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

• ClinicalTrials.gov Identifier: NCT02242097
• Recruitment Status: Active, not recruiting
• First Posted: September 16, 2014
• Last Update Posted: December 17, 2018
• Sponsor: Northwestern University
• Collaborators: Janssen Scientific Affairs, LLC; National Cancer Institute (NCI)
• Information provided by (Responsible Party): Northwestern University

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Contiguous Stage II Mantle Cell Lymphoma; Noncontiguous Stage II Mantle Cell Lymphoma; Stage I Mantle Cell Lymphoma; Stage III Mantle Cell Lymphoma; Stage IV Mantle Cell Lymphoma	Drug: ibrutinib; Other: laboratory biomarker analysis	Phase 2

Detailed Description:

PRIMARY OBJECTIVES:

I. To determine the progression-free survival (PFS) rate after 2 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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 36 participants
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Clinical Trial Evaluating Ibrutinib Maintenance Following Intensive Induction for Patients With Previously Untreated Mantle Cell Lymphoma (MCL)
• Study Start Date: January 2015
• Estimated Primary Completion Date: June 2019
• Estimated Study Completion Date: January 2020

Arms and Interventions

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.	Drug: ibrutinib; Given PO; Other Names: Bruton's tyrosine kinase inhibitor PCI-32765; BTK inhibitor PCI-32765; CRA-032765; Imbruvica; PCI-32765; Other: laboratory biomarker analysis; Correlative studies

Outcome Measures

Primary Outcome Measures :

1. Determine the progression-free survival (PFS) rate after 2 years [ Time Frame: Assessed at 2 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.

Secondary Outcome Measures :

1. Incidence of adverse events, defined according to the National Cancer Institute's Common Terminology Criteria for Adverse Events version 4.0 [ Time Frame: Up to 30 days after completion of study treatment, maximum 4 years post-first dose ]
   To assess toxicity, all adverse events will be summarized as to type, severity, frequency, timing and attribution.
2. Rate of conversion from Partial Response (PR) to Complete Response (CR) [ Time Frame: Up to 4 years ]
   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.
3. Determine median Overall Survival (OS) after 4 years [ Time Frame: Up to 4 years post-first dose ]
   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). Median OS after 4 years will be calculated.

Other Outcome Measures:

1. Compare Minimum Residual Disease (MRD) results overtime by Polymerase Chain Reaction (PCR) and correlate these with PFS and OS [ Time Frame: Four time-points: baseline (pre-treatment), after 1 month and 6 months of treatment, and approximately 18-24 months post-first dose of treatment ]
   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.

Eligibility Criteria

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

Criteria

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

Contacts and Locations

Locations

United States, Illinois

Northwestern University

Chicago, Illinois, United States, 60611

Northwestern University- Lake Forest Hospital

Lake Forest, Illinois, United States, 60045

United States, Massachusetts

Dana-Farber Cancer Institute

Boston, Massachusetts, United States, 02215

United States, Ohio

Cleveland Clinic

Cleveland, Ohio, United States, 44195

United States, Utah

University of Utah

Salt Lake City, Utah, United States, 84132

Sponsors and Collaborators

Northwestern University

Janssen Scientific Affairs, LLC

National Cancer Institute (NCI)

Investigators

• Principal Investigator: Barbara Pro, MD; Northwestern University

More Information

• Responsible Party: Northwestern University
• ClinicalTrials.gov Identifier: NCT02242097 History of Changes
• Other Study ID Numbers: NU 14H06; NCI-2014-01777 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); PCI-32765MCL2003; STU00098385; NU 14H06 ( Other Identifier: Northwestern University ); P30CA060553 ( U.S. NIH Grant/Contract )
• First Posted: September 16, 2014
• Last Update Posted: December 17, 2018
• Last Verified: December 2018

Additional relevant MeSH terms:

Lymphoma; Lymphoma, Mantle-Cell; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Lymphoma, Non-Hodgkin