Clinical trial NCT02489123
Conditions: Ann Arbor Stage I Mantle Cell Lymphoma Ann Arbor Stage II Mantle Cell Lymphoma Ann Arbor Stage III Mantle Cell Lymphoma Ann Arbor Stage IV Mantle Cell Lymphoma Recurrent Mantle Cell Lymphoma Refractory Mantle Cell Lymphoma
Sponsor: University of Washington
Start date: 2015-08-11; Completion date: 2020-06-16
Enrollment: 8 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This pilot clinical trial studies enzalutamide in treating patients with mantle cell lymphoma that has returned after a period of improvement (relapsed) or has not responded to previous treatment (refractory). Androgens can cause the growth of cancer cells. Antihormone therapy, such as enzalutamide, may lessen the amount of androgen made by the body.

Detailed description:
PRIMARY OBJECTIVES:

I. Perform a preliminary assessment of the efficacy of single-agent enzalutamide, based on overall response rate, in subjects with relapsed/refractory mantle cell lymphoma (MCL) or previously untreated MCL.

SECONDARY OBJECTIVES:

I. To evaluate the duration of disease control (progression free survival) in patients with MCL treated with enzalutamide.

II. To evaluate the safety profile of enzalutamide in MCL.

III. To gain preliminary data on clinical activity and toxicity of this regimen in male versus (vs.) female patients.

OUTLINE:

Patients receive enzalutamide orally (PO) once daily (QD). Courses 1-3 repeat every 4 weeks (28 days) and subsequent courses repeat every 12 weeks (84 days) in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for up to 5 years.

Arms: arm 1: Patients receive enzalutamide PO QD. Courses 1-3 repeat every 4 weeks (28 days) and subsequent courses repeat every 12 weeks (84 days) in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Enzalutamide intervention 2: Laboratory Biomarker Analysis
Intervention descriptions: intervention 1: Given PO intervention 2: Correlative studies

Protocol documents:
Prot_SAP_000.pdf: 
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PROTOCOL 
 
 
 
Androgen Receptor Targeting in Mantle Cell Lymphoma: A Pilot Trial of Enzalutamide 
 
 
 
Trial of the Fred Hutchinson Cancer Research Center (FHCRC), the University of 
Washington (UW), and the Seattle Cancer Care Alliance (SCCA) 
 
 
 
Protocol Version Date: 01-02-2018 
 
 
Investigator:  
 
 
 
 
                        Sub-Investigator 
 
Ajay Gopal, MD 
Professor, Division of Medical Oncology  
University of Washington  
Member, Fred Hutchinson Cancer Research Center 
Clinical Research Director, Hematology and Hematologic 
Malignancies 
E-mail: agopal@uw.edu 
Phone: (206) 606-2037 
Fax: (206) 606-1130 
 
Elahe Mostaghel, MD, PhD 
Associate Professor,  
Division of Medical Oncology, UW  
Associate Member, FHCRC 
E-mail: emostagh@fhcrc.org 
Phone: (206) 667-3506 
Fax: (206) 667-5456 
 
 
Lead Sub-Investigator:  
Victor Chow, MD 
Fellow, UW/FHCRC 
Email: vicachow@uw.edu 
Phone: (206) 314-5772 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
This trial is supported by a grant from the National Comprehensive Cancer Network (NCCN) 
Oncology Research Program. 
IRO REC'D JUN 02 2020
FHCRC IRB Approval  
06 26 2020 
Document Released Date


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SCHEMA 
Registration 
 
 
 
 
Baseline staging  
 
 
 
Start enzalutamide monotherapy 160mg QD continuously 
 
 
 
Restaging on q3 month basis 
 
 
 
Continue therapy until intolerance, progressive disease, or the discretion of patient / clinician 
 
 
 
 
 
 
 


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TABLE OF CONTENTS 
1.0 
Objectives ..................................................................................................................4 
2.0 
Background and Rationale .........................................................................................4 
3.0 
Drug Information .......................................................................................................7 
4.0 
Staging Criteria ..........................................................................................................10 
5.0 
Eligibility Criteria  .....................................................................................................10 
6.0 
Registration  ...............................................................................................................12 
7.0 
Treatment Plan  ..........................................................................................................12 
8.0 
Dosage Modifications  ...............................................................................................13 
9.0 
Study Calendar  ..........................................................................................................16 
10.0 
Endpoint Definitions and Criteria for Evaluation ......................................................17 
11.0 
Statistical Considerations ...........................................................................................19 
12.0 
Study Monitoring and Reporting Procedures ............................................................19 
13.0 
Elements of Informed Consent  .................................................................................23 
14.0 
Correlative Studies .....................................................................................................23 
15.0 
References ..................................................................................................................24 
 
 
 


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1.0 
OBJECTIVES  
 
1.1 
Primary objectives 
1.1.1 Perform a preliminary assessment of the efficacy of single-agent 
enzalutamide, based on overall response rate, in subjects with 
relapsed/refractory mantle cell lymphoma (MCL) or previously untreated 
MCL. 
 
 
1.2 
Secondary objectives 
1.2.1 To evaluate the duration of disease control (progression free survival) in 
patients with MCL treated with enzalutamide. 
 
1.2.2 To evaluate the safety profile of enzalutamide in MCL. 
 
 
1.2.3 To gain preliminary data on clinical activity and toxicity of this regimen in 
male vs. female patients. 
 
 
 
2.0 
BACKGROUND 
 
2.1 
Mantle Cell Lymphoma (MCL) 
MCL represents approximately 5-10% of non-Hodgkin lymphoma (NHL) 
diagnosed annually in the US and Europe, with an average incidence rate of 
approximately 0.5 cases per 100,000 person-years [1].  The average age at 
diagnosis is 70 and recent reports indicate, in contrast to other NHLs, the 
incidence of MCL is potentially on the rise [2].  Interestingly, and pertinent to this 
protocol, MCL demonstrates a clear male predominance with a male to female 
ratio ranging from 2-2.5:1 across multiple studies.  Moreover, the aforementioned 
trend in increased incidence of MCL is largely accounted for by an annual percent 
increase in men (7.8%, vs 2.5% in women) [2].  The pathobiology underlying this 
gender-distribution imbalance is unknown, although anecdotal observations of 
decreased clinical aggressiveness of MCL in male patients who have been treated 
with androgen deprivation for prostate cancer (PCa) and in vitro evidence of 
relative androgen receptor (AR) overexpression in MCL cell lines implicate the 
AR signaling axis as a potential driver of leukemogenesis in MCL. 
 
The clinicopathological features of MCL are intermediate between classically 
indolent and aggressive NHLs; demonstrating adverse features of aggressive 
lymphoma with frequent rapid disease progression, as well as adverse features of 
indolent lymphoma, being essentially incurable. As such, MCL presents uniquely 
challenging treatment paradigm which has garnered increased attention in basic 
and clinical research over the recent years.  While these research efforts have led 
to approval of myriad new MCL-directed therapies (bortezomib, bendamustine, 
lenalidomide, ibrutinib) and improved clinical outcomes for patients afflicted with 


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this disease, MCL remains a largely incurable malignancy with a 3 year overall 
survival of 40-80% depending on age, gender and treatment regimen (i.e. 
chemoimunotherapy +/- ASCT) [3].  These data indicate that, despite 
improvements in therapeutic options for MCL, most patients will still relapse and 
eventually succumb to their malignancy.  There exists, however, a subset of MCL 
patients that presents with an indolent form of the disease who are able to go 
months to years without MCL-directed therapy and whose long term prognosis is 
favorable.  Defining patients with this indolent form of MCL at initial diagnosis is 
a clinical challenge and, thus far, there have been no clearly defined clinical or 
pathological features able to reproducible identify this subgroup; further 
prospective research is ongoing. 
 
2.2 
Enzalutamide and the AR axis in MCL 
Sex steroid receptors are widely expressed in the hematopoietic system, and are 
characterized by sex-related differences, such as higher AR in leucocytes and 
macrophages from male donors [4, 5]. Steroid hormone signaling mediates 
pleomorphic effects, influencing dendritic cell, lymphocyte, NK cell, neutrophil, 
macrophage, platelet and red cell physiology [6-9], and resulting in gender-related 
differences in immune surveillance, cytokine production, and inflammatory 
responses [10]. Disease-specific differences in receptor expression have also been 
described, including aberrant methylation and expression of the AR in leukemia 
cells and non-Hodgkin’s lymphomas (NHL) [11-13]. Of particular relevance to 
this protocol, the AR gene is preferentially hypermethylated (and therefore not 
expressed) in follicular and diffuse large B cell lymphomas, but remains 
unmethylated and open to transcription in MCL [14-15].  ER expression has also 
been demonstrated in human lymphomas, including Hodgkin’s, Burkitt’s and 
multiple myeloma cell lines[1] and ER signaling has been shown to modulate 
growth and proliferation in myeloma and Burkitt’s cell lines[16, 17]. 
 
Preclinical studies at our institution have shown AR levels in MCL lines were ~26 
fold higher than those in non-MCL cell lines or AR- PCa cell lines (Figure 1A).  
Additionally, expression of the AR target gene PSA in MCL cell lines was 
directly correlated with that of AR (Figure 1B) suggesting functional AR 
transactivation. Of note, lymphoma cell lines are known to express functional 
estrogen receptors, and although lower, AR transcript levels were within several 
fold of ER transcript levels in most MCL lines (Figure 1C). 
 
Figure 1. (A) Expression of AR (white squares) and PSA (red triangles) by qRT-PCR in prostate cancer, mantle cell 
lymphoma (MCL) and non-MCL lymphoma cell lines (normalized to the house-keeping gene RPL13A). (B) Linear 
regression of PSA and AR expression in the eight MCL lines and three non MLC lymphoma lines shown in A. (C) 
Concomitant expression levels of estrogen receptors alpha and beta in lymphoma lines. 
J V M -1 3
M a v e r-1
J e k o -1
R E C -1
J V M -2
G ra n ta
M IN O
Z -1 3 8
S U D H L 4
F L 1 8
R A M O S
-2 0
-1 5
-1 0
-5
0
5
1 0
E R -A
ER-B
A R
d C T  v s  R P L 1 3 A
M a n tle  c e ll ly m p h o m a
 (M C L ) c e ll lin e s
n o n -M C L  lin e s
(D L B C L , F o llic u la r,
B u rk itts )
-2 5
-2 0
-1 5
-1 0
-2 5
-2 0
-1 5
-1 0
-5
0.7150
r =
0.0010
p =
d C T  A R
d C T  P S A
A .
B .
C .
L N C a P
V C a P
P C 3
D u 1 4 5
J V M -1 3
M a v e r-1
J e k o -1
R E C -1
J V M -2
G ra n ta
M IN O
Z -1 3 8
S U D H L 4
F L 1 8
R A M O S
-2 0
-1 6
-1 2
-8
-4
0
A R +  P C a
c e ll lin e s
M a n tle  c e ll ly m p h o m a
 (M C L ) c e ll lin e s
n o n -M C L  lin e s
(D L B C L , F o llic u la r,
B u rk itts )
d C T  v s . R P L 1 3 A
A R - P C a
c e ll lin e s
A R
PSA II
P SA  I


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Treatment of 4 different AR+ MCL lines with the AR agonist R1881, the potent 
AR antagonist enzalutamide (Section 3.1 below) or the combination demonstrated 
somewhat limited stimulation by agonist, but consistent suppression of 
proliferation by enzalutamide (Figure 2). Minimal change was observed in an AR 
negative MCL line (Ramos), and the magnitude of suppression in  AR+ male and 
female MCL lines (Granta and Jeko, resp.) was comparable to that observed in the 
AR+ LNCaP PCa cell line. We detected AR, PSA and ER transcripts in human 
MCL tumors in the ranges observed in the panel of MCL cell lines (Figure 3, 
left), as well as variable but detectable levels of AR protein by IHC (Figure 3, 
right).  In addition to this compelling preclinical data, in collaboration with our 
institution’s GU oncology group and others, we have identified a very small 
subset of patient with both MCL and PCa on androgen-blocking therapies who 
have been observed anecdotally to have a more indolent course with regard to 
their MCL (personal communication); further informing the potential therapeutic 
role of AR axis blockade in patients with MCL.  
 
2.3 
Summary 
Despite recent advances in treatment strategies, MCL remains a largely incurable 
disease prone to short-interval relapses, ultimately resulting in a significant 
Figure 2 Response of 4 AR+ MCL lines to treatment with control (hatched bars), the AR agonist R1881 (black bars), 
Enzalutamide (MDV3100, gray bars) or the combination (white bars), at 24, 48 or 72 hours, compared to the AR- non 
MCL lymphoma cell line, Ramos, and the AR+ prostate cancer cell line LnCaP. Gender of patients from which cell lines 
G ra n ta  (M C L  lin e )
C ontrol 72hr
R 1881
M D V 3100
C om bo
 C ontrol 96hr
R 1881
M D V 3100
C o m b o
C ontrol 120hr
R 1881
M D V 3 1 0 0
C o m b o
0
1 0 0 0
2 0 0 0
3 0 0 0
4 0 0 0
5 0 0 0
cpm
J e k o -1  (M C L  lin e )
C ontrol 72hr
R 1881
M D V 3100
C om bo
 C ontrol 96hr
R 1881
M D V 3100
C o m b o
C ontrol 120hr
R 1881
M D V 3 1 0 0
C o m b o
0
1 0 0 0
2 0 0 0
3 0 0 0
4 0 0 0
5 0 0 0
cpm
R e c -1   (M C L  lin e )
C ontrol 72hr
R 1881
M D V 3100
C om bo
 C ontrol 96hr
R 1881
M D V 3100
C o m b o
C ontrol 120hr
R 1881
M D V 3 1 0 0
C o m b o
0
3 0 0 0
6 0 0 0
9 0 0 0
1 2 0 0 0
1 5 0 0 0
cpm
M a v e r-1  (M C L  lin e )
C ontrol 72hr
R 1881
M D V 3100
C om bo
 C ontrol 96hr
R 1881
M D V 3100
C o m b o
C ontrol 120hr
R 1881
M D V 3 1 0 0
C o m b o
0
1 0 0 0
2 0 0 0
3 0 0 0
4 0 0 0
5 0 0 0
cpm
R a m o s  (n o n -M C L  ly m p h o m a  lin e )
C ontrol 72hr
R 1881
M D V 3100
C om bo
 C ontrol 96hr
R 1881
M D V 3100
C o m b o
C ontrol 120hr
R 1881
M D V 3 1 0 0
C o m b o
0
2 0 0 0
4 0 0 0
6 0 0 0
8 0 0 0
cpm
L N C a P  (P ro s ta te  c a n c e r lin e )
C o n tro l 7 2 h r
R 1 8 8 1
M D V 3 1 0 0
C o m b o
 C o n tro l 9 6 h r
R 1 8 8 1
M D V 3 1 0 0
C o m b o
C o n tro l 1 2 0 h r
R 1 8 8 1
M D V 3 1 0 0
C o m b o
0
1 0 0 0
2 0 0 0
3 0 0 0
4 0 0 0
5 0 0 0
cpm
Fig 3. Left  –  Expression of AR, PSA, ERa and ERb by qrt-pcr in replicate RNA isolates from tumor cells of 3 MCL patients.  Right - Expression
of AR by IHC in normal prostate, prostate cancer, negative isotype control, and 3 human MCL tumors (AR SC C-19) (different patients than
those shown on left). 
Normal Prostate
Prostate Ca
Rabbit IgG
MCL tumor 1
MCL tumor 2
MCL tumor 3
J L E  - 1
J L E   - 2
A S  - 1
A S  - 2
T J C  - 1
T J C  - 2
-2 0
-1 5
-1 0
-5
0
5
1 0
ERa
Erb
d C T  v s  R P L 1 3 A
P S A
A R


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foreshortening of quality adjusted life years for those afflicted with the disease.    
Based on the strong male predominance of MCL, the clinical observation of MCL 
tumor control following standard androgen deprivation therapy, and our 
preliminary data suggesting a role for AR-axis activity in MCL, we hypothesize 
that the potent AR antagonist enzalutamide will yield anti-tumor activity in MCL, 
induce downstream biological effects consistent with inhibition of steroid receptor 
signaling, and thus provide an additional effective therapeutic modality toward 
improving patient outcomes in this challenging disease process. 
 
 
 
3.0 
DRUG INFORMATION 
   
3.1 
General Information 
Enzalutamide (MDV3100) is an androgen receptor signaling inhibitor that targets 
several steps in the AR signaling pathway. Enzalutamide competitively inhibits 
binding of androgens to ARs, inhibits nuclear translocation of receptors and 
inhibits the association of the AR with DNA.  Enzalutamide is currently FDA 
approved for the treatment of metastatic, castration-resistant prostate cancer 
(CRPC).  As this medication has not previously been studied in patients with 
MCL, we will extrapolate dosing and adverse effect monitoring from clinical 
experience with enzalutamide in the setting of CRPC.  Enzalutamide is sold and 
distributed by Astellas/Medivation, Inc. under the brand name XtandiTM. 
 
3.2 
Administration  
Enzalutamide is provided as liquid-filled soft gelatin capsule for oral 
administration. Each capsule contains 40 mg of the active pharmaceutical 
ingredient.  The approved therapeutic dose (CRPC) is 160 mg once daily (4 
capsules, each 40 mg). 
 
 
3.3 
Toxicity 
3.3.1 Adverse events 
The safety and tolerability of enzalutamide have been evaluated in a 
combined safety analysis including metastatic CRPC patients from 2 large 
randomized, 
placebo-controlled 
phase 
3 
studies 
(MDV3100-03) 
[NCT01212991] and CRPC2 [NCT00974311]).  These data are 
summarized below.  Please refer to the current FDA-approved package 
insert and/or the Physician Desk Reference for complete details.  
 
The most common adverse reactions (≥ 10%) in patients with CRPC 
treated with enzalutamide are asthenia/fatigue, back pain, decreased 
appetite, constipation, arthralgia, diarrhea, hot flush, upper respiratory 
tract infection, peripheral edema, dyspnea, musculoskeletal pain, weight 
decreased, headache, hypertension, and dizziness/vertigo. 
3.3.2 Seizure 
Seizure occurred in 0.9% of patients receiving enzalutamide who 
previously received docetaxel and in 0.1% of patients who were 
chemotherapy-naive.  Patients will be informed of the increased risk of 


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seizure and advised to inform their provider of any seizure or loss of 
consciousness. Patients who have a prior seizure history or chronic use of 
drugs that lower the seizure threshold will not be enrolled.  Enzalutamide 
will be permanently discontinued for any subjects who develop a seizure 
during treatment. 
 
3.3.3 Hypertension 
Hypertension was reported in 10.6% of patients receiving enzalutamide 
and 4.3% of patients receiving placebo. No patients experienced 
hypertensive crisis. Patients will be informed of hypertension risk.. 
 
3.3.4 Falls and fall related injuries 
Falls occurred in 9% of patients treated with enzalutamide compared to 
4% of patients treated with placebo. Falls were not associated with loss of 
consciousness or seizure. Fall-related injuries were more severe in patients 
treated with enzalutamide and included non-pathologic fractures, joint 
injuries, and hematomas.  Patients will be informed of fall risk. 
 
3.3.5   Infection 
1% of patients treated with enzalutamide compared to 0.3% of patients 
treated with placebo died from infections or sepsis.  However, this 
increase in infection rate was not seen across all trials involving 
enzalutamide.   Patients will be informed of potential increased infection 
risk. 
 
3.3.6  Laboratory Abnormalities 
Grade 1-4 neutropenia occurred in 15% of patients on enzalutamide (1% 
Grade 3-4) and in 6% of patients on placebo (no Grade 3-4). The 
incidence of Grade 1-4 thrombocytopenia was similar in both arms; 0.5% 
of patients on enzalutamide and 1% on placebo experienced Grade 3- 4 
thrombocytopenia. Grade 1-4 elevations in ALT occurred in 10% of 
patients on enzalutamide (0.3% Grade 3-4) and 18% of patients on 
placebo (0.5% Grade 3-4). Grade 1-4 elevations in bilirubin occurred in 
3% of patients on enzalutamide and 2% of patients on placebo. 
 
3.3.7 Hallucinations 
1.6% of patients treated with enzalutamide were reported to have Grade 1 
or 2 hallucinations compared to 0.3% of patients on placebo. Of the 
patients with hallucinations, the majority were on opioid containing 
medications at the time of the event. Hallucinations were visual, tactile, or 
undefined. 
 
3.4 
Pregnancy/Breast Feeding:  
Enzalutamide is a pregnancy category X medication and is contraindicated in 
women who are pregnant or who are planning to become pregnant.  A confirmed 
negative pregnancy test will be required for all female subjects prior to enrollment 
and both male and female subjects will be counseled on and required to employ 
effective use of barrier contraception from the start of therapy through a minimum 


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of 3 months after the last dose.  Enzalutamide has not been studied in breast 
feeding mothers and its excretion characteristics in breast milk remain unknown.  
We will not enroll any patients who are actively breastfeeding. 
 
3.5 
Drug Interactions 
3.5.1 Metabolism, CYP2C8: 
Co-administration of a strong CYP2C8 inhibitor (gemfibrozil) increased 
the composite area under the plasma concentration-time curve (AUC) of 
enzalutamide plus N-desmethyl enzalutamide by 2.2-fold in healthy 
volunteers.  In current study, co-administration of enzalutamide with 
strong CYP2C8 inhibitors will be avoided if possible and, if unavoidable, 
dose reductions will be made according to the manufacture guidelines and 
SCCA pharmacy assistance.  
 
The effects of CYP2C8 inducers on the pharmacokinetics of enzalutamide 
have not been evaluated in vivo. Co-administration of enzalutamide with 
strong or moderate CYP2C8 inducers (e.g., rifampin) may alter the plasma 
exposure of enzalutamide and will be avoided in this trial if possible. 
 
3.5.2  Metabolism, CYP34A: 
Co-administration of a strong CYP3A4 inhibitor (itraconazole) increased 
the composite AUC of enzalutamide plus N-desmethyl enzalutamide by 
1.3-fold in healthy volunteers. Co-administration of enzalutamide with 
strong CYP3A4 inducers (e.g., carbamazepine, phenobarbital, phenytoin, 
rifabutin, rifampin, rifapentine) may decrease the plasma exposure of 
enzalutamide and will be avoided if possible.  The effects of CYP3A4 
inducers on the pharmacokinetics of enzalutamide have not been evaluated 
in vivo. Selection of an alternative medication with no or minimal 
CYP3A4 induction potential is recommended by the manufacturer and this 
strategy will be utilized whenever possible.  
 
Enzalutamide is a strong CYP3A4 inducer and a moderate CYP2C9 and 
CYP2C19 inducer in humans.  Co-administration with drugs that are 
metabolized 
by 
CYP3A4 
(e.g., 
alfentanil, 
cyclosporine, 
dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus 
and tacrolimus), CYP2C9 (e.g., warfarin) and CYP2C19 (e.g., S-
mephenytoin) will be avoided when possible and closely monitored when 
concurrent use is unavoidable. 
 
3.6 
Supplier  
Enzalutamide 
used 
under 
this 
study 
will 
be 
provided 
by 
from 
Astellas/Medivation, Inc. and distributed by NCCN’s vendor CRMG. 
 
3.7 
Drug Accountability   
The investigator, or a responsible party designated by the investigator, must 
maintain a careful record of the receipt, disposition, and return of all drugs 
received for this study using the study specific Investigational Agent 
Accountability form. 


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3.7.1 Return of unused enzalutamide 
Patients will be instructed to return unused enzalutamide. All unused drug 
will be destroyed per institutional Investigational Drug Services policy. 
 
 
 
4.0 
STAGING CRITERIA 
When applicable, the Lugano staging criteria [18] (see Appendix A) will be used; staging 
should be the highest stage established, either at diagnosis or relapse of disease.   
 
For patients from whom data are available, the mantle cell lymphoma international 
prognostic index (MIPI) [19] will be documented at the time of diagnosis and enrollment 
(see Appendix B).  
 
 
 
5.0 
ELIGIBILITY CRITERIA 
 
5.1 
Inclusion Criteria 
5.1.1 Patients must have histologically confirmed relapsed/refractory or 
previously untreated mantle cell lymphoma (any stage). 
 
5.1.2 Patients with untreated MCL should be asymptomatic or minimally 
symptomatic from their MCL and without aggressive clinicopathological 
features that would otherwise warrant immediate intensive therapy. These 
will generally be patients who qualify for an initial period of “watch and 
wait” per clinical discretion. 
 
5.1.3 Patients must have metabolically active (PET scan positive, as defined in 
section 10.3), measurable disease (defined as lesions greater than 1.5 cm 
long axis that can be accurately measured in two dimensions by CT). 
 
5.1.4 Patients must have an ECOG performance status of 0-2 (see Appendix C).   
 
5.1.5 Patients must be 18 years of age or older.  
 
5.1.6 Hematology values must be within the following limits independent of 
growth factor or transfusion support:   
 
5.1.6.1 Absolute neutrophil count (ANC) ≥ 1000/mm3 or ≥ 750/ mm3 in 
the setting of marrow involvement by disease. 
5.1.6.2 Platelets ≥50,000/mm3 or ≥ 30,000 /mm3 in the setting of marrow 
involvement by disease or splenomegaly due to disease. 
5.1.7 Biochemical values within the following limits: 
5.1.7.1 Alanine aminotransferase (ALT) and aspartate aminotransferase 
(AST) ≤ 3 x upper limit of normal (ULN) 


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5.1.7.2 Total bilirubin ≤ 1.5 x ULN unless bilirubin rise is due to Gilbert’s 
syndrome or of non-hepatic origin 
5.1.7.3 Creatinine clearance (CrCl) > 30 mL/min (as calculated by 
Cockcroft-Gault Equation) 
5.1.8 All patients must be informed of the investigational nature of this study 
and have given written consent in accordance with institutional and federal 
guidelines. Patient must sign an informed consent document indicating 
that they understand the purpose of and procedures required for the study, 
and are willing to participate in and comply with the guidelines of the 
study. 
 
5.1.9 Women of childbearing potential and men who are sexually active must 
affirm they are practicing a highly effective method of barrier birth control 
during and after the study consistent with local regulations regarding the 
use of birth control methods for subjects participating in clinical trials. 
Men must agree to not donate sperm during or after the study. These 
restrictions apply throughout the treatment period and for three months 
after the last dose of enzalutamide. 
5.1.10 Women of childbearing potential must have a negative serum (beta-human 
chorionic gonadotropin [β-hCG]) or urine pregnancy test at screening. 
Women who are pregnant or breastfeeding are ineligible for this study. 
 
5.2 
Exclusion Criteria 
5.2.1 Uncontrolled 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 within 6 months of enrollment. 
 
5.2.2 Known active central nervous system lymphoma.  
 
5.2.3  Known clinically significant heart disease as evidenced by: 
• 
Myocardial infarction within 6 months of enrollment. 
• 
Uncontrolled angina within 6 months of enrollment. 
• 
Congestive heart failure NYHA Class III or IV, or a history of 
congestive heart failure NYHA Class III or IV in the past, unless a 
screening ECHO or MUGA within 3 months results in a left 
ventricular ejection fraction ≥45%. 
• 
Clinically significant ventricular arrhythmias. 
• 
History of Mobitz II second degree or third degree heart block without 
a permanent pacemaker in place. 
• 
Bradycardia as indicated by a heart rate < 50 beats per minute at 
screening visit. 
• 
Hypotension as indicated by SBP ≤ 85 on 2 consecutive measurements 
at screening visit. 


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• 
Uncontrolled hypertension as indicated by SBP > 170 mmHg or DBP 
> 105 mmHg on 2 consecutive measurements at screening visit. 
 
5.2.3 Child Pugh class C hepatic dysfunction. 
 
5.2.4 History of seizures.  
 
5.2.5 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 
enzalutamide, or put the study outcomes at undue risk. 
5.2.6 Patients with other prior malignancies except for adequately treated basal 
cell carcinoma, squamous cell carcinoma of the skin, breast or cervical 
cancer in situ, or other cancer from which the patient has been disease-free 
for 5 years or greater, unless approved by the protocol Investigator / Lead-
Sub-Investigator. 
5.2.7 Chemotherapy, immunotherapy, biologically targeted therapy, other 
investigational agent, or radiation therapy within 3 weeks of initiation of 
enzalutamide therapy.  For patients with objectively progressive disease 
on a BTK-targeting agent whom in the opinion of the investigator would 
not tolerate a 21 day washout period, a >5 half-lives washout period will 
be allowed. 
 
5.2.8 Prior 
allogeneic 
transplant 
with 
GVHD 
requiring 
ongoing 
immunosuppressive therapy.  
5.2.9 
HIV-positive individuals on combination antiretroviral therapy are ineligible 
because of the potential for pharmacokinetic interactions with enzalutamide.  
 
5.2.10 Ongoing treatment with hormonal agents (e.g. finasteride, dutasteride, 
ketoconazole, hormonal birth control, estrogen replacement therapy, 
testosterone replacement therapy) or herbal products that may have 
hormonal activity (saw palmetto, black cohosh). Patients taking these 
agents are eligible for screening, but must be willing to undergo a washout 
period of 4 weeks prior to starting study treatment. 
 
 
6.0 
REGISTRATION 
Patients must be registered prior to the start of protocol therapy.  A completed eligibility 
checklist with source documentation, a copy of the signed consent form, and a signed 
HIPAA authorization are required for registration.  All of the eligibility requirements 
according to Section 5 must have been met. 
 
 
7.0 
TREATMENT PLAN 
 


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7.1 
Contact 
For treatment or dose-modification related questions, please contact Dr. Martin at 
(206) 667-3132 or Dr. Gopal at (206) 606-2037.  (MedCon may also be used to 
contact MDs at 206-543-5300.) 
 
7.2 
Administration of Enzalutamide  
Enzalutamide is taken orally at a starting dose of 160 mg daily.  Enzalutamide can 
be taken with or without food. Enzalutamide may be taken at any time during the 
day, but should be taken at the same time each day. A missed dose should be 
taken as soon it is remembered. If twelve or more hours have lapsed since a 
missed dose, participants should not take the missed dose; rather the participant 
should resume dosing at the next scheduled dose. 
 
 
Drug 
Dose  
Route 
Days 
Duration 
Enzalutamide Starting dose of 160 mg, as four 40 mg 
capsules. Can be taken with or without 
food. Capsules should be swallowed 
whole with water. Do not chew, 
dissolve, or open capsules. 
PO 
Once daily 
Until disease 
progression, intolerance, 
or decision of patient or 
treating physician 
 
 
7.3   
Prophylaxis 
No prophylactic therapy is required for enzalutamide.  Supportive care should be 
provided as clinically indicated. 
 
 
7.4  
Criteria for removal from protocol treatment: 
• Documented progression of disease (see section 10.4).  
• Development of seizures, or any therapy-related non-hematologic grade ≥ 
4 toxicity or other serious adverse event as defined in section 12.0 will 
qualify for consideration of removal from protocol treatment. 
• Development of any other unacceptable toxicity. 
• Delay of treatment for more than 21 days due to toxicity. 
• The patient may withdraw from the treatment at any time for any reason. 
• Taking prohibited medications concurrent with enzalutamide therapy may 
result in removal from protocol treatment. 
 
 
 
8.0       DOSAGE MODIFICATIONS 
 
8.1 
Toxicity Management, Dose Modification and Dose Delay 
If a patient experiences a ≥ Grade 3 non-hematological toxicity related to the 
study drug or an intolerable side effect, treatment will be withheld for one week 
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be resumed at the same dose or at a reduced dose (120 mg or 80 mg), based on 
clinician judgment.   
 
 
8.2 
Concomitant Therapy 
Medications used during the course of the study should be documented. 
 
8.2.1 Prohibited Concomitant Therapy:  
The administration of concurrent medications intended to treat the primary 
cancer is not allowed during protocol therapy.  This includes any 
chemotherapy, investigational agent, biologic agent or other anti-tumor 
agents.  
 
The administration of concomitant medications with effects on drug 
metabolizing enzymes known to be involved in the metabolism of 
enzalutamide should be avoided where possible, as detailed in section 3.5 
and summarized in the table below. 
 
 
Class 
Example Drugs 
Recommendation 
Strong CYP2C8 
Inhibitors 
Gemfibrozil 
If co-administration with 
gemfibrozil cannot be avoid, 
reduce enzalutamide dose 
Strong CYP2C8 
Inducers 
Rifampin 
Avoid concomitant use 
Strong CYP3A4 
Inhibitors 
Itraconazole 
No initial dose adjustment 
Strong/Moderate 
CYP3A4 
Inducers 
Carbamazepine, phenobarbital, phenytoin, rifabutin, 
rifamin, rifapentine, osentan, efavirenz, etravirine, 
modafinil, nafcillin, St. John’s Wort 
Avoid concomitant use 
CYP3A4 
Substrate 
Alfentanil, cyclosporine, dihydroergotamine, 
ergotamine, fentanyl, pimozide, quinidine, sirolimus 
and tacrolimus 
Avoid concomitant use of 
substrates with a narrow 
therapeutic index 
CYP2C9 
Substrate 
Phenytoin, warfarin 
Avoid concomitant use of 
substrates with a narrow 
therapeutic index 
CYP2C19 
Substrate 
S-mephenytoin 
Avoid concomitant use of 
substrates with a narrow 
therapeutic index 
CYP2C8 
Substrate 
Pioglitazone 
No dose adjustment 
 
Patients should be strongly discouraged from taking any “alternative” or 
“naturopathic” medications since these agents may interact with study 
treatment. Concomitant use of these medications should be documented 
and evaluated by the treating investigator. 
 
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Localized radiation therapy will be allowed for symptom control as 
needed. 
 
 
 
 
9.0 
STUDY CALENDAR 
• The first three treatment cycles will be 4 weeks (28 days). All subsequent cycles 
starting with Cycle 4 will be 12 weeks (84 days). Patients may be seen for 
additional optional mid cycle visits at the discretion of their provider. 
• Study drug will be dispensed in a four week supply  for the first three cycles, then 
in a 12 week supply for subsequent cycles 
  
Required Studies 
Screening 
(within 4 weeks of 
initiation of 
treatment) 
During 
treatment 
Post 
Therapy 
Follow-
up10 
Physical 
 
 
 
 
Medical History 
X 
 
 
 
Physical Exam 
X 
X7 
X9 
 
Performance Status 
X 
X7 
X9 
 
Clinical Disease Assessment 
X 
X7 
X9 
 
Adverse Event Assessment 
X 
X7 
X9 
 
EKG 
X 
 
 
 
Lab 
 
 
 
 
CBC and differential 
X 
X7 
X9 
 
Serum creatinine, total bilirubin, 
SGOT (AST), SGPT (ALT), 
electrolytes, calcium, glucose  
X 
X7 
X9 
 
Albumin, LDH, B2M 
                X 
 
X9 
 
Bone marrow studies 
X1 
X1 
 
 
Pregnancy test 
X2 
 
 
 
Tissue collection, if feasible 
                X11 
 
 
 
PSA (prostate specific antigen)  
X3 
X3 
 
 
Total testosterone and estradiol 
X4 
X4 
 
 
Research Labs5 
X5 
X5 
X9 
 
Radiology 
 
 
 
 
CT Chest, abdomen and pelvis  
(+ neck if clinical involvement) 
                X 
X8 
 
 


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FDG-PET (skull base to proximal 
femur) 
X6 
X8 
 
 
 
1 Bone marrow studies include aspirate and unilateral or bilateral biopsy for standard analysis with 
additional correlative studies as specified in Section 14.  Bone marrow studies should be performed at 
screening unless approved by the Investigator or Lead Sub-Investigator.  If all bone marrow studies are 
negative at screening, these do not need to be repeated except in the case of progressive disease by CT 
imaging, if feasible.  If bone marrow status is unknown or positive at screening, patients will need to a 
have bone marrow study to confirm a suspected CR.  
2 Pregnancy test is only required in women of childbearing potential. Pregnancy test will be repeated on 
the first day of study drug therapy if  > 1 week has lapsed from initial screening pregnancy test and start 
of treatment. 
3 PSA is only required in men. To be drawn at screening, after 4 weeks of treatment (+/- 6 days), and at 
treatment discontinuation (+/- 6 days). 
4 Total testosterone and estradiol to be drawn at screening, after 4 weeks of treatment (+/- 6 days), and at 
treatment discontinuation (+/- 6 days).  
5Research Labs include blood samples for serum hormone levels (DHT, DHEA, Androstenedione, 
Estrone). To be drawn at screening, after 4 weeks of treatment (+/- 6 days), after 12 weeks of treatment 
(+/- 6 days), and then every 12 weeks (+/- 6 days) during treatment. 6 May be obtained up to 8 weeks in 
advance of initiation of therapy (provided no additional anti-cancer therapies are administered during the 
interval). A Deauville score should be assigned. 
7 At the beginning of therapy (within 3 days), then every four weeks for the first 12 weeks (+/- 6 days), 
then at a minimum of every 12 weeks (+/- 6 days) while on therapy, depending on clinical course. For the 
first day of therapy, pre-entry H&P, PS, disease assessment, and adverse event assessment may be used 
(these do not need to be repeated within 3 days) and labs done within 14 days are acceptable. 
8 During treatment, restaging CT imaging will be performed every 12 weeks of therapy (+/- 7 days), or as 
indicated to evaluate clinical suspicion of disease progression.  First restaging CT (three months after 
initiating therapy) should include PET imaging to ascertain metabolic response to therapy.  Subsequently, 
restaging PET/CT should also be performed to confirm metabolic CR in patients with stable PR on 2 
consecutive CT staging exams or in patients with a CR based on CT staging and baseline FDG-avid 
disease to determine metabolic CR and CR (resp.). A Deauville score should be assigned when restaging 
PET is performed. 
9 Post therapy evaluation will be completed 30 days (+/-7 days) after the last dose of enzalutamide or prior 
to initiation of new therapy, whichever comes sooner. 
10Long-term follow-up should be performed according to the patient’s physician’s standard of care. This 
may be performed at patients’ local physician’s offices. Long-term follow-up will assess survival and 
disease progression; subjects may be contacted by the study team until five years out from study 
completion, subject withdrawal of consent, lost to follow-up, or study termination by the investigator, 
whichever occurs first. 
11 When appropriate, archival tissue or fresh samples from clinical biopsies may be used. 
 
 
 
10.0 
ENDPOINT DEFINITIONS AND CRITERIA FOR EVALUATION 
 
10.1  Endpoint Definitions: 
 
10.1.1 Primary endpoint:  
Best overall response rate (ORR) which will include complete responses 
(CR) and partial responses (PR) as measured by standard criteria (Cheson 
et al, 2014) . 
 


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10.1.2 Secondary Endpoints:  
1. Time to treatment failure (TTF)  
2. Progression-free survival (PFS)  
3. Overall survival (OS)  
4. Adverse events (AEs) as measured by NCI-CTCAE 4.0.  
5. Disease control rate (CR+PR+SD>3 months) 
 
Clinical endpoints of ORR, CR, PR, TTF, PFS and AEs will be stratified by 
gender. 
 
10.2 
Selection of Indicator (Target) Lesions 
Up to six of the largest dominant nodes or tumor masses selected according to all 
of the following:  
• 
Clearly measurable in at least two perpendicular dimensions  
Abnormal lymph nodes are those that are either  
>1.5 cm in the greatest transverse diameter (GTD) regardless of the short 
axis diameter, or 1.0 cm in short axis diameter regardless of long axis 
• 
If possible, they should be from disparate regions of the body  
• 
Should include mediastinal and retroperitoneal areas of disease whenever 
these sites are involved  
• 
Extranodal lesions within the liver or spleen must be at least 1.0 cm in two 
perpendicular dimensions. 
 
 
10.3  PET Scans 
Visual assessment currently is considered adequate for determining whether a 
PET scan is positive. A Deauville score should be reported. In brief, a positive 
scan is defined as focal or diffuse FDG uptake above background in a location 
incompatible with normal anatomy or physiology.  
 
10.4  Response Criteria  
Response will be defined by standard NCI criteria (Cheson et al, 2014) for 
lymphoid malignancies [18]. 
 
10.5 
Progression-free Survival (PFS)  
PFS will be measured as time from first study drug administration to the first 
occurrence of disease progression or death from any cause. Data for subjects 
without disease progression or death will be censored at the date of last disease 
assessment or date last known to be alive, respectively. The estimates will be 
formed using the all treated population. Progression-free survival will be 
calculated using assessments by investigators. Kaplan-Meier methodology will be 
used to estimate event-free curves and corresponding quartiles (including the 
median). 
 
10.6 
Assessment Inadequate, Objective Status Unknown 
Progression has not been documented and one or more target lesions or other sites 
of disease have not been assessed or inconsistent methods of assessment were 
used. 
 


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10.7 
Bone Marrow Status 
Bone marrow status is evaluated as follows:  
 
Positive:  
Unequivocal 
morphological, 
immunohistochemical, 
or 
immunophenotypic evidence of malignancy.   
 
Negative:  
No aggregates or only a few well-circumscribed lymphoid  
aggregates without morphological, immunohistochemical, or 
immunophenotypic evidence of malignancy 
 
Indeterminate: Does not qualify for either positive or negative status.  *Note this  
typically consists of increased number or size of aggregates 
without 
morphological, 
immunohistochemical, 
or 
immunophenotypic atypia. 
 
11.0  STATISTICAL CONSIDERATIONS 
The primary objective of this pilot trial is to derive an estimate of the overall response 
rate (ORR, see section 10.4) in this population.  Secondary clinical endpoints will include 
time to progression, progression-free survival, and safety.  The study is not formally 
powered to reject a specified null hypothesis and as such the sample size is not based on 
the number of patients needed to reject the null hypothesis under a specified alternative.  
That said, with 20 patients the estimated ORR will be within 0.11 of the true ORR if the 
hypothesized ORR is 20%.  An ORR of 20% will be taken as a benchmark for success for 
the primary endpoint of this pilot study.  If the observed ORR is at least 20% (4 or more 
responses among the 20 patients), we would consider this treatment sufficiently 
meritorious to warrant further study in a future Phase II trial that will formally evaluate 
potential efficacy.  If the true ORR is 10%, then the probability of 4 or more responses 
among 20 patients is only 0.13; if the true ORR is 30%, then the probability of 4 or more 
responses among 20 patients is 0.89.  As stated above, the sample size for this trial is not 
based on specific null and alternative hypotheses.  That said, if the assumed-true ORR 
with this regimen is 35%, then 20 patients will provide 86% power to observe a 
statistically significant (at the one-sided significance level of .15) improvement in ORR 
compared to the fixed ORR of 15%.   
 
We will also be encouraged if patients have prolonged disease stability/lack of 
progression that may be observed with a cytostatic biological agent, though this 
secondary endpoint will deemed exploratory. For this secondary endpoint, a median PFS 
of ≥6 months would also be scored as a pilot success. 
 
11.1 
Stopping Rules 
If we see no responses nor any evidence of disease stabilization (as defined above 
as stable disease ≥6mo) after the first 10 patients, then the trial will be halted for 
futility.  If we see at least one response or capture at least one instance of disease 


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stabilization ≥6mo among the first 10 patients, then enrollment will continue to 
goal enrollment of 20 patients. 
 
 
 
11.2  Anticipated Accrual 
We expect to accrue approximately 1 patient per month and anticipate complete 
study accrual in 24 months.      
 
11.3 
Estimated Distribution of Study Population by Gender, Race and Ethnicity 
 
 
Ethnic Category 
Females 
Males 
American Indian/Alaska Native 
 
 
Asian 
1 
1 
Native Hawaiian or Other Pacific Islander 
 
 
Black or African American 
1 
1 
White 
4 
12 
More than one race 
 
 
Unknown or not reported 
 
 
Racial Categories: Total of all subjects 
6 
14 
 
.    
 
 
12.0  STUDY MONITORING AND REPORTING PROCEDURES 
 
 
12.1 
Adverse Event (AE) Reporting  
AEs of Grade 3 and above, and Serious Adverse Events (SAEs) occurring at 
any grade will be monitored and recorded in study-specific case report forms 
(CRFs) from the time of the first dose of study treatment through 30 days 
following the end of study treatment, or until the patient receives an 
alternative anti-cancer therapy, whichever date comes first. AEs related to 
lymph node (tumor)  biopsies  that are done solely  for research study 
screening  purposes will be monitored, recorded, and reported  according to  
the  same  standards,  with  the  exception  that  assessment   of  study  drug 
attribution  will be excluded from reporting criteria. 
 
The Investigator will assess AE grading, attribution, expectedness and whether 
the event is of interest to Astellas/Medivation Inc. 
 
The NCI Common Terminology Criteria for Adverse Events v4.0 (CTCAE) will 
be used to classify and grade toxicities. 
 
12.2  Definitions and Descriptions of Terms Used in AE Reporting 
12.2.1  Adverse Event (AE) 
An AE is any undesirable sign, symptom or medical condition or 
experience that develops or worsens in severity after starting the first dose 
of study treatment or any procedure specified in the protocol, even if the 
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Abnormal laboratory values or diagnostic test results constitute AEs only 
if they induce clinical signs or symptoms or require treatment or further 
diagnostic tests. 
 
12.2.2  Serious Adverse Event (SAE) or Adverse Drug Reaction (ADR) 
The term “Serious Adverse Event” (or “SAE”) shall mean any adverse 
drug experience occurring at any dose that results in any of the following 
outcomes: death, is life-threatening (life-threatening means that the person 
was at immediate risk of death from the reaction as it occurred, i.e., it does 
not include a reaction which hypothetically might have caused death had it 
occurred in a more severe form), requires inpatient hospitalization or 
prolongation of an existing hospitalization, results in a persistent or 
significant disability or incapacity, results in a congenital anomaly or birth 
defect, results in cancer, or results in an important medical event. 
Important medical events which are AEs that may not result in death, be 
Life-Threatening, or require hospitalization may be considered SAEs 
when, based upon appropriate medical judgment, they may jeopardize the 
Study Participant and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition.  
 
Disease progression should not be recorded as an adverse event or serious 
adverse event term; instead, signs and symptoms of clinical sequelae 
resulting from disease progression/lack of efficacy will be reported if they 
fulfill the serious adverse event definition. 
 
12.2.3  Grade 
Grade is defined as the severity of the adverse event.  The CTCAE 
Version 4.0 must be used to determine the grade of the adverse event. If 
toxicity is not listed in the CTCAE use the following general criteria for 
grading.   
 
 
0 – No adverse event or within normal limits 
 
 
1 – Mild adverse event 
 
 
2 – Moderate adverse event 
 
 
3 – Severe adverse event 
 
 
4 – Life-threatening or disabling adverse event 
 
 
5 – Fatal adverse event 
 
12.2.5  Attribution 
Attribution is defined as the determination of whether an adverse event is 
related to a medical treatment or procedure.  Attribution categories are as 
follows: 
• Unrelated The adverse event is clearly NOT related to therapy 
• Unlikely 
The adverse event is doubtfully related to therapy 
• Possible 
The adverse event may be related to therapy 
• Probable The adverse event is likely related to therapy 
• Definite 
The adverse event is clearly related to therapy 


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12.2.6  Suspected Adverse Reaction  
Any adverse event for which there is a reasonable possibility that the drug 
caused the adverse event. 
 
12.2.7  Unexpected Adverse Event  
An AE that is not consistent in nature or severity with the product 
information documented in the current Investigator’s Brochure or package 
insert, or in the protocol, consent form, and/or prior reports.   
 
Note:  The following events are not identified as AEs in this study: 
• 
Disease progression or relapse.    However, clinical events 
 
associated with progression/relapse may be reportable as AEs. 
• 
Medical  or  surgical  procedures  in  and  of  themselves, 
 
including those  that require hospitalization (e.g., surgery,  
endoscopy, biopsy procedures) are not considered AEs. However, 
an event or condition requiring such procedures may be an AE. 
• 
Abnormal   laboratory  values  will  be  identified  and  recorded   
 
As AEs only if clinical intervention is required as a result. 
 
 
12.3    Expedited Reporting  
Expedited reporting will be conducted in accordance with FHCRC/Cancer 
Consortium IRB policies, applicable FDA regulations under 21 CFR 312.32, 
including regulations pertaining to reporting of Serious and Unexpected 
Suspected Adverse Reactions, and agreement with NCCN. 
 
12.4 
Routine Reporting 
Routine reporting will be conducted in accordance with FHCRC/Cancer 
Consortium IRB policies, applicable FDA regulations, and agreements with 
NCCN. 
 
      
12.4 
Serious Adverse Event Reporting to NCCN and Astellas/Medivation Inc. 
Expedited reporting will be conducted in accordance with FHCRC/Cancer 
Consortium IRB policies, FDA regulations, and agreements with NCCN.  
Reportable events and required time frames include: 
• SAEs/Suspected Adverse Reactions that are fatal or life-threatening, 
unexpected, and possibly related to the study drug will be reported to the FDA 
as an IND Safety Report (via narrative report or MedWatch form 3500A) 
within 7 calendar days of the Investigator’s awareness of the event.  
Notification to the FDA will be submitted concurrently to NCCN and 
Astellas.   
• SAEs/Suspected Adverse Reactions that are unexpected and possibly related 
to the study drug (but are not fatal or life-threatening) will be reported to the 
FDA as an IND Safety Report (via narrative report or MedWatch form 


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3500A) within 15 calendar days of the Investigator’s awareness of the event.  
Notification to the FDA will be submitted concurrently to NCCN and 
Astellas.   
• AEs that are unexpected, possibly related to the study drug, and serious or 
suggest a risk of greater harm from the research than previously known will 
be reported to the IRB within 10 calendar days of the Investigator’s awareness 
of the event.   
 
Initial reporting will occur in the time frames noted above, with follow-up 
information, if needed, submitted as available. 
 
Expedited reports should be emailed or faxed to both: 
• Astellas Pharma Global Development – United States 
Email: Safety-us@us.astellas.com 
Fax number: (888) 396-3750 
 
• NCCN Oncology Research Program (ORP) 
 
 
Email: ORPReports@nccn.org 
 
 
Fax number: (215) 358-7699 
 
The following minimum information is required: 
• Study number/IIT regulatory identifier 
• Subject number, sex and age 
• The date of report 
• A description of the SAE (event, seriousness of the event) 
• Causal relationship to the study drug 
 
Follow-up information for the event should be sent promptly (within 7 days) as 
necessary. 
 
 
 
 
12.5 
Reporting to the IRB 
Local IRB guidelines and policies will be followed for reporting serious adverse 
events in a timely manner.   
 
  
 
12.7 
Data Safety and Monitoring Plan 
All serious adverse events are communicated to the study Investigator and 
regulatory agencies as described above.  A status report including accrual, adverse 
events, and death information will be reviewed by the Investigator and the Fred 
Hutchinson Cancer Research Center (FHCRC) Protocol Data Monitoring 
Committee (PDMC) annually.  In addition, the study will be monitored by 
Clinical Research Support (CRS)according to the Fred Hutchinson/University of 
Washington Cancer Consortium data and safety monitoring plan (DSMP). 
 
 
 
 12.8 Records  


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Under the supervision of the investigators, research staff will maintain case 
report forms and secured databases on the relevant clinical and laboratory 
data.   Records maintained in investigators' offices will be secured with access 
limited to study personnel.  Authorization for access to medical records will be 
obtained from all patients in accordance with provisions of the Health 
Insurance Portability and Accountability Act (HIPAA). 
 
 
13.0 
ELEMENTS OF INFORMED CONSENT 
All Institutional, NCI, State and Federal regulations concerning informed consent and 
peer judgment will be fulfilled.  Written consent will be obtained from all patients 
entering the study. 
 
 
14.0 
 CORRELATIVE STUDIES 
 
14.1 
   Objectives 
14.1.1 To determine whether pre-treatment expression of AR and ER in tumor, or 
levels of androgens and estrogens in serum associate with response to 
therapy in MCL patients treated with enzalutamide. 
 
14.1.2 To determine whether lack of AR expression or presence of truncated AR 
splice variants associate with poor response to therapy in MCL patients 
treated with enzalutamide. 
 
 
14.2 
  
Methodology  
14.2.1 Serial measurement of serum hormone levels as outlined in the study 
calendar.  
 
14.2.2 Analysis of AR and ER expression by immunohistochemistry (IHC) on 
formalin fixed pre-treatment tumor biopsy samples as outlined in the study 
calendar.   
 
14.2.3 Additionally, patients with circulating tumor cells, those undergoing 
clinical bone marrow evaluation, and those undergoing clinical tumor 
biopsies may have fresh tumor cells collected for evaluation of AR and ER 
transcript levels by RNA isolation as well as measurement of tumor 
steroid levels (in the case of tissue biopsy). 
 
 
 
 
 
 


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15.0 
REFERENCES 
 
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Appendix A: Revised staging system for primary nodal lymphomas (Lugano classification) 
 
Stage 
Involvement 
Extranodal (E) status 
I 
One node or a group of adjacent nodes 
Single extranodal lesions 
without nodal involvement 
II 
Two or more nodal groups on the same side of the 
diaphragm 
Stage I or II by nodal extent with 
limited contiguous extranodal 
involvement 
II bulky* 
II as above with "bulky" disease 
Not applicable 
III 
Nodes on both sides of the diaphragm; nodes above 
the diaphragm with spleen involvement 
Not applicable 
IV 
Additional noncontiguous extralymphatic 
involvement 
Not applicable 
 
* A single nodal mass of 10cm or greater than a third of the transthoracic diameter at any level of 
thoracic vertebrae as determined by CT 


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Appendix B: Mantle cell lymphoma international prognostic index (MIPI) 
 
POINTS 
AGE (YEARS) 
ECOG PS 
LDH:UHN 
RATIO 
WBC (109/L) 
0 
<50 
0 to 1 
<0.67 
<6.7 
1 
50-59 
 
0.67-0.99 
6.7-9.9 
2 
60-69 
2 to 4 
1.00-1.49 
10.0-14.9 
3 
≥70 
 
≥1.50 
≥15.0 
 
 
SCORE 
RISK GROUP 
0 to 3 points 
Low risk 
4 to 5 points 
Intermediate risk 
6 to 12 points 
High risk 
 
 


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Appendix C: ECOG Performance Status 
 
0   –  Asymptomatic (Fully active, able to carry on all pre-disease activities without restriction) 
 
1   –  Symptomatic but completely ambulatory (Restricted in physically strenuous activity but  
ambulatory and able to carry out work of a light or sedentary nature. For example, light 
housework, office work) 
 
2   –  Symptomatic, <50% in bed during the day (Ambulatory and capable of all self-care but 
unable to carry out any work activities. Up and about more than 50% of waking hours) 
 
3   –  Symptomatic, >50% in bed, but not bedbound (Capable of only limited self-care, 
confined to bed or chair 50% or more of waking hours) 
 
4   –  Bedbound (Completely disabled. Cannot carry on any self-care. Totally confined to bed 
or chair) 
 
5   –  Death