A clinical study to assess the safety and effectiveness of Ibrutinib in subjects with relapsed/refractory marginal zone lymphoma.

Phase 1

Conditions: Relapsed or refractory marginal zone lymphoma
MedDRA version: 19.1Level: HLTClassification code 10029621Term: Non-Hodgkin's lymphomas unspecified histology indolentSystem Organ Class: 100000004851
Therapeutic area: Diseases [C] - Cancer [C04]

Registration Number: EUCTR2013-003561-34-BE

Lead Sponsor: Pharmacyclics LLC

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: ot Recruiting

Sex: All

Target Recruitment: 60

Inclusion Criteria

Subjects must meet all of the following criteria in order to be eligible:
1)Histologically documented marginal zone lymphoma including splenic, nodal, and extranodal sub-types,subjects with splenic MZL must have an additional measurable lesion, nodal or extranodal, as described in inclusion criteria 5
2)Previously received one or more lines of therapy including at least one CD20-directed regimen (either as monotherapy or as chemoimmunotherapy) with documented failure to achieve at least partial remission (PR) or documented disease progression after, the most recent systemic treatment regimen
3)Men and women =18 years of age
4)Eastern Cooperative Oncology Group (ECOG) performance status of =2
5)=1 measurable lesion on computed tomography (CT) scan (>1.5 cm in longest dimension). Lesions in anatomical locations (such as extremities or soft tissue lesions) that are not well visualized by CT may be measured by magnetic resonance imaging (MRI) instead.(Subjects with spleen-only disease are
considered as not having measurable disease.)
6)Life expectancy of >3 months, in the opinion of the investigator
7)Female subjects who are of non-reproductive potential (ie, post-menopausal by history - no menses for =2 years; OR history of hysterectomy; OR history of bilateral tubal ligation; OR history of bilateral oophorectomy). Female subjects of childbearing potential must have a negative serum pregnancy test upon study entry.
8)Male and female subjects who agree to use highly effective methods of birth control (eg, condoms, implants, injectables, combined oral contraceptives, some intrauterine devices [IUDs], sexual abstinence, or sterilized partner) during the period of therapy and for 30 days (females) and 90 days (males) after the last dose of study drug
9)Documented evidence of need for treatment, including, but not limited to, threatened end-organ function, bulky disease (>5 cm), symptoms, requirement for transfusion or growth factor support, or medically significant need for intervention
10)For subjects with presumptive evidence of transformation based on clinical assessment of factors such as, but not limited to, increasing lactate dehydrogenase (LDH), rapidly worsening disease, or frequent B-symptoms, a pre-treatment biopsy is required to rule out large cell transformation

Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 36
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 24

Exclusion Criteria

Subjects who meet any of the following criteria are not eligible:
1)Medically apparent central nervous system lymphoma or leptomeningeal disease
2)History of other malignancies except adequately treated non-melanoma skin cancer, curatively treated in-situ cancer, or other solid tumors curatively treated with no evidence of disease for =2 years
3)History of allogeneic stem-cell (or other organ) transplantation
4)Any chemotherapy, anticancer antibodies, or other systemic anticancer therapy within 21 days of the first dose of study drug
5)Any external beam radiation therapy within 6 weeks prior to the first dose of study drug
6)Use of radio- or toxin-immunoconjugates within 70 days of the first dose of study drug
7)Concurrent use of warfarin or other vitamin K antagonists
8)Concurrent use of a strong cytochrome P450 (CYP) 3A inhibitor. Subjects who have received a strong CYP3 A inhibitor prior to entering the study must have discontinued therapy for at least 5 half lives of the prohibited medication
9)Concurrent systemic immunosuppressant therapy (eg, cyclosporine A, tacrolimus, etc., or chronic administration of >20 mg/day of prednisone) within 28 days of the first dose of study drug
10)Significant screening electrocardiogram (ECG) abnormalities including, but not limited to, left bundle branch block, 2nd degree atrioventricular (AV) block type II, 3rd degree block, or corrected QT interval (QTc) =470 msec.Subjects with a cardiac pacemaker who have a QTc interval of =470 msec may be eligible if these findings are considered not clinically significant as documented via a cardiology evaluation.
11)Clinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure (New York Heart Association >Class 2), unstable angina, uncontrolled hypertension, 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
12)Recent infection requiring intravenous anti-infective treatment that was completed =14 days before the first dose of study drug
13)Unresolved toxicities from prior anti-cancer therapy, defined as having not resolved to Common Terminology Criteria for Adverse Event (CTCAE, version 4.03), Grade 0 or 1, or to the levels dictated in the inclusion/exclusion criteria with the exception of alopecia
14)Known bleeding diathesis (eg, von Willebrand’s disease) or hemophilia
15)Known history of infection with human immunodeficiency virus (HIV) or history of active or chronic infection with hepatitis C virus (HCV) or hepatitis B virus (HBV), or any uncontrolled active systemic infection
16)Any of the following abnormalities:
oAbsolute neutrophil count (ANC) <750 cells/mm3 (0.75 x 109/L), unless there is documented bone marrow involvement
oPlatelet count <50,000 cells/mm3 (50 x 109/L) independent of transfusion support, unless there is documented bone marrow involvement
oSerum aspartate transaminase (AST) or alanine transaminase (ALT) =3.0 x upper limit of normal (ULN)
oCreatinine >2.0 x ULN or Estimated Glomerular Filtration Rate (GFR [Cockcroft Gault]) < 30 mL/min
oHemoglobin <8.0 g/dL
oBilirubin >1.5 x ULN (unless bilirubin rise is due to Gilbert’s syndrome or of non-hepatic origin)
oPT/INR >1.5 x ULN and PTT (aPTT) >1.5 x ULN
17)Unable to swallow capsules or disease significantly affecting gastrointestinal function such as malabsorption syndrome, resection of the stom

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: To evaluate the efficacy of ibrutinib therapy in subjects with marginal zone lymphoma (MZL) using the overall response rate (ORR) as assessed by an Independent Review Committee (IRC);Secondary Objective: •To evaluate efficacy parameters such as the duration of response (DOR), progression-free survival (PFS), and overall survival (OS) to ibrutinib therapy in subjects with MZL<br>•To evaluate the safety and tolerability of ibrutinib in subjects with MZL<br>•To determine the plasma pharmacokinetics of ibrutinib and the metabolite, PCI-45227<br><br>Exploratory Objectives:<br>•To evaluate prognostic and predictive biomarkers relative to treatment outcomes<br><br>;Primary end point(s): •Overall response rate (complete remission [CR] + partial remission [PR]);Timepoint(s) of evaluation of this end point: at the earliest 52 weeks after the last subject is enrolled

Secondary Outcome Measures

Name	Time	Method
Secondary end point(s): •Efficacy:<br> oDuration of response (DOR)<br> oProgression-free survival (PFS)<br> oOverall survival (OS)<br>•Safety:<br> oFrequency, severity, and relatedness of adverse events (AEs)<br> oFrequency of AEs requiring discontinuation of study drug or dose reductions<br>;Timepoint(s) of evaluation of this end point: at the earliest 52 weeks after the last subject is enrolled

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