Pevonedistat and Ibrutinib in Treating Participants With Relapsed or Refractory CLL or Non-Hodgkin Lymphoma

NCT03479268 | Active Not Recruiting Phase 1 DMC FDA Drug

• 4 other identifiers: 19565NCI-2018-00315STUDY00017005P30CA069533
• Study Type: interventional
• Target: 18
• Locations: 1 country
• Sites: 2

Brief Summary

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.

Conditions

Recurrent Chronic Lymphocytic Leukemia; Recurrent Diffuse Large B-Cell Lymphoma; Recurrent Follicular Lymphoma; Recurrent Lymphoplasmacytic Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Non-Hodgkin Lymphoma; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Diffuse Large B-Cell Lymphoma; Refractory Follicular Lymphoma; Refractory Lymphoplasmacytic Lymphoma; Refractory Mantle Cell Lymphoma; Refractory Marginal Zone Lymphoma; Refractory Non-Hodgkin Lymphoma; Refractory Small Lymphocytic Lymphoma; B-Cell Prolymphocytic Leukemia; Richter Syndrome

Outcome Measures

Primary Outcomes (2)

• Incidence of dose limiting toxicities (DLTs)

  Up to 42 days

• Incidence of adverse events (AEs), serious AEs (SAEs), dose interruptions, reductions and dose intensity Common Terminology Criteria for Adverse Events version 4.03

  All adverse events will be tabulated and summarized by major organ category, grade, anticipation, and drug attribution. SAE specific incidence and exact 95% confidence interval will be provided where appropriate.

  Up to 30 days after last course of treatment

Secondary Outcomes (2)

• Overall response rate (ORR) determined based on proportion of participants who achieve complete response (CR), with incomplete marrow recovery (CRi), partial response (PR), or nodular partial response (nPR)

  Up to 1 year

• Event-free survival (EFS)

  From date of first study treatment until progression, start of anti-leukemic therapy, or death, assessed up to 4 years

Study Arms (1)

Treatment (pevonedistat, ibrutinib)

EXPERIMENTAL

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.

Drug: Ibrutinib; Other: Laboratory Biomarker Analysis; Drug: Pevonedistat; Other: Pharmacokinetic Study; Other: Pharmacological Study

Interventions

Ibrutinib DRUG

Given PO

Also known as: BTK Inhibitor PCI-32765, CRA-032765, Imbruvica, PCI-32765

Treatment (pevonedistat, ibrutinib)

Laboratory Biomarker Analysis OTHER

Correlative studies

Treatment (pevonedistat, ibrutinib)

Pevonedistat DRUG

Given IV

Also known as: MLN4924, Nedd8-Activating Enzyme Inhibitor MLN4924

Treatment (pevonedistat, ibrutinib)

Pharmacokinetic Study OTHER

Correlative studies

Also known as: PHARMACOKINETIC, PK Study

Treatment (pevonedistat, ibrutinib)

Pharmacological Study OTHER

Correlative studies

Treatment (pevonedistat, ibrutinib)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Dose escalation cohort:
• Histologically or flow cytometry confirmed diagnosis of B-CLL/small lymphocytic lymphoma (SLL) according to National Cancer Institute sponsored Working Group (NCI-WG) 1996 guidelines
• The following types of NHL as documented by medical records and with histology based on criteria established by the World Health Organization (WHO):
• Mantle cell lymphoma (MCL)
• Follicular lymphoma (FL) - grades 1-3a
• Lymphoplasmacytic lymphoma (LPL)
• Marginal zone lymphoma (MZL)
• CLL in Richter's transformation
• B-cell prolymphocytic leukemia (B-PLL)
• Diffuse large B-cell lymphoma (DLBCL)
• Expansion cohort - histologically or flow cytometry confirmed diagnosis of B-CLL/SLL according to NCI-WG 1996 guidelines; patients who lack CD23 expression on their leukemia cells should be examined for (and found NOT to have) either t(11;14) or cyclin D1 overexpression, to rule out mantle cell lymphoma
• Patients with MCL underwent \>= 1 chemoimmunotherapy-based regimen; patients with FL and MZL underwent \>= 1 prior chemotherapy-based and/or immunotherapy-based regimen; patients with DLBCL and CLL in Richter's transformation underwent \>= 1 chemoimmunotherapy-based regimen and are not transplant-eligible; patients with CLL, B-PLL and LPL underwent \>= 1 chemotherapy-based, or immunotherapy-based or targeted therapy regimen (e.g., PI3K inhibitors \[idelalisib\], venetoclax, ibrutinib or an investigational agent, including an investigational BTK inhibitor); all regimens must have been administered for \>= 2 cycles, and patients must have had either documented disease progression or no response (stable disease) to the most recent treatment regimen
• Patients with CLL/SLL demonstrate active disease meeting at least 1 of the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 criteria for requiring treatment:
• A minimum of any one of the following constitutional symptoms:
• Unintentional weight loss \> 10% within the previous 6 months prior to screening

You may not qualify if:

• Prior therapeutic intervention with any of the following:
• Therapeutic anticancer antibodies (rituximab, obinutuzumab) within 4 weeks
• Radio- or toxin-immunoconjugates within 10 weeks
• Inhibitors of PI3K (idelalisib), ibrutinib, BH3-mimetic venetoclax, lenalidomide, and other targeted therapy (including investigational BTK inhibitors and other investigational therapy) within 6 half-lives
• All other chemotherapy, radiation therapy within 3 weeks prior to initiation of therapy
• Intolerance of ibrutinib
• Inadequate recovery from adverse events related to prior therapy to grade =\< 1 (excluding grade 2 alopecia and neuropathy)
• Chronic use of corticosteroids in excess of prednisone 20 mg/day or its equivalent
• Stem cell transplant recipients must have no evidence of active graft-versus-host disease and should not be receiving treatment for it
• Known involvement of central nervous system
• Use of full dose, therapeutic anti-coagulation or patients with uncontrolled coagulopathy or bleeding disorder
• Treatment with strong CYP3A inhibitors or inducers within 14 days before the first dose of study drug; strong CYP3A inhibitors/inducers are not permitted during the study, including nutraceutical preparations, e.g., grapefruit juice and St John's wort; patients must have no prior history of amiodarone in the 6 months prior to the first dose of pevonedistat
• Patient requiring chronic treatment with BCRP inhibitors (cyclosporine, eltrombopag)
• History prior malignancy except:
• Malignancy treated with curative intent and no known active disease present for \>= 2 years prior to initiation of therapy on current study

Sponsors & Collaborators

• City of Hope Medical Center: lead
• National Cancer Institute (NCI): collaborator

Study Sites (2)

City of Hope Medical Center

Duarte, California, 91010, United States

Location

Roswell Park Comprehensive Cancer Center

Buffalo, New York, 14263, United States

Location

Related Publications (1)

• Torka P, Thiruvengadam SK, Chen L, Wang X, Chen C, Vuong D, Qin H, Muir A, Orand K, Borja I, Lynne Smith D, Herrera AF, Spurgeon SEF, Park B, Lewis LD, Hernandez-Ilizaliturri F, Xia Z, Danilov AV. Pevonedistat, a Nedd8-activating enzyme inhibitor, in combination with ibrutinib in patients with relapsed/refractory B-cell non-Hodgkin lymphoma. Blood Cancer J. 2023 Jan 11;13(1):9. doi: 10.1038/s41408-022-00763-w.

  PMID: 36631449 DERIVED

MeSH Terms

Conditions

Leukemia, Prolymphocytic, B-Cell; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Follicular; Lymphoma, B-Cell, Marginal Zone; Lymphoma, Mantle-Cell; Lymphoma, Non-Hodgkin

Interventions

ibrutinib; pevonedistat; Pharmacogenomic Variants

Condition Hierarchy (Ancestors)

Leukemia, B-Cell; Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Leukemia, Prolymphocytic; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Lymphoma, B-Cell; Lymphoma

Intervention Hierarchy (Ancestors)

Polymorphism, Genetic; Genetic Variation; Genetic Phenomena

Study Officials

• Alexey Danilov

  City of Hope Medical Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 14, 2018
• First Posted: March 27, 2018
• Study Start: April 27, 2018
• Primary Completion (Estimated): November 5, 2026
• Study Completion (Estimated): November 5, 2026
• Last Updated: April 27, 2026

Record last verified: 2025-11

Locations

US (2)