Clinical Trials /

Ibrutinib and Rituximab in Treating Patients With Relapsed or Refractory Mantle Cell Lymphoma or Older Patients With Newly Diagnosed Mantle Cell Lymphoma

NCT01880567

Description:

This phase II trial studies how well ibrutinib and rituximab work in treating patients with mantle cell lymphoma that has come back or has not responded to treatment or older patients with newly diagnosed mantle cell lymphoma. Ibrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as rituximab, may find cancer cells and help kill them. Giving ibrutinib and rituximab may be an effective treatment for mantle cell lymphoma.

Related Conditions:
  • Mantle Cell Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Ibrutinib and Rituximab in Treating Patients With Relapsed or Refractory Mantle Cell Lymphoma or Older Patients With Newly Diagnosed Mantle Cell Lymphoma
  • Official Title: A Phase II Study of Ibrutinib Plus Rituximab in Patients With Relapsed/Refractory Mantle Cell Lymphoma or Elderly Patients With Newly Diagnosed MCL

Clinical Trial IDs

  • ORG STUDY ID: 2013-0090
  • SECONDARY ID: NCI-2013-01304
  • SECONDARY ID: 2013-0090
  • SECONDARY ID: P30CA016672
  • NCT ID: NCT01880567

Conditions

  • CCND1 Positive
  • CCND2 Positive
  • CCND3 Positive
  • CD20 Positive
  • Mantle Cell Lymphoma
  • Recurrent Mantle Cell Lymphoma
  • Refractory Mantle Cell Lymphoma

Interventions

DrugSynonymsArms
IbrutinibBTK Inhibitor PCI-32765, CRA-032765, Imbruvica, PCI-32765Treatment (ibrutinib, rituximab)
RituximabABP 798, BI 695500, C2B8 Monoclonal Antibody, Chimeric Anti-CD20 Antibody, CT-P10, IDEC-102, IDEC-C2B8, IDEC-C2B8 Monoclonal Antibody, MabThera, Monoclonal Antibody IDEC-C2B8, PF-05280586, Rituxan, Rituximab Biosimilar ABP 798, Rituximab Biosimilar BI 695500, Rituximab Biosimilar CT-P10, Rituximab Biosimilar GB241, Rituximab Biosimilar IBI301, Rituximab Biosimilar PF-05280586, Rituximab Biosimilar RTXM83, Rituximab Biosimilar SAIT101, RTXM83Treatment (ibrutinib, rituximab)

Purpose

This phase II trial studies how well ibrutinib and rituximab work in treating patients with mantle cell lymphoma that has come back or has not responded to treatment or older patients with newly diagnosed mantle cell lymphoma. Ibrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as rituximab, may find cancer cells and help kill them. Giving ibrutinib and rituximab may be an effective treatment for mantle cell lymphoma.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To evaluate the response rate of ibrutinib plus rituximab in patients with relapsed and/or
      refractory mantle cell lymphoma (MCL).

      II. To evaluate the safety and response rate of ibrutinib plus rituximab in elderly patients
      (> 65) with newly-diagnosed, untreated MCL.

      SECONDARY OBJECTIVES:

      I. To further evaluate the toxicity profile of the combination of ibrutinib and rituximab in
      patients with relapsed and/or refractory MCL.

      II. To estimate the overall response rate (ORR); (partial response [PR] or better), the
      response duration (DOR), progression-free survival (PFS), time to progression (TTP) and
      overall survival (OS) in patients with relapsed and/or refractory MCL; clinical benefit
      response (CBR) = (minimal response [MR] + ORR) will also be evaluated.

      III. To estimate the response duration, PFS, time to progression (TTP), and OS in elderly
      patients (> 65) with newly-diagnosed, untreated MCL.

      TERTIARY OBJECTIVES:

      I. To correlate detected gene mutations and changes in gene and/or protein expression with
      response to treatment.

      OUTLINE:

      Patients receive ibrutinib orally (PO) daily on days 1-28 and rituximab intravenously (IV)
      over 4-8 hours on days 1, 8, 15, and 22 of course 1; on day 1 of courses 3-8; and on day 1 of
      every other course for all subsequent courses. Treatment with rituximab repeats every 28 days
      for up to 2 years in the absence of disease progression or unacceptable toxicity. Courses
      with ibrutinib repeat every 28 days in the absence of disease progression or unacceptable
      toxicity.

      After completion of study treatment, patients are followed up every 3 months for 1 year and
      then every 6 months thereafter.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (ibrutinib, rituximab)ExperimentalPatients receive ibrutinib PO daily on days 1-28 and rituximab IV over 4-8 hours on days 1, 8, 15, and 22 of course 1; on day 1 of courses 3-8; and on day 1 of every other course for all subsequent courses. Treatment with rituximab repeats every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Courses with ibrutinib repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Ibrutinib
  • Rituximab

Eligibility Criteria

        Inclusion Criteria:

          -  Relapsed/refractory MCL: Confirmed diagnosis of mantle cell lymphoma with cluster of
             differentiation (CD)20 and cyclin D1 through cyclin D3 positivity in tissue biopsy

          -  Relapsed/refractory MCL: Patient has relapsed and or refractory MCL and must have
             received at least one prior treatment regimen for their disease; patient with leukemia
             phase (peripheral blood involvement), leptomeningeal disease, cerebral spinal fluid
             (CSF) MCL, central nervous system (CNS) MCL, non-measurable disease, gastrointestinal
             (GI) MCL, or bone marrow (BM) MCL are also eligible

          -  Relapsed/refractory MCL: Understand and voluntarily sign an Institutional Review Board
             (IRB)-approved informed consent form

          -  Relapsed/refractory MCL: Patients with bone marrow or gastrointestinal (GI) only
             involvement are acceptable

          -  Relapsed/refractory MCL: Eastern Cooperative Oncology Group (ECOG) performance status
             of 2 or less

          -  Relapsed/refractory MCL: Absolute neutrophil count (ANC) >= 500/mm^3; (patients who
             have bone marrow infiltration by MCL are eligible if their ANC is >= 500/mm^3 [growth
             factor allowed]; these patients should be discussed with either the principal
             investigator [PI] or Co-PI of the study for final approval)

          -  Relapsed/refractory MCL: Platelet count >= 30,000/mm^3 (transfusion to reach platelet
             count allowed); (patients who have bone marrow infiltration by MCL are eligible if
             their platelet level is equal to or > than 15,000/mm^3; these patients should be
             discussed with either the PI or Co-PI of the study for final approval)

          -  Relapsed/refractory MCL: Aspartate transaminase (AST) (serum glutamic oxaloacetic
             transaminase [SGOT]) and alanine transaminase (ALT) (serum glutamate pyruvate
             transaminase [SGPT]) < 2 x upper limit of normal or < 5 x upper limit of normal if
             hepatic metastases are present

          -  Relapsed/refractory MCL: Serum bilirubin < 1.5 mg/dl

          -  Relapsed/refractory MCL: Creatinine (Cr) clearance >= 30 mL/min

          -  Relapsed/refractory MCL: Patients must be willing to receive transfusions of blood
             products

          -  Relapsed/refractory MCL: Willing and able to participate in all study related
             procedures and therapy including swallowing capsules without difficulty

          -  Newly diagnosed MCL: Confirmed diagnosis of MCL with CD20 and cyclin D1 positivity in
             tissue biopsy; patients must have never received any prior therapy for their disease

          -  Newly diagnosed MCL: Understand and voluntarily sign an IRB-approved informed consent
             form

          -  Newly diagnosed MCL: Age > 65 years at the time of signing the informed consent

          -  Newly diagnosed MCL: Patients should in general have bi-dimensional measurable disease
             with their biggest tumor less than 10 cm; (bone marrow or gastrointestinal [GI] only
             involvement is acceptable)

          -  Newly diagnosed MCL: Eastern Cooperative Oncology Group (ECOG) performance status of 2
             or less

          -  Newly diagnosed MCL: Absolute neutrophil count (ANC) > 750/mm^3; patients who have
             bone marrow infiltration by MCL are eligible if their ANC is equal to or > than 500

          -  Newly diagnosed MCL: Platelet count > 50,000/mm^3; patients who have bone marrow
             infiltration by MCL are eligible if their platelet level is equal to or > than 15,000
             /mm^3; (platelet transfusions are allowed; these patients should be discussed with
             either the PI or Co-PI of the study for final approval)

          -  Newly diagnosed MCL: AST (SGOT) and ALT (SGPT) < 2 x upper limit of normal or < 5 x
             upper limit of normal if hepatic metastases are present

          -  Newly diagnosed MCL: Uric acid within normal limits (allopurinol is allowed to bring
             abnormal level to within normal limits)

          -  Newly diagnosed MCL: Serum bilirubin < 1.5 mg/dl

          -  Newly diagnosed MCL: Creatinine (Cr) Clearance >= 30 mL/min

          -  Newly diagnosed MCL: Ki67 protein (Ki67) < 50%

          -  Newly diagnosed MCL: Disease free of prior malignancies of equal to or greater than 6
             months with exception of currently treated basal cell, squamous cell carcinoma of the
             skin, carcinoma "in situ" of the cervix or breast, or other malignancies in remission
             (including prostate cancer patients in remission from radiation therapy, surgery or
             brachytherapy), not actively being treated, with a life expectancy > 3 years

          -  Newly diagnosed MCL: Patients must be willing to receive transfusions of blood
             products

          -  Newly diagnosed MCL: Willing and able to participate in all study related procedures
             and therapy including swallowing capsules without difficulty

        Exclusion Criteria:

          -  Relapsed/refractory MCL: Any serious medical condition that places the patient at
             unacceptable risk and/or would prevent the subject from signing the informed consent
             form; examples include but are not limited to, uncontrolled hypertension, uncontrolled
             diabetes mellitus, active/symptomatic coronary artery disease, active infection,
             active hemorrhage, or psychiatric illness

          -  Relapsed/refractory MCL: Pregnant or breast feeding females

          -  Relapsed/refractory MCL: Known human immunodeficiency virus (HIV) infection; patients
             with active hepatitis B infection (not including patients with prior hepatitis B
             vaccination; or positive serum hepatitis B antibody); known hepatitis C infection is
             allowed as long as there is no active disease and is cleared by gastrointestinal (GI)
             consultation

          -  Relapsed/refractory MCL: The patient has a prior or concurrent malignancy that in the
             opinion of the investigator, presents a greater risk to the patient's health and
             survival, than of the MCL, within the subsequent 6 months at the time of consent

          -  Relapsed/refractory MCL: History of stroke or intracranial hemorrhage within 6 months
             prior to signing the consent

          -  Relapsed/refractory MCL: Clinically significant cardiovascular disease such as
             uncontrolled or symptomatic arrhythmias, congestive heart failure or myocardial
             infarction within 6 months at the time of consent or any class 3 (moderate) or 4
             (severe) cardiac disease defined by the New York Heart Association classification

          -  Relapsed/refractory MCL: Significant screening electrocardiogram (ECG) abnormalities
             including left bundle branch block, 2nd degree atrioventricular (AV) block type II,
             3rd degree block, bradycardia (< 50 beats per minute [bpm]), or corrected QT (QTc) >
             500 msec

          -  Relapsed/refractory MCL: Malabsorption syndrome, disease significantly affecting
             gastrointestinal function, or resection of the stomach or small bowel or ulcerative
             colitis, symptomatic inflammatory bowel disease, or partial or complete bowel
             obstruction

          -  Relapsed/refractory MCL: Prior chemotherapy within 3 weeks, nitrosoureas within 6
             weeks, therapeutic anticancer antibodies within 4 weeks, radio- or
             toxin-immunoconjugates within 10 weeks, radiation therapy or other investigational
             agents within 3 weeks, major surgery within 4 weeks or vaccination with live
             attenuated vaccines within 4 weeks of the first dose of study drug

          -  Relapsed/refractory MCL: Prior treatment with ibrutinib

          -  Relapsed/refractory MCL: Requires anticoagulation with warfarin or equivalent vitamin
             K antagonist

          -  Relapsed/refractory MCL: Requires treatment with strong cytochrome P450, family 3,
             subfamily A, polypeptide 4/5 (CYP3A4/5) inhibitors

          -  Newly Diagnosed MCL: Any serious medical condition that places the patient at
             unacceptable risk and/or would prevent the subject from signing the informed consent
             form; examples include but are not limited to, uncontrolled hypertension, uncontrolled
             diabetes mellitus, active/symptomatic coronary artery disease, active infection
             requiring treatment with systemic antibiotics, antiviral or antifungal agents, active
             hemorrhage, or psychiatric illness

          -  Newly diagnosed MCL: Known HIV infection; patients with active hepatitis B infection
             (not including patients with prior hepatitis B vaccination; or positive serum
             Hepatitis B antibody); known hepatitis C infection is allowed as long as there is no
             active disease and is cleared by GI consultation

          -  Newly diagnosed MCL: The patient has a prior or concurrent malignancy that in the
             opinion of the investigator, presents a greater risk to the patient's health and
             survival, than of the MCL, within the subsequent 6 months at the time of consent

          -  Newly diagnosed MCL: History of stroke or intracranial hemorrhage within 6 months
             prior to signing the consent

          -  Newly diagnosed MCL: Clinically significant cardiovascular disease such as
             uncontrolled or symptomatic arrhythmias, congestive heart failure or myocardial
             infarction within 6 months at the time of consent or any class 3 (moderate) or 4
             (severe) cardiac disease defined by the New York Heart Association Classification

          -  Newly diagnosed MCL: Significant screening electrocardiogram (ECG) abnormalities
             including left bundle branch block, 2nd degree AV block type II, 3rd degree block,
             bradycardia (< 50 bpm), or QTc > 500 msec

          -  Newly diagnosed MCL: Malabsorption syndrome, disease significantly affecting
             gastrointestinal function, or resection of the stomach or small bowel or ulcerative
             colitis, symptomatic inflammatory bowel disease, or partial or complete bowel
             obstruction

          -  Newly diagnosed MCL: Major surgery within 4 weeks or vaccination with live attenuated
             vaccines within 4 weeks of the first dose of study drug

          -  Newly diagnosed MCL: Prior treatment with ibrutinib

          -  Newly diagnosed MCL: Requires concomitant anticoagulation with warfarin or equivalent
             vitamin K antagonist

          -  Newly diagnosed MCL: Requires treatment with strong CYP3A4/5 inhibitors

          -  Newly diagnosed MCL: Patients with blastoid and pleomorphic variants

          -  Newly diagnosed MCL: Ki-67 to be equal or more than 50%

          -  Newly diagnosed MCL: Central nervous system lymphoma

          -  Newly diagnosed MCL: Patients with bi-dimensional measurable disease with a tumor >=
             10 cm
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall response (complete response and partial response), assessed by the International Workshop Standardized Response Criteria for non-Hodgkin lymphoma
Time Frame:Up to 8 weeks
Safety Issue:
Description:Overall response will be monitored using the Bayesian stopping boundaries calculated based on beta-binomial distribution.

Secondary Outcome Measures

Measure:Clinical benefit response (minimal response + overall response rate),
Time Frame:Up to 6 years
Safety Issue:
Description:Will be assessed by the International Workshop Standardized Response Criteria for non-Hodgkin lymphoma.
Measure:Duration of response
Time Frame:Up to 6 years
Safety Issue:
Description:Duration of response will be estimated using the method of Kaplan and Meier. Comparison by important subgroups will be made using the log-rank test. Cox proportional hazards will be employed for multivariate analysis.
Measure:Progression-free survival
Time Frame:Up to 6 years
Safety Issue:
Description:Progression-free survival will be estimated using the method of Kaplan and Meier. Comparison of time-to-event endpoints by important subgroups will be made using the log-rank test. Cox proportional hazard regression will be employed for multivariate analysis on time-to-events outcomes.
Measure:Time to progression
Time Frame:Up to 6 years
Safety Issue:
Description:Comparison of time-to-event endpoints by important subgroups will be made using the log-rank test. Cox proportional hazard regression will be employed for multivariate analysis on time-to-events outcomes.
Measure:Overall survival
Time Frame:Up to 6 years
Safety Issue:
Description:Overall survival will be estimated using the method of Kaplan and Meier. Comparison by important subgroups will be made using the log-rank test. Cox proportional hazards will be employed for multivariate analysis.
Measure:Duration of response in elderly patients with newly diagnosed, untreated mantle cell lymphoma
Time Frame:Up to 6 years
Safety Issue:
Description:Intend-to-treat analysis will be applied to the eligible patients.
Measure:Progression-free survival in elderly patients with newly diagnosed, untreated mantle cell lymphoma
Time Frame:Up to 6 years
Safety Issue:
Description:Intend-to-treat analysis will be applied to the eligible patients.
Measure:Overall survival in elderly patients with newly diagnosed, untreated mantle cell lymphoma
Time Frame:Up to 6 years
Safety Issue:
Description:Overall response will be monitored using the Bayesian stopping boundaries calculated based on beta-binomial distribution.
Measure:Time to progression in elderly patients with newly diagnosed, untreated mantle cell lymphoma
Time Frame:Up to 6 years
Safety Issue:
Description:

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:M.D. Anderson Cancer Center

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