Ibrutinib in Treating Patients With Refractory Metastatic Cutaneous Melanoma

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT02581930
• Collaborator: (none)
• Enrollment: 18
• Locations: 13
• Arm: 1
• Patients Per Site: 1.4

Study Details

Study Description

Brief Summary

This phase II trial studies how well ibrutinib works in treating patients with stage IV melanoma of the skin that has not responded to previous treatment. Ibrutinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Condition or Disease	Intervention/Treatment	Phase
Metastatic Melanoma; Recurrent Cutaneous Melanoma; Stage IV Cutaneous Melanoma AJCC v6 and v7	Drug: Ibrutinib; Other: Laboratory Biomarker Analysis; Other: Pharmacogenomic Study; Other: Pharmacological Study	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. Estimate rate of objective response (OR: complete response [CR] + partial response [PR]) to ibrutinib administered as single agent in patients with immune checkpoint inhibitor-refractory, or immune checkpoint inhibitor ineligible and mitogen-activated protein kinase (MAPK) inhibitor-refractory (if B-Raf proto-oncogene, serine/threonine kinase [BRAF]V600-mutant) or MAPK inhibitor-intolerant distant metastatic cutaneous melanoma.

SECONDARY OBJECTIVES:

1. Estimate progression-free survival (PFS) rate at 6 months after initiation of ibrutinib in patients with immune checkpoint inhibitor-refractory or immune checkpoint ineligible and MAPK inhibitor-refractory (if BRAFV600-mutant) or MAPK inhibitor-intolerant distant metastatic cutaneous melanoma.

2. Estimate overall survival (OS) after initiation of ibrutinib in patients with immune checkpoint inhibitor-refractory or immune checkpoint ineligible and MAPK inhibitor-refractory (if BRAFV600-mutant) or MAPK inhibitor-intolerant distant metastatic cutaneous melanoma.

3. Explore the association of ITK protein expression with OR and PFS.

TERTIARY OBJECTIVES:

1. Explore association between other putative targets of ibrutinib (e.g. Tec, ErbB4, Hck, Yes, BTK) in melanoma cells, as assessed by 2-color immunofluorescence (IF) in representative tissue sections obtained from pretreatment archived formalin-fixed paraffin-embedded (FFPE) tumor blocks or FFPE blocks obtained from fresh tissue biopsy from enrolled patients, with overall response (OR) and PFS.

2. Explore ibrutinib-mediated effect(s) on immune cell subsets associated with immunomodulation by performing multiparameter flow cytometric analysis in peripheral blood mononuclear cell (PBMC) obtained prior to treatment, on day 29 (i.e., predose day 1 of cycle

1. following initiation of treatment with ibrutinib, and at the time of disease progression (3 time points).

1. Determine pharmacokinetics (PK) of ibrutinib following daily dosing at 840 mg on day 8 of cycle 1 (Css).

OUTLINE:

Patients receive ibrutinib orally (PO) once daily (QD) on days 1-28. Courses 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 up to 2 years.

Study Design

• Study Type: Interventional
• Actual Enrollment: 18 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 2 Study of Ibrutinib (PCI-32765) in Refractory Distant Metastatic Cutaneous Melanoma: Correlation of Biomarkers With Response and Resistance
• Actual Study Start Date: Aug 17, 2016
• Actual Primary Completion Date: Feb 10, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment (ibrutinib) Patients receive ibrutinib PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.	Drug: Ibrutinib; Given PO; Other Names: BTK Inhibitor PCI-32765 CRA-032765 Imbruvica PCI-32765 ; Other: Laboratory Biomarker Analysis; Correlative studies; Other: Pharmacogenomic Study; Correlative studies; Other Names: PHARMACOGENOMIC ; Other: Pharmacological Study; Correlative studies

Outcome Measures

Primary Outcome Measures

1. Number of Subjects With Antitumor Response as Evaluated by Response Evaluation Criteria in Solid Tumors (RECIST) Criteria 1.1 [1 year]

   Antitumor response defined as the sum of complete response (CR) and partial response (PR). CR is the disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm (<1 cm). PR is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.

Secondary Outcome Measures

1. Progression Free Survival [1 year]

   Progression free survival (PFS) is defined as the duration of time from Day 1 of treatment to time of progression (based on clinical or radiographic grounds) or death as a result of any cause, whichever occurs first.

2. Overall Survival [Duration of time from day 1 of treatment to death as a result of any cause, assessed up to 1 year]

   Estimated using the Kaplan Meier method.

Other Outcome Measures

1. Expression Levels of ITK and Putative Targets of Ibrutinib (e.g. Tec, ErbB4, Hck, Yes, BTK) [Up to 1 year]

   Assessed by IHC and 2-color IF and analyzed by Aperio imaging. Exploratory analysis will also be performed to assess the predictive ability of each tissue biomarker by fitting logistic model or Cox model with biomarker as a covariate. Antitumor response rate or PFS information will be used to investigate possible cut-points for the biomarker. Logistic regression analysis will be conducted to assess whether a profile of immune response in tumor biopsies (or in peripheral blood) can be developed that distinguishes patients who respond to treatment versus those who do not.

2. Change in Th1, Th2, and Various Immune Regulatory Cell Populations in Peripheral Blood Mononuclear Cells and Assessed by Flow Cytometry [Baseline up to 1 year]

   Will be assessed by comparisons using analysis of variance followed by paired t-test or other tests (Wilcoxon rank-sum test), if normality assumption is not satisfied even when data transformation is performed.

3. Pharmacokinetic Analysis on Ibrutinib Concentrations in Plasma Using WinNonlin [Pre-dose on days 1 and day 8 of course 1 and post-dose, 0.5, 1, 2, 4, 6, and 24 hours on day 8 of course 1]

   The following parameters will be estimated: maximum concentration, time of maximum concentration, area under the concentration verses time curve, half-life, apparent clearance, apparent volume of distribution.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Histologically confirmed melanoma of cutaneous primary; metastatic melanoma from unknown primary are allowed

• Measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as >= 10 mm (>= 1 cm) with spiral computed tomography (CT) scan, magnetic resonance imaging (MRI), or calipers by clinical exam

• Stage IV disease

• If BRAFV600-mutant, documented refractory disease to at least one BRAF inhibitor (dabrafenib or vemurafenib) and/or a MEK inhibitor (trametinib or cobimetinib), defined as progression of measurable disease as per Response Evaluation Criteria in Solid Tumors (RECIST) criteria while on treatment; subjects with MAPK inhibitor-intolerance are eligible if they meet criteria

• Documented disease refractory to at least one PD1/PD-L1 inhibitor, defined as disease progression following at least 2 infusions of the same drug; radiographic disease progression will be documented by the institutional radiologist based on any radiographic evidence (magnetic resonance imaging [MRI], computed tomography [CT], positron emission tomography [PET], or other modalities, etc.) of disease progression on two separate radiographic scans assessment obtained at least 4 weeks apart; this minimum 4-week interval is required to define PD-1 inhibitor resistance based on imaging; alternatively, clinical disease progression may be documented on examination by the treating investigator

• Prior treatment-related toxicity resolved to =< grade 1 or baseline with the exception of alopecia and permanent grade =< 2 toxicities related to prior immune checkpoint inhibitor treatment (e.g. PD-1/PD-L1, CTLA-4, CD40, LAG3) treatment with the review and approval by the lead principal investigator (PI)

• Prior radiation allowed (no restriction on amount); measurable lesion(s) may not have been previously irradiated

• Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)

• Life expectancy of greater than 3 months

• Hemoglobin >= 9.0 g/dL

• Absolute neutrophil count (ANC) > 1,500/uL

• Platelets > 100,000/uL

• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2 x upper limit of normal (ULN); =< 5 x ULN, if liver metastasis

• Total bilirubin =< 1.5 x ULN unless Gilbert's syndrome of disease infiltration of the liver is present

• Creatinine clearance estimated glomerular filtration rate (GFR) >= 30 mL/min/1.73 m^2 (Cockcroft-Gault)

• Patients with brain metastases are allowed provided that:

• No leptomeningeal disease is present

• Intracranial disease is controlled by prior local therapies (craniotomy, stereotactic radiosurgery, whole brain irradiation), as evidenced by brain MRI 4 weeks post treatment indicating no new intracranial disease

• Stable or decreasing dose of steroids provided patient on =< 20 mg of prednisone or its equivalent daily

• Ibrutinib should be held at least 3 to 7 days pre- and post-surgery, depending upon the type of surgery and risk of bleeding

• Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation and for 90 days after completion of ibrutinib administration; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately; men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 90 days after completion of ibrutinib administration

• Negative serum pregnancy test within 7 days of treatment initiation with ibrutinib in women of childbearing potential (WOCBP)

• Ability to swallow oral medications

• Patients with autoimmune disease requiring systemic corticosteroid treatment (and previously ineligible to receive systemic immunotherapies for melanoma) are allowed on condition that they do not receive more than 20 mg of daily dose methylprednisolone, prednisone, or its equivalent; this does not include autoimmune diseases caused by previous immunotherapy treatments for melanoma that require ongoing treatment with corticosteroids (e.g. autoimmune colitis or autoimmune hepatitis receiving corticosteroids)

• Willing to consent to allow access to known archival tumor tissue (NOTE: designated pathologist from participating site OR lead principal investigator must sign-off to ensure "sufficient" tumor should be available for support of tumor imaging studies [multi-color immunofluorescence])

• If archival tumor tissue from a metastatic melanoma lesion is unavailable OR designated pathologist from participating site cannot sign-off to ensure that "sufficient" tumor is available from existing archival tumor block for support of tumor imaging studies, patients must be willing to consent to undergo a biopsy to collect metastatic tumor tissue; collection of fresh biopsy tissue does not guarantee enrollment, unless the pathologist from the participating site signs-off that "sufficient" tumor has been collected

• Ability to understand and the willingness to sign a written informed consent document

• Subjects who are unable to tolerate BRAF inhibitor and/or MEK inhibitor therapy due to grade >= 2 toxicity (Common Terminology Criteria for Adverse Events [CTCAE] version [v]4.0) from these agents, irrespective of antitumor response, are eligible on condition that: (a) toxicities persisted despite change from doublet to singlet therapy (i.e. from concurrent BRAF inhibition plus MEK inhibition to BRAF inhibition alone), (b) toxicities are attributed to a class effect, and therefore switch from one drug to another is expected to induce the same type of toxicity (e.g. ocular toxicities or cardiac dysfunction from MEK inhibitor), (c) drug-specific toxicities that do not resolve with switch from one BRAF inhibitor to another (i.e. dabrafenib to vemurafenib, or vice versa), will be eligible for enrollment in 9922; in other words, patients will be allowed to enroll into the NCI9922 study despite lack of progression to MAPK inhibitor treatments, on condition that grade 2 or higher toxicities attributed to MAPK inhibitors resolve to grade 1, or less, at the time of study enrollment

Exclusion Criteria:

• Patients with melanoma of mucosal or ocular primary

• Patients who have had chemotherapy or immunotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) or radiotherapy within 2 weeks prior to cycle 1 day 1; patients who have had tyrosine kinase inhibitors (such as Braf or MEK inhibitors) within 15 days of cycle 1 day 1

• Patients who are receiving any other biologic, cytotoxic or investigational agents

• History of allergic reactions attributed to compounds of similar chemical or biologic composition to ibrutinib (difficulty breathing, lip swelling, itching or rash)

• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements

• Pregnant and breastfeeding women are excluded from this study; breastfeeding should be discontinued if the mother is treated with ibrutinib

• Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are eligible; unless the patient's cluster of differentiation (CD)4+ count is below the institutional lower limit of normal

• Uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenic purpura (ITP) resulting in (or as evidenced by) declining platelet or hemoglobin (Hgb) levels within the 4 weeks prior to first dose of study drug

• Presence of transfusion-dependent thrombocytopenia

• Need for daily corticosteroids at high doses (prednisone >= 20 mg daily, or an equivalent) is prohibited from 28 days prior to first dose and during treatment with ibrutinib; brief (up to 7 days) and episodic use of systemic corticosteroids for other general conditions (e.g. pre-medication for radiographic imaging due to intravenous [IV] contrast allergy, chronic obstructive pulmonary disease [COPD] exacerbation, poison ivy, etc.) is allowed

• Prior exposure to ibrutinib or other ITK inhibitors

• History of prior malignancy, with the exception of the following:

• Non-melanoma skin cancers, non-invasive bladder cancer, and carcinoma in situ of the cervix

• Prostate cancer not under active systemic treatment other than hormonal therapy and with documented undetectable prostate-specific antigen (PSA) (< 0.2 ng/mL)

• Chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) provided patient has isolated lymphocytosis (Rai stage O), and does not require systemic treatment (for "B" symptoms, Richter's transformation, lymphocyte doubling time [< 6 months], lymphadenopathy or hepatosplenomegaly)

• Lymphoma of any type of hairy-cell leukemia provided patient is not on active systemic treatment and is in complete remission, as evidenced by PET/CT scans and bone marrow biopsies for at least 3 months

• History of malignancy provided that patient has completed therapy and is free of disease for >= 2 years; if patient had other malignancy within the last 2 years from which he may have been completely cured by surgery alone, he may be considered to be enrolled on condition that the risk of development of distant metastatic disease based on American Joint Committee on Cancer (AJCC) staging system is less than 30%

• Currently active clinically significant cardiovascular disease, such as uncontrolled arrhythmia, congestive heart failure, any class 3 or 4 cardiac disease, as defined by the New York Heart Association Functional Classification, or history of myocardial infarction within 6 months prior to first dose with study drug

• Unable to swallow capsules, or disease significantly affecting gastrointestinal function and/or inhibiting small intestine absorption, such as malabsorption syndrome, resection of portions of small bowel larger than 3 feet, or poorly controlled inflammatory bowel disease affecting the small intestine

• Known serologic status reflecting active hepatitis B or C infection; patients that are hepatitis B core antibody positive, but antigen negative, will need a negative polymerase chain reaction (PCR) prior to enrollment (NOTE: hepatitis B antigen or PCR positive patients will be excluded)

• History of stroke or intracranial hemorrhage within 6 months prior to enrollment

• Current life-threatening illness, medical condition, or organ system dysfunction, which, in the investigator's opinion, could compromise the patient's safety, or put the study at risk

• Received anticoagulation therapy with warfarin, or equivalent vitamin K antagonists, within the last 28 days prior to day 1 of ibrutinib; patients with familial coagulopathic diseases (e.g. hemophilia, von Willebrand disease) are also excluded; if applicable, subjects must discontinue fish oil and vitamin E supplements within 7 days prior to initiating ibrutinib therapy

• Subjects with known hepatic insufficiency (i.e. Child-Pugh score A [mild], Child-Pugh score B [moderate] or Child-Pugh score C [severe]) according to Child-Pugh criteria

• Subjects who received a strong cytochrome P450 (CYP) 3A inhibitor within 7 days prior to the first dose of ibrutinib or subjects who require continuous treatment with a strong CYP 450 3A inhibitor

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Los Angeles County-USC Medical Center	Los Angeles	California	United States	90033
2	USC / Norris Comprehensive Cancer Center	Los Angeles	California	United States	90033
3	University of California Davis Comprehensive Cancer Center	Sacramento	California	United States	95817
4	University of Colorado Hospital	Aurora	Colorado	United States	80045
5	Moffitt Cancer Center	Tampa	Florida	United States	33612
6	University of Kentucky/Markey Cancer Center	Lexington	Kentucky	United States	40536
7	Washington University School of Medicine	Saint Louis	Missouri	United States	63110
8	UNC Lineberger Comprehensive Cancer Center	Chapel Hill	North Carolina	United States	27599
9	Duke University Medical Center	Durham	North Carolina	United States	27710
10	Case Western Reserve University	Cleveland	Ohio	United States	44106
11	Ohio State University Comprehensive Cancer Center	Columbus	Ohio	United States	43210
12	University of Virginia Cancer Center	Charlottesville	Virginia	United States	22908
13	University of Wisconsin Carbone Cancer Center	Madison	Wisconsin	United States	53792

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Stergios J Moschos, Duke University - Duke Cancer Institute LAO

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - May 8, 2018

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT02581930
• Other Study ID Numbers: NCI-2015-01744; NCI-2015-01744; NCI9922; 9922; 9922; UM1CA186644; UM1CA186686; UM1CA186688; UM1CA186689; UM1CA186690; UM1CA186691; UM1CA186704; UM1CA186709; UM1CA186712; UM1CA186716; UM1CA186717; NCT03427398
• First Posted: Oct 21, 2015
• Last Update Posted: Jul 28, 2022
• Last Verified: Jan 1, 2022

• Additional relevant MeSH terms: Melanoma; Skin Neoplasms

Study Results

Participant Flow

Recruitment Details	Dates of the recruitment period were 12/12/16-12/14/17 in medical clinic.

Arm/Group Title	Treatment (Ibrutinib)
Arm/Group Description	Patients receive ibrutinib PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Ibrutinib: Given PO Laboratory Biomarker Analysis: Correlative studies Pharmacogenomic Study: Correlative studies Pharmacological Study: Correlative studies
Period Title: Overall Study
STARTED	18
COMPLETED	16
NOT COMPLETED	2

Baseline Characteristics

Arm/Group Title	Treatment (Ibrutinib)
Arm/Group Description	Patients receive ibrutinib PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Ibrutinib: Given PO Laboratory Biomarker Analysis: Correlative studies Pharmacogenomic Study: Correlative studies Pharmacological Study: Correlative studies
Overall Participants	18
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	60
Sex: Female, Male (Count of Participants)
Female	5 27.8%
Male	13 72.2%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 5.6%
Not Hispanic or Latino	17 94.4%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	17 94.4%
More than one race	0 0%
Unknown or Not Reported	1 5.6%
Region of Enrollment (Count of Participants)
United States	18 100%

Outcome Measures

1. Primary Outcome

Title	Number of Subjects With Antitumor Response as Evaluated by Response Evaluation Criteria in Solid Tumors (RECIST) Criteria 1.1
Description	Antitumor response defined as the sum of complete response (CR) and partial response (PR). CR is the disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm (<1 cm). PR is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Ibrutinib)
Arm/Group Description	Patients receive ibrutinib PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Ibrutinib: Given PO Laboratory Biomarker Analysis: Correlative studies Pharmacogenomic Study: Correlative studies Pharmacological Study: Correlative studies
Measure Participants	18
Count of Participants [Participants]	0 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Treatment (Ibrutinib)
	Comments	The primary comparison was between the response rate of an ineffective drug, such as investigators' choice chemotherapy (5%), and the response rate of ibrutinib.
	Type of Statistical Test	Other
	Comments	Exact binomial test
Statistical Test of Hypothesis	p-Value	1.00
	Comments	Significant if p-value is less than 0.1
	Method	Exact binomial test, 1-sided
	Comments
Method of Estimation	Estimation Parameter	Probability of response
	Estimated Value	0.00
	Confidence Interval	(1-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments	Estimated as proportion of subjects with response

2. Secondary Outcome

Title	Progression Free Survival
Description	Progression free survival (PFS) is defined as the duration of time from Day 1 of treatment to time of progression (based on clinical or radiographic grounds) or death as a result of any cause, whichever occurs first.
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Ibrutinib)
Arm/Group Description	Patients receive ibrutinib PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Ibrutinib: Given PO Laboratory Biomarker Analysis: Correlative studies Pharmacogenomic Study: Correlative studies Pharmacological Study: Correlative studies
Measure Participants	18
Median (Full Range) [months]	1.3

3. Secondary Outcome

Title	Overall Survival
Description	Estimated using the Kaplan Meier method.
Time Frame	Duration of time from day 1 of treatment to death as a result of any cause, assessed up to 1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Ibrutinib)
Arm/Group Description	Patients receive ibrutinib PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Ibrutinib: Given PO Laboratory Biomarker Analysis: Correlative studies Pharmacogenomic Study: Correlative studies Pharmacological Study: Correlative studies
Measure Participants	18
Median (Full Range) [months]	6

4. Other Pre-specified Outcome

Title	Expression Levels of ITK and Putative Targets of Ibrutinib (e.g. Tec, ErbB4, Hck, Yes, BTK)
Description	Assessed by IHC and 2-color IF and analyzed by Aperio imaging. Exploratory analysis will also be performed to assess the predictive ability of each tissue biomarker by fitting logistic model or Cox model with biomarker as a covariate. Antitumor response rate or PFS information will be used to investigate possible cut-points for the biomarker. Logistic regression analysis will be conducted to assess whether a profile of immune response in tumor biopsies (or in peripheral blood) can be developed that distinguishes patients who respond to treatment versus those who do not.
Time Frame	Up to 1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

5. Other Pre-specified Outcome

Title	Change in Th1, Th2, and Various Immune Regulatory Cell Populations in Peripheral Blood Mononuclear Cells and Assessed by Flow Cytometry
Description	Will be assessed by comparisons using analysis of variance followed by paired t-test or other tests (Wilcoxon rank-sum test), if normality assumption is not satisfied even when data transformation is performed.
Time Frame	Baseline up to 1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

6. Other Pre-specified Outcome

Title	Pharmacokinetic Analysis on Ibrutinib Concentrations in Plasma Using WinNonlin
Description	The following parameters will be estimated: maximum concentration, time of maximum concentration, area under the concentration verses time curve, half-life, apparent clearance, apparent volume of distribution.
Time Frame	Pre-dose on days 1 and day 8 of course 1 and post-dose, 0.5, 1, 2, 4, 6, and 24 hours on day 8 of course 1

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	1 year
Arm/Group Title	Treatment (Ibrutinib)
Arm/Group Description	Patients receive ibrutinib PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Ibrutinib: Given PO Laboratory Biomarker Analysis: Correlative studies Pharmacogenomic Study: Correlative studies Pharmacological Study: Correlative studies
All Cause Mortality
	Treatment (Ibrutinib)
	Affected / at Risk (%)	# Events
Total	15/18 (83.3%)
Serious Adverse Events
	Treatment (Ibrutinib)
	Affected / at Risk (%)	# Events
Total	9/18 (50%)
Blood and lymphatic system disorders
decreased lymphocyte count	1/18 (5.6%)
anemia	1/18 (5.6%)
Gastrointestinal disorders
constipation	1/18 (5.6%)
Hepatobiliary disorders
hypoalbuminemia	1/18 (5.6%)
Immune system disorders
cytokine release syncrome	1/18 (5.6%)
Infections and infestations
sepsis	1/18 (5.6%)
pneumonia	1/18 (5.6%)
Metabolism and nutrition disorders
dehydration	1/18 (5.6%)
Renal and urinary disorders
hyponatremia	4/18 (22.2%)
Vascular disorders
hypotension	1/18 (5.6%)
hypertension	1/18 (5.6%)
Other (Not Including Serious) Adverse Events
	Treatment (Ibrutinib)
	Affected / at Risk (%)	# Events
Total	17/18 (94.4%)
Blood and lymphatic system disorders
anemia	7/18 (38.9%)
decreased neutrophil count	1/18 (5.6%)
decreased platelet count	1/18 (5.6%)
decreased WBC	1/18 (5.6%)
increased neutrophil count	1/18 (5.6%)
increased WBC count	1/18 (5.6%)
Cardiac disorders
hypertension	2/18 (11.1%)
palpitations	1/18 (5.6%)
sinus tachycardia	1/18 (5.6%)
Eye disorders
blurry vision	1/18 (5.6%)
eye redness	1/18 (5.6%)
Gastrointestinal disorders
anorexia	10/18 (55.6%)
nausea	5/18 (27.8%)
diarrhea	4/18 (22.2%)
vomiting	4/18 (22.2%)
constipation	1/18 (5.6%)
oral mucositis	2/18 (11.1%)
dysgeusia	2/18 (11.1%)
dysphagia	1/18 (5.6%)
hiccups	1/18 (5.6%)
General disorders
fatigue	10/18 (55.6%)
fever	3/18 (16.7%)
chills	2/18 (11.1%)
lethargy	1/18 (5.6%)
pain	2/18 (11.1%)
abdominal pain	1/18 (5.6%)
flank pain	1/18 (5.6%)
Hepatobiliary disorders
hypoalbuminemia	3/18 (16.7%)
Bilirubin increased	1/18 (5.6%)
Infections and infestations
tooth infection	1/18 (5.6%)
urinary tract infection	1/18 (5.6%)
sinusitis	1/18 (5.6%)
Metabolism and nutrition disorders
hypomagnesemia	2/18 (11.1%)
hypophosphatemia	1/18 (5.6%)
hyponatremia	1/18 (5.6%)
hypokalemia	1/18 (5.6%)
hypocalcemia	1/18 (5.6%)
dehydration	1/18 (5.6%)
AlPhos increased	1/18 (5.6%)
Musculoskeletal and connective tissue disorders
limb edema	2/18 (11.1%)
restless legs	1/18 (5.6%)
joint effusion	1/18 (5.6%)
facial edema	1/18 (5.6%)
trunk edema	1/18 (5.6%)
Nervous system disorders
headaches	2/18 (11.1%)
diziness	2/18 (11.1%)
anxiety	1/18 (5.6%)
tremor	2/18 (11.1%)
insomnia	1/18 (5.6%)
Renal and urinary disorders
hematuria	1/18 (5.6%)
proteinuria	1/18 (5.6%)
Respiratory, thoracic and mediastinal disorders
dyspnea	4/18 (22.2%)
hoarseness	1/18 (5.6%)
Skin and subcutaneous tissue disorders
rash	4/18 (22.2%)
bruising	2/18 (11.1%)
flushing	1/18 (5.6%)
pruritus	1/18 (5.6%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.