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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new combination of treatments for acute myeloid leukemia (AML). Researchers aim to find the best dose and evaluate how well pevonedistat, an experimental treatment, works with two chemotherapy drugs, cytarabine and idarubicin. Pevonedistat may stop cancer cells from growing by blocking certain necessary enzymes. The trial seeks participants diagnosed with AML who have not received prior treatment, particularly those with specific genetic features or who developed AML after conditions like myelodysplastic syndrome (MDS). As a Phase 1 trial, this research focuses on understanding the treatment's effects in people, offering participants the opportunity to be among the first to receive this new combination.

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.

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

Research has shown that pevonedistat is generally well-tolerated by patients with acute myeloid leukemia (AML). Studies indicate that its side effects mainly affect blood, such as causing low blood cell counts, but these can be managed. One study found that combining pevonedistat with another drug is safe and shows promising results against AML.

Idarubicin, a chemotherapy drug often used to treat AML, has been shown to be safe, with no major differences in side effects compared to similar treatments. It has been a standard part of AML therapy for a long time, demonstrating good safety for patients.

Cytarabine is another important drug for AML treatment. Its safety is well-known, with side effects similar to other standard chemotherapy drugs. These may include low blood cell counts and a risk of infection, but the drug has been used effectively for many years.

Overall, pevonedistat, idarubicin, and cytarabine have been thoroughly studied and are considered safe for treating AML, with side effects that are usually manageable with proper medical care. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatment?

Researchers are excited about pevonedistat in combination with chemotherapy for acute myeloid leukemia (AML) because it introduces a novel mechanism of action. Unlike the standard chemotherapy drugs, which target and kill rapidly dividing cells, pevonedistat inhibits a specific enzyme called NEDD8-activating enzyme. This inhibition disrupts protein regulation within cancer cells, potentially leading to cancer cell death. By adding pevonedistat to the mix, researchers hope to enhance the effectiveness of traditional chemotherapy and improve outcomes for patients with AML.

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

In this trial, participants will receive a combination of pevonedistat, idarubicin, and cytarabine. Research has shown that pevonedistat, a new type of drug, has promising effects against leukemia. In earlier studies, it helped half of the older patients who were trying treatment for the first time. Idarubicin, a well-known treatment for acute myeloid leukemia (AML), has helped 53.4% of patients live for at least two years. Cytarabine is another important drug in AML treatment and is often used in combinations that lead to high cure rates. Together, these treatments may effectively stop cancer from growing, kill cancer cells, and prevent them from spreading. ^{2 3 5 6 7}

Who Is on the Research Team?

Kevin Kelly, MD

Principal Investigator

University of Southern California

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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 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 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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7900255/

Acute myeloid leukemia: current progress and future ... The new regimens utilizing fludarabine, high-dose cytarabine and GO, with or without idarubicin, may be better, producing cure rates of 75–80+%. The CBF AML ...

2. ashpublications.org ashpublications.org/blood/article/142/Supplement%201/5922/505830/Real-World-Outcomes-of-CPX-351-Compared-to

Real World Outcomes of CPX-351 Compared to Traditional ... Twenty-five percent of patients achieved CR/CRi in the CPX-351 arm with one induction cycle, compared to 95.5% in the 7+3 group. Median ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6839888/

A real-world study of clofarabine and cytarabine ... Progression-free survival (PFS) at 2 years was 16% (95% CI 8–27%) and overall survival (OS) at 2 years was 21% (95% CI 11–33%) for all patients. The 30-day ...

4. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0006497123125225

Real World Outcomes of CPX-351 Compared to Traditional ... Introduction: Outcomes in patients with secondary AML (sAML) are inferior to those with de novo AML which has led investigators to seek ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT01802333

Cytarabine and Daunorubicin Hydrochloride or Idarubicin ... This randomized phase III trial studies cytarabine and daunorubicin hydrochloride or idarubicin and cytarabine with or without vorinostat to see how well they ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40348597/

The Clinical Safety and Efficacy of Cytarabine ... Results: CPX-351 exhibited an adverse event profile that was comparable to that of conventional chemotherapy. It resulted in complete remission rates of 18%-41% ...

7. asco.org asco.org/abstracts-presentations/ABSTRACT74020

Etoposide and cytarabine as an effective and safe ... A combination of mitoxantrone, etoposide and cytarabine (MEC) is commonly used as second-line therapy and confers response rates of 18-28% with a median OS of ...