Ibrutinib After Intensive Induction in Treating Patients With Previously Untreated Mantle Cell Lymphoma

A Phase II Clinical Trial Evaluating Ibrutinib Maintenance Following Intensive Induction for Patients With Previously Untreated Mantle Cell Lymphoma (MCL)

This study is being done to see whether or not a drug called ibrutinib can be given to patients with mantle cell lymphoma (MCL) as maintenance therapy after induction chemotherapy. This drug blocks an enzyme that affects how the lymphocytes grow and survive. The investigators hope to learn how safe and effective ibrutinib is for treating patients with MCL after responding to induction chemotherapy.

Study Overview

• Status: Active, not recruiting
• Conditions: Stage III Mantle Cell Lymphoma; Stage IV Mantle Cell Lymphoma; Contiguous Stage II Mantle Cell Lymphoma; Noncontiguous Stage II Mantle Cell Lymphoma; Stage I Mantle Cell Lymphoma
• Intervention / Treatment: Other: laboratory biomarker analysis; Drug: ibrutinib

Detailed Description

PRIMARY OBJECTIVES:

I. To determine the progression-free survival (PFS) rate after 3 years.

SECONDARY OBJECTIVES:

I. Assess toxicity. II. Determine rates of conversion from partial response (PR) to complete response (CR).

III. Determine median overall survival (OS) after 4 years.

TERTIARY OBJECTIVES:

I. Compare minimal residual disease (MRD) results overtime by polymerase chain reaction (PCR) and correlate these with PFS and OS.

OUTLINE:

Patients receive ibrutinib orally (PO) once daily (QD) on days 1-28. Courses repeat every 28 days for up to 4 years in the absence of disease progression, unacceptable toxicity or patient preference.

After completion of study treatment, patients who completed 4 years of treatment are followed up at 30 days. Patients who did not complete 4 years of treatment are followed up for up to 4 years post-first dose of treatment (every 3 months for 2 years and then every 6 months for 4 years).

• Study Type: Interventional
• Enrollment (Actual): 37
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University
    • Lake Forest, Illinois, United States, 60045
      • Northwestern University- Lake Forest Hospital
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Dana-Farber Cancer Institute
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • University of Utah

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Patients must have histologically confirmed mantle cell lymphoma (MCL)

  • Please note: Measurable disease is not required, but will be followed if it exists

• Patients must have received 4 or more cycles of one of the following prior systemic induction chemotherapy regimens:

  • Rituximab, cyclophosphamide, doxorubicin hydrochloride (hydroxydaunomycin), vincristine sulfate (Oncovin), prednisone (R-CHOP) (with or without alternating rituximab, dexamethasone, cytarabine [ara-c], cisplatin [platinum] [R-DHAP]) with or without autologous (auto) stem cell transplant (SCT)
  • Hyper-cyclophosphamide, vincristine sulfate, doxorubicin hydrochloride (adriamycin), dexamethasone (CVAD) with or without auto SCT

  • Bendamustine + rituximab with or without auto SCT

    • Please note:

      • Patients who received combinations of the above regimens are not eligible for enrollment
      • At the time of registration, patients must be at least 14 days out from last dose of cytotoxic chemotherapy, but no more than 90 days; if a patient underwent auto SCT, he/she must demonstrate engraftment (per treating investigator's discretion) and must meet all other hematological requirements as outlined below
• Patients must have achieved a response to induction chemotherapy (either CR or PR by Cheson 2007 criteria) and be without known progression
• Patients may have received prior radiotherapy
• Patients must exhibit an Eastern Cooperative Oncology Group (ECOG) performance status =< 2
• Absolute neutrophil count (ANC) >= 1000/mm^3, independent of growth factor support
• Platelets >= 100,000/mm^3, or >= 50,000 in cases of ongoing bone marrow involvement (in either case, these must be independent of transfusion support)
• Total bilirubin =< 1.5 x upper limit of normal (ULN)
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SPGT]) =< 3 x ULN
• Creatinine clearance >= 25 ml/min
• Please note: Patients who do not meet the above criteria because of Gilbert's Syndrome are still eligible

• Women of child-bearing potential (WOCBP) and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation (see timelines below for women and men); in addition, men must agree not to donate sperm during and after study participation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately

  • NOTE: For female patients, these restrictions apply for 1 month after the last dose of study drug; for male patients, these restrictions apply for 3 months after the last dose of study drug

  • NOTE: A female of child-bearing potential is any woman (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria:

    • Has not undergone a hysterectomy or bilateral oophorectomy; or
    • Has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months)
• Female patients must have a negative pregnancy test (blood or urine) within 28 days prior to registration
• Patients must be willing and able to avoid consuming food and beverages containing grapefruit or Seville oranges while on ibrutinib study therapy
• Patients must have the ability to understand and the willingness to sign a written informed consent prior to registration on study

Exclusion Criteria:

• Patients who have received >= 7 days of prior ibrutinib or any prior treatment with another Bruton tyrosine kinase (BTK) inhibitor are not eligible
• Patients receiving ongoing treatment with any other investigational agents are not eligible
• Patients receiving live/attenuated vaccinations within 4 weeks prior to registration are not eligible
• Patients with a known central nervous system (CNS) involvement of lymphoma are not eligible (CNS staging not required)
• Patients who have undergone major surgery within 4 weeks prior to registration are not eligible

• Patients diagnosed or treated for malignancy other than MCL are not eligible unless they meet one of the following exceptions:

  • Malignancy treated with curative intent and with no known active disease present for >= 3 years before registration and felt to be at low risk for recurrence by the treating physician
  • Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
  • Adequately treated cervical carcinoma in situ without evidence of disease
• Patients with a history of stroke or intracranial hemorrhage within 6 months prior to registration are not eligible
• Patients who require anticoagulation with warfarin or equivalent vitamin K antagonists are not eligible

• Patients who require chronic treatment with strong cytochrome P450, family 3, subfamily A, polypeptide 4/5 (CYP3A4/5) inhibitors are not eligible

  • NOTE: Patients who are currently on treatment with strong CYP3A4/5 inhibitors may be eligible if they are able to be switched to an alternative therapy that is not a strong CYP3A4/5 inhibitor prior to registration on study
• Patients with a history of allergic reactions attributed to compounds of similar chemical or biologic composition to ibrutinib are not eligible

• Patients with uncontrolled intercurrent illness including, but not limited to, any of the following are not eligible:

  • Ongoing or active systemic infection
  • Symptomatic congestive heart failure
  • Myocardial infarction within 6 months prior to registration
  • Unstable angina pectoris
  • Uncontrolled or symptomatic cardiac arrhythmias
  • Any class 3 (moderate) or class 4 (severe) cardiac disease as defined by the New York Heart Association Functional Classification
  • Psychiatric illness/social situations that would limit compliance with study requirements
• Patients who have any life-threatening illness, medical condition, or organ system dysfunction which, in the investigator's opinion, could compromise the subject's safety, interfere with the absorption or metabolism of ibrutinib capsules, or put the study outcomes at risk are not eligible
• Patients with a known human immunodeficiency virus (HIV) infection are not eligible (HIV testing not required)
• Patients with a known John Cunningham (JC) virus infection and/or progressive multifocal leukoencephalopathy (PML) are not eligible
• Patients with clinically active hepatitis A, B, or C infections are not eligible
• Female patients who are pregnant and/or lactating are not eligible

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 orally PO QD on days 1-28. Courses repeat every 28 days for up to 4 years in the absence of disease progression, unacceptable toxicity, or patient preference.	Other: laboratory biomarker analysis; Correlative studies; Drug: ibrutinib; Given PO; Other Names: PCI-32765; Imbruvica; CRA-032765; Bruton's tyrosine kinase inhibitor PCI-32765; BTK inhibitor PCI-32765

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Determine the Progression-free Survival (PFS) Rate After 3 Years	PFS will be measured from start of treatment to time of progression. Evidence of clinical progression will be documented by imaging (CT scan) for patients who have measurable disease. Progression is defined using the LUGANO Criteria, as a Deauville score of 4 or 5 (increased uptake compared to baseline) or the appearance of new lesions	Assessed at 3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Adverse Events, Defined According to the National Cancer Institute's Common Terminology Criteria for Adverse Events Version 4.0	To assess toxicity, all adverse events will be summarized as to type, severity, frequency, timing and attribution. Treatment related Adverse Events Occurring with Incidence of greater that or equal to 20% of patients treated with Ibrutinib Maintenance are shown here.	Up to 30 days after completion of study treatment, maximum 4 years post-first dose
Rate of Conversion From Partial Response (PR) to Complete Response (CR)	Progression will be evaluated using Cheson 2007 criteria, only patients who had a PR at the time of registration and who complete ≥ 1 complete cycle of ibrutinib maintenance therapy will be evaluable for this endpoint.	Up to 4 years
Overall Survival (OS) After 4 Years	Patients will be evaluated monthly for the first 6 months on treatment, then every 3 months thereafter. Patients who go off treatment will continue to be followed for up to 4 years post-first dose. Follow-up will occur every 3 months (up to 2 years after the first dose of treatment) and then every 6 months thereafter (up to 4 years post-first dose). OS after 4 years will be calculated as a percentage of patient alive.	Up to 4 years post-first dose

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Compare Minimum Residual Disease (MRD) Results Overtime by Polymerase Chain Reaction (PCR) and Correlate These With PFS and OS	Archived tissue from a previous biopsy from all patients will be obtained for baseline clone identification; in addition, peripheral whole blood samples will be collected at four time points. MRD analysis will be conducted using PCR methods and results will be compared over time and correlated with PFS and OS.	Four time-points: baseline (pre-treatment), after 1 month and 6 months of treatment, and approximately 18-24 months post-first dose of treatment

Collaborators and Investigators

• Sponsor: Northwestern University
• Collaborators: National Cancer Institute (NCI); Janssen Scientific Affairs, LLC
• Investigators: Principal Investigator: Barbara Pro, MD, Northwestern University

Study record dates

Study Major Dates

• Study Start (Actual): January 12, 2015
• Primary Completion (Actual): January 5, 2023
• Study Completion (Estimated): January 1, 2025

Study Registration Dates

• First Submitted: September 12, 2014
• First Submitted That Met QC Criteria: September 12, 2014
• First Posted (Estimated): September 16, 2014

Study Record Updates

• Last Update Posted (Actual): March 12, 2024
• Last Update Submitted That Met QC Criteria: February 16, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma, Non-Hodgkin; Lymphoma; Lymphoma, Mantle-Cell; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protein Kinase Inhibitors; Ibrutinib; Tyrosine Kinase Inhibitors
• Other Study ID Numbers: NU 14H06 (Other Identifier: Northwestern University); P30CA060553 (U.S. NIH Grant/Contract); NCI-2014-01777 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); PCI-32765MCL2003; STU00098385