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Nivolumab and Ibrutinib in Treating Patients With Relapsed or Refractory Central Nervous System Lymphoma

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ClinicalTrials.gov Identifier: NCT03770416
Recruitment Status : Recruiting
First Posted : December 10, 2018
Last Update Posted : May 20, 2019
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
M.D. Anderson Cancer Center

Brief Summary:
This phase II trial studies the side effects and how well nivolumab and ibrutinib works in treating patients with central nervous system lymphoma that has come back or does not respond to treatment. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Ibrutinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving nivolumab and ibrutinib may work better in treating patients with central nervous system lymphoma.

Condition or disease Intervention/treatment Phase
Central Nervous System B-Cell Non-Hodgkin Lymphoma Recurrent Central Nervous System Lymphoma Refractory Central Nervous System Lymphoma Drug: Ibrutinib Biological: Nivolumab Phase 2

Detailed Description:

PRIMARY OBJECTIVES:

I. Determine the overall response rate of nivolumab and ibrutinib in central nervous system (CNS) lymphoma.

SECONDARY OBJECTIVES:

I. Determine the overall response rate of 4 weeks of ibrutinib single agent in CNS lymphoma.

II. Determine the complete response rate of nivolumab and ibrutinib in CNS lymphoma.

III. Determine the 1-year progression free and overall survival outcomes in CNS lymphoma.

IV. Safety and toxicity of nivolumab and ibrutinib.

EXPLORATORY OBJECTIVES:

I. Assess activation of T cells in peripheral blood and cerebrospinal fluid. II. Assess the cytokine profile from microglial cells in cerebrospinal fluid. III. Correlate features of peripheral blood T cell activation with toxicities. IV. Correlate features of peripheral blood T cell activation with response and progression free survival (PFS).

V. Correlate baseline tumor characteristics with response and PFS. VI. Evaluate the ability of minimal residual disease testing to monitor response and differentiate from pseudo progression.

OUTLINE: Patients are assigned to 1 of 2 cohorts.

COHORT A: Patients receive ibrutinib orally (PO) daily on days 1-28. Beginning course 1, patients also receive nivolumab intravenously (IV) over 1 hour on days 1 and 15. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

COHORT B: Patients receive ibrutinib PO daily on days 1-28 and nivolumab IV over 1 hour on days 1 and 15. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

Patients who achieve at least a partial response after 6 courses may continue therapy for up to 2 years.

After completion of study treatment, patients are followed up within 3-4 weeks and then every 3 months for 2 years.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 40 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Nivolumab and Ibrutinib for Relapsed or Refractory Central Nervous System Lymphoma
Actual Study Start Date : February 15, 2019
Estimated Primary Completion Date : June 15, 2023
Estimated Study Completion Date : June 15, 2023


Arm Intervention/treatment
Experimental: Cohort A
Patients receive ibrutinib PO daily on days 1-28. Beginning course 1, patients also receive nivolumab IV over 1 hour on days 1 and 15. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients who achieve at least a partial response after 6 courses may continue therapy for up to 2 years.
Drug: Ibrutinib
Given PO
Other Names:
  • BTK Inhibitor PCI-32765
  • CRA-032765
  • Imbruvica
  • PCI-32765

Biological: Nivolumab
Given IV
Other Names:
  • BMS-936558
  • MDX-1106
  • NIVO
  • ONO-4538
  • Opdivo

Experimental: Cohort B
Patients receive ibrutinib PO daily on days 1-28 and nivolumab IV over 1 hour on days 1 and 15. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients who achieve at least a partial response after 6 courses may continue therapy for up to 2 years.
Drug: Ibrutinib
Given PO
Other Names:
  • BTK Inhibitor PCI-32765
  • CRA-032765
  • Imbruvica
  • PCI-32765

Biological: Nivolumab
Given IV
Other Names:
  • BMS-936558
  • MDX-1106
  • NIVO
  • ONO-4538
  • Opdivo




Primary Outcome Measures :
  1. Overall response rate (ORR) [ Time Frame: Up to 2 years ]
    The overall response rate and its 95% confidence interval will be estimated. Fisher's exact test will be used to evaluate the association between response and other categorical patient variables.


Secondary Outcome Measures :
  1. ORR [ Time Frame: At 4 weeks of ibrutinib single agent ]
    The overall response rate and its 95% confidence interval will be estimated. Fisher's exact test will be used to evaluate the association between response and other categorical patient variables.

  2. Progression free survival (PFS) [ Time Frame: From study entry to objective disease progression or death from any cause, assessed at 1 year ]
    Will be estimated using the method of Kaplan and Meier.

  3. Overall survival [ Time Frame: From study entry to death, assessed at 1 year ]
    Will be estimated using the method of Kaplan and Meier.

  4. Incidence of adverse events (AEs) [ Time Frame: Baseline up to 30 days after the last dose of study drug ]
    AE data will be summarized by frequency tables for all patients. For the toxicity endpoint, per-treated analysis will be performed to include any patient who received the treatment regardless of the eligibility nor the duration or dose of the treatment received.


Other Outcome Measures:
  1. T cells activation in peripheral blood and cerebrospinal fluid [ Time Frame: Baseline up to 2 years ]
    Descriptive statistics including plots, mean, median and standard deviations will be used to summarize data. T-test and analysis of variance (ANOVA) will be used to compare outcome measures across patient characteristics. Dunnett's and Tukey's test that properly adjust for multiplicity in multiple tests will be implemented. Pair-wise comparisons will be performed using pre- and post-therapy samples from each patient. The chi-square (c2) test or Fisher's exact test will be used to test the association between two categorical variables such as disease state and performance status. Both univariate and multivariate logistic regressions will be performed to model prognostic factors.

  2. Cytokine profile from microglial cells in cerebrospinal fluid [ Time Frame: Baseline up to 2 years ]
    Descriptive statistics including plots, mean, median and standard deviations will be used to summarize data. T-test and ANOVA will be used to compare outcome measures across patient characteristics. Dunnett's and Tukey's test that properly adjust for multiplicity in multiple tests will be implemented. Pair-wise comparisons will be performed using pre- and post-therapy samples from each patient. The chi-square (c2) test or Fisher's exact test will be used to test the association between two categorical variables such as disease state and performance status. Both univariate and multivariate logistic regressions will be performed to model prognostic factors.

  3. Tumor characteristics [ Time Frame: Baseline up to 2 years ]
    Correlation baseline tumor characteristics with response and PFS will be calculated. Pair-wise comparisons will be performed using pre- and post-therapy samples from each patient. The chi-square (c2) test or Fisher's exact test will be used to test the association between two categorical variables such as disease state and performance status.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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

Inclusion Criteria:

  • Relapsed refractory central nervous system lymphoma, pathology confirmed B cell lymphoma either by biopsy or by cerebrospinal fluid (CSF) review. Patient must previously have had one line of systemic therapy for CNS lymphoma
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 2
  • Total bilirubin =< 1.5 x upper limit of normal (ULN). For patients with Gilbert's disease, total bilirubin up to =< 3 x ULN is allowed provided normal direct bilirubin
  • Serum creatinine =< 1.5 x ULN
  • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 3 x ULN
  • Females of childbearing potential must have a negative serum or urine beta human chorionic gonadotrophin (beta-hCG) pregnancy test result within 24 hours prior to the first dose of treatment and must agree to use a highly effective contraception method during the study and for 23 weeks following the last dose of the study drugs. Females of non- childbearing potential are those who are postmenopausal greater than 1 year or who have had a bilateral tubal ligation or hysterectomy. Males who have partners of childbearing potential must agree to use an effective contraceptive method during the study and for 31 weeks following the last dose of study drugs. Men must agree not to donate sperm during and for 3 months after the last dose of study drug. Women who are pregnant or breastfeeding are ineligible for this study
  • Patients or their legally authorized representative must provide written informed consent
  • Absolute neutrophil count (ANC) >= 1000/mm^3 independent of growth factor support
  • Platelets >= 100,000/mm^3 or >= 50,000/mm^3 if bone marrow involvement independent of transfusion support in either situation
  • Creatinine clearance (CrCl) > 25 ml/min

Exclusion Criteria:

  • History of another primary invasive malignancy that has not been definitively treated or in remission for at least 2 years. Patients with non-melanoma skin cancers or with carcinomas in situ are eligible regardless of the time from diagnosis (including concomitant diagnoses). If patients have another malignancy that was treated within the last 2 years, such patients may be enrolled if the likelihood of requiring systemic therapy for this other malignancy within 2 years is less than 10%, as determined by an expert in that particular malignancy at MD Anderson Cancer Center and after consultation with the principal investigator
  • Any major surgery or wound that has not healed, radiotherapy, cytotoxic chemotherapy, biologic therapy, immunotherapy, immunomodulatory drugs, experimental therapy within 4 weeks prior to the first dose of the study drugs
  • Significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening, or any class 3 or 4 cardiac disease as defined by the New York Heart Association functional classification
  • History of stroke or cerebral hemorrhage within 6 months of enrollment
  • Patients who have uncontrolled hypertension (defined as sustained systolic blood pressure >= 160 mmHg or diastolic >= 100 mmHg)
  • Prior history of BTK inhibitor or PD1 inhibitor prior to start of trial
  • Active, uncontrolled autoimmune hemolytic anemia or immune thrombocytopenia requiring steroid therapy
  • Patients with autoimmune diseases are excluded: Patients with a history of inflammatory bowel disease (including Crohn's disease and ulcerative colitis) are excluded from this study as are patients with a history of autoimmune disease (e.g., rheumatoid arthritis, systemic progressive sclerosis, systemic lupus erythematosus, Wegener's granulomatosis)
  • Patients with previous allogeneic stem cell transplant (SCT) within 6 months or with active acute or chronic graft-versus host disease are excluded. Patients must be off immunosuppression for graft versus host disease (GVHD) for at least 30 days before cycle 1 day 1
  • Patients with organ allografts (such as renal transplant) are excluded
  • History of biopsy proven interstitial lung disease or pneumonitis which has impacted pulmonary function test (PFT) in a clinically significant manner
  • Patients who are on high dose steroids (> 10 mg daily of prednisone or equivalent) or immune suppression medications

    • Note: Patients on high-dose steroids (doses > 10 mg/day of prednisone or equivalent) or immune suppression medications are eligible provided these drugs are discontinued at least 3 days prior to starting on the study drugs
  • Patients with uncontrolled active infection (viral, bacterial, and fungal) are not eligible
  • Active current hepatitis B or C infection/reactivation as measured by deoxyribonucleic acid (DNA)/ribonucleic acid (RNA) quantification, or known seropositivity for human immunodeficiency virus (HIV)
  • Patient is pregnant or breast-feeding
  • Malabsorption syndrome or other condition that precludes enteral route of administration
  • Concomitant use of warfarin or other vitamin K antagonists.
  • Requires chronic treatment with a strong cytochrome P450 (CYP) 3A inhibitor
  • Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that in the opinion of the investigator may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and/or would make the patient inappropriate for enrollment into this study
  • Vaccinated with live, attenuated vaccines within 4 weeks of enrollment
  • 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 undue risk

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03770416


Contacts
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Contact: Jason Westin 713-792-2860 jwestin@mdanderson.org

Locations
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United States, Texas
M D Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: Jason Westin    713-792-2860      
Principal Investigator: Jason Westin         
Sponsors and Collaborators
M.D. Anderson Cancer Center
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Jason Westin M.D. Anderson Cancer Center
Additional Information:
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Responsible Party: M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier: NCT03770416    
Other Study ID Numbers: 2018-0510
NCI-2018-02181 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
2018-0510 ( Other Identifier: M D Anderson Cancer Center )
P30CA016672 ( U.S. NIH Grant/Contract )
First Posted: December 10, 2018    Key Record Dates
Last Update Posted: May 20, 2019
Last Verified: May 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Additional relevant MeSH terms:
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Lymphoma
Lymphoma, B-Cell
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Lymphoma, Non-Hodgkin
Nivolumab
Antineoplastic Agents, Immunological
Antineoplastic Agents