDR1 expression.

Idarubicin also showed superior efficacy in high MDR1 expressers with favorable or intermediate risk, while no significant differences were observed between the two treatments in low MDR1 expressers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Idarubicin is superior to daunorubicin in remission induction of de novo acute myeloid leukemia patients with high MDR1 expression. Shi, P., Zha, J., Guo, X., et al.[2018]

The novel IAC regimen (idarubicin, cytarabine, and cladribine) showed a significantly higher complete remission rate in acute myeloid leukemia (AML) patients compared to the low-dose IA regimen, indicating its enhanced efficacy without increasing toxicity.

Prognostic factors such as high white blood cell counts at diagnosis and unfavorable karyotypes were associated with poorer treatment responses, highlighting the importance of these factors in predicting outcomes for AML patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Addition of Cladribine to Idarubicin and Cytarabine during Induction Increases the Overall Efficacy Rate in Adult Patients with Acute Myeloid Leukemia: A Matched-Pair Retrospective Comparison. Shen, Y., Chen, J., Liu, Y., et al.[2015]

In a study of 327 adult patients with acute myeloid leukaemia (AML), 82% achieved complete remission after receiving idarubicin- and cytarabine-based intensive chemotherapy, indicating the regimen's effectiveness for this age group.

Patients with favourable karyotypes had significantly better long-term outcomes, with a 5-year survival rate of 71%, while those with adverse karyotypes had only an 8% survival rate, highlighting the need for new treatment strategies for patients with poorer genetic profiles.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term outcome of intensive chemotherapy for adults with de novo acute myeloid leukaemia (AML): the nationwide AML-92 study by the Finnish Leukaemia Group. Koistinen, P., Räty, R., Itälä, M., et al.[2007]

In a study involving five patients with therapy-related acute myeloid leukemia, a combination of idarubicin, high-dose cytarabine, and etoposide achieved complete remission in all patients after just one course of treatment.

The treatment was well-tolerated, with low levels of toxicity and no deaths during the induction therapy, suggesting it is a promising option for inducing remission in secondary acute myeloid leukemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Idarubicin, high-dose cytarabine and etoposide for remission induction in therapy-related acute myeloid leukemia. Philpott, N., Mehta, J., Treleaven, J., et al.[2019]

In a study of 43 patients under 60 years old with untreated acute myeloid leukemia, the combination of idarubicin, etoposide, and carboplatin achieved a remission rate of 67% with a median leukemia-free survival of 15.4 months.

The treatment was associated with significant mucosal toxicity, including severe gastrointestinal side effects in a substantial number of patients, indicating that while effective, the regimen's tolerability may need improvement through adjustments in postremission therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Remission induction therapy of untreated acute myeloid leukemia using a non-cytarabine-containing regimen of idarubicin, etoposide, and carboplatin. Bow, EJ., Gallant, G., Williams, GJ., et al.[2015]

References

1. China pubmed.ncbi.nlm.nih.gov

[Comparison of 10 mg/m² or 8 mg/m² idarubicin plus cytarabine regimen as induction chemotherapy for adult patients with newly diagnosed acute myeloid leukemia]. [2020]

2. England pubmed.ncbi.nlm.nih.gov

Idarubicin is superior to daunorubicin in remission induction of de novo acute myeloid leukemia patients with high MDR1 expression. [2018]

3. China pubmed.ncbi.nlm.nih.gov

[Efficacy and safety analysis of different dose idarubicin plus cytarabine regimen as induction chemotherapy for young patients with de-novo acute myeloid leukemia]. [2020]

4. Switzerland pubmed.ncbi.nlm.nih.gov

Addition of Cladribine to Idarubicin and Cytarabine during Induction Increases the Overall Efficacy Rate in Adult Patients with Acute Myeloid Leukemia: A Matched-Pair Retrospective Comparison. [2015]

5. England pubmed.ncbi.nlm.nih.gov

Long-term outcome of intensive chemotherapy for adults with de novo acute myeloid leukaemia (AML): the nationwide AML-92 study by the Finnish Leukaemia Group. [2007]

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

Idarubicin, high-dose cytarabine and etoposide for remission induction in therapy-related acute myeloid leukemia. [2019]

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

Remission induction therapy of untreated acute myeloid leukemia using a non-cytarabine-containing regimen of idarubicin, etoposide, and carboplatin. [2015]

8. Italy pubmed.ncbi.nlm.nih.gov

Idarubicin and cytosine arabinoside in the induction and maintenance therapy of high-risk myelodysplastic syndromes. [2013]

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

Comparison of Three Doses of Cytarabine Consolidation for Intermediate- and Adverse-risk Acute Myeloid Leukemia: Real World Evidence From Thai Acute Myeloid Leukemia Registry. [2022]

10. England pubmed.ncbi.nlm.nih.gov

Epigenetic priming with decitabine followed by low dose idarubicin and cytarabine in acute myeloid leukemia evolving from myelodysplastic syndromes and higher-risk myelodysplastic syndromes: a prospective multicenter single-arm trial. [2020]