Pevonedistat + Ibrutinib for CLL and Non-Hodgkin Lymphoma

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

18 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This phase I trial studies the side effects and best dose of pevonedistat when given together with ibrutinib in participants with chronic lymphocytic leukemia or non-Hodgkin lymphoma that has come back or has stopped responding to other treatments. Pevonedistat and ibrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

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 the combination of Pevonedistat and Ibrutinib safe for humans?

Ibrutinib, also known as Imbruvica, is generally well tolerated in patients with chronic lymphocytic leukemia (CLL), but it can cause side effects like atrial fibrillation (irregular heartbeat) and hypertension (high blood pressure). While Pevonedistat (MLN4924) is not specifically mentioned in the provided research, Ibrutinib's safety profile suggests it is generally safe, though monitoring for specific side effects is important. ^{1 2 3 4 5}

What makes the drug combination of Pevonedistat and Ibrutinib unique for treating CLL and Non-Hodgkin Lymphoma?

The combination of Pevonedistat and Ibrutinib is unique because Pevonedistat inhibits a specific enzyme (Nedd8-activating enzyme) that downregulates NFκB signaling, which is crucial for cancer cell survival, while Ibrutinib targets the B-cell receptor pathway. This dual approach may offer enhanced effectiveness in treating relapsed or refractory cases of CLL and Non-Hodgkin Lymphoma. ^{6 7 8 9 10}

What data supports the effectiveness of the drug combination Pevonedistat + Ibrutinib for CLL and Non-Hodgkin Lymphoma?

Ibrutinib has shown significant effectiveness in treating chronic lymphocytic leukemia (CLL) by improving survival rates and is approved for use in various CLL patient groups. It works by targeting a key protein involved in the survival of cancerous B cells, which are a type of white blood cell. ^{7 8 11 12 13}

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

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

Specific contraceptive requirements for female and male patients

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 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 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]

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 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 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]

Citations

1. England pubmed.ncbi.nlm.nih.gov

Comparison of ibrutinib and idelalisib plus rituximab in real-life relapsed/resistant chronic lymphocytic leukemia cases. [2021]

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

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

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

Ibrutinib combinations in CLL therapy: scientific rationale and clinical results. [2022]

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

Ibrutinib (imbruvica): a novel targeted therapy for chronic lymphocytic leukemia. [2021]

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

Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. [2022]

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

Safety and efficacy analysis of long-term follow up real-world data with ibrutinib monotherapy in 58 patients with CLL treated in a single-center in Greece. [2021]

7. Italy pubmed.ncbi.nlm.nih.gov

BCR Signaling Inhibitors: an Overview of Toxicities Associated with Ibrutinib and Idelalisib in Patients with Chronic Lymphocytic Leukemia. [2020]

8. England pubmed.ncbi.nlm.nih.gov

Adverse event burden in older patients with CLL receiving bendamustine plus rituximab or ibrutinib regimens: Alliance A041202. [2023]

9. England pubmed.ncbi.nlm.nih.gov

Bruton's tyrosine kinase inhibitors: first and second generation agents for patients with Chronic Lymphocytic Leukemia (CLL). [2021]

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

Experience with ibrutinib for first-line use in patients with chronic lymphocytic leukemia. [2023]

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

Pevonedistat, a Nedd8-activating enzyme inhibitor, in combination with ibrutinib in patients with relapsed/refractory B-cell non-Hodgkin lymphoma. [2023]

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

Ibrutinib (PCI-32765) in chronic lymphocytic leukemia. [2021]

13. New Zealand pubmed.ncbi.nlm.nih.gov

Ibrutinib: first global approval. [2022]