Pevonedistat + Ibrutinib for CLL and Non-Hodgkin Lymphoma

Not currently recruiting at 2 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: City of Hope Medical Center

Must be taking: Ibrutinib

Must not be taking: CYP3A inhibitors, CYP3A inducers

Disqualifiers: HIV, Hepatitis B, Hepatitis C, others

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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: Unknown

Duration: 18-21 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the combination of two drugs, pevonedistat (MLN4924) and ibrutinib (Imbruvica), to determine their effectiveness in treating chronic lymphocytic leukemia (CLL) or non-Hodgkin lymphoma (NHL) that has returned or stopped responding to other treatments. Researchers aim to find the optimal dose and understand potential side effects. The trial seeks participants with CLL or certain types of NHL, such as mantle cell lymphoma or follicular lymphoma, especially if past treatments no longer work or the disease has relapsed. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants a chance to be among the first to receive this new combination therapy.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it does exclude those using certain drugs like strong CYP3A inhibitors or inducers and BCRP inhibitors. It's best to discuss your current medications with the trial team to see if any adjustments are needed.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research has shown that the combination of pevonedistat and ibrutinib is being tested for safety in people with chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma. Earlier studies suggest that this treatment is generally well-tolerated. In one study, 24% of patients had stable disease, meaning their condition did not worsen during treatment.

Ibrutinib, part of this combination, is already known to help lower the risk of death in CLL. However, it can increase the chances of an irregular heartbeat and bleeding. Pevonedistat has shown activity against certain cancer cells in lab studies.

Since this trial is in an early stage, the main goal is to find the best dose and check for side effects. The complete safety profile is still being developed. However, the fact that both drugs have shown some effectiveness on their own is a hopeful sign for their combined use. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about combining pevonedistat and ibrutinib for treating Chronic Lymphocytic Leukemia (CLL) and Non-Hodgkin Lymphoma because of their unique mechanisms. Unlike standard treatments that often target cancer cells directly, pevonedistat works by inhibiting a protein called NEDD8, disrupting cancer cell survival pathways. Ibrutinib is already known for targeting Bruton's tyrosine kinase (BTK), which is crucial for cancer cell growth and survival. Together, these drugs may offer a more comprehensive attack on cancer cells, potentially improving outcomes compared to current options.

What evidence suggests that pevonedistat and ibrutinib could be effective for CLL and non-Hodgkin lymphoma?

This trial will evaluate the combination of pevonedistat and ibrutinib for treating chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma. Studies have shown that using pevonedistat and ibrutinib together yields promising early results, with about 24% of participants experiencing stable disease. Pevonedistat blocks enzymes that help cancer cells grow, while ibrutinib is already known to reduce death rates in CLL. This combination targets specific parts of cancer cells, potentially increasing its effectiveness. Overall, these initial findings suggest that the treatment may help manage these conditions, especially when previous treatments have stopped working. ^{1 2 3 4 6}

Who Is on the Research Team?

Alexey Danilov

Principal Investigator

City of Hope Medical Center

Are You a Good Fit for This Trial?

This trial is for people with certain types of blood cancers like CLL or non-Hodgkin lymphoma that have not improved with other treatments. Participants must be in fairly good health, able to perform daily activities (ECOG 0-2), and meet specific lab criteria indicating their organs are functioning well. They should agree to use contraception and not donate eggs or sperm during the study.

Inclusion Criteria

Specific contraceptive requirements for female and male patients

Your blood tests must show certain levels for bilirubin, AST/ALT, creatinine clearance, platelets, neutrophil count, albumin, and hemoglobin.

My CLL/SLL requires treatment based on specific health criteria.

Exclusion Criteria

I cannot swallow or keep down oral medication.

I have not taken certain medications or undergone specific therapies recently.

I haven't taken strong CYP3A affecting drugs in the last 14 days.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive pevonedistat IV on days 1, 3, and 5, and ibrutinib PO daily on days 2-21 of course 1 and days 1-21 of subsequent courses. Treatment repeats every 21 days for up to 8 courses, followed by ibrutinib alone for up to 10 courses.

18-21 months

Follow-up

Participants are monitored for safety and effectiveness after treatment completion every 3 months

Up to 4 years

What Are the Treatments Tested in This Trial?

Interventions

• Ibrutinib
• Pevonedistat

Trial Overview The trial is testing the combination of two drugs, Pevonedistat and Ibrutinib, to find out the safest doses and how they affect cancer cell growth. It's a phase I study which means it's early in the clinical trials process focusing on safety rather than effectiveness.

How Is the Trial Designed?

Group I: Treatment (pevonedistat, ibrutinib) Experimental Treatment 5 Interventions

Participants receive pevonedistat IV over 1 hour on days 1, 3, and 5, and ibrutinib PO daily on days 2-21 of course 1 and days 1-21 of subsequent courses. Treatment repeats every 21 days for up to 8 courses in the absence of disease progression or unacceptable toxicity. Participants then receive only ibrutinib PO daily on days 1-21. Treatment repeats every 21 days for up to 10 courses in the absence of disease progression or unacceptable toxicity.

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

Approved in European Union as Imbruvica for:

• Chronic lymphocytic leukemia
• Mantle cell lymphoma
• Waldenström's macroglobulinemia
• Marginal zone lymphoma
• Graft-versus-host disease

Approved in United States as Imbruvica for:

• Chronic lymphocytic leukemia/small lymphocytic lymphoma
• Mantle cell lymphoma
• Waldenström's macroglobulinemia
• Marginal zone lymphoma
• Graft-versus-host disease

Approved in Canada as Imbruvica for:

• Chronic lymphocytic leukemia
• Mantle cell lymphoma
• Waldenström's macroglobulinemia
• Marginal zone lymphoma

Approved in Japan as Imbruvica for:

• Chronic lymphocytic leukemia
• Mantle cell lymphoma
• Waldenström's macroglobulinemia

Who Is Running the Clinical Trial?

City of Hope Medical Center

Lead Sponsor

Trials

614

Recruited

1,924,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

Ibrutinib is a targeted therapy that has significantly improved treatment outcomes for patients with chronic lymphocytic leukemia (CLL), particularly for those who have previously undergone therapy or have a specific genetic marker (17p deletion).

The drug is generally well-tolerated, with discontinuation due to side effects being rare, although some patients may experience specific toxicities like lymphocytosis, major bleeding, and atrial fibrillation, which require careful management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The clinical safety of ibrutinib in chronic lymphocytic leukemia. Molica, S.[2021]

Ibrutinib is a first-in-class selective inhibitor of Bruton tyrosine kinase that shows promise in inhibiting the survival and proliferation of chronic lymphocytic leukemia (CLL) cells, based on preclinical studies.

Early clinical data indicate that ibrutinib may significantly impact CLL treatment, suggesting it could become a key part of therapy targeting the B-cell receptor signaling pathway.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ibrutinib (PCI-32765) in chronic lymphocytic leukemia. Jain, N., O'Brien, S.[2021]

Ibrutinib has significantly improved treatment outcomes for chronic lymphocytic leukemia (CLL) by irreversibly inhibiting Bruton tyrosine kinase (BTK), leading to better overall and progression-free survival in various patient subgroups, including those with relapsed disease and 17p deletion.

Despite its effectiveness, ibrutinib has limitations such as low complete remission rates and the potential for resistance, prompting research into combination therapies, particularly with venetoclax, which has shown high complete response rates and undetectable minimal residual disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ibrutinib combinations in CLL therapy: scientific rationale and clinical results. Timofeeva, N., Gandhi, V.[2022]

Ibrutinib is a first-in-class oral Bruton's tyrosine kinase inhibitor that effectively blocks B-cell signaling, leading to reduced proliferation and increased cell death in B cell malignancies, including chronic lymphocytic leukaemia (CLL) and mantle cell lymphoma (MCL).

It has received FDA approval for treating MCL in previously treated patients based on phase Ib/II study results and is currently undergoing further phase III trials for CLL, diffuse large B cell lymphoma (DLBCL), and other B cell cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ibrutinib: first global approval. Cameron, F., Sanford, M.[2022]

Ibrutinib and idelalisib, two B-cell receptor signaling inhibitors, have shown significant clinical activity in treating chronic lymphocytic leukemia (CLL), particularly in relapsed or refractory cases, and have been FDA-approved for this use.

Both drugs are generally well tolerated, even by older patients, with mild and self-resolving side effects; however, clinicians should be aware of specific adverse events that could limit their use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

BCR Signaling Inhibitors: an Overview of Toxicities Associated with Ibrutinib and Idelalisib in Patients with Chronic Lymphocytic Leukemia. Falchi, L., Baron, JM., Orlikowski, CA., et al.[2020]

Ibrutinib is a targeted therapy specifically designed for treating chronic lymphocytic leukemia (CLL), which is a type of cancer that affects the blood and bone marrow.

This novel treatment works by inhibiting Bruton's tyrosine kinase (BTK), a key enzyme that helps cancer cells survive and proliferate, leading to improved patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ibrutinib (imbruvica): a novel targeted therapy for chronic lymphocytic leukemia. Parmar, S., Patel, K., Pinilla-Ibarz, J.[2021]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9834208/

Pevonedistat, a Nedd8-activating enzyme inhibitor, in ... Thus, pevonedistat combined with ibrutinib demonstrated safety and promising early efficacy in NHL and CLL. NAE inhibition downregulated NFκB ...

2. onclive.com onclive.com/view/pevonedistat-plus-ibrutinib-showcases-preliminary-efficacy-and-tolerability-in-cll-and-mcl

Pevonedistat Plus Ibrutinib Showcases Preliminary Efficacy ... Additional results showed that 4 patients (24%) had stable disease with pevonedistat plus ibrutinib; one of these patients had CLL, SLL, or B- ...

3. mdpi.com mdpi.com/2072-6694/17/3/533

Distinct NF-kB Regulation Favors a Synergic Action of ... MLN4924 has been demonstrated to reduce the viability of B-CLL cells and synergizes with inhibitors of BCR-activated pathways [11]. The results of a clinical ...

4. researchgate.net researchgate.net/publication/367029318_Pevonedistat_a_Nedd8-activating_enzyme_inhibitor_in_combination_with_ibrutinib_in_patients_with_relapsedrefractory_B-cell_non-Hodgkin_lymphoma

(PDF) Pevonedistat, a Nedd8-activating enzyme inhibitor ... PURPOSE Ibrutinib reduces mortality in chronic lymphocytic leukemia (CLL). It increases the risk of atrial fibrillation (AF) and bleeding and there are ...

5. sciencedirect.com sciencedirect.com/science/article/pii/S0006497120303967

Pevonedistat, a NEDD8-activating enzyme inhibitor, is ... Pevonedistat had been shown to be active in activated B-cell/diffuse large B-cell lymphoma, chronic lymphocytic leukemia, and AML preclinical ...

6. oncotarget.com oncotarget.com/article/15050/text/

Pevonedistat, a Nedd8-activating enzyme inhibitor, ... Here we demonstrate that diffuse large B-cell lymphoma, particularly activated B-cell type, and primary chronic lymphocytic leukemia cells are ...