Ibrutinib in Treating Patients With Relapsed or Refractory Classical Hodgkin Lymphoma

A Phase II Multicenter Single Arm Study to Evaluate the Efficacy and Safety of Single Agent Bruton's Tyrosine Kinase Inhibitor, Ibrutinib, in Patients With Relapsed Refractory Classical Hodgkin's Lymphoma

This phase II trial evaluates how effective 560 mg of ibrutinib taken by mouth daily is in the treatment of classical Hodgkin lymphoma which recurs or does not respond to initial treatment. Ibrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth, by altering the environment around the tumor or by affecting the immune system.

Study Overview

• Status: Completed
• Conditions: Recurrent Hodgkin Lymphoma; Refractory Hodgkin Lymphoma; Classical Hodgkin Lymphoma
• Intervention / Treatment: Other: Laboratory Biomarker Analysis; Other: Pharmacological Study; Drug: Ibrutinib

Detailed Description

PRIMARY OBJECTIVES:

I. To determine the antitumor efficacy of single agent ibrutinib as measured by the overall response rate in patients with relapsed/refractory Hodgkin's lymphoma who have relapsed or not responded to chemotherapy, immunotherapy and/or radiation.

SECONDARY OBJECTIVES:

I. To assess duration of tumor control including duration of response (DOR) II. To assess progression free survival (PFS). III. To assess the safety and tolerability of 560mg of ibrutinib in Hodgkin lymphoma (HL) patients.

TERTIARY OBJECTIVES:

I. To assess the mechanism(s) by which ibrutinib may be active in patients with classical Hodgkin lymphoma (cHL) by the correlation of potential biomarkers with clinical outcomes.

OUTLINE:

Patients receive ibrutinib orally (PO) once daily (QD). Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days then every 9 weeks for 1 year.

• Study Type: Interventional
• Enrollment (Actual): 28
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan Health System
    • Detroit, Michigan, United States, 48201
      • Wayne State University/Karmanos Cancer Institute
  • Tennessee
    • Knoxville, Tennessee, United States, 37920
      • University of Tennessee
  • Texas
    • Houston, Texas, United States, 77030
      • M D Anderson Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria

• Patients with relapsed or refractory classical HL who have previously received autologous stem cell transplant and/or allogeneic stem cell transplant. Patients must have received prior autologous stem cell transplant at least 12 weeks (3 months) before the first dose of ibrutinib and/or allogeneic stem cell transplant must have been completed at least 6 months prior to the first dose of Ibrutinib. OR

• Patients with relapsed or refractory HL who have failed at least 2 lines of prior therapy and are not eligible for autologous stem cell transplant due to:

  • Inability to achieve a CR or PR prior to transplant
  • Age or comorbid conditions
  • Inability to collect stem cells
• Completion of any prior treatment with radiation, chemotherapy, biologics, and/or other investigational agents at least 4 weeks prior to the first dose of ibrutinib. Patients must have completed any prior immunotherapy (e.g., rituximab or PD-1 inhibition) or antibody drug conjugate therapy (e.g. brentuximab vedotin) at least 4 weeks prior to the first dose of ibrutinib in the absence of clear disease progression.
• Prior treatment with at least 2 lines of therapy for HL including brentuximab vedotin. In those patients who cannot receive brentuximab vedotin, treatment with 2 prior therapeutic regimens is sufficient.
• Fluorodeoxyglucose (FDG)-avid disease by PET and measurable disease of at least 1.5 cm in minimum dimension by CT scan with contrast, as assessed by the site radiologist.

• Adequate hematologic function independent of transfusion and growth factor support for at least 7 days prior to screening and randomization, with the exception of PEGylated GCSF (pegfilgrastim) and darbopoeitin which require at least 14 days prior to screening and randomization defined as:

  • Absolute neutrophil count >750 cells/mm3 (0.75 x 109/L).
  • Platelet count >50,000 cells/mm3 (50 x 109/L).
  • Hemoglobin >8.0 g/dL.

• Adequate hepatic and renal function defined as:

  • Serum aspartate transaminase (AST) or alanine transaminase (ALT) ≤ 3.0 x upper limit of normal (ULN).
  • Estimated Creatinine Clearance ≥30 ml/min (Cockcroft-Gault)
  • Bilirubin ≤1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin)
• PT/INR <1.5 x ULN and PTT (aPTT) <1.5 x ULN.
• Men and women ≥ 18 years of age.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2.
• Female subjects who are of non-reproductive potential (i.e., post-menopausal by history-no menses for ≥1 year; OR history of hysterectomy; OR history of bilateral tubal ligation; OR history of bilateral oophorectomy). Female subjects of childbearing potential must have a negative serum pregnancy test upon study entry.
• Male and female subjects who agree to use highly effective methods of birth control (e.g., condoms, implants, injectables, combined oral contraceptives, some intrauterine devices [IUDs], sexual abstinence, or sterilized partner) during the period of therapy and for 90 days after the last dose of study drug
• Sign (or their legally-acceptable representatives must sign) an informed consent document indicating that they understand the purpose of and procedures required for the study and are willing to participate in the study.

Exclusion Criteria:

• Prior allogeneic Stem cell transplant within 6 months.
• Active GVHD or concurrent treatment with immunosuppressive medications as prophylaxis for GVHD
• Previous therapy with BTK inhibition
• Known cerebral/meningeal disease
• Nodular lymphocyte predominant Hodgkin's Lymphoma subtype
• Concurrent therapy with other systemic anti-neoplastic or investigational agents
• Patients with a known hypersensitivity to any excipient contained in the drug formulation

• History of other malignancies, except:

  • Malignancy treated with curative intent and with no known active disease present for

    ≥3 years before the first dose of study drug and felt to be at low risk for recurrence by treating physician.

  • Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease.
  • Adequately treated carcinoma in situ without evidence of disease.
• Concurrent systemic immunosuppressant therapy (e.g., cyclosporine A, tacrolimus, etc., or chronic administration [>14 days] of >20 mg/day of prednisone) within 28 days of the first dose of study drug.
• Vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug
• Recent infection requiring systemic treatment that was completed ≤14 days before the first dose of study drug.
• Unresolved toxicities from prior anti-cancer therapy, defined as having not resolved to Common Terminology Criteria for Adverse Event (CTCAE, version 4), grade ≤1, or to the levels dictated in the inclusion/exclusion criteria with the exception of alopecia.
• Known bleeding disorders (e.g., von Willebrand's disease) or hemophilia.
• History of stroke or intracranial hemorrhage within 6 months prior to enrollment.
• Known history of human immunodeficiency virus (HIV) or active with hepatitis C virus (HCV) or hepatitis B virus (HBV). Subjects who are positive for hepatitis B core antibody or hepatitis B surface antigen must have a negative polymerase chain reaction (PCR) result before enrollment. Those who are PCR positive will be excluded.
• Any uncontrolled active systemic infection
• Major surgery within 4 weeks of first dose of study drug.
• Any life-threatening illness, medical condition, or organ system dysfunction that, in the investigator's opinion, could compromise the subject's safety or put the study outcomes at undue risk.
• Currently active, clinically significant cardiovascular disease, such as uncontrolled arrhythmia or Class 3 or 4 congestive heart failure as defined by the New York Heart Association Functional Classification; or a history of myocardial infarction, unstable angina, or acute coronary syndrome within 6 months prior to randomization
• Unable to swallow capsules or malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel, symptomatic inflammatory bowel disease or ulcerative colitis, or partial or complete bowel obstruction.
• Concomitant use of warfarin or other Vitamin K antagonists.
• Requires treatment with a strong cytochrome P450 (CYP) 3A4/5 inhibitor
• Currently active, clinically significant hepatic impairment Child-Pugh class B or C according to the Child Pugh classification
• Lactating or pregnant
• Unwilling or unable to participate in all required study evaluations and procedures.
• Unable to understand the purpose and risks of the study and to provide a signed and dated informed consent form (ICF) and authorization to use protected health information (in accordance with national and local subject privacy regulations).

Potential subjects must be willing and able to adhere to the following prohibitions and restrictions during the course of the study to be eligible for participation. During the study, subjects should avoid consuming food and beverages containing grapefruit or Seville oranges as these contain certain ingredients that inhibit CYP3A4/5 enzymes.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment (ibrutinib); Patients receive ibrutinib PO QD. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.	Other: Laboratory Biomarker Analysis; Correlative studies; Other: Pharmacological Study; Correlative studies; Drug: Ibrutinib; Given PO; Other Names: PCI-32765; BTK Inhibitor PCI-32765; CRA-032765

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Response Rate (ORR)	Overall response rate (ORR) defined as the proportion of participants having a complete (CR) and partial (PR) response. A one-sample binomial test will be used to assess ORR.	From date of study entry to date of progression or death up to 24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Duration of Response (DOR)	Kaplan-Meier estimate of median DOR will be reported with 95% confidence intervals.	From date of documented tumor response, CR or PR, to date of disease progression or death, up to 24 months
Progression Free Survival (PFS)	Kaplan-Meier estimate of median PFS will be reported with 95% confidence intervals.	From date of study entry to date of progression or death up to 24 months.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Identify which genes and immune alterations are affected by ibrutinib.	analysis of tumor and blood samples for gene expression, mutation analysis, and immune alterations.	From date of study entry until completion of testing up to 24 months

Collaborators and Investigators

• Sponsor: Barbara Ann Karmanos Cancer Institute
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Dipenkumar Modi, M.D., Barbara Ann Karmanos Cancer Institute

Publications and helpful links

General Publications

• Muqbil I, Chaker M, Aboukameel A, Mohammad RM, Azmi AS, Ramchandren R. Pre-clinical anti-tumor activity of Bruton's Tyrosine Kinase inhibitor in Hodgkin's Lymphoma cellular and subcutaneous tumor model. Heliyon. 2019 Aug 31;5(8):e02290. doi: 10.1016/j.heliyon.2019.e02290. eCollection 2019 Aug.

Study record dates

Study Major Dates

• Study Start: June 1, 2016
• Primary Completion (Actual): May 12, 2023
• Study Completion (Actual): January 8, 2025

Study Registration Dates

• First Submitted: June 20, 2016
• First Submitted That Met QC Criteria: June 30, 2016
• First Posted (Estimated): July 6, 2016

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: January 27, 2025
• Last Verified: January 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Immune System Diseases; Neoplasms by Histologic Type; Lymphatic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Lymphoma; Hodgkin Disease; Tyrosine Kinase Inhibitors; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protein Kinase Inhibitors; Ibrutinib
• Other Study ID Numbers: 2016-033 (Other Identifier: Wayne State University/Karmanos Cancer Institute); P30CA022453 (U.S. NIH Grant/Contract); NCI-2016-00879 (Registry Identifier: CTRP (Clinical Trial Reporting Program))