Clinical trial NCT02784834
Conditions: Chronic Lymphocytic Leukemia Small Lymphocytic Lymphoma
Keywords: CLL cancer DMF SLL dimethylfumarate relapsed refractory
Sponsor: Michael Choi
Start date: 2016-06-01; Completion date: 2019-02-01
Enrollment: 2 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of the study is to investigate the safety of the investigational drug called dimethylfumarate (DMF). DMF is a type of drug called an immunomodulatory drug. This drug is approved by the United States (U.S.) Food and Drug Administration (FDA) as a treatment for patient with multiple sclerosis.

Although there is evidence from tests on laboratory animals that DMF can decrease the number of CLL cells, we do not know if this will work in humans with CLL. This drug will be given to humans with CLL for the first time in this study. Therefore, the goal of this study is to see if DMF is safe and tolerable in study participants. Participants will be evaluated to find out what effects (good and bad) DMF has on the body and see how long the drug stays in the body.

Detailed description:
This is a phase I clinical trial to evaluate the safety, tolerability, and maximum tolerated dose of DMF in patients with chronic lymphocytic leukemia. Patients with relapsed/refractory CLL not amenable to available therapies are eligible. This patient population is in need of novel therapies, particularly if progressing after, intolerant of, or unable to receive oral tyrosine kinase inhibitors (ie ibrutinib, idelalisib).

For Dose Level 1, DMF (Tecfidera formulation) will be administered at a dose of 120 mg PO BID (approximately 12 hours apart) for 2 x 28 day cycles.

For Dose Level 2, DMF will be administered at the currently used dose for patients with multiple sclerosis: at the standard FDA approved dose of 120 mg PO BID (approximately 12 hours apart) for 1 week, then escalating to the assigned dose of (240mg PO BID for the remainder of 2 x 28 day cycles. The 1 week lead-in at 120 mg is to assist in toleration and initial side effects and is as per the standard prescribing information.

For Dose Level 3, DMF will be administered at the currently used dose for patients with multiple sclerosis: 120 mg PO BID for 1 week, then escalate to the dose of 360mg PO BID for the remainder of 2 x 28 day cycles.

Arms: arm 1: Cohort 1: dimethyl fumarate 120 mg PO BID (approximately 12 hours apart) for 2 x 28 day cycles.

Cohort 2: dimethyl fumarate 120 mg PO BID (approximately 12 hours apart) for 1 week, then escalating to the assigned dose of (240mg PO BID for the remainder of 2 x 28 day cycles.

Cohort 3: dimethyl fumarate 120 mg PO BID for 1 week, then escalate to the dose of 360mg PO BID for the remainder of 2 x 28 day cycles.
Interventions: intervention 1: dimethyl fumarate
Intervention descriptions: intervention 1: None

Protocol documents:
Prot_SAP_000.pdf: 
 
Principal Investigator:  Michael Choi, MD  
HRPP Project 151567  
 
 
 
 
 
 
Page 1 of 37 
 
 
 
 
 
 
  
 
A phase I clinical trial to evaluate dimethylfumarate (DMF) in relapsed/refractory patients with 
chronic lymphocytic leukemia/small lymphocytic lymphoma. 
 
 
 
 
PRINCIPAL INVESTIGATOR 
Michael Choi, MD. 
Assistant Professor 
Hematology/Oncology 
University of California, San Diego 
Moores Cancer Center 
3855 Health Sciences Drive #0820 
La Jolla, CA 92093 
Phone: 858-534-1765 
Fax: 858-534-5620 
E-mail:  mychoi@ucsd.edu  
 
 
 
Protocol Number: 
151567 
 
Study Agent:  
Dimethyl fumarate (DMF) 
 
IND Number:  
130625 
 
IND Holder Name: 
Michael Choi, MD 
 
 
Initial Version:  
March 1, 2016 
Amendment 1: 
May 10. 2017 
 
 
 
 
 
 
 
 
 


 
Principal Investigator:  Michael Choi, MD  
HRPP Project 151567  
 
 
 
 
 
 
Page 2 of 37 
 
 
 
 
 
LIST OF INVESTIGATORS 
 
 
PRINCIPAL INVESTIGATOR 
Michael Choi, MD. 
University of California, San Diego 
Moores Cancer Center 
3855 Health Sciences Drive #0820 
La Jolla, CA 92093 
Phone: 858-534-1765 
Fax: 858-534-5620 
E-mail:  mychoi@ucsd.edu 
 
 
CO-INVESTIGATOR(S) 
Thomas Kipps, M.D./Ph.D. 
Department of Medicine / Division of Hematology/Oncology 
3855 Health Sciences Drive #0820 
La Jolla, CA 92093 
tkipps@ucsd.edu 
 
Januario Castro, M.D. 
Department of Medicine / Division of Bone Marrow Transplant 
3855 Health Sciences Drive #0820 
La Jolla, CA 92093 
jecastro@ucsd.edu 
 
 
BIOSTATISTICIANS 
Hongying Li, PhD 
Biostatistics 
3855 Health Sciences Drive, #0901 
La Jolla, CA 92093-0901 
Phone: 858-822-4818 
hol031@ucsd.edu 
 
Karen Messer, PhD 
Biostatistics 
3855 Health Sciences Drive, #0901 
La Jolla, CA 92093-0901 
Phone: 858-822-4334 
kmesser@ucsd.edu  
 
 
 
 


 
Principal Investigator:  Michael Choi, MD  
HRPP Project 151567  
 
 
 
 
 
 
Page 3 of 37 
 
 
Signature Page 
 
 
The signature below constitutes the approval of this protocol and the attachments, and provides 
the necessary assurances that this trial will be conducted according to all stipulations of the 
protocol, including all statements regarding confidentiality, and according to local legal and 
regulatory requirements and applicable U.S. federal regulations and ICH guidelines. 
 
 
 
Principal Investigator (PI) Name: _____________________________ 
 
 
 
PI Signature: _____________________________ 
 
 
 
Date: ____________________ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Principal Investigator:  Michael Choi, MD  
HRPP Project 151567  
 
 
 
 
 
 
Page 4 of 37 
 
TABLE OF CONTENTS 
STUDY SUMMARY .................................................................................................................................................. 6 
1.0 
BACKGROUND AND RATIONALE .................................................................................................................. 8 
1.1 
DISEASE BACKGROUND: CHRONIC LYMPHOCYTIC LEUKEMIA ......................................................................................... 8 
1.2 
STUDY AGENT: DIMETHYL FUMARATE (DMF) ........................................................................................................... 9 
1.3 
OVERVIEW AND JUSTIFICATION FOR STUDY AND STUDY POPULATION ............................................................................ 11 
2.0 
STUDY OBJECTIVES .................................................................................................................................... 11 
PRIMARY OBJECTIVE: .................................................................................................................................................... 11 
SECONDARY OBJECTIVES ............................................................................................................................................... 11 
3.0 
ENDPOINTS ................................................................................................................................................ 11 
3.1 
PRIMARY ENDPOINT: .......................................................................................................................................... 11 
3.2 
SECONDARY ENDPOINTS ...................................................................................................................................... 11 
4.0 
PHASE I PATIENT ELIGIBILITY...................................................................................................................... 12 
4.1 
INCLUSION CRITERIA ........................................................................................................................................... 12 
4.2 
EXCLUSION CRITERIA .......................................................................................................................................... 13 
5.0 
TREATMENT PLAN...................................................................................................................................... 14 
5.1 
TREATMENT DOSAGE AND ADMINISTRATION ........................................................................................................... 14 
5.2 
DEFINITION OF DOSE-LIMITING TOXICITY ................................................................................................................ 14 
5.3 
PRE-MEDICATIONS ............................................................................................................................................ 15 
5.4 
PERMITTED CONCOMITANT THERAPY ..................................................................................................................... 15 
5.5 
PROHIBITED CONCOMITANT THERAPY ..................................................................................................................... 15 
5.6 
OTHER MODALITIES OR PROCEDURES .................................................................................................................... 15 
5.7 
TOXICITIES AND DOSING DELAYS/DOSE MODIFICATIONS ........................................................................................... 15 
5.8 
DURATION OF THERAPY ...................................................................................................................................... 16 
5.9 
DURATION OF FOLLOW UP .................................................................................................................................. 16 
6.0 
STUDY PROCEDURES .................................................................................................................................. 17 
6.1 
SCHEDULE OF EVENTS ......................................................................................................................................... 17 
6.2 
SCREENING/BASELINE PROCEDURES ...................................................................................................................... 18 
6.3 
PROCEDURES DURING TREATMENT ....................................................................................................................... 19 
6.4 
CORRELATIVE STUDIES ........................................................................................................................................ 22 
6.5 
REMOVAL OF SUBJECTS FROM STUDY TREATMENT AND STUDY ................................................................................... 23 
7.0 
MEASUREMENT OF EFFECT ........................................................................................................................ 24 
7.1 
RESPONSE CRITERIA FOR PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA ................................................................. 24 
7.2 
SAFETY/TOLERABILITY ......................................................................................................................................... 25 
8.0 
ADVERSE EVENTS ....................................................................................................................................... 26 
8.1 
ADVERSE EVENT MONITORING ............................................................................................................................. 26 
8.2 
SEVERITY .......................................................................................................................................................... 26 
8.3 
SERIOUSNESS .................................................................................................................................................... 27 
8.4 
RELATIONSHIP ................................................................................................................................................... 27 
8.5 
PRIOR EXPERIENCE ............................................................................................................................................. 27 
8.6 
REPORTING REQUIREMENTS FOR ADVERSE EVENTS................................................................................................... 27 
9.0 
AGENT INFORMATION ............................................................................................................................... 28 
9.1 
DIMETHYLFUMARATE .......................................................................................................................................... 28 


 
Principal Investigator:  Michael Choi, MD  
HRPP Project 151567  
 
 
 
 
 
 
Page 5 of 37 
 
10.0 
STATISTICAL CONSIDERATIONS................................................................................................................ 30 
10.1 
STUDY DESIGN/STUDY ENDPOINTS ..................................................................................................................... 30 
10.2 
SAMPLE SIZE AND ACCRUAL ............................................................................................................................... 31 
10.3 
EVALUABLE COHORT AND SUBJECT REPLACEMENT ................................................................................................. 31 
10.4 
DATA ANALYSES PLANS ..................................................................................................................................... 31 
11.0 
STUDY MANAGEMENT............................................................................................................................. 32 
11.1 
CONFLICT OF INTEREST...................................................................................................................................... 32 
11.2 
INSTITUTIONAL REVIEW BOARD (IRB) APPROVAL AND CONSENT .............................................................................. 32 
11.3 
SUBJECT DATA PROTECTION .............................................................................................................................. 32 
11.4 
DATA AND SAFETY MONITORING/AUDITING ......................................................................................................... 32 
11.5 
ADHERENCE TO THE PROTOCOL .......................................................................................................................... 33 
11.6 
AMENDMENTS TO THE PROTOCOL ....................................................................................................................... 34 
11.7 
RECORD RETENTION ......................................................................................................................................... 34 
11.8 
OBLIGATIONS OF INVESTIGATORS ........................................................................................................................ 34 
12.0 
REFERENCES ............................................................................................................................................ 35 
APPENDIX A. PERFORMANCE STATUS .............................................................................................................................. 36 
APPENDIX B. HEMATOLOGIC AE GRADING SCALE ............................................................................................................... 37 
 
 
 


 
Principal Investigator:  Michael Choi, MD  
HRPP Project 151567  
 
 
 
 
 
 
Page 6 of 37 
 
STUDY SUMMARY 
Title 
A phase I clinical trial to evaluate dimethylfumarate (DMF) in 
relapsed/refractory patients with chronic lymphocytic leukemia/small 
lymphocytic lymphoma. 
Short Title 
Dimethylfumarate for CLL 
Phase 
1 
Methodology 
Open label, non-randomized, single-arm  
Study Duration 
2 year 
Study Center(s) 
Single-center 
Objectives 
Primary Objective: To determine the maximum tolerated dose or 
biologically optimal dose of dimethylfumarate for patients with chronic 
lymphocytic leukemia. 
Secondary Objectives  
1. To determine the safety and tolerability of DMF by evaluation of 
adverse events 
2. To assess the clinical activity of DMF based on international 
working group guidelines (iwCLL 2008).  
3. To evaluate the pharmacodynamic activity of dimethylfumarate 
(DMF) in chronic lymphocytic leukemia (CLL) or small lymphocytic 
lymphoma (SLL) by evaluation of the Wnt and STAT pathways. 
4. To assess the durability of clinical activity of DMF. 
Number of Subjects 
15-21 (3 cohorts of 3+3; one expansion cohort with 3 additional 
patients) 
Diagnosis and Main 
Inclusion / Exclusion 
Criteria 
Main Eligibility Criteria: 
1. Clinical and phenotypic verification of B cell CLL/ SLL and 
measurable disease. Immunophenotyping of the leukemic cells 
(blood, lymph node, or bone marrow) must demonstrate a 
monoclonal (kappa or lambda light chain restricted) B cell 
population with immunophenotype diagnostic for CLL (eg: co-
expressing CD19 and CD5). 
2. Disease Status/ Prior Therapy: Previously treated with at least 1 
regimen for CLL/SLL   
3. Not eligible or amenable to available standard therapies (see 
page 11 for specific criteria). 
4. Has recovered from the toxic effects of prior therapy to their 
clinical baseline. 
5. Requires treatment for CLL/SLL by working group guidelines 
(iwCLL 2008, Hallek et al.) 
6. Adequate hematologic function:  
a. 
Platelet count ≥ 50,000/µL; AND 
b. 
Hemoglobin ≥ 8.0 g/dL (may be supported by erythropoietin); 
AND 
c. 
Absolute neutrophil count > 1000 /uL   
Study 
Product(s), 
Dose, 
Route, 
DMF will be evaluated in 2 dose cohorts. 
 


 
Principal Investigator:  Michael Choi, MD  
HRPP Project 151567  
 
 
 
 
 
 
Page 7 of 37 
 
Regimen 
Cohort 1: DMF will be administered 120 mg twice daily for 2 x 28 day 
cycles. 
 
Cohort 2: DMF will be administered 120 mg twice daily for 7 days, 
then 240mg orally twice daily (the approved dosage in MS) for the 
remainder of 2 x 28 day cycles.  
 
Cohort 3: DMF will be administered 120 mg twice daily for 7 days, 
then 360mg orally twice daily (a dosage tested previously in 
psoriasis) for the remainder of 2 x 28 day cycles. 
 
DMF should be taken at approximately the same times each day. It 
should be swallowed whole and intact. It should not be crushed or 
chewed. It can be taken with or without food.  
 
Duration 
of 
administration 
2 x 28 day cycles 
Reference therapy 
None 


 
Principal Investigator:  Michael Choi, MD  
HRPP Project 151567  
 
 
 
 
 
 
Page 8 of 37 
 
Statistical 
Methodology 
 
A standard 3+3 dose escalation design will be used. There are three 
test dose levels with a potential de-escalation dose. A minimum of 
three subjects will be treated at each dose level. All three subjects in 
a cohort will be evaluated for DLT in the defined DLT evaluation 
period (within 56 days of starting study treatment) before enrollment 
of subjects at the next dose level may begin. For all dose levels, if no 
DLTs are observed during the evaluation period among the three 
treated patients, escalation to the next dose level may begin. If a DLT 
is observed in one of the first three subjects in the cohort, the cohort 
will be expanded to six subjects. If zero or one of six subjects in the 
cohort experiences a DLT within the evaluation period, escalation to 
the next dose level will occur. If a DLT is seen in two or more subjects 
in a cohort, escalation will be stopped and the Maximum Tolerated 
Dose (MTD) will be considered to have been exceeded. The next 
lower dose will be considered as MTD if six patients have already 
been treated at that dose. Otherwise if only three patients have been 
treated at the next lower dose, then an additional three patients 
should be enrolled at the next lower dose level for a total of six 
patients. If zero or one has DLTs among the 6 patients, then this dose 
is declared as MTD. Otherwise, there is further de-escalation 
according to the same scheme. As a result, the MTD is the highest 
dose where at most one-sixth of the patients developed DLT. If MTD 
is not reached, the higher dose will be selected. As with MTD, 
another 3 subjects will be treated at this dose if only 3 subjects have 
been treated. 
 
1 additional cohort with 3 patients will be recruited at the selected 
dose to further evaluate the safety. The sample size of 9 subjects is 
considered to be sufficient to support preliminary tolerability, safety, 
and DLTs based on the established safety profile of this compound.   
1.0 
BACKGROUND AND RATIONALE 
1.1 
Disease Background: Chronic Lymphocytic Leukemia 
 
Chronic Lymphocytic Leukemia (CLL)/ small lymphocytic lymphoma (SLL) are a malignancies of 
B-cells that comprise approximately 7% of new diagnosed cases of non-Hodgkin’s lymphoma. It 
remains the most common adult leukemia in western world, with an incidence of 3-5 per 
100,000 (Maurer and Hallek, 2013). The National Cancer Institute estimates that 15,680 
Americans were diagnosed and 4,580 died from the disease in 2013. 
 
CLL and SLL are closely related, both manifestations of a clonal proliferation of small, mature, 
aberrant 
B-lymphocytes 
that 
are 
typically 
CD5 
positive 
by 
flow 
cytometry 
or 
immunohistochemistry. CLL is characterized by accumulation of these leukemic cells in the 
peripheral blood, bone marrow, and lymphoid tissues, whereas SLL is characterized by 
predominance of disease in the lymph nodes and less than 5000 clonal B-cell per microliter in 
the peripheral blood (Hallek et al., 2008). CLL and SLL are managed in the same way, so 
CLL/SLL will be referred to simply as CLL for the remainder of this document (Hallek et al., 
2008). 


 
Principal Investigator:  Michael Choi, MD  
HRPP Project 151567  
 
 
 
 
 
 
Page 9 of 37 
 
 
Although treatments for CLL have improved with the development of chemoimmunotherapy 
regimens and tyrosine kinase inhibitors, CLL remains an incurable disease. Treatment regimens 
that combine chemotherapy and immunotherapy (eg: Fludarabine + Cyclophosphamide + 
Rituximab) have produced high response rates and have been associated with an improved 
overall survival (Hallek et al., 2010). However, patients inevitably relapse and many patients 
cannot tolerate chemoimmunotherapy regimens in the relapsed/refractory setting due to age, 
comorbidities, or compromised bone marrow function (Brown, 2011). Obinutuzumab (GA-101) 
in combination with chlorambucil was approved by the FDA in November 2013 based on 
efficacy as front-line therapy for patients older than 65.  However, responses were not durable 
with this treatment either (Goede et al., 2014).  
 
Ibrutinib, an oral agent that inhibits the B-cell receptor associated tyrosine kinase, Bruton’s 
tyrosine kinase (BTK), has been approved by the FDA for the treatment of patients with 
relapsed CLL (Byrd et al., 2013). According to the package insert, the overall response rate is 
58.3%, consisting of partial responses with no complete responses and duration of response 
ranging from 5.6 to 24.2 months.  Ibrutinib intolerance related to diarrhea in 62% of patients and 
thrombocytopenia in over 20% of patients with bleeding events in 63% of patients and subdural 
hematomas in 4% of patients, infections, fatigue, renal insufficiency and other side effects have 
limited the number of patients amenable to chronic therapy. In addition, disease progression 
associated with resistance to ibrutinib has been noted to develop over time.  Emergence of 
mutations in leukemia initiating cells renders patients resistant to ibrutinib therapy (Woyach et 
al., 2014). Thus, to maximize the therapeutic potential of tyrosine kinase and other inhibitors, to 
prevent therapeutic resistance, and to obviate relapse, development of combination therapies 
has become the mainstay of recent CLL eradication strategies. Thus, development and testing 
of novel therapeutic strategies are warranted. 
1.2 
Study Agent: Dimethyl fumarate (DMF) 
Dimethyl fumarate (DMF) is the methyl ester of fumaric acid. It has been evaluated formulated 
with other fumaric acid esters (FAE) in the treatment of various conditions. Specifically, DMF 
combined with three other FAEs was licensed in Germany under the trade name Fumaderm as 
an oral therapy for psoriasis. A DMF formulation, BG-12 (trade name Tecfidera) was also 
approved for the treatment of patients with multiple sclerosis, based on a phase III clinical trial 
that showed that DMF successfully reduced relapse rate and increased time to progression of 
disability in multiple sclerosis. (Gold et al., 2012) See section 10.1 for full details. 
 
DMF was identified by the Carson laboratory as a potential agent with activity in CLL due to 
inhibition of the Wnt pathway. The Wnt pathway is an embryonic pathway that is important in 
fetal development or maintenance of stem cells, but typically not active in normal adult tissues. 
In 2004, our group first reported that the canonical Wnt pathway is also active in CLL.(Lu et al., 
2004) We described several-fold elevated levels of mRNAs encoding multiple Wnt ligands 
(including Wnt16, a pro-B cell marker), Frizzled (FZD) receptors, the Wnt-activated transcription 
factor LEF1, and Wnt induced genes involves in growth and survival (cyclin D1 and cMyc) in 
CLL cells compared to normal B-lymphocytes. Pharmacologic stimulation of the canonical Wnt 
pathway by activation of GSK3/beta-catenin or by addition of Wnt5a promotes CLL 
survival.(Filipovich et al., 2010) Furthermore, the non-canonical Wnt pathway is also active in 
CLL cells, and likely involved in migration and cell survival.(Kaucka et al., 2013) This includes 
selective expression of the orphan Wnt5a receptor ROR1 in CLL.(Fukuda et al., 2008) As the 
Wnt pathway is important in early embryonic development and in the maintenance of stem cells 
throughout life,(Lu and Carson, 2011) we hypothesize that the aberrant activation of the Wnt 
pathway in CLL reflects disordered de-differentiation and/or malignant transformation of a 


 
Principal Investigator:  Michael Choi, MD  
HRPP Project 151567  
 
 
 
 
 
 
Page 10 of 37 
 
primitive B cell population.  For those reasons, the Wnt pathway is an attractive target for further 
drug development in CLL. 
 
DMF inhibits the canonical Wnt signaling pathway. We 
used a cell based screening assay to identify agents with 
specific Wnt inhibiting activity. CellSensor® LEF/TCF-bla 
SW480 cells were plated at 50,000 cells per well and 
incubated with increasing concentrations of DMF for 16 
hours. Wnt pathway inhibition was detected using the 
LiveBLAzer FRET-B/G Loading kit (Life Technologies) 
according to the manufacture’s instruction. Emission ratios 
were calculated from these values and normalized with 
vehicle control. EC50 was calculated using Graphpad Prism 
6 to be less than 10 uM (FIGURE 2). We suspect that the 
alpha-beta unsaturated ketone on DMF is reacting with 
essential free cysteines in LEF1 to 
account for this activity. 
 
DMF inhibits the viability of 
primary 
CLL 
cells 
in 
vitro.  
Leukemic 
cells 
from 
10 
CLL 
patients 
were 
cultured 
with 
increasing concentrations of single 
agent DMF (0.4 to 100 µM), 
Ibrutinib (10 µM), or a combination 
of both. Ibrutinib was selected for 
this assay as a potential clinically 
available agent for combination 
therapy.  The cells were incubated 
for 48 hours and cell viability was 
measured 
using 
MTT 
(3-(4,5-
dimethyl-2-thiazolyl)-2,5-diphenyl-
2H-tetrazolium bromide).  Data 
were transformed to percent of viable cells relative to vehicle control (FIGURE 3).  The in vitro 
effect of DMF on relative viability was noted to be modest, although this assay did not assess 
the effect of microenvironment or stromal-derived Wnt factors. 
 
DMF induces clearance of CLL cells in a murine CLL 
xenograft model at the equivalent of human doses. To 
evaluate the in vivo activity of DMF in a supportive 
microenvironment, , we implanted primary leukemic cells from 
patients with CLL into the peritoneum of Rag2 deficient 
immunocompromised mice. Groups of mice (n=3) were then 
treated with DMF alone (doses ranging from 3 to 30 mg/kg oral 
gavage BID for 1 week). These doses are the same as those 
used 
in 
prior 
publications, 
and 
are 
equivalent 
to 
pharmacologically available doses in humans. DMF treatment 
dose dependently inhibited the survival of CLL cells in this 
model (FIGURE 4). 
  
DMF inhibits the Wnt and STAT pathways in CLL cells. To 
 
Figure 3. In vitro effect of DMF: Percent viability relative to vehicle 
control for each of three drug treatments, using leukemia cells from 
10 CLL patients. Statistical analysis was performed using one way 
ANOVA with Tukey’s multiple comparison test. * indicates 
significance in comparison to control (open bar); ** in comparison to 
ibrutinib (yellow bar). All concentrations are µM. 
 
 
Figure 4. In vivo efficacy of 
DMF: Representative plot of 
percent viability relative to 
vehicle control for CLL cells 
recovered from the peritoneum 
of RAG2 deficient mice after 1 
week of oral therapy. DMF 
treatment inhibits survival of 
CLL cells in this in vivo model. 
 
Figure 2: Plot of Wnt signaling 
activity and inhibition by DMF using 
cell based reporter gene assay. 
Concentration in µM.  


 
Principal Investigator:  Michael Choi, MD  
HRPP Project 151567  
 
 
 
 
 
 
Page 11 of 37 
 
identify candidate biomarkers of DMF activity for use in future clinical trials and to further 
explore the mechanism of action of DMF in CLL cells, we evaluated gene expression in CLL 
cells and normal peripheral blood mononuclear cells treated with DMF using the Nanostring 
PanCancer Pathway mRNA profiling assay. Following a 4-hour incubation of CLL cells with 
DMF or vehicle control, 20 genes from the Nanostring profile were significantly altered. Based 
on pathway analysis, not only was the WNT signaling pathway modulated, but the JAK/STAT 
pathway was also significantly affected by DMF.  
1.3 
Overview and justification for study and study population 
This is a phase I clinical trial to evaluate the safety, tolerability, and maximum tolerated dose of 
DMF in patients with chronic lymphocytic leukemia. Patients with relapsed/refractory CLL not 
amenable to available therapies are eligible. This patient population is in need of novel 
therapies, particularly if progressing after, intolerant of, or unable to receive oral tyrosine kinase 
inhibitors (ie ibrutinib, idelalisib). The trial will initiate at the dose of DMF that is approved by the 
FDA for the treatment of patients with multiple sclerosis, with dose escalation to a dose 
previously tested in patients with psoriasis. 
2.0 
STUDY OBJECTIVES 
Primary Objective: 
To determine the maximum tolerated dose or biologically optimal dose of dimethylfumarate for 
patients with chronic lymphocytic leukemia. 
Secondary Objectives  
1. To determine the safety and tolerability of DMF by evaluation of adverse events 
 
2. To assess the clinical activity of DMF in the treatment of patients with CLL by iwCLL  
3. To evaluate the pharmacodynamic activity of dimethylfumarate (DMF) in chronic lymphocytic 
leukemia (CLL) or small lymphocytic lymphoma (CLL) by evaluation of the Wnt and STAT 
pathways. 
4. To assess the durability of clinical activity of DMF. 
 
3.0 
Endpoints 
3.1 
Primary Endpoint: 
3.1.1 Rate of dose limiting toxicities (DLTs) and the maximum tolerated dose or biologically 
active dose. 
3.2 
Secondary Endpoints  
3.2.1 Treatment-emergent adverse events, including infections (description, timing, grade 
[CTCAE v4.03], severity, seriousness, and relatedness) 
3.2.2 Percent of patients who achieve an objective response (partial response, complete 
response, or nodular complete response) by international working group in CLL 
guidelines (iwCLL). 
3.2.3 Pharmacodynamic activity including measurement of expression of LEF1, c-myc; Wnt 
and STAT pathway expression; and STAT1 phosphorylation. 


 
Principal Investigator:  Michael Choi, MD  
HRPP Project 151567  
 
 
 
 
 
 
Page 12 of 37 
 
3.2.4 Percent of patients able to complete 2 months of therapy without intolerance or disease 
progression. 
3.2.5 Progression free survival, also based on the iwCLL definition of disease progression. 
 
 
4.0 
PHASE I PATIENT ELIGIBILITY 
4.1 
Inclusion Criteria 
Subjects must meet all of the inclusion criteria to participate in this study. 
1. Ability to understand and the willingness to sign a written informed consent. 
2. Clinical and phenotypic verification of B cell CLL/ SLL/ or MBL and measurable disease. 
Immunophenotyping of the leukemic cells (blood, lymph node, or bone marrow) must 
demonstrate a monoclonal (kappa or lambda light chain restricted) B cell population with 
immunophenotype diagnostic for CLL (eg: co-expressing CD19 and CD5). 
3. Relapsed or refractory disease, defined by failure to achieve a partial response within 6 
months of initiation of therapy, or a 50% increase of baseline disease measurements 
after achieving a clinical response.  
4. Previously treated with at least 1 regimen for CLL/SLL   
5. Not appropriate or amenable to all approved therapies.  
a. All patients must have progressed on or after B-cell receptor targeted kinase 
inhibitor (eg: ibrutinib, idelalisib, ACP-196, CC-292), unless there is a relative 
contraindication (eg: history of recent bleeding, history of atrial fibrillation, 
unacceptable high out-of-pocket cost despite patient assistance programs). 
b. Patients with Del(17p) CLL must have progressed on or after BCL-2 inhibitor 
therapy (eg: venetoclax), unless there is a relative contraindication (eg: 
Creatinine clearance < 50ml/min, or unable to monitor for TLS due to living 
remotely from the medical center, unacceptably high out-of-pocket cost). 
c. Patients must have received a CD20-directed monoclonal antibody (eg: 
obinutuzumab, ofatumumab, rituximab), unless there is a relative contraindication 
(eg: history of hepatitis virus infection). 
6. Has recovered from the toxic effects of prior therapy to their clinical baseline. 
7. Subjects must be aged 18 years or older.  
8. Both men and women of all races and ethnic groups are eligible for this trial. 
9. Women of childbearing potential (not postmenopausal for at least one year or not 
surgically incapable of bearing children) must agree not to become pregnant for the 
duration of the study. Both men and women must agree to use a barrier method of 
contraception for the duration of the study and until 8 weeks after the final dose. 
10. Subjects must have at least one of the following indications for treatment:  
• 
Symptomatic or progressive splenomegaly;  
• 
Symptomatic lymph nodes, nodal clusters, or progressive lymphadenopathy;  
• 
Progressive anemia (hemoglobin ≤ 11 g/dL);  
• 
Progressive thrombocytopenia (platelets ≤ 100 x 109/L); 
• 
Weight loss > 10% body weight over the preceding 6 month period;  
• 
Fatigue attributable to CLL; 
• 
Fever or night sweats for > 2 weeks without evidence of infection;  


 
Principal Investigator:  Michael Choi, MD  
HRPP Project 151567  
 
 
 
 
 
 
Page 13 of 37 
 
• 
Progressive lymphocytosis with an increase of > 50% over a 2-month period or an 
anticipated doubling time of less than 12 months.  
11. Subjects must have an ECOG performance status of 0-2.  
12. Adequate hematologic function: 
 
a. Platelet count ≥ 50,000/µL; AND 
b. Hemoglobin ≥ 8.0 g/dL (may be supported by erythropoietin); AND 
c. Absolute neutrophil count > 1000 /uL  
13. Adequate renal function: 
a. Serum creatinine <1.5 times upper limit of normal; OR 
b. Calculated Creatinine clearance (CrCl) ≥ 50 mL/min (based upon the Cockcroft-
Gault Equation [CrCl = (140-age) * actual wt (in kg) * (0.85 if female) / (72 * Cr)]. 
14. Adequate hepatic function: 
a. Total bilirubin ≤ 2.5 times upper limit of normal; AND 
b. ALT ≤ 2.5 times upper limit of normal. 
 
4.2 
Exclusion Criteria 
Subjects meeting any of the exclusion criteria at baseline will be excluded from study 
participation. 
 
1. Pregnant or breast-feeding women will not be entered on this study. Women of childbearing 
potential must obtain a pregnancy test. Child-bearing potential is defined as having neither 
of the following: 
a. ≥  12 months of non-therapy-induced amenorrhea) 
b. Surgically sterile (absence of ovaries and/or uterus 
2. Patients who are currently receiving another investigational agent are excluded. 
3. Patients who have had chemotherapy (e.g., purine analogues, alkylating agents), radiation 
therapy, or participation in any investigational drug treatment within 4 weeks of initiation of 
DMF or at any time during the study. 
4. Patients who have had prior (within 8 weeks of initiation of DMF) or concurrent antibody 
therapy directed against CLL (i.e., Rituxan® and Campath®) 
5. Patients who have had tyrosine kinase inhibitor therapy (eg: ibrutinib or idelalisib) within 7 
half lives (or 28 days, which ever is shorter) of initiation of DMF. 
6. Current infection requiring parenteral antibiotics.  
7. Active malignancy within the previous 2 years (other than completely resected non-
melanoma skin cancer or carcinoma in situ).  
8. Insufficient recovery from surgical-related trauma or wound healing. 
9. Impaired cardiac function including any of the following: 
a. Myocardial infarction within 6 months of starting study drug; 
b. Other clinically significant heart disease (e.g. congestive heart failure, uncontrolled 
hypertension, history of labile hypertension, or history of poor compliance with an 
antihypertensive regimen) 
10. Patients who in the opinion of the investigator are unable to comply with the safety 
monitoring requirements of the study. 
 


 
Principal Investigator:  Michael Choi, MD  
HRPP Project 151567  
 
 
 
 
 
 
Page 14 of 37 
 
5.0 
TREATMENT PLAN 
5.1 
Treatment Dosage and Administration 
For Dose Level 1, DMF (Tecfidera formulation) will be administered at a dose of 120 mg PO BID 
(approximately 12 hours apart) for 2 x 28 day cycles.  
 
For Dose Level 2, DMF will be administered at the currently used dose for patients with multiple 
sclerosis: 120 mg PO BID for 1 week, then escalate to the dose of 240mg PO BID for the 
remainder of 2 x 28 day cycles. The 1 week lead-in at 120 mg is to assist in toleration and initial 
side effects and is as per the standard prescribing information. 
 
For Dose Level 3, DMF will be administered at the currently used dose for patients with multiple 
sclerosis: 120 mg PO BID for 1 week, then escalate to the dose of 360mg PO BID for the 
remainder of 2 x 28 day cycles. 
 
The medication can be taken with or without food. Capsules should not be crushed or chewed. 
Capsules will be self-administered on an outpatient basis. On days in which patients are 
scheduled for assessment, capsules will be taken in clinic. Missed or vomited doses will be 
skipped. Patients are assessed for safety and tolerability on Day 8, Day 1 of each subsequent 
cycle, and 28 days and 56 days following the last dose of DMF. 
 
Dose Level 
DMF dose (all cohorts start at 120 mg PO BID dose for 1 week, then 
increase to the assigned dose) 
1 
120 mg PO BID 
2 
240 mg PO BID 
3 
360 mg PO BID 
 
5.2 
Definition of Dose-Limiting Toxicity 
 
Dose Limiting Toxicity (DLT) is defined as any of the following adverse events that are 
considered by the investigator to be possibly, probably or definitely related to DMF within the 
DLT evaluation timeframe.  
• 
Non-hematologic adverse events: grade 3 (CTCAE 4) or higher, lasting more than 7 
days despite appropriate medical management. 
• 
Hematologic adverse events: grade 3 (iwCLL 2008) or higher, lasting more than 7 days 
despite appropriate medical management, with the exception of: any grade 
lymphopenia ; or any grade lymphocytosis. 
• 
Grade 4 non-hematologic (CTCAE 4) of any duration 
• 
Grade 4 hematologic (iwCLL 2008) of any duration. 
• 
Any clinically significant toxicity that precludes administration of the next scheduled 
dose beyond 14 days 
 
Replacement patients may be enrolled for patients who withdraw from investigational treatment 
for a reason that is definitely unrelated to toxicity of the study agent or disease progression (e.g. 
patient preference, loss to follow-up). Replacement patients will ensure enough patients are 
enrolled to evaluate the primary endpoint. 
 
The DLT evaluation timeframe is from the first dose of DMF until day 56 of the trial. 


 
Principal Investigator:  Michael Choi, MD  
HRPP Project 151567  
 
 
 
 
 
 
Page 15 of 37 
 
 
5.3 
Pre-Medications 
None required. Anti-emetics may be administered per clinical discretion. 
 
5.4 
Permitted concomitant therapy 
Medications required to treat adverse events, manage cancer symptoms or concurrent stable 
disease (e.g., controlled hypertension), or manage pain are permitted. 
 
Supportive care agents, including erythropoietin, granulocyte growth factors, or blood 
transfusions are permitted only after patients have developed grade 3 or higher anemia or 
neutropenia. 
 
Corticosteroids for the treatment of conditions other than CLL/SLL are permitted at maximum 
doses of prednisone 20mg daily (or steroid equivalent) are permitted, and at a stable does (ie. 
no higher than 20mg for at least 28 days prior to initiation of DMF). 
 
The patient needs to notify the investigational site about any new medications he/she takes after 
the start of the study medication. All medications (other than study drug) and significant non-
drug therapies (including physical therapy and blood transfusions) administered after the patient 
starts treatment with study drug must be listed on the CRF. 
 
5.5 
Prohibited concomitant therapy 
Other investigational therapies must not be used while the patient is on the study. Anticancer 
therapy (chemotherapy, biologic or radiation therapy, and surgery) other than the study 
treatments must not be given to patients while the patient is on the study medication. If such 
agents are required for a patient then the patient must be discontinued from the treatment 
portion of the study.  
5.6 
Other Modalities or Procedures 
Not applicable. 
5.7 
Toxicities and Dosing Delays/Dose Modifications 
Any patient who receives treatment on this protocol will be evaluable for toxicity. Each patient 
will be assessed for the development of toxicity according to the NCI Common Toxicity Criteria 
for Adverse Events (CTCAE), version 4.03 for non-hematologic adverse events, and 2008 
international working group criteria (iwCLL, Hallek et al, appendix B) for hematologic adverse 
events. Dose adjustments should be made according to the system showing the greatest 
degree of toxicity. Patients are assessed for safety and tolerability on Day 8, Day 28, and Day 
42 after starting DMF.  
 
Toxicity – NCI CTCAE Grade  
(Hematologic- iwCLL) 
Occurrence 
Dose Modification 
Non-hematologic 
Grade ≥ 3 
1st 
Withhold study treatment until resolved to 
Grade ≤ 1. 
 


 
Principal Investigator:  Michael Choi, MD  
HRPP Project 151567  
 
 
 
 
 
 
Page 16 of 37 
 
Resume study treatment at the next lower 
dose level. 
Repeat 
Discontinue therapy. 
Hematologic* 
Grade ≥ 3 
1st 
Withhold study treatment until resolved to ANC 
≥1000/mm3, hemoglobin is ≥ 8 gm/dL, and 
platelet count ≥50,000/mm3.  
Resume study treatment at same dose. 
2nd 
Withhold study treatment until resolved to ANC 
≥1000/mm3, hemoglobin is ≥ 8 gm/dL, and 
platelet count ≥50,000/mm3.  
Resume study treatment at the next lower 
dose level. 
3rd 
Permanently discontinue study treatment. 
*Dose adjustments or dose holds for hematologic toxicity will apply even if the baseline values 
are lower than these thresholds due to heavily infiltrated marrow. In those cases, growth factors 
and/or blood product transfusion may be administered prior to continuing with DMF. 
Notes:  
1. If any of the above are noted, the patient will be re-assessed within 7 days by the 
treating physician or investigator. Isolated laboratory abnormalities may be re-evaluated 
by laboratory draw only, or based on physician or investigator discretion. 
2. DMF can be delayed for a maximum of 14 days; if not restarted in that time-span, study 
treatment will be permanently discontinued. 
3. If dose is decreased for toxicity, dose re-escalation is not planned. 
4. For invasive procedures, not including biopsies or venous catheter placement: withhold 
study treatment for 1 week prior to procedure, and at least 1 week following surgery until 
satisfactory wound healing has been achieved. 
5.8 
Duration of Therapy 
In the absence of treatment delays due to adverse events, DMF will continue for 56 days as part 
of the clinical trial, or until: 
• 
Disease progression 
• 
Inter-current illness that prevents further administration of treatment 
• 
Unacceptable adverse event(s) 
• 
Patient decides to withdraw from the study, OR 
• 
General or specific changes in the patient’s condition render the patient unacceptable for 
further treatment in the judgment of the investigator. 
 
Patients are not prohibited from continuing DMF through commercial source after the response 
assessment visit. 
5.9 
Duration of Follow Up 
Patients will be followed for 1 year after removal from treatment or until disease progression, 
initiation of subsequent CLL therapy, or death, whichever occurs first. Patients removed from 
treatment for unacceptable adverse events will be followed until resolution or stabilization of the 
adverse event.  


 
Principal Investigator:  Michael Choi, MD  
HRPP Project 151567  
 
 
 
 
 
 
Page 17 of 37 
 
 
6.0 
STUDY PROCEDURES 
6.1 
Schedule of Events 
 
 
 
Screening  
Cycle 1 
Day 
1 
(C1D1) 
C1 D8 
C2, D1 
Up to 28 days 
after 
last 
DMF dose 
56 
days 
after 
last 
DMF dose 
Follow-up 
(q 
56 days until 
1 year) 
Visit Number 
1 
2 
3 
4 
5 
6 
7-  
Window 
+/- 
3 
days 
 
+/- 2 d +/-7 d 
+/-7 d 
+/-7 d 
+/-14 d 
Informed 
Consent 
X 
 
 
 
 
 
 
Serum 
Pregnancy test 
X 
 
 
 
 
 
 
History and PE 
X 
X 
X 
X 
X 
X 
X 
Performance 
Status 
X 
X 
 
X 
X 
X 
X 
Toxicity (include 
DLT) 
Evaluations 
 
X 
X 
X 
X 
X 
 
Tumor 
Measurements 
by 
physical 
examination 
X 
X 
X 
X 
X 
X 
X 
CBC 
with 
differential 
X 
X (x2 – 
pre and 
post 
dose) 
 
X 
X 
X 
X 
Comprehensive 
Metabolic Panel 
* 
X 
X (x2 – 
pre and 
post 
dose) 
X 
X 
X 
X 
X 
LDH, uric acid, 
phos 
 
X (x2 – 
pre and 
post 
dose) 
 
 
 
 
 
Correlative 
laboratory 
collection ** 
X 
X (x2 – 
pre and 
post 
dose) 
X 
X 
X 
X 
 
CT or MRI scan 
with contrast of 
chest, 
abdomen, 
pelvis  
 
 
 
 
X  
 
 
Bone 
marrow 
biopsy 
and 
aspirate *** 
 
 
 
 
X (if clinical 
response 
and 
imaging is 
consistent 
with CR) 
 
 
 
 
 
 
 
 
 
 


 
Principal Investigator:  Michael Choi, MD  
HRPP Project 151567  
 
 
 
 
 
 
Page 18 of 37 
 
 
*  
Comprehensive metabolic panel (CMP) to include: albumin, alkaline phosphatase, 
ALT/SGPT, AST/SGOT, total bilirubin, electrolytes (sodium, potassium, calcium, chloride, 
bicarbonate), BUN, creatinine, glucose.  
 
**  
Up to 30 mL in anti-coagulated (ACD) tubes for screening visit; up to 20 mL in 
anticoagulated (ACD) tubes for subsequent visits. To be drawn prior to DMF dosing. 
 
*** 
With flow cytometric and immunohistochemical evaluation of CLL cell infiltrate; and 
chromosome and FISH analysis (including 11q, 12p, 13q, and 17p). 
6.2 
Screening/Baseline Procedures 
Assessments performed exclusively to determine eligibility for this study will be done only after 
obtaining informed consent. Assessments performed for clinical indications (not exclusively to 
determine study eligibility) may be used for baseline values even if the studies were done before 
informed consent was obtained. 
 
All screening procedures must be performed within 30 days prior to registration unless 
otherwise stated. The screening procedures include: 
6.2.1 Informed Consent 
6.2.2 Medical history 
Complete medical, surgical and oncology history as well as history of infections are 
obtained at screening. Any changes from Screening (e.g. worsening severity or 
abnormal findings) are considered to be adverse events (AEs). 
6.2.3 Demographics 
 Demographic profile will include date of birth, gender, race, and ethnicity. 
6.2.4 Review subject eligibility criteria 
Review of eligibility criteria as described in Section 3 to ensure subject qualification for 
study entry. 
6.2.5 Review previous and concomitant medications 
All prior medication taken by the subject within 4 weeks before starting the study is to be 
recorded. Concomitant medications taken by the subject during the study are to be 
recorded up until 28-days after last study dose. If a reportable adverse event (see 
Section 7) occurs within 28-days after last study dose, recording of concomitant 
medications should continue until resolution of the adverse event. 
6.2.6 Physical exam including vital signs, height and weight 
Vital signs (temperature, pulse, respirations, blood pressure), height, weight. 
(height is only required at screening.) 
 
Physical exam including bidimensional measurement of palpable lymph nodes, spleen 
size (below the costal margin), and liver size (craniocaudal size at the right midclavicular 
line). 
 
6.2.7 Performance status 


 
Principal Investigator:  Michael Choi, MD  
HRPP Project 151567  
 
 
 
 
 
 
Page 19 of 37 
 
Performance status evaluated prior to study entry, using ECOG grading scale. 
6.2.8 Adverse event assessment 
Baseline assessment of subject status for determining adverse events. See Section 9 for 
Adverse Event monitoring and reporting. 
6.2.9 Hematology 
Hematology to include hemoglobin (Hgb), platelets, total white blood cell count (WBC), 
and differential. 
6.2.10 Serum chemistries 
Comprehensive metabolic panel (CMP) to include: albumin, alkaline phosphatase, 
ALT/SGPT, AST/SGOT, total bilirubin, electrolytes (sodium, potassium, calcium, 
chloride, bicarbonate), BUN, creatinine, glucose, and LDH.  
6.2.11 Blood draw for correlative studies 
Up to 20 mL in anticoagulated tubes. 
6.2.12 Pregnancy test (for females of child bearing potential) 
Serum pregnancy test (in women of childbearing potential only, see definition in section 
4.2); if serum pregnancy test has not been performed 14 days prior to dosing, a urine 
pregnancy test must be performed 7 days prior to dosing. If the test result is positive, 
patient dosing will be postponed until the patient’s status is confirmed by a serum 
pregnancy test. 
6.2.13 Tumor assessment 
CT scan or MRI scan with contrast of thorax, abdomen, and pelvis. This may be done 
within 90 days prior to D1. Physical exam including bidimensional measurement of 
palpable lymph nodes, spleen size (below the costal margin), and liver size 
(craniocaudal size at the right midclavicular line). 
 
6.3 
Procedures During Treatment 
 
6.3.1 Visit 2: Day 1 
6.3.1.1 Review concomitant medications 
6.3.1.2 Physical exam including vital signs (temperature, pulse, respirations, blood 
pressure), weight; and including bidimensional measurement of palpable lymph 
nodes, spleen size (below the costal margin), and liver size (craniocaudal size 
at the right midclavicular line). 
6.3.1.3 Performance status using ECOG grading scale. 
6.3.1.4 Adverse event assessment: See Section 9 for adverse Event monitoring and 
reporting. 
6.3.1.5 Hematology: hemoglobin (Hgb), platelets, total white blood cell count (WBC), 
and differential. 
6.3.1.6 Serum chemistries: Comprehensive metabolic panel (CMP) to include: 
albumin, alkaline phosphatase, ALT/SGPT, AST/SGOT, BUN, creatinine, 


 
Principal Investigator:  Michael Choi, MD  
HRPP Project 151567  
 
 
 
 
 
 
Page 20 of 37 
 
electrolytes (sodium, potassium, calcium, chloride, bicarbonate), glucose, and 
total bilirubin. Also: LDH, uric acid, phosphorous 
6.3.1.7 Blood draw for correlative studies: Up to 20 mL in anti-coagulated (ACD) tubes. 
6.3.1.8 Dispense DMF 120 mg PO BID  x 7 day supply. 
 
6.4.1.9    6-8 hours after DMF dosing: Repeat Hematology and serum chemistries, in  
 
 
   addition to LDH, uric acid, and phosphorous. Blood draw for correlative studies: 
 
 
   Up to 10 mL in anti-coagulated (ACD) tubes. 
 
6.3.2 Visit 3: Day 8 
6.3.2.1 Review concomitant medications 
6.3.2.2 Physical exam including vital signs (temperature, pulse, respirations, blood 
pressure), weight; and including bidimensional measurement of palpable lymph 
nodes, spleen size (below the costal margin), and liver size (craniocaudal size 
at the right midclavicular line). 
6.3.2.3 Performance status using ECOG grading scale. 
6.3.2.4 Adverse event assessment: See Section 9 for adverse Event monitoring and 
reporting. 
6.3.2.5 Hematology: hemoglobin (Hgb), platelets, total white blood cell count (WBC), 
and differential. 
6.3.2.6 Serum chemistries: Comprehensive metabolic panel (CMP) to include: 
albumin, alkaline phosphatase, ALT/SGPT, AST/SGOT, BUN, creatinine, 
electrolytes (sodium, potassium, calcium, chloride, bicarbonate), glucose, and 
total bilirubin.  
6.3.2.7 Blood draw for correlative studies: Up to 20 mL in anticoagulated tubes. 
6.3.2.8 Dispense DMF at assigned dose x 21 day supply 
 
6.3.3 Visits 4: Day 1 of cycles 2 
6.3.3.1 Review concomitant medications 
6.3.3.2 Physical exam including vital signs (temperature, pulse, respirations, blood 
pressure), weight; and including bidimensional measurement of palpable lymph 
nodes, spleen size (below the costal margin), and liver size (craniocaudal size 
at the right midclavicular line). 
6.3.3.3 Performance status using ECOG grading scale. 
6.3.3.4 Adverse event assessment: See Section 9 for adverse Event monitoring and 
reporting. 
6.3.3.5 Hematology: hemoglobin (Hgb), platelets, total white blood cell count (WBC), 
and differential. 
6.3.3.6 Serum chemistries: Comprehensive metabolic panel (CMP) to include: 
albumin, alkaline phosphatase, ALT/SGPT, AST/SGOT, BUN, creatinine, 
electrolytes (sodium, potassium, calcium, chloride, bicarbonate), glucose, and 
total bilirubin.  


 
Principal Investigator:  Michael Choi, MD  
HRPP Project 151567  
 
 
 
 
 
 
Page 21 of 37 
 
6.3.3.7 Blood draw for correlative studies: Up to 20 mL in anticoagulated tubes. 
6.3.3.8 Dispense DMF at assigned dose x 28 day supply 
 
6.3.4 Visit 5: Between 1 day and 28 days after cycle 2 day 28: Primary Endpoint 
Response Assessment 
6.3.4.1 Review concomitant medications 
6.3.4.2 Physical exam including vital signs (temperature, pulse, respirations, blood 
pressure), weight; and including bidimensional measurement of palpable lymph 
nodes, spleen size (below the costal margin), and liver size (craniocaudal size 
at the right mid-clavicular line). 
6.3.4.3 Performance status using ECOG grading scale. 
6.3.4.4 Adverse event assessment: See Section 9 for adverse Event monitoring and 
reporting. 
6.3.4.5 Hematology: hemoglobin (Hgb), platelets, total white blood cell count (WBC), 
and differential. 
6.3.4.6 Serum chemistries: Comprehensive metabolic panel (CMP) to include: 
albumin, alkaline phosphatase, ALT/SGPT, AST/SGOT, BUN, creatinine, 
electrolytes (sodium, potassium, calcium, chloride, bicarbonate), glucose, and 
total bilirubin.  
6.3.4.7 Blood draw for correlative studies: Up to 20 mL in anticoagulated tubes. 
6.3.4.8 Tumor assessment: Only if there are no lymph nodes that are 1.5 cm or larger 
by physical exam: CT scan or MRI scan with contrast of thorax, abdomen, and 
pelvis. This may be done within 7 days prior to or after Visit 10. 
6.3.4.9 Only if clinical response and imaging are consistent with a complete response, 
subjects will have bone marrow aspirate and biopsy with samples sent for 
differential, morphology, and >/= 4-color flow cytometry for MRD. This may be 
done within 7 days prior, or 28 days following visit 10. 
 
6.3.5 Visit 6: 56 days after the last dose of DMF 
6.3.5.1 Review concomitant medications 
6.3.5.2 Physical exam including vital signs (temperature, pulse, respirations, blood 
pressure), weight; and including bidimensional measurement of palpable lymph 
nodes, spleen size (below the costal margin), and liver size (craniocaudal size 
at the right midclavicular line). 
6.3.5.3 Performance status using ECOG grading scale. 
6.3.5.4 Adverse event assessment: See Section 9 for adverse Event monitoring and 
reporting. 
6.3.5.5 Hematology: hemoglobin (Hgb), platelets, total white blood cell count (WBC), 
and differential. 
6.3.5.6 Serum chemistries: Comprehensive metabolic panel (CMP) to include: 
albumin, alkaline phosphatase, ALT/SGPT, AST/SGOT, BUN, creatinine, 


 
Principal Investigator:  Michael Choi, MD  
HRPP Project 151567  
 
 
 
 
 
 
Page 22 of 37 
 
electrolytes (sodium, potassium, calcium, chloride, bicarbonate), glucose, and 
total bilirubin.  
6.3.5.7 Blood draw for correlative studies: Up to 20 mL in anticoagulated tubes. 
 
6.3.6 Visits 7-10: Every 56 days to one year (typically month 6, 8, 10, 12) 
Patients will be followed every 56 days after completion of (or early withdrawal from) study 
treatment until subsequent CLL therapy, death, or discontinuation of trial participation. Follow-up 
will consist of survival contacts via medical record review, telephone call, or review of the Social 
Security Index. 
6.4 
Correlative Studies 
Studies will be performed in the Kipps and/or Carson laboratories (though sample processing 
will occur in the Kipps laboratory using long-established SOPs for CLL cell isolation and 
storage). Biomarker assays will correlate with clinical responses. Samples will be taken at 
baseline/screening, during treatment and after treatment. However, not all assays will be 
performed for all time points for all patients, based on sample availability and leukemic cell 
number. Specimens will be banked in the Kipps laboratory (see below). 
 
Assays from patient plasma may include:  
• 
Measurement of cytokine levels (including IL2, IL12, and TNFα)  
 
Isolation of leukemic cells by Ficoll-hypaque separation and assessment, which may include: 
• 
Assessment of signaling modulation, including the canonical Wnt pathway by multiplex 
qPCR (eg: Nanostring PanCancer assay) 
• 
Measurement of phosphorylation of STAT1 by intracellular flow cytometry. 
• 
ZAP-70, CD38, and Immunoglobulin heavy chain variable region (IgVH) mutation in CLL 
cells  
 
6.4.1 Sample Collection Guidelines 
Sampling Schedule  
Blood sample for correlative studies will be collected at the following time points: 
• 
Screening  
• 
Day 1 of each cycle, pre-treatment  
• 
Day 8 of cycle 1. 
• 
Between 1 day and 28 days after Cycle 2, day 28 
• 
56 days after last DMF dose visit. 
 
Sample Collection and Handling Instructions 
Blood samples (approximately 20-30 ml as specified in the protocol) will be collected in 
anticoagulated (ACD) tubes. The exact time that the sample is drawn along with the exact time 
that the drug is administered should be recorded. 
 
Sample Processing 
Samples will be processed in the translational lab of Dr. Thomas Kipps, with separation of 
plasma, followed by isolation of mononuclear cells by Ficoll differential centrifugation. 
 


 
Principal Investigator:  Michael Choi, MD  
HRPP Project 151567  
 
 
 
 
 
 
Page 23 of 37 
 
Sample Labeling 
Each tube must be labeled with the patient’s study number and the date and time the sample 
was drawn.  Data should be recorded on the Correlative Study Form, which must accompany 
the sample(s). 
 
6.4.2 Specimen Banking 
Patient samples collected for this study will be retained at the UCSD School of Medicine (Kipps 
Laboratory). Specimens will be stored indefinitely or until they are used up. If future use is 
denied or withdrawn by the patient, best efforts will be made to stop any additional studies and 
to destroy the specimens. Samples will be labeled with the subject’s de-identified study number 
and collection date. The link between study number and medical record number will be viewed 
over a password secured encrypted server-client.   
 
Dr. Kipps, Carson, and Choi will be responsible for reviewing and approving requests for 
research specimens from potential research collaborators outside of UCSD. Collaborators will 
be required to complete an agreement (a Material Transfer Agreement or recharge agreement) 
that states specimens will only be released for use in disclosed research.  Any data obtained 
from the use of clinical specimens will be the property of UCSD for publication and any licensing 
agreement will be strictly adhered to.   
 
The study research coordinator will review the subject's medical record for demographic and 
clinical information pertaining to the subject's general medical history, diagnosis, and outcomes 
of any treatments received.  Samples and data extracted from the subject's medical record will 
be coded with a de-identified study number, and the subject's name and identifying information 
will be removed.  A log that links the subject's name and identifiers to the study number will be 
maintained in a secure database distinct from the secure database into which the subject's 
clinical information will be entered 
 
The specimens and their derivatives may have significant therapeutic or commercial value.  The 
Informed Consent form contains this information and informs the subject that there is the 
potential for financial gain by UCSD, the investigator or a collaborating researcher or entity.  
 
The following information obtained from the subject's medical record may be provided to 
research collaborators when specimens are made available:   
• 
Diagnosis  
• 
Collection time in relation to study treatment 
• 
Clinical outcome – if available 
• 
Demographic data 
6.5 
Removal of Subjects from Study Treatment and Study 
Patients can be taken off the study treatment and/or study at any time at their own request, or 
they may be withdrawn at the discretion of the investigator for safety, behavioral or 
administrative reasons. The reason(s) for discontinuation will be documented and may include: 
6.5.1 Patient completed study treatment; 
6.5.2 Patient voluntarily withdraws from treatment (follow-up permitted);  
6.5.3 Patient withdraws consent (termination of treatment and follow-up); 
6.5.4 Patient is unable to comply with protocol requirements; 


 
Principal Investigator:  Michael Choi, MD  
HRPP Project 151567  
 
 
 
 
 
 
Page 24 of 37 
 
6.5.5 Patient demonstrates disease progression (unless continued treatment with study drug 
is deemed appropriate at the discretion of the investigator); 
6.5.6 Patient experiences toxicity that makes continuation in the protocol unsafe; 
6.5.7 Treating physician judges continuation on the study would not be in the patient’s best 
interest; 
6.5.8 Patient becomes pregnant (pregnancy to be reported along same timelines as a serious 
adverse event); 
6.5.9 Development of second malignancy (except for basal cell carcinoma or squamous cell 
carcinoma of the skin) that requires treatment, which would interfere with this study; 
6.5.10 Lost to follow-up.  
If a research subject cannot be located to document survival after a period of 2 years the 
subject may be considered “lost to follow-up.” All attempts to contact the subject during 
the two years must be documented. 
 
7.0 
Measurement of Effect 
7.1 
Response Criteria for Patients with Chronic Lymphocytic Leukemia 
Criteria for response will utilize the IWCLL Guidelines for response, which includes clinical, 
hematological, and bone marrow features as outlined below (Hallek et al., 2008). 
 
Minimal Residual Disease negative: less than 0.01% CLL cell involvement by 4-color flow 
cytometry of bone marrow aspirate (less than 1 in 10,000 events) and meeting all other criteria 
for complete response. 
 
Complete response: Requires all of the following for a period of at least two months from 
completion of therapy:  
• 
Absence of significant lymphadenopathy (e.g. >1.5cm in diameter) on physical exam; 
• 
No hepatomegaly or splenomegaly on physical exam; 
• 
Absence of constitutional symptoms; 
• 
Blood counts corresponding to the following values: Lymphocytes < 4,000/uL, 
polymorphonuclear leukocytes >1500/μL, platelets >100,000/μL, hemoglobin >11.0 g/dL 
(untransfused) 
• 
Bone marrow aspirate and biopsy must be normocellular for age with <30% of nucleated 
cells being lymphocytes. Lymphoid nodules must be absent. If the marrow is 
hypocellular, a repeat determination should be performed in one month. 
• 
The marrow should be analyzed by flow cytometry and/or immunohistochemistry to 
demonstrate that the marrow is free of clonal B- CLL cells. 
• 
A CT scan or MRI documenting absence of significant lymphadenopathy should be 
performed if previously abnormal. 
• 
Patients who fulfill the criteria for CR with the exception of a persistent cytopenia that is 
believed to be treatment related will be considered CR with incomplete bone marrow 
recovery (CRi). Additionally, patients who fulfill the criteria of CR with exception of 
having bone marrow lymphoid nodules will be considered a nodular PR. 
 
Partial response: Requires at least 2 of the following criteria from group A, and at least one of 
the criteria from group B, and for a period of at least 2 months: 


 
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HRPP Project 151567  
 
 
 
 
 
 
Page 25 of 37 
 
Group A: 
• 
≥50% decrease in peripheral absolute lymphocyte count from pretreatment value, or less 
than 4,000/uL. 
• 
≥50% reduction in lymphadenopathy by examination or scan, or less than 1.5cm in size. 
• 
≥50% reduction in splenomegaly (cm below costal margin) by examination or scan 
• 
≥50% reduction hepatomegaly (total liver span) by examination or scan 
• 
≥50% reduction in marrow infiltrate or B-lymphoid nodules 
Group B: 
• 
Polymorphonuclear leukocytes ≥1,500/μL or 50% improvement from pre-treatment 
value; 
• 
Platelets >100,000/μL or 50% improvement from pre-treatment value; 
• 
Hemoglobin >11.0 g/dl (un-transfused) or 50% improvement from pre-treatment value. 
 
Progressive Disease: Characterized by any one of the following events:  
• 
≥50% increase in the products of at least two lymph nodes on two consecutive 
determinations two weeks apart (at least one lymph node must be ≥2 cm); appearance 
of new palpable lymph nodes. 
• 
≥50% increase in the size of the liver and/or spleen as determined by measurement 
below the respective costal margin; appearance of palpable hepatomegaly or 
splenomegaly, which was not previously present. 
• 
An increase in the number of blood lymphocytes by 50% or more with at least 5000 B 
lymphocytes per microliter. 
• 
Transformation to a more aggressive histology (i.e., Richter’s syndrome or 
prolymphocytic leukemia with ≥56% prolymphocytes). 
• 
During therapy, patients not fulfilling the above criteria for progressive disease but 
demonstrating a decrease in hemoglobin >2 gm/dL, decrease >50% in platelet or 
granulocyte count will not be rated as progressive disease because these may occur as 
both a consequence of therapy. A bone marrow biopsy in such settings is strongly 
encouraged.  
• 
After treatment, The progression of any cytopenia (unrelated to autoimmune cytopenia), 
as documented by a decrease of Hb levels by more than 20 g/L (2 g/dL) or to less than 
100 g/L (10 g/dL), or by a decrease of platelet counts by more than 50% or to less than 
100 × 109/L (100 000/μL), which occurs at least 3 months after treatment, defines 
disease progression, if the marrow biopsy demonstrates an infiltrate of clonal CLL cells. 
 
Stable Disease: Patients who do not fulfill the criteria for complete or partial response as 
defined above but do not exhibit progressive disease will be considered as having stable 
disease. 
7.1.1 Progression-Free Survival 
Progression-free survival (PFS) is defined as the duration of time from start of treatment 
until objective tumor progression or death. 
7.2 
Safety/tolerability 
Analyses will be performed for all patients having received at least one dose of study drug. The 
study will use the CTCAE version 4.03 (http://ctep.cancer.gov/reporting/ctc.html) for reporting of 
non-hematologic adverse events and modified iwCLL criteria for hematologic adverse events 
(Appendix B). 
 


 
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Page 26 of 37 
 
8.0 
ADVERSE EVENTS 
An adverse event (AE) is any untoward medical occurrence in a patient receiving study 
treatment and which does not necessarily have a causal relationship with this treatment. An AE 
can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of an experimental 
intervention, whether or not related to the intervention.  
8.1 
Adverse Event Monitoring 
Adverse event data collection and reporting, which are required as part of every clinical trial, are 
done to ensure the safety of subjects enrolled in the studies as well as those who will enroll in 
future studies using similar agents. Adverse events are reported in a routine manner at 
scheduled times during a trial. Additionally, certain adverse events must be reported in an 
expedited manner to allow for optimal monitoring of patient safety and care.  
 
As far as possible, each adverse event should be evaluated to determine: 
• 
duration (start and end dates) 
• 
severity (grade) 
• 
seriousness 
• 
relationship to study agent 
• 
action taken (i.e., none, study agent modification, medical intervention) 
• 
outcome (i.e., resolved without sequelae, resolved with sequelae, ongoing) 
 
Adverse events monitoring begins after initiation of study treatment and ends 28 days following 
the last administration of study treatment or study discontinuation/termination, whichever is 
earlier. 
 
All patients experiencing an adverse event, regardless of its relationship to study drug (or at 
least possibly related to the drug), will be monitored until:  
 the adverse event resolves or the symptoms or signs that constitute the adverse 
event return to baseline;  
 any abnormal laboratory values have returned to baseline;  
 there is a satisfactory explanation other than the study drug for the changes 
observed; or 
 death. 
8.2 
Severity 
Hematologic adverse events will be graded using a modified iwCLL criteria (appendix 2).  
 
All non-hematologic adverse events will be graded according to the NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.03. The CTCAE v4.03 is available at 
http://ctep.cancer.gov/reporting/ctc.html 
 
If no CTCAE grading is available, the severity of an AE is graded as follows: 
Mild (grade 1): the event causes discomfort without disruption of normal daily activities. 
Moderate (grade 2): the event causes discomfort that affects normal daily activities. 
Severe (grade 3): the event makes the patient unable to perform normal daily activities 
or significantly affects his/her clinical status. 


 
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Page 27 of 37 
 
Life-threatening (grade 4): the patient was at risk of death at the time of the event. 
Fatal (grade 5): the event caused death. 
8.3 
Seriousness 
A “serious” adverse event is defined in regulatory terminology as any untoward medical 
occurrence that: 
1. Results in death. 
If death results from (progression of) the disease, the disease should be reported as 
event (SAE) itself. 
2. Is life-threatening. 
(the patient was at risk of death at the time of the event; it does not refer to an event that 
hypothetically might have caused death if it were more severe). 
3. Requires in-patient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours. 
4. Results in persistent or significant disability or incapacity. 
5. Is a congenital anomaly/birth defect 
6. Is an important medical event 
Any event that does not meet the above criteria, but that in the judgment of the 
investigator jeopardizes the patient, may be considered for reporting as a serious 
adverse event. The event may require medical or surgical intervention to prevent one of 
the outcomes listed in the definition of “Serious Adverse Event“.  
For example: allergic bronchospasm requiring intensive treatment in an emergency room 
or at home; convulsions that may not result in hospitalization; development of drug 
abuse or drug dependency. 
8.4 
Relationship 
Attribution categories for adverse events in relationship to protocol therapy are as follows: 
Definite – The AE is clearly related to the study treatment. 
Probable – The AE is likely related to the study treatment. 
Possible – The AE may be related to the study treatment. 
Unlikely – The AE is doubtfully related to the study treatment. 
Unrelated – The AE is clearly NOT related to the study treatment. 
8.5 
Prior experience 
Expected events are those that have been previously identified as resulting from administration 
of the agent. An adverse event is considered unexpected, for expedited reporting purposes 
only, when either the type of event or the severity of the event is not listed in the current known 
adverse events listed in the agent clinical experience section of this protocol or the current 
product label. 
8.6 
Reporting Requirements for Adverse Events 
8.6.1 Expedited Reporting 
• 
The Principal Investigator must be notified within 24 hours of learning of any 
serious adverse events, regardless of attribution, occurring during the study or 
within 30 days of the last administration of the study drug.  
• 
The UCSD Human Research Protections Program (HRPP) must be notified 
within 10 business days of “any unanticipated problems involving risk to subjects or 


 
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others” (UPR). 
The following events meet the definition of UPR: 
1. Any serious event (injuries, side effects, deaths or other problems), which in 
the opinion of the Principal Investigator was unanticipated, involved risk to 
subjects or others, and was possibly related to the research procedures. 
2. Any serious accidental or unintentional change to the IRB-approved protocol 
that alters the level of risk. 
3. Any deviation from the protocol taken without prior IRB review to eliminate 
apparent immediate hazard to a research subject. 
4. Any new information (e.g., publication, safety monitoring report, updated 
sponsor safety report), interim result or other finding that indicates an 
unexpected change to the risk/benefit ratio for the research. 
5. Any breach in confidentiality that may involve risk to the subject or others. 
6. Any complaint of a subject that indicates an unanticipated risk or that cannot 
be resolved by the Principal Investigator. 
• 
The FDA will be notified within 7 calendar days of any unexpected fatal or life-
threatening adverse event with possible relationship to study drug, and 15 calendar 
days of any event that is considered: 1) serious, 2) unexpected, and 3) at least 
possibly related to study participation. 
8.6.2 Routine Reporting Requirements 
• 
The UCSD HRPP will be notified of any adverse events that are not unanticipated 
problems involving risk to subjects or others (non-UPRs) at the time of the annual 
Continuing Review.  
• 
The FDA will be notified of all non-serious adverse events annually at the time of 
the annual report. 
9.0 
AGENT INFORMATION 
9.1 
Dimethylfumarate 
Please refer to package insert / prescribing information for more comprehensive information. 
 
Other names for the drug: Tecfidera 
 
Mechanism of action (or Product description):  The mechanism of action of DMF is 
unknown. DMF and its metabolite, monomethyl fumarate (MMF) have been shown to activate 
the Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway in vitro and in vivo in animals and 
humans. The Nrf2 pathway is involved in the cellular response to oxidative stress. Preliminary 
studies in CLL have demonstrated inhibition of the Wnt pathway and other pro-survival 
pathways (eg: NFKB, JAK) in cancer cells, including CLL cells. 
 
Availability: commercially available, will be provided for 8 weeks by the clinical trial.  
 
How supplied: Available as hard gelatin delayed-release capsules in two strengths containing 
either 120 mg or 240 mg of dimethyl furcate. The green and white 120 mg capsules are printed 
with “BG-12 120 mg” in black ink. The green 240 mg capsules are printed with “BG-12 240 mg” 


 
Principal Investigator:  Michael Choi, MD  
HRPP Project 151567  
 
 
 
 
 
 
Page 29 of 37 
 
in black ink.   
 
Storage and stability: Store at 15 degrees C to 20 degrees C (59 to 86 degrees F). Protect the 
capsules from light. Store in original container. Once opened, discard bottles after 90 days.  
 
Route of administration for this study: oral  
 
Side effects: 
 
Adverse reactions occurring in >10% of patients: 
Cardiovascular: Flushing (40%) 
Gastrointestinal: Abdominal pain (18%), diarrhea (14%), nausea (12%) 
Infection: Infection (60%; placebo: 58%) 
 
Adverse reactions occurring in 1% to 10%: 
Dermatologic: Pruritus (8%), skin rash (8%), erythema (5%) 
Gastrointestinal: Vomiting (9%), dyspepsia (5%) 
Genitourinary: Proteinuria (6%) 
Hematologic: Lymphocytopenia (2% to 6%) 
Hepatic: Increased serum AST (4%) 
 
Adverse reactions occurring in <1% (Limited to important or life-threatening): Eosinophilia 
(transient) 
 
There are no contraindications listed within the manufacturer's U.S. product labeling. 
 
Concerns related to adverse effects: 
• 
Dermatitis/irritation: May cause rash, pruritus, or erythema. There are case reports of 
contact dermatitis resulting from dimethyl fumarate (DMF) exposure after use as a fungicide 
and desiccant in the shipping of furniture (Bruze, 2011; Giménez-Arnau, 2011; Ropper, 
2012). 
• 
Flushing: Commonly causes mild-to-moderate flushing (eg, warmth, redness, itching, 
burning sensation); flushing generally appears soon after initiation, and improves or resolves 
with subsequent dosing. Administration with food may decrease flushing incidence. The 
Canadian labeling suggests that a temporary dosage reduction or short-term (≤4 days) 
administration of aspirin (nonenteric coated) 30 minutes prior to dimethyl fumarate may also 
reduce the incidence and severity of flushing. Use of aspirin > 4 days has not been studied; 
long-term use of aspirin is not recommended. 
• 
Gastrointestinal events: GI events (eg, nausea, vomiting, diarrhea, abdominal pain, 
dyspepsia) commonly occur with use; GI events generally occur in the first month of use and 
decrease thereafter. To improve tolerability, the Canadian labeling recommends 
administering with food or temporarily reducing the dosage. 
• 
Hepatic effects: Transaminase elevations (usually <3 times ULN) were observed, generally 
occurring in the first 6 months of treatment. 
• 
Lymphopenia: Decreased lymphocyte counts may occur with use. Prior to initiation, a recent 
CBC (within 6 months) should be reviewed to identify patients with preexisting low 
lymphocyte counts. Obtain CBC at least annually (or more frequently if indicated) during 
use. In trials, mean lymphocyte counts decreased ~30% over the first year of therapy (then 
stabilized), and lymphocyte counts increased (but did not return to baseline) 4 weeks 
following discontinuation. No difference in incidence of infection or series infections has 


 
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Page 30 of 37 
 
been observed in treated patients when compared to placebo; consider temporarily 
discontinuing therapy in patients with serious infections. Has not been studied in patients 
with preexisting low lymphocyte counts. Canadian labeling recommends treatment not be 
initiated in patients with signs/symptoms of a serious infection. 
• 
Proteinuria: In clinical trials, proteinuria was reported at a slightly higher incidence than that 
observed with placebo; significance of these findings is unknown. 
 
9.1.1 Return and Retention of Study Drug 
Remaining drug is to be destroyed according to Moores Cancer Center Investigational Drug 
Services destruction policy. 
 
9.1.2 Drug Accountability/Subject Compliance 
Records of study medications used, dosages administered, and intervals between visits will be 
kept during the study.  Patients will be asked to fill out a pill diary and bring with them for review 
after each cycle of study treatment. Drug accountability will be noted at the completion of the 
trial.  Patients will be asked to return all unused medication at the end of the study. 
 
 
10.0 
STATISTICAL CONSIDERATIONS 
10.1 
Study Design/Study Endpoints 
 
This is a single arm, open-label, non-randomized phase I study, to evaluate the tolerability, 
safety, and clinical activity of DMF. Relapsed/refractory CLL patients will be recruited. The 
primary endpoint is the maximum tolerated dose or biologically active dose and the rate of 
DLTs.  
 
Secondary endpoints include the rate of adverse events including infections, the proportion of 
patients able to complete 2 months of therapy without intolerance or disease progression, 
the objective response rate (including partial response, complete response, or nodular complete 
response) by international working group in CLL guidelines (iwCLL), progression free survival, 
the change of expression of LEF1, c-myc, Wnt pathway, STAT pathway, and STAT1 
phosphorylation.  
 
10.1.1  Statistical Design 
A standard 3+3 dose escalation design will be used. There are two test dose levels with a 
potential de-escalation dose. A minimum of three subjects will be treated at each dose level. All 
three subjects in a cohort will be evaluated for DLT in the defined DLT evaluation period (within 
56 days of starting study treatment) before enrollment of subjects at the next dose level may 
begin. For all dose levels, if no DLTs are observed during the evaluation period among the three 
treated patients, escalation to the next dose level may begin. If a DLT is observed in one of the 
first three subjects in the cohort, the cohort will be expanded to six subjects. If zero or one of six 
subjects in the cohort experiences a DLT within the evaluation period, escalation to the next 
dose level will occur. If a DLT is seen in two or more subjects in a cohort, escalation will be 
stopped and the Maximum Tolerated Dose (MTD) will be considered to have been exceeded. 
The next lower dose will be considered as MTD if six patients have already been treated at that 
dose. Otherwise if only three patients have been treated at the next lower dose, then an 
additional three patients should be enrolled at the next lower dose level for a total of six 


 
Principal Investigator:  Michael Choi, MD  
HRPP Project 151567  
 
 
 
 
 
 
Page 31 of 37 
 
patients. If zero or one has DLTs among the 6 patients, then this dose is declared as MTD. 
Otherwise, there is further de-escalation according to the same scheme. As a result, the MTD is 
the highest dose where at most one-sixth of the patients developed DLT. If MTD is not reached, 
the higher dose will be selected. As with MTD, another 3 subjects will be treated at this dose if 
only 3 subjects have been treated. 
 
1 additional cohort with 3 patients will be recruited at the selected dose to further evaluate the 
safety. The sample size of 9 subjects is considered to be sufficient to support preliminary 
tolerability, safety, and DLTs based on the established safety profile of this compound.   
 
10.2 
Sample Size and Accrual 
15 to 21 patients may be recruited. 
10.3 
Evaluable Cohort and Subject Replacement 
A subject will be considered evaluable for assessment of DLT if the subject receives at least 7 
days of DMF and completes the safety follow-up through the DLT evaluation period, or the 
subject experiences a DLT at any time during the DLT evaluation period. Any non-evaluable 
subject will be replaced in the same dose cohort to complete the number of evaluable subjects 
for the MTD analysis. 
 
Any subject who receives at least one dose of DMF is evaluable for safety. The safety 
population will be used to evaluate baseline characteristics as well as all descriptive endpoints 
for safety. 
 
All patients who undergo at least one dose of the study treatment will be included in the efficacy 
analysis. If the response for a patient cannot be assessed (for example, a patient dies early) 
prior to 2 months assessments, it will be considered to be an event that does not favor the study 
therapy (e.g., non-response).   
 
10.4 
Data Analyses Plans 
Primary Analysis 
The rate of DLTs will be estimated along with its exact 95% confidence interval using the 
patients treated at the selected dose in Phase I. 
 
Secondary analyses 
The adverse events from the treatment beginning to 56 days after treatment completion or study 
discontinuation will be recorded for all patients. Incidence of adverse events will be summarized 
by event type,grade and relatedness, separately for the two dose levels.   
 
The proportion of patients that received the selected dose and are able to complete 2 months of 
therapy without intolerance or disease progression will be reported. The reason for patient 
discontinuing treatment early will be recorded. 
 
The objective response rate (including partial response, complete response, or nodular 
complete response) based on iwCLL will be estimated along with its exact 95% confidence 
interval. 
 


 
Principal Investigator:  Michael Choi, MD  
HRPP Project 151567  
 
 
 
 
 
 
Page 32 of 37 
 
If follow-up is available, median progression-free survival and overall survival will be estimated 
using the Kaplan-Meier method. 
 
The expressions of LEF1, c-myc, Wnt pathway, STAT pathway, and STAT1 phosphorylation will 
be measured over time. The trajectories will be showed by graphs. We will test if the average 
level of these measurements throughout the treatment is significantly changed from the pre-
treatment level by a paired t-test at 5% significance level. We will use the methods of Smyth 
(2005) to fit linear models to assess differential expression between pre- and post-treatment 
measurements. As we plan to conduct a large number of hypothesis tests within the gene 
expression outcome, we will use the Benjamini-Hochberg method to control the false discovery 
rate (FDR), setting it to 5%. 
 
11.0 
STUDY MANAGEMENT 
11.1 
Conflict of Interest 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, or 
financial gain greater than the minimum allowable by their institution, etc.) must have the conflict 
reviewed according to UCSD conflict of interest policy. 
11.2 
Institutional Review Board (IRB) Approval and Consent  
The IRB should approve the consent form and protocol prior to any study-related activities.  It is 
expected that the IRB will have the proper representation and function in accordance with 
federally mandated regulations.  
 
In obtaining and documenting informed consent, the investigator should comply with the 
applicable regulatory requirement(s), and should adhere to Good Clinical Practice (GCP) and to 
ethical principles that have their origin in the Declaration of Helsinki. 
 
 
Before recruitment and enrollment onto this study, the patient will be given a full explanation of 
the study and will be given the opportunity to review the consent form. Each consent form must 
include all the relevant elements currently required by the FDA Regulations and local or state 
regulations. Once this essential information has been provided to the patient and the 
investigator is assured that the patient understands the implications of participating in the study, 
the patient will be asked to give consent to participate in the study by signing an IRB-approved 
consent form. 
 
Prior to a patient’s participation in the trial, the written informed consent form should be signed 
and personally dated by the patient and by the person who conducted the informed consent 
discussion. 
11.3 
Subject Data Protection 
In accordance with the Health Information Portability and Accountability Act (HIPAA), subjects 
who have provided written informed consent must also sign a subject authorization to release 
medical information to the study Sponsor and allow a regulatory authority, or Institutional 
Review Board access to subject’s medical information relevant to the study. 
11.4 
Data and Safety Monitoring/Auditing 
In addition to adverse event monitoring and clinical oversight by the principal investigator and 
co-investigators, quality assurance of the study will be performed by the clinical trials office 


 
Principal Investigator:  Michael Choi, MD  
HRPP Project 151567  
 
 
 
 
 
 
Page 33 of 37 
 
internal monitor. Monitoring intervals will be dependent upon the number of patients enrolled 
and the complexity of the study.  
 
This study will also use the UCSD Moores Cancer Center Data Safety and Monitoring Board 
(DSMB) to provide oversight in the event that this treatment approach leads to unforeseen 
toxicities. Data from this study will be reported after every 6 patients or sooner if required for 
clinical study stopping rules, and will include: 
 
1) 
the protocol title, IRB protocol number, and the activation date of the study.  
2) 
the number of patients enrolled to date  
3) 
the date of first and most recent patient enrollment 
4) 
a summary of all adverse events regardless of grade and attribution   
5) 
a response evaluation for evaluable patients when available 
6) 
a summary of any recent literature that may affect the ethics of the study.  
 
11.5 
Adherence to the Protocol 
Except for an emergency situation in which proper care for the protection, safety, and well-being 
of the study patient requires alternative treatment, the study shall be conducted exactly as 
described in the approved protocol.  
11.5.1 Emergency Modifications 
Investigators may implement a deviation from, or a change of, the protocol to eliminate an 
immediate hazard(s) to trial subjects without prior IRB approval.  
 
For any such emergency modification implemented, a IRB modification form must be completed 
within five (5) business days of making the change.  
11.5.2 Other Protocol Deviations/Violations 
All other planned deviations from the protocol must have prior approval by the Principal 
Investigator and the IRB. According to the IRB, a protocol deviation is any unplanned variance 
from an IRB approved protocol that:  
• 
Is generally noted or recognized after it occurs 
• 
Has no substantive effect on the risks to research participants 
• 
Has no substantive effect on the scientific integrity of the research plan or the value of 
the data collected  
• 
Did not result from willful or knowing misconduct on the part of the investigator(s).  
 
An unplanned protocol variance is considered a violation if the variance: 
• 
Has harmed or increased the risk of harm to one or more research participants. 
• 
Has damaged the scientific integrity of the data collected for the study. 
• 
Results from willful or knowing misconduct on the part of the investigator(s). 
• 
Demonstrates serious or continuing noncompliance with federal regulations, State laws, 
or University policies. 
 
If a deviation or violation occurs without prior approval from the Principal Investigator, please 
follow the guidelines below: 
 


 
Principal Investigator:  Michael Choi, MD  
HRPP Project 151567  
 
 
 
 
 
 
Page 34 of 37 
 
Protocol Deviations: Personnel will report to any sponsor or data and safety monitoring 
committee in accordance with their policies. Deviations should be summarized and reported to 
the IRB at the time of continuing review. 
 
Protocol Violations: Study personnel should report violations within one (1) week of the 
investigator becoming aware of the event using the same IRB online mechanism used to report 
Unanticipated Problems.  
11.6 
Amendments to the Protocol 
Should amendments to the protocol be required, the amendments will be originated and 
documented by the Principal Investigator. It should also be noted that when an amendment to 
the protocol substantially alters the study design or the potential risk to the patient, a revised 
consent form might be required.  
 
The written amendment, and if required the amended consent form, must be sent to the IRB for 
approval prior to implementation. 
11.7 
Record Retention 
Study documentation includes all Case Report Forms, data correction forms or queries, source 
documents, Sponsor-Investigator correspondence, monitoring logs/letters, and regulatory 
documents (e.g., protocol and amendments, IRB correspondence and approval, signed patient 
consent forms). 
 
Source documents include all recordings of observations or notations of clinical activities and all 
reports and records necessary for the evaluation and reconstruction of the clinical research 
study. 
 
Government agency regulations and directives require that the study investigator must retain all 
study documentation pertaining to the conduct of a clinical trial. In the case of a study with a 
drug seeking regulatory approval and marketing, these documents shall be retained for at least 
two years after the last approval of marketing application in an International Conference on 
Harmonization (ICH) region. In all other cases, study documents should be kept on file until 
three years after the completion and final study report of this investigational study. 
11.8 
Obligations of Investigators 
The Principal Investigator is responsible for the conduct of the clinical trial at the site in 
accordance with Title 21 of the Code of Federal Regulations and/or the Declaration of Helsinki. 
The Principal Investigator is responsible for personally overseeing the treatment of all study 
patients. The Principal Investigator must assure that all study site personnel, including sub-
investigators and other study staff members, adhere to the study protocol and all FDA/GCP/NCI 
regulations and guidelines regarding clinical trials both during and after study completion. 
 
The Principal Investigator at each institution or site will be responsible for assuring that all the 
required data will be collected and entered onto the Case Report Forms. Periodically, 
monitoring visits will be conducted and the Principal Investigator will provide access to his/her 
original records to permit verification of proper entry of data. At the completion of the study, all 
case report forms will be reviewed by the Principal Investigator and will require his/her final 
signature to verify the accuracy of the data. 
 
 


 
Principal Investigator:  Michael Choi, MD  
HRPP Project 151567  
 
 
 
 
 
 
Page 35 of 37 
 
12.0 
REFERENCES 
 
1. 
Maurer C, Hallek M. [Chronic lymphocytic leukemia]. Dtsch Med Wochenschr. 2013;138 
(42):2153-2166. 
2. 
Hallek M, Cheson BD, Catovsky D et al. Guidelines for the diagnosis and treatment of 
chronic lymphocytic leukemia: a report from the International Workshop on Chronic 
Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 
guidelines. Blood. 2008;111 (12):5446-5456. 
3. 
Hallek M, Fischer K, Fingerle-Rowson G et al. Addition of rituximab to fludarabine and 
cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-
label, phase 3 trial. Lancet. 2010;376 (9747):1164-1174. 
4. 
Brown JR. The treatment of relapsed refractory chronic lymphocytic leukemia. Hematology 
Am Soc Hematol Educ Program. 2011;2011 (110-118. 
5. 
Goede V, Fischer K, Busch R et al. Obinutuzumab plus Chlorambucil in Patients with CLL 
and Coexisting Conditions. N Engl J Med. 2014 
6. 
Byrd JC, Furman RR, Coutre SE et al. Targeting BTK with Ibrutinib in Relapsed Chronic 
Lymphocytic Leukemia. N Engl J Med. 2013 
7. 
Woyach JA, Furman RR, Liu TM et al. Resistance Mechanisms for the Bruton's Tyrosine 
Kinase Inhibitor Ibrutinib. N Engl J Med. 2014 
8. 
Gold R, Kappos L, Arnold DL et al. Placebo-controlled phase 3 study of oral BG-12 for 
relapsing multiple sclerosis. N Engl J Med. 2012;367 (12):1098-1107. 
9. 
Lu D, Zhao Y, Tawatao R et al. Activation of the Wnt signaling pathway in chronic 
lymphocytic leukemia. Proc Natl Acad Sci U S A. 2004;101 (9):3118-3123. 
10. Filipovich A, Gandhirajan RK, Gehrke I et al. Evidence for non-functional Dickkopf-1 (DKK-
1) signaling in chronic lymphocytic leukemia (CLL). Eur J Haematol. 2010;85 (4):309-313. 
11. Kaucka M, Plevova K, Pavlova S et al. The planar cell polarity pathway drives 
pathogenesis of chronic lymphocytic leukemia by the regulation of B-lymphocyte 
migration. Cancer Res. 2013;73 (5):1491-1501. 
12. Fukuda T, Chen L, Endo T et al. Antisera induced by infusions of autologous Ad-CD154-
leukemia B cells identify ROR1 as an oncofetal antigen and receptor for Wnt5a. Proc Natl 
Acad Sci U S A. 2008;105 (8):3047-3052. 
13. Lu D, Carson DA. Inhibition of Wnt signaling and cancer stem cells. Oncotarget. 2011;2 
(8):587. 
 
 
 


 
Principal Investigator:  Michael Choi, MD  
HRPP Project 151567  
 
 
 
 
 
 
Page 36 of 37 
 
APPENDICES 
Appendix A. Performance Status 
 
ECOG Performance Status Scale 
Grade 
Descriptions 
0 
Normal activity.  Fully active, 
able to carry on all pre-
disease performance without 
restriction. 
1 
Symptoms, but ambulatory. 
Restricted 
in 
physically 
strenuous 
activity, 
but 
ambulatory and able to carry 
out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
2 
In bed < 50% of the time. 
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 
In bed > 50% of the time.  
Capable of only limited self-
care, confined 
to bed or chair more than 
50% of waking hours 
4 
100% 
bedridden.  
Completely 
disabled.  
Cannot carry on any 
self-care.  Totally confined to 
bed or chair 
5 
Dead. 
 
 
 
 
 
 
 


 
Principal Investigator:  Michael Choi, MD  
HRPP Project 151567  
 
 
 
 
 
 
Page 37 of 37 
 
Appendix B. Hematologic AE grading scale 
 
Taken from iwCLL guidelines, Hallek et al, 2008.