Clinical trial NCT02100423
Conditions: Contiguous Stage II Small Lymphocytic Lymphoma Noncontiguous Stage II Small Lymphocytic Lymphoma Stage 0 Chronic Lymphocytic Leukemia Stage I Chronic Lymphocytic Leukemia Stage I Small Lymphocytic Lymphoma Stage II Chronic Lymphocytic Leukemia
Sponsor: Paolo Caimi, MD
Start date: 2014-10-16; Completion date: 2018-12-13
Enrollment: 35 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase II trial studies the efficacy (activity), and tolerability of curcumin and cholecalciferol combination in treating patients with previously untreated stage 0-II chronic lymphocytic leukemia or small lymphocytic lymphoma. Curcumin and cholecalciferol may prevent or slow the growth of cancer cells.

Detailed description:
PRIMARY OBJECTIVES:

I. To determine the overall response rate (ORR) based on National Cancer Institute-Working Group (NCI-WG) criteria in chronic lymphocytic leukemia (CLL) or the Cheson criteria in small lymphocytic lymphoma (SLL).

SECONDARY OBJECTIVES:

I. To determine the time to first cytotoxic treatment (TFCT), progression free survival (PFS), and overall survival (OS) using this regimen.

OUTLINE:

Patients receive curcumin orally (PO) daily on days 1-28 and cholecalciferol PO daily on days 8-28 of course 1 and days 1-28 of subsequent courses. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients achieving partial response or better may receive treatment for a total of 2 years.

After completion of study treatment, patients are followed up for 30 days and then every 3-6 months for 2 years.

Arms: arm 1: Patients receive curcumin PO daily on days 1-28 and cholecalciferol PO daily on days 8-28 of course 1 and days 1-28 of subsequent courses. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients achieving partial response or better may receive treatment for a total of 2 years.
Interventions: intervention 1: curcumin intervention 2: cholecalciferol intervention 3: laboratory biomarker analysis intervention 4: pharmacological study
Intervention descriptions: intervention 1: Given PO intervention 2: Given PO intervention 3: Correlative studies intervention 4: Correlative studies

Protocol documents:
Prot_SAP_000.pdf: 
CASE 5913  
Protocol Version 7 Dated 10/2/2018 
 
CASE COMPREHENSIVE CANCER CENTER 
__________________________________________________________________ 
 
STUDY NUMBER:  CASE 5913 
 
STUDY TITLE:  
A Phase II Study of Curcumin and Vitamin D in Previously Untreated 
Patients with Early Stage Chronic Lymphocytic Leukemia (CLL) or 
Small Lymphocytic Lymphoma (SLL)  
 
PRINCIPAL INVESTIGATOR: Paolo Caimi, MD 
 
 
 
 
Case Comprehensive Cancer Center 
University Hospitals Cleveland Medical Center 
 
 
 
 
Seidman Cancer Center 
11100 Euclid Avenue  
Cleveland, OH  44106 
  
 
 
CO- INVESTIGATORS;  
 
 
 
 
 
Brenda Cooper, MD 
 
 
 
 
Marcos de Lima, MD 
 
 
 
 
 
 
 
 
 
Ehsan Malek, MD 
 
 
 
 
Case Comprehensive Cancer Center 
University Hospitals Cleveland Medical Center 
 
 
 
 
Seidman Cancer Center 
11100 Euclid Avenue  
 
 
 
 
Cleveland, OH   44106 
 
STATISTICIAN:  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
   
 
  
 
 
 
 
 
 
SPONSOR:  
 
 
Case Comprehensive Cancer Center 
 
SUPPORT: 
 
 
Early Phase Clinical Research Support (EPCRS), Case 
Comprehensive Cancer Center 
 
SUPPLIED AGENT: 
 
Pharmaceutical grade curcumin 
 
 
 
 
Supplied by Sabinsa Corporation,  
 
 
 
 
East Windsor, NJ 


 
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OTHER AGENT:  
 
Vitamin D3 (obtained from commercial source)  
 
 
APPROVALS:  
PRMC:   
 
10/07/2013 
Initial IRB:    
02/20/2014 
Amendment 2  
09/11/2014 (protocol version date 02/17/2014) 
Open to Accrual 
09/26/2014 (protocol version date 02/17/2014) 
Amendment 3  
11/13/2014 (protocol version date 10/08/2014) 
CR and Amend 4 
01/05/2015 (protocol version date 12/29/2014) 
Amendment 5  
02/22/2015 (protocol version date 02/16/2015) 
Amendment 6  
04/14/2015 (protocol version date 02/16/2015) 
Amendment 7  
n/a (protocol version date 6/26/2015) 
Amendment 8  
n/a (protocol version date 10/2/2018) 
 
 
SUMMARY OF CHANGES: 
 
Amendment 8, protocol v7 date 10/2/2018 
   Protocol: Added shipping de-identified samples to Basem William MD at OSU under a       
   Material Transfer Agreement 
 
Administrative Change, Consent and Protocol, no version change/IRB approval exempt 
Updated Name of UHCMC to University Hospitals Cleveland Medical Center 
 
Amendment 7, Consent v7 date 6/26/2015, Protocol v6 date 6/26/2015 
Revised protocol and consent to change PI from Dr. William to Dr. Caimi 
 
Amendment 6, Consent v date 4/3/2015 
Consent:  revised to clarify which activities are routine versus research related. 
Protocol: no changes to protocol or protocol version date. 
 
Amendment 5, v date 2/16/2015 
Protocol:  Quality of life assessments at baseline and at end of treatment added. 
Curcumin dose reduction adjusted to 4g daily with grade 3 diarrhea. 
Consent:  Consent updated to include mandatory QOL assessments. 
 
Amendment 4, v date 12/29/2014 
Protocol:  changes to study calendar item c to correctly indicate ALC<5000, change to 
section 11.2 to include a window for PE visits +/- 3 days to avoid deviations, revision to 
schema to indicate that all labs are mandatory. 
Consent:  updated to revised CCCC IRB approved template v date 12/10/2014. 
 
Amendment 3, v date 10/08/2014 


 
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Protocol: revised timeframe for prescreening for bone marrow biopsy, flow cytometry, 
cytoegenics, and interphase FISH to be acceptable if completed within 5 years of 
enrollment. 
Consent:  revised to new CCCC IRB approved template, prescreening information 
revised to reflect protocol.  
 
Amendment 2, v date 2/17/2014 
Protocol approved with initial submission was not correctly documented with the IRB.  
There were no changes to the protocol with this submission.  It was administrative.   


 
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Eligibility, consent, registration
Cycle 1, Day 1* 
• 
Vitals, physical exam, laboratory assessments 
• 
Curcumin 8 grams/day orally  
• 
Mandatory Correlative studies blood draw 
Cycle 1, Day 8 
• 
Vitals, physical exam, laboratory assessments 
• 
Curcumin 8 grams/day orally  
• 
D3 10,000 IU/day orally 
• 
Adverse events assessments 
• 
Mandatory Correlative studies blood draw 
Cycles 2 through 6, Day 1 
• 
Vitals, physical exam, laboratory assessments 
• 
Curcumin 8 grams/day orally  
• 
D3 10,000 IU/day orally 
• 
Adverse events assessments 
• 
Mandatory Correlative studies blood draw (Cycle 2 only) 
*Each cycle is 28 days 
If evidence of disease 
progression: 
Discontinue study treatment  
If attaining a partial response or better: 
Study treatment may continue for up to 
two years 
 
Cycles 7+, Day 1 
• 
Vitals, physical exam, laboratory 
assessments 
• 
Curcumin 8 grams/day orally  
• 
D3 10,000 IU/day orally 
• 
Adverse events assessments 
End of Treatment (within 1 week of discontinuation) 
• 
Vitals, physical exam, laboratory assessments 
• 
Adverse events assessments 
Long Term Follow up (up to two years post treatment) 
• 
Vitals, physical exam, laboratory assessments 
• 
Adverse events assessments 


 
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TABLE OF CONTENTS 
1.0  
INTRODUCTION  
1.1 Early Phase Chronic Lymphocytic Leukemia (CLL) 
1.2  
Curcumin 
 
1.2.1 History of curcumin use as a medicinal agent 
 
1.2.2 Biochemistry of curcumin 
 
1.2.3 Antineoplastic properties of curcumin 
 
1.2.4 Preclinical data in CLL 
 
1.2.5 Clinical Data to Date 
 
1.2.6 Clinical Pharmacokinetics 
 
 
      1.2.6.1 Absorption and systemic bioavailability 
 
 
      1.2.6.2 Detection of systemic curcumin 
 
 
      1.2.6.3 Urinary excretion of curcumin 
 
 
      1.2.6.4 Toxicity 
 
 
      1.2.6.5 Dosing for pharmacologic effect 
1.3       Vitamin D 
1.3.1 Vitamin D and hematological malignancies 
1.3.2 Vitamin D activity in lymphoid malignancies 
1.3.3 Vitamin D and CLL 
1.3.4 Clinical Data to Date 
1.3.5 Clinical Pharmacokinetics 
1.4       Rationale   
 
2.0 
OBJECTIVES 
2.1 
Primary Objective 
2.2  
Secondary Objective(s) 
 
3.0 
STUDY DESIGN 
3.1  
Study design  
3.2 
Number of Subjects 
3.3 
Replacement of Subjects  
 
4.0  
PATIENT SELECTION 
4.1 
Inclusion Criteria 
4.2  
Exclusion Criteria 
4.3 
Inclusion of Women and Minorities 
 
5.0 
REGISTRATION  
 
6.0  
TREATMENT PLAN 
6.1 
Agent Administration  
 
6.1.1 Curcumin 
 
6.1.2 Vitamin D3 
6.2  
General Concomitant Medications and Supportive Care Guidelines 
6.3 
Duration of Therapy 


 
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6.4 
Duration of Follow Up 
7.0 
DOSE DELAYS / DOSE MODIFICATIONS 
 
8.0 
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS  
 
8.1 
Adverse Events and Potential Risk List  
 
8.1.1 Curcumin 
 
8.1.2 Vitamin D3 
8.2       Definitions 
 
            8.2.1 Adverse Events 
 
            8.2.2 Significance of an Adverse Event 
 
            8.2.3 Serious Adverse Events 
 
            8.2.4 Expectedness 
 
            8.2.5 Attribution 
            8.3       Reporting Procedures for All Adverse Events 
            8.4       Serious Adverse Event Reporting Procedures 
 
            8.4.1 Reporting 
 
            8.4.2 FDA Reporting 
           8.5        Data Safety Toxicity Committee    
 
 
9.0 
PHARMACEUTICAL INFORMATION  
9.1 
Curcumin 
9.2 
Vitamin D3 
 
10.0 
CORRELATIVE / SPECIAL STUDIES  
10.1     Vitamin D receptor expression in CLL cells 
10.2 
Pharmacodynamic analysis of NF-κB and bcl-2 in CLL cells 
10.3  Curcumin and vitamin D3 pharmacokinetics 
10.4 
Quality of life assessments 
10.5 
Additional correlative studies 
 
11.0 
STUDY PARAMETERS AND CALENDAR 
 11.1  Study Parameters 
 
  
11.1.1 Screening Evaluation   
 
  
11.1.2 Treatment Period 
11.2  Calendar 
 
12.0 
MEASUREMENT OF EFFECT  
12.1 
Response Criteria for CLL 
12.2 
Definitions for SLL with radiographically measurable lesions 
12.3 
Response Criteria for SLL 
12.4 
Biologic response criteria CLL and SLL 
12.5 
Duration of response 
12.6 
Progression-free survival (PFS) 
12.7 
Time to first cytotoxic treatment (TFCT) 
 
13.0 
RECORDS TO BE KEPT/REGULATORY CONSIDERATIONS 


 
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13.1     Data Reporting  
13.2     Regulatory Considerations 
             13.2.1 Written Informed consent 
           13.2.2 Subject Data Protection 
            13.2.3 Accessing Electronic Medical Records for University Hospitals Health 
System   
            13.2.4 Retention of records 
            13.2.5 Audits and inspections  
            13.2.6 Data Safety and Monitoring Plan  
 
14.0 
STATISTICAL CONSIDERATIONS 
14.1 
Study Design/Endpoints 
14.2 
Sample Size/Accrual Rate 
14.3 
Analysis of Secondary Endpoints 
14.4 
Reporting and Exclusions 
   
14.4.1 Evaluation of toxicity  
  
14.4.2 Evaluation of response 
  
14.4.3 Expected Accrual   
 
15.0 
REFERENCES 
 
APPENDICES  
 
 
 
APPENDIX A 
 
Eastern Cooperative Oncology group (ECOG) performance status 
 
 
 
APPENDIX B 
 
Indications for treatment per NCI working group criteria for CLL 
 
 
APPENDIX C 
 
Patient pill diary for cycle 1  
 
 
APPENDIX D 
 
Patient pill diary for cycles 2-6 
 
 
APPENDIX E 
 
Potential CYP3A4 and CYP2A6 interactions 
 
 
APPENDIX F 
 
Potential CYP3A4 interactions 
 
 
APPENDIX G 
 
Functional assessment of chronic illness-Lymphoma (FACT-Lym) questionnaire 


 
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1.0 
INTRODUCTION 
 
1.1 
Early Phase Chronic Lymphocytic Leukemia 
Chronic lymphocytic leukemia (CLL) is a heterogeneous disease with an extremely variable 
course. Patients with ‘‘smoldering’’ CLL appear to have a life span similar to age-matched 
controls in the general population. Similarly, early stage asymptomatic CLL (Rai stage 0-II 
without active disease as defined by the National Cancer Institute Working Group [NCI-WG] 
Criteria) is associated with a favorable prognosis with a reported median overall survival 
(OS) that ranges from 8 to 12 years. Currently, management of asymptomatic early stage 
CLL centers on expectant surveillance for active disease warranting chemotherapy (1). 
However, survival outcomes vary considerably within this subset depending on prognostic 
factors at presentation. Early stage patients with unfavorable features are at higher risk for 
disease progression, and, therefore, may benefit from early intervention rather than the 
traditional watch-and-wait approach. 
 
The large randomized clinical trials conducted by the French Cooperative Group in the 1980s 
for asymptomatic early stage CLL were limited to potentially toxic chemotherapeutics 
(alkylating 
agents). 
Early 
treatment 
with 
daily 
chlorambucil 
or 
intermittent 
chlorambucil/prednisone was associated with slower disease progression, but not longer 
survival when compared with the observation arms (2, 3). The lack of survival benefit was 
attributed to selection of resistant CLL clones due to early exposure to chlorambucil, limited 
availability at that time of effective salvage regimens, and excess deaths from secondary 
epithelial cancers. With regard to the clinical course of the disease, these randomized trials 
showed that at least 40% of patients with early stage CLL eventually require therapy for 
progressive disease, and that approximately 25% ultimately die of disease-related causes (2, 
3).  
 
1.2 
Curcumin 
 
1.2.1  History of curcumin use as a medicinal agent 
Turmeric is a rhizomatous plant (Curcuma longa) consisting of approximately 3% curcumin. 
Turmeric use in the field of medicine was described in Asia thousands of years ago. Evidence 
suggests curcumin has the potential to prevent or treat various pathophysiological processes, 
including cardiovascular disease, carcinogenesis, wound healing and inflammation. 
Curcumin exists as a bright yellow powder that provides the pigmentation to turmeric, and is 
used in the dye industry. It carries food additive number E100. The extracted powder will 
typically contain 75% curcumin in addition to derivatives of the parent compound in the form 
of 
other 
curcuminoids; 
approximately16% 
demethoxycurcumin 
(DMC), 
8% 
bisdemethoxycurcumin (bDMC) and a small amount of cyclocurcumin. BDMC and DMC 
possess similar molecular and biological properties. It is proposed that, within natural 
pathways, bDMC converts to DMC which then converts to curcumin. The powder is 
exported for encapsulation and subsequent distribution within world nutraceutical markets. 
Capsules are readily obtainable as a health food supplement (4). 
 


 
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1.2.2  Biochemistry of curcumin 
Curcumin (or diferuloylmethane) is a poly-phenolic molecule existing as a keto-enol 
tautomer, with the enol isomer probably the more stable in both solid state and solution (Fig. 
1) (5). The molecule is lipophilic consisting of two aromatic rings connected by two 
unsaturated carbonyl groups and therefore has poor water solubility. The molecule is 
stabilised by hydrogen-bonding associated with the central OH group. This may be one of the 
important functional sites responsible for the array of molecular biological activities (6). 
Curcumin is photosensitive and precautions should be taken to avoid exposure and 
subsequent degradation. Much of the interest to medical research lies within the ability of 
curcumin to counteract the generation and subsequent effects of reactive oxygen species and 
nitrogen free-radicals, typically manifesting from damaged cells. Curcuminoids can avidly 
donate hydrogen ions and undergo nucleophilic addition. They possess several moieties with 
the potential to undergo biochemical modification (6) and impart the important reduction–
oxidation, anti-oxidant and proton donating properties that can combat cell damage. The 
mechanisms which enable curcumin to scavenge and trap radicals are numerous and complex 
(7). One of the key attributes of curcuminoids likely to evoke this benefit is the chain-
breaking anti-oxidant activity from hydrogen atoms, most probably donated from the phenol 
(OH) groups (8). Curcumin is unstable under alkaline conditions and degrades in less than 30 
min (9). Under acidic conditions, the rate of decomposition is significantly reduced with less 
than 20% of total curcumin degraded in 1 h (10). This may explain why curcumin seems to 
be stable within the gastrointestinal tract where the pH range is 1–6.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure-1: Proposed molecular pathway for the conversion of bDMC to DMC and finally to 
curcumin and the co-existence of keto and enol isomers of curcumin (4). 
 


 
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1.2.3  Antineoplastic properties of curcumin 
Many pathways are dysregulated in cancer. Curcumin may be able to modulate multiple 
cellular pathways involved in carcinogenesis and thus behave as a multi-targeted drug. This 
is of particular interest in the management of neoplastic conditions. By not relying on a 
single target pathway, it may have activity across a wider population of tumor genotypes. 
The loss of cell cycle control can lead to the bypassing of DNA-damage checkpoints and 
replication of damaged cells with malignant potential. Curcumin promotes inhibition or arrest 
at all stages of the cell cycle. This is in part due to a curcumin-induced increase in p53 and 
p21 expression, however, curcumin can also inhibit G1/S mitotic arrest independently from 
p53 and p21 activity (11). Curcumin-induced down-regulation of cyclin D (12) prevents cells 
progressing from the G1 to the S phase, thus favoring apoptosis. In addition, it blocks the 
effect of cyclin-dependent kinases (CDK), in particular CDK4 and CDK6, the activation of 
which are required for cell cycle turnover. This may also be achieved by a curcumin-induced 
decrease in telomerase activity and by the inhibition of growth factor receptors (GFR). 
Apoptosis is ultimately achieved either by caspase induction or p53 signaling. Several cell 
line models demonstrate that curcumin promotes apoptosis via both these routes. Curcumin 
inhibits colorectal cancer cell growth by ~20% in vitro at concentrations as low as 5 µmol 
(13) and is a potent stimulator of caspase-3-induced apoptosis in hepatic cancer cell lines 
(14). It also increases the activation of caspase-7 (11) and (15) and caspase-8 and induces 
cytochrome-C release (16). Curcumin increases p53 expression, p53-driven apoptosis and 
subsequent p21 expression in response to DNA damage (17) and (13). In cell lines absent in 
p53, curcumin still enhances apoptosis via alternative pathways (e.g. death receptor 
dependent) utilising caspase and NF-κB signaling (18) and (16). Breast cancer cells treated 
with curcumin have been observed to undergo apoptosis accompanied by an increase in p53, 
p53 DNA binding activity and subsequent rise in Bax expression (19). C-Jun N-terminal 
kinases (JNK) and MAPK/p38 lie upstream from p53 in the apoptotic pathway. Curcumin 
may increase MAPK/p38 activation thus promoting apoptosis (20) though this has been 
disputed following other studies (21). This may be explained by a dose effect or differences 
between cancer cell lines. Curcumin also blocks the action or expression of the anti-apoptotic 
protein Bcl-2 in a number of cell lines (22). Curcumin inhibited NF-κB signaling, 
upregulated p53, and induced apoptosis in BCR-ABL acute lymphoblastic leukemia (ALL) 
cell lines; including cell lines driven by the T 315I BCR-ABL mutant that is resistant to 
tyrosine kinase inhibitors, and it prolonged survival of murine models of BCR-ABL driven 
ALL (23).  
 
1.2.4 Preclinical data in CLL 
As an inhibitor of NF-κB signaling, curcumin would be expected to induce apoptosis in B 
cell malignancies especially CLL where nuclear NF-κB is constitutively active (24). Everett 
and colleagues have shown that curcumin induced apoptosis in B-CLL cells from 14 patients 
with a mean EC(50) of 5.5 µM. In contrast, the EC(50) for whole mononuclear cells from a 
healthy donor was 21.8 µM confirming the fact that B-CLL are more sensitive to curcumin 
compared to normal lymphocytes. In a 48 hr wash-out time course, curcumin-induced 
apoptosis was time-dependent, with a substantial reduction in apoptosis observed when 
curcumin was removed after 5 hr. Curcumin treatment reduced basal nuclear NF-κB levels 
and 1 µM curcumin augmented both vinca alkaloid and PDE4 inhibitor-induced apoptosis in 


 
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B-CLL cells (25). Ghosh and colleagues have subsequently shown that curcumin induced 
apoptosis in CLL cells in a dose-dependent (5-20 µM /L) manner and inhibited constitutively 
active prosurvival pathways, including signal transducers and activators of transcription 3 
(STAT3), AKT, and NF-κB. Moreover, curcumin suppressed expression of the anti-apoptotic 
proteins Mcl-1 and X-linked inhibitor of apoptosis protein (XIAP), and up-regulated the pro-
apoptotic protein BIM (26). More recently, curcumin was shown to sensitize lymphoma cells 
to the effects of ionizing radiation through blockade of NF-κB signaling (27, 28).The in vitro 
efficacy of curcumin in inducing apoptosis in cell lines deficient in p53 (18), through 
alternative pathways like NF-κB, Akt, and spleen tyrosine kinase (Syc) (23, 25, 29, 30), 
makes in clinically attractive agent to develop as there it has the potential to be effective in 
treating CLL patients with 17p/p53 deletion which are resistant to conventional cytotoxic 
agents (31).  
 
1.2.5 Clinical Data to Date  
Safety of oral curcumin was demonstrated from almost 40 clinical trials involving over 800 
participants (please see toxicity below). Dhillon and colleagues reported results of 25 patients 
with advanced pancreatic cancer treated with curcumin in a phase II single-institution trial 
(32). Patients received about 8g of oral curcumin that was well tolerated and no significant 
toxicities 
were 
observed. 
Despite 
poor 
curcumin 
bioavailability 
(see 
clinical 
pharmacokinetics below), steady state serum levels of 22-41 ng/ml of conjugated curcumin 
were achieved with such oral dosing within 3 days. All patients who donated blood samples 
had constitutively active NF-κB in their peripheral blood leukocytes and that was decreased 
after treatment with oral curcumin although such decrease wasn’t statistically significant. 
Curcumin also led to a significant decrease in cyclooxygenase-2 in leukocytes as well.  Only 
2/21 evaluable patients in this study had a response. Two patients showed clinical biological 
activity. One had ongoing stable disease for >18 months; interestingly, one additional patient 
had a brief, but marked, tumor regression (73%) accompanied by significant increases (4- to 
35-fold) in serum cytokine levels (IL-6, IL-8, and IL-10). Despite the absence of meaningful 
clinical activity in advanced pancreatic cancer, this study provided proof of concept that oral 
curcumin, despite its poor bioavailability, had biologic activity and is able to modulate NF-
κB signaling among a myriad of other biological effects (32). Golombick and colleagues 
reported the results of a randomized clinical trial of oral curcumin, given also at 8g daily 
dose, versus placebo in 36 patients with monoclonal gammopathy of undetermined 
significance (MGUS) and smoldering multiple myeloma (SMM) (33). Despite small sample 
size, curcumin treatment resulted in a significant decrease of free light chain ratio (36% from 
baseline) as well as markers of bone resorbtion. Also, no toxic effects of treatment were 
observed. Results suggest that curcumin might have the potential to slow the disease process 
in patients with MGUS and SMM (33). 
 
1.2.6 Clinical Pharmacokinetics  
1.2.6.1 Absorption and systemic bioavailability 
Clinical and in vivo studies report a limited systemic bioavailability of curcuminoids, with 
most of an oral dose excreted in faeces (34) and (35) and intravenous and intraperitoneal 
doses excreted in bile (36) and (37). Curcumin is poorly absorbed but easily detectable in the 
gastrointestinal tract (35), (38) and (39). Traces of parent compound have been found in rat 
liver and kidney (34) and (37) confirming that uptake does occur in organs distal to the 


 
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intestine albeit at low concentrations. In humans, plasma levels of curcumin reach a peak (27 
nM) around 1–2 h (40) after oral administration further confirming low bioavailability. It 
may be that exposure to low nanomolar concentrations is sufficient, and perhaps only briefly, 
to exert a therapeutic effect. Despite the low bioavailability reported from animal and human 
studies, early evidence of both local and systemic efficacy is apparent from the reduced 
tumour burden that has been observed in mouse models of familial adenomatous polyposis 
(FAP) (41) and (42) and colorectal liver metastases (12) and some efficacy is suggested from 
a clinical trial of curcumin in patients with pancreatic cancer (32). Hence, in the face of very 
low levels of detectable curcumin at the target site, biological activity may occur. 
Approximately a third of faecal curcumin is excreted without being systemically metabolized 
(34), (36), (39) and (43). Curcumin is reduced and conjugated within the gastrointestinal tract 
and liver, resulting in very low amounts of the parent compound detected in the hepatic 
system (44).  
 
1.2.6.2 Detection of systemic curcumin 
Curcumin detection in plasma is variable due to poor bioavailability and a short plasma half-
life. Initial studies using murine models consistently report low serum concentrations with 
the majority of the compounds being undetectable after 1 h following enteric (up to 2 g/kg) 
and parenteric (up to 40 mg/kg) administration (36) and (40). These data are mirrored by 
clinical trials where up to 12 g per day of oral curcumin has been given to patients and peak 
plasma levels occur 1–2 h following loading with trough levels at approximately 12 h (45). 
Only trace levels of curcumin are found in serum following oral doses less than 2 g per day. 
Following 4 g and 8 g of daily curcumin, serum levels of 0.51 µmol and 1.77 µmol have been 
reported (45) and similar values are achieved with 3.6 g per day (38). 
 
1.2.6.3 Urinary excretion of curcumin 
Curcumin is poorly excreted in urine (35) and (39). Murine models report negligible amounts 
are found in the urine even following intravenous doses of 1 g/kg (35) and (37). In humans 
receiving oral curcumin for four months, at doses greater than 3.6 g daily it becomes possible 
to detect curcuminoids in urine (43). Human renal excretion remains poor even with 
increasing doses (46). It is unlikely that curcumin metabolism either effects or is affected by 
renal function. Adverse events due to curcumin relating to renal function have not been 
reported in any trial and there is some evidence that curcumin may even improve function in 
renal disease (47). 
 
1.2.6.4 Toxicity 
Toxicity or changes in body weight have not been seen in pre-clinical studies of long-term 
curcumin use (48) and (36). Little demonstrable toxicity is observed at in vivo doses of up to 
5 g/kg (35). No significant toxicities have been reported from almost 40 clinical trials 
involving over 800 participants. Patients have tolerated up to 8 g oral curcumin daily for 
three months (45) and escalation beyond this, although safely achievable, was limited by the 
volume of capsules necessary to deliver the dose. Side-effects are dose-related and typically 
gastrointestinal in origin, including loose stools, bloating, reflux and discomfort. Dose 
reduction usually leads to improvement. Trials consistently report curcumin has no effect on 
biochemical and haematological parameters during administration. There have been 
anecdotal reports of transient rises in liver enzymes although causality is unclear. 


 
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1.2.6.5 Dosing for pharmacological effect 
The relative instability, rapid metabolism and short plasma half-life present difficulties when 
establishing an appropriate dose for pharmacological effect. Determining a dose that is both 
tolerated and efficacious is challenging. Several trials have used oral regimens of 
approximately 4 g daily curcumin however in vivo reports imply a daily dose of 1.6 g in 
humans may be enough to exert a biological effect in the lumen, achieving a colonic mucosal 
concentration of 0.1 µmol/g (42). Pre-clinical data is difficult to extrapolate into a human 
dosing regimen. Other clinical studies have required 8 g orally (45) to achieve serum levels 
suggested by in vivo studies to be necessary for efficacy. However, an increase in dose may 
not equate to a proportional increase in systemic absorption (34). Detection of curcuminoids 
in hepatic tissue has been demonstrated in small amounts following 3.6 g per day for one 
week although not with lower doses (46). Trace levels are detected in human serum at doses 
of 2 g. Based on that which is necessary to furnish detectable levels of curcumin in serum, 
portal blood or hepatic tissue, it is possible that a dose in the region of 2–4 g is the minimum 
required to have pharmacological effect in organs distal to the gut (46).  
 
1.3  
Vitamin D3 
 
1.3.1 
Vitamin D and hematological malignancies 
Vitamin D is a fat-soluble vitamin that also acts as a pleiotropic hormone. There are two major 
forms of vitamin D. Vitamin D3 is normally produced in the skin after sun exposure and can also 
be acquired from diet. On the other hand vitamin D2 is only obtained exogenously. Very few 
foods in nature contain vitamin D but both vitamins D2 and D3 are used as dietary supplements 
in the United States. During exposure to solar ultraviolet B (UVB) radiation, 7-
dehydrocholesterol in the skin is converted to previtamin D3, which is immediately converted to 
vitamin D3, which is then converted to 25-hydroxycholecalciferol [25(OH)D3] in the liver by 
25-hydroxylase and consequently becomes its active form, 1,25-dihydroxycholecalciferol 
[1,25(OH)2D3], in the kidney by 1-α-hydroxylase; see figure-2 (49). The expression of the 
vitamin D receptor (VDR) in immune system cells as well as extrarenal expression of 1-α-
hydroxylase and 25-hydroxylase by macrophages, dendritic cells, B- and T-cells indicates 
autocrine and paracrine mechanisms by which 1,25(OH)2D3 production is regulated to exert its 
effects on the key players of the immune system (50).  
 


 
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Figure-2: Vitamin D metabolism in humans 
 
The discovery that vitamin D and its derivatives may have roles beyond the classical role of 
calcium absorption has led to a greater research focus on the use of vitamin D against various 
cancers. With epidemiological studies indicating that there is a significant correlation between 
vitamin D deficiency and the greater incidence of cancer (51), more evidence of the anti-tumor 
effects of vitamin D in various tissue types is being collected. An especially prominent focus in 
current literature regarding the use of vitamin D against hematological diseases is the study of 
acute leukemia and myelodysplastic syndrome through treatment of myeloid precursor cells. The 
application of vitamin D to treat other hematological malignancies, such as Hodgkin’s 
lymphoma, non-Hodgkin’s lymphoma, and myeloma, have been under research as well. The 
appeal of vitamin D in treatment against these neoplastic diseases stems from the fact that 
vitamin D appears to halt the proliferation and induce the maturation of hematopoietic precursor 
cells, indicating its ability to induce terminal differentiation in the neoplastic cells that 
characterize hematological malignancies as well. The biochemical mechanisms through which 
vitamin D and its derivatives exert their effects have certainly become a topic of interest due to 
the implication that treatments targeting these pathways can be developed to produce desirable 
results, both in vitro and in vivo (52). 
 
1.3.2 
Vitamin D activity in lymphoid malignancies 
With research indicating that vitamin D has anti-proliferative and pro-differentiation activities 
against cells possessing VDR, it is plausible that vitamin D can be used in therapy against other 
hematological malignancies, such as the lymphoid cancer types: Hodgkin’s lymphoma, non-
Hodgkin’s lymphoma, and myeloma. A correlation between ultraviolet light exposure and the 


 
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decreased risk for Hodgkin’s and non-Hodgkin’s lymphoma has elicited studies on the possible 
protective role of vitamin D against the development of these lymphoproliferative diseases. One 
epidemiological study discovered a relationship between the season of Hodgkin’s lymphoma 
diagnoses and the risk of death in patients, with the level of endogenous calcidiol considered to 
be a prognostic factor. Patients diagnosed with Hodgkin’s lymphoma (HL) in autumn were found 
to have a lower fatality risk than those diagnosed during the winter, with serum levels of 
calcidiol found to be higher during summer and autumn than winter (53). A similar relationship 
between UV exposure and non-Hodgkin’s lymphoma (NHL) has been reported in a separate 
epidemiological study, with lower risk of NHL associated with greater outdoor activity and sun 
exposure in warmer months (54). A statistical analysis of five different case-control studies led 
to the finding that greater sun exposure was found to significantly correlate with lower risk of 
both B and T cell lymphomas, although a decreasing risk for B cell lymphoma seemed to 
correlate more directly with greater sun exposure (55). Other efforts to discover an association 
between vitamin D levels and risk for NHL and HL include studies of serum levels and dietary 
intake of vitamin D. A study of fasting serum 25(OH)D levels revealed no significant 
relationship between circulating 25(OH)D and various lymphoid cancers, such as myeloma, HL, 
and NHL, but higher 25(OH)D did appear to have some protective effect against risk of NHL 
(56). The biochemical basis by which vitamin D could confer protection against Hodgkin’s and 
non-Hodgkin’s lymphoma was studied through examination of VDR polymorphisms in human 
populations. Single nucleotide polymorphisms in FokI, BsmI and TaqI restriction sites in the 
VDR gene were not found to have a clear relationship with risk for NHL and VDR 
polymorphism. However, the study did find certain Bsml and TaqI alleles to be associated with 
increased risk for diffuse large B-cell lymphoma and a FokI allele to be related to increased risk 
for T cell lymphoma, possibly due to decreased transactivation of VDR (57). Another study 
found no significant relationship between NHL risk and VDR polymorphisms, although 
relationships were seen with breast, skin, and prostate cancers (58). 
 
While the relationship between VDR polymorphism and lymphoid malignancies has not been 
firmly established, vitamin D has been found to exert anti-proliferative and differentiating effects 
on VDR-expressing lymphocytes and lymphocytic precursors. 1,25(OH)2D3 as well as its 
analog MC903, which has a higher affinity for VDR, have been used to treat B cell lines SU-
DHL4 and SU-DUL5 derived from high grade B-cell lymphoma. Results of this treatment 
include equal anti-proliferative effects seen in both cell lines by 1,25D and MC903, with 
terminal B-cell maturation indicated by the expression of markers B1, B4, and CD38 (59). 
Another study of vitamin D treatment on B-cells found that vitamin D suppressed proliferation 
and differentiation of activated B-cells while also inducing B-cell apoptosis. Up-regulation of 
transcription activity in B cells also led to greater expression of VDR, lymphocytic marker 
CD38, and cyclin kinase inhibitor p27Kip1(60). The effect of vitamin D on a malignant B-cell 
progenitor lineage as well as normal B and T progenitor cells was also revealed that 1,25D 
caused inhibition of clonal proliferation in malignant and normal lymphoid progenitor cells 
without any cytotoxic effects (61). The use of the vitamin D analog EB1089 on B cell 
progenitors has also proven to be anti-proliferative (62), as stated in the discussion on analog 
treatments. 1,25D was also found to be anti-proliferative in T cells by inhibiting transition from 
the early phase of G1 to late phase of G1 in the cell cycle; inhibition of IL-2 production was also 
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Thus, in consideration of the suppressing effect vitamin D exerts on malignant lymphoid cells, its 
use for treatment of lymphoid cancers seems to be a promising area of ongoing research. 
 
1.3.3 
Vitamin D and CLL 
Shanafelt and colleagues (63) evaluated the relationship of 25(OH)D serum levels with time-to-
treatment (TTT) and overall survival (OS) in newly diagnosed CLL patients participating in a 
prospective cohort study (discovery cohort) and a separate cohort of previously untreated 
patients participating in an observational study (confirmation cohort). Of 390 CLL patients in the 
discovery cohort, 119 (30.5%) were 25(OH)D insufficient. After a median follow-up of 3 years, 
TTT (hazard ratio[HR] = 1.66; P = .005) and OS (HR = 2.39; P = .01) were shorter for 
25(OH)D-insufficient patients. In the validation cohort, 61 of 153 patients (39.9%) were 
25(OH)D insufficient. After a median follow-up of 9.9 years, TTT (HR = 1.59; P = .05) and OS 
(HR 1.63; P = .06) were again shorter for 25(OH)D-insufficient patients. On pooled 
multivariable analysis of patients in both cohorts adjusting for age, sex, Rai stage, CD38 status, 
ZAP-70 status, immunoglobulin heavy chain variable (IGHV) gene mutation status, CD49d 
status, and cytogenetic abnormalities assessed by interphase fluorescent in situ hybridization 
testing, 25(OH)D insufficiency remained an independent predictor of TTT (HR = 1.47; P = 
.008), although the association with OS was not significant (HR = 1.47; P = .07) (63). There is 
also anecdotal evidence that consumption of dairy products with higher vitamin D levels 
decreases absolute lymphocyte counts in patients with CLL (64). 
 
1.3.4 Clinical Data to Date 
Amir et al reported the results of a A phase 2 trial exploring the effects of high-dose (10,000 
IU/day) vitamin D(3) in breast cancer patients with bone metastases. Forty patients were 
enrolled. No significant changes in bone resorption markers were seen. Despite no change in 
global pain scales, there was a significant reduction in the number of sites of pain. A small but 
statistically significant increase in serum calcium was seen, as was a significant decrease in 
serum parathyroid hormone (65). Most discussions of the role of vitamin D in cancer therapy 
express the concern that high-dose calcitriol is too toxic to be administered to patients with 
cancer. There are now many clinical studies that clearly establish that calcitriol can be safely 
administered in very high doses if an intermittent treatment schedule is used. Administration of 
oral calcitriol on a daily schedule (1.5–2.5 µg/d, weekly dose intensity ~10.5–17.5 µg/wk) is 
associated with a 20% to 30% frequency of hypercalcemia in men with PCa and in 
postmenopausal women.(66), (67), (68) and (69)  
 
1.3.3  Clinical Pharmacokinetics 
Calcitriol administered by mouth daily for 3 days every week (28 µg daily for 3 days) + 
dexamethasone (4 mg daily for 4 days) weekly is very safe and well tolerated in men with 
advanced prostate cancer. In 2 studies of patients with advanced prostate cancer, doses of 
calcitriol of 38 µg every day for 3 days weekly and 28 µg every day for 3 days monthly were 
safely administered together with paclitaxel and carboplatin, respectively (70). Fakih and 
colleagues (71) studied intravenous calcitriol (Calcijex, Roche Pharmaceutical Corporation) 
weekly + gefitinib and reported that very high doses of calcitriol can be administered safely. The 
dose-limiting toxicity of weekly intravenous calcitriol + gefitinib was grade 3 hypercalcemia at a 
dose of 98 µg/wk. The phase II dose of this regimen is 77 µg weekly alone and 98 µg/kg weekly 
when calcitriol is combined with high-dose dexamethasone.(71) and (72) The systemic exposure 


 
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of calcitriol following 98 µg is approximately 30 ng/h/24 h which is in the range of exposure we 
have reported in murine models in which calcitriol has clear-cut antitumor activity.(73). 
Beer and colleagues (74) have studied high-dose oral calcitriol (as Rocaltrol) and concluded that 
0.5 µg/kg, weekly is very safe. Studies with DN-101 demonstrated that 45 µg weekly was safe 
and well tolerated and that 165 µg given on week 1, followed by 45 µg weekly produced no 
toxicity.(75) A linear relationship between dose of DN-101 administered and area under the 
curve (AUC) was maintained up to 165 µg. Studies using an intermittent schedule of 
administration (weekly or every day for 3 days weekly) have encountered dose-limiting 
hypercalcemia only at doses 100 µg following intravenous administration; transient increase in 
serum calcium (11–13 mg/dL) does occur 1 to 3 days after completion of a single or daily for 3 
days schedule. However, only at doses achieving AUC more than ~30 ng/h/ml has dose-limiting 
hypercalcemia been encountered. Hypercalciuria is universal following administration of high-
dose calcitriol. Dietary calcium restriction is very difficult for patients to maintain and there is 
little evidence that it reduces hypercalciuria. There has been no deterioration of renal function in 
patients receiving high-dose intermittent calcitriol for more than 12 months. Radiographic 
monitoring for urinary tract stones (ultrasound or computed tomography) in our studies suggests 
that newly discovered urinary tract stones may occur in 1% to 3% of patients (69). 
 
1.4 
Rationale  
 
The rationale of this study is built upon the demonstrated safety and biologic activity of both 
curcumin and vitamin D3 in animal models and human studies. There is no evidence of 
overlapping toxicities between both agents. Both curcumin and vitamin D3 have demonstrated 
preclinical activities in CLL and there is preclinical data to suggest potential synergism between 
both agents: Mosieniak and colleagues have shown that curcumin overcomes the resistance of 
calcitriol-differentiated HL-60 cells, an acute promyelocytic leukemia cell line, to DNA-damage-
induced apoptosis by activating other cell signaling pathways leading to cell death of HL-60; 
such curcumin-induced cell death did not involve DNA-damage-initiated signaling pathways, to 
which differentiated HL-60 cells are highly resistant (76). Curcumin, in concentrations as low as 
50 µMol increased the expression of VDR in BCR-ABL driven B-ALL murine cells (23). Also, 
curcumin was shown to directly activate VDR in colon cancer cell lines to induced VDR target 
genes including CYP3A4, CYP24, p21 and TRPV6 (77). Since both curcumin and vitamin D3, 
and its analogues, seem to induce cell death through pathways that don’t require DNA damage, 
they have the potential to have clinical activity in 17p/TP53 deleted CLL; a disease that carries a 
bad prognosis because of resistance to conventional cytotoxic therapeutic agents (31). 
 
We hypothesize that curcumin-vitamin D3 combination would have a synergistic activity against 
CLL beyond each agent given alone. We hypothesize that this effect is likely related to curcumin 
upregulating intracellular VDR cells in CLL cells rendering them more susceptible to vitamin 
D3. We propose to use a curcumin daily dose of 8g as this is dose was shown to have biologic 
activity, modulation of NF-κB signaling, and steady state pharmacokinetics, and no toxic effects 
after up to 9 months of therapy (32, 33). We propose to use vitamin D3 daily dose of 10,000 IU 
as this dose has shown safety and biologic activity in clinical trials of patients with metastatic 
breast cancer (65). Despite more predictable pharmacokinetics of calcitriol, which made it the 
more preferred agent in clinical trials for metastatic prostate cancer, we elected to choose vitamin 
D3 as it has a lower risk for hypercalcemia (66), (67), (68) and (69). As the impact of early 


 
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treatment of CLL on survival remains uncertain, we felt that exposing patients to 20% risk of 
hypercalcemia with calcitriol therapy is unacceptable under the “do no harm” principle. We 
propose continuous treatment with both agents analogous to prior clinical trials with curcumin to 
start 1 week before vitamin D3; for the theoretical advantage of attaining serum steady state of 
curcumin and upregulating VDR levels in CLL cells making them more susceptible to vitamin 
D3. We propose an initial duration of treatment of 6 months followed up observation analogous 
to prior clinical interventions in early stage CLL (78) and analogous to the duration of traditional 
chemotherapy treatments for advanced CLL (79). At least 4 studies support the concept that 
maximal cutaneous synthesis of vitamin D (ie, full-body, maximal exposure to sunlight) can be 
equivalent to an oral vitamin D3 intake of 10,000 IU/day (80-83). Furthermore, a review of data 
from vitamin D supplementation studies reveals a dose-response curve for vitamin D that is 
relatively linear up to 10,000 IU of vitamin D3 per day, suggesting that this dose may be a 
physiologic upper limit (84).  
 
For more than 5 decades, chlorambucil was the standard first-line treatment for CLL and, 
historically, the overall response rate (ORR) to chlorambucil was 30%. Chlorambucil fell out of 
favor with the development of purine analogues in the early 1980 but remains an option for 
elderly frail symptomatic patients who cannot tolerate more forms of aggressive therapy (1). An 
ORR response rate of 30% had been considered a benchmark for development of CLL therapies 
after chlormabucil . We rationed that the curcumin/vitamin D3 combination would be worth 
further clinical development if we observe an ORR response of 30% or better (please refer to 
section 12.0 for description of response criteria). 
 
 
2.0  
OBJECTIVES 
 
To determine the efficacy, and tolerability, of curcumin and vitamin D3 combination in 
patients with early stage, untreated, chronic lymphocytic leukemia (CLL) or small 
lymphocytic lymphoma (SLL). 
 
2.1  
Primary Objective  
To determine the overall response rate (ORR) based on NCI-WG criteria in CLL or the Cheson 
criteria in SLL. Will also examine biologic response rate (78); defined as at least 20% reduction of 
absolute lymphocyte count (ALC) that is sustained over 2 months or a ≥ 30% reduction in palpable 
lymphadenopathy using this regimen. 
 
2.2 
Secondary Objective(s) 
To determine the Time to first cytotoxic treatment (TFCT), progression free survival (PFS), and 
Overall survival (OS) using this regimen. 
 
 
3.0  
STUDY DESIGN 
 
3.1  
Study design  
This is Case Comprehensive Cancer Center open label phase II trial.  
 


 
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3.2 
Number of Subjects 
We plan to enroll a maximum of 35 patients to obtain 29 evaluable patients (assuming a 20% 
dropout rate). 
3.3  
Replacement of Subjects  
All subjects who have received at least one dose of study agent, but have discontinued study 
agent prior to the first scheduled response assessment are evaluable for toxicity, but are not 
evaluable for study endpoints. Subjects need to have received at least 2 cycles of treatment to 
evaluable for response. Therefore, subjects who are not evaluable for study endpoints may be 
replaced.  
 
 
4.0 
PATIENT SELECTION 
Each of the criteria in the checklist that follows must be met in order for a patient to be 
considered eligible for this study.  Use the checklist to confirm a patient’s eligibility.  The 
checklist must be completed for each patient and must be signed and dated by the treating 
physician.   
 
Patient’s Name _____________________________________________________________ 
 
Medical Record # ___________________________________________________________ 
 
Research Nurse /  
Study Coordinator Signature: _________________________________ Date __________ 
 
Treating Physician [Print] ____________________________________________________ 
 
Treating Physician Signature:  ________________________________ Date __________ 
 
4.1 
Inclusion Criteria 
 
Patients must meet all of the following inclusion criteria to be eligible for enrollment:  
 
_____ 4.1.1 Have a diagnosis of CLL based on peripheral blood flow cytometry and/or 
bone marrow aspiration and biopsy OR diagnosis of SLL based on lymph node or 
bone marrow biopsy. Patients with SLL need to have measurable disease (see section 
12.2 for definition of measurable disease) 
 
_____ 4.1.2 Subject, age ≥ 18 years (children are excluded from this study as CLL/SLL 
being exceptionally rare) 
 
_____ 4.1.3 Performance Status (ECOG) 0-2 (see appendix A) 
 
 
ECOG PS = ______________ 
 
Date: ___________________ 
 
_____ 4.1.4 Patients must have not received any prior treatment for CLL or SLL. 
 


 
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_____ 4.1.5 Patients must be stage 0-II based on Rai staging system. Must have no 
indication for treatment for SLL per NCI-WG criteria (see appendix B) 
 
 
_____ 4.1.6 Adequate bone marrow, renal, and hepatic function, per local reference 
 
laboratory ranges as follows: 
 
_____ 4.1.6.1 Absolute neutrophil count (ANC) ≥ 1,500/mm3 
 
 
 
ANC= __________________ Date: ________________ 
 
_____ 4.1.6.2 Platelet count ≥ 100,000/mm3 
 
 
 
Platelets= __________________ Date: ________________ 
 
_____ 4.1.6.3 Hemoglobin ≥ 10 g/dL 
 
 
 
Hemoglobin= __________________ Date: ________________ 
 
_____ 4.1.6.4 Serum creatinine ≤ 2.0 g/dL or calculated creatinine clearance 
 
 
 
 (CrCl) ≥ 60mL/min (Cockcroft-Gault method) 
 
 
 
Creatinine= __________________ Date: ________________ 
 
 
 
         Crcl = __________________ Date: ________________ 
 
_____ 4.1.6.5 AST and ALT ≤ 2.5 x institutional upper limit of normal  
 
 
 
(ULN)  
 
 
 
AST= __________________ Date: ________________ 
 
 
 
ALT= __________________ Date: ________________ 
 
_____ 4.1.6.6 Bilirubin < 2.0 x ULN, unless subject has Gilbert’s disease  
 
 
 
Bilirubin= __________________ Date: ________________ 
 
_____ 4.1.6.7 Calcium <10.1 mg/dL (corrected to serum albumin as follows: 
Corrected Calcium = (0.8 x (4 - patient albumin)) + serum Ca  
 
Corrected calcium=___________ Date: ________________ 
 
_____ 4.1.7 Females will be either postmenopausal for at least 1 year or surgically sterile 
for at least 3 months OR Females of child-bearing potential must have a negative 
pregnancy test at screening and agree to take appropriate precautions to avoid 
pregnancy (double barrier method of birth control or abstinence) from screening 
through 3 months after the last dose of treatment   
 
_____ 4.1.8 Able to comprehend and willing to sign an Informed Consent Form (ICF) 
 
_____ 4.1.9 Subjects must be off any steroids 7 days prior to the initiation of treatment.  
 
_____ 4.1.10 Subjects must be off any curcumin, tumeric, or vitamin D supplements for 14 
days prior to the initiation of treatment. 
 
_____ 4.1.11 Subjects must be able to take oral medications 


 
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4.2 
Exclusion Criteria 
The presence of any of the following will exclude a patient from study enrollment. 
 
_____ 4.2.1 Presence of malignancy (other than the one treated in this study) which 
required systemic treatment within the past 3 years 
 
_____ 4.2.2 Any indication to start treatment for CLL based on NCI-WG criteria 
 
(see appendix B) 
 
_____ 4.2.3 Prior therapy for CLL/SLL 
 
_____ 4.2.4 Subjects who are pregnant or breast-feeding 
Pregnant or breastfeeding women are excluded from this study because the safety of 
curcumin had not been established with pregnancy and is unknown. Because there is 
an unknown, but potential risk for adverse events in nursing infants secondary to 
treatment of the mother with curcumin, breastfeeding should be discontinued if the 
mother is treated with curcumin.   
 
_____ 4.2.5 Concurrent medical condition which may increase the risk of toxicity, 
including: 
 
_____ 4.2.5.1 Hypercalcemia of any cause 
_____ 4.2.5.2 Untreated hyperparathyroidism 
_____ 4.2.5.3 Paget’s disease of bone 
 
_____ 4.2.6 Uncontrolled intercurrent illness including, but not limited to, ongoing active 
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia, or psychiatric illness/social situation that would limit compliance with 
study requirements as judged by treating physician; subjects receiving antibiotics that 
are under control  may be included in the study 
 
_____ 4.2.7 Inability to take oral medications. 
 
_____ 4.2.8 Patients receiving other investigational agent 
 
_____ 4.2.9 History of allergic reactions attributed to compounds of similar chemical or 
biologic composition to curcumin or vitamin D or other agents used in this study. 
 
_____ 4.2.10 Patients on therapeutic anticoagulation, with heparin (or low-molecular weight 
heparin), warfarin, or a direct thrombin inhibitor as the safety of concurrent 
administration of curcumin has not been established 
 


 
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_____ 
4.2.11 HIV-positive patients on combination antiretroviral therapy are ineligible 
because of the potential for pharmacokinetic interactions with curcumin.   
 
 
 
4.3 
Inclusion of Women and Minorities   
Both men and members of all races and ethnic groups are eligible for this trial. 
 
 
5.0 
REGISTRATION  
All subjects who have been consented are to be registered in the OnCore Database. For those 
subjects who are consented, but not enrolled, the reason for exclusion must be recorded. 
 
All subjects will be registered through University Hospitals Cleveland Medical Center and 
will be provided a study number. 
 
 
6.0  
TREATMENT PLAN 
Patients will take both Curcumin and Vitamin D3 for 6 cycles (cycle = 28 days).   
 
Patients who sustained a partial response (PR) or better can elect to extend therapy for 
a total of 2 years.  
 
6.1 
Agent Administration 
As both agents are well-tolerated with no expected grade 3-4 toxicities, dose modifications 
are as outlined in section 7.0. Reported adverse events and potential risks of curcumin and 
vitamin D3 are described in Section 8.0. No investigational or commercial agents or 
therapies other than those described below may be administered with the intent to treat the 
patient's malignancy. 
 
 
TREATMENT REGIMEN DESCRIPTION 
 
Agent 
 
 
Dose 
 
Route 
 
Schedule 
 
Cycle Length 
 
Curcumin 
 
 8 grams 
 
PO 
 
daily  
 
 
 
 
 
28 day (continuous 
treatment) 
 
Vitamin D3 
 
10,000 IU 
 
PO 
 
Daily starting on D8 of 
cycle 1 and on D1 on all 
subsequent cycles 
 
The patient will be provided a Patient Pill Diary [Appendix C and D] and instructed in its 
use to record each dose of oral medication.   
 
6.1.1 Curcumin Administration 


 
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Patients will take Curcumin 8 grams/day orally with food continuously.  Patients will be 
provided a Patient Pill Diary (Appendix C and D) and instructed in its use to record each 
dose of oral medication. Curcumin can be administered with other medications.  
 
 
 
6.1.2 Vitamin D3 Administration 
Patients will take vitamin D3 10,000 IU/day orally with food continuously.   For cycle 1, 
vitamin D3 will start 1 week after curcumin (on D8) only with initiation of treatment and will 
be given with curcumin continuously there after. Patients will be provided a Patient Pill 
Diary (Appendix C and D) and instructed in its use to record each dose of oral medication. 
Vitamin D3 can be administered with other medications.. 
 
6.2 
General Concomitant Medications and Supportive Care Guidelines 
Because there is a potential for interaction of curcumin with other concomitantly administered 
drugs through the cytochrome P450 system, the case report form must capture the concurrent use 
of all other drugs, over-the-counter medications, or alternative therapies. The Principal 
Investigator should be alerted if the patient is taking any agent known to affect or with the 
potential to affect CYP1A2 and CYP2A6 activity (85). Please refer to Appendix E-F for a 
complete list.   
 
As patients with early stage CLL/SLL are frequently asymptomatic, have no significant 
cytopenias at baseline, and as both high dose vitamin D3 and curcumin were both well tolerated 
in clinical trials, we don’t expect that study subjects will need supportive care. 
 
6.3  
Duration of Therapy 
In the absence of treatment delays due to adverse events, which are not generally expected, 
treatment may continue for 6 cycles  [or can be extended for a total of 2 years if sustained a 
partial response (PR) or better] until one of the following criteria applies: 
 
• Disease progression, 
• Intercurrent illness that prevents further administration of treatment, 
• The investigator considers it, for safety reasons, to be in the best interest of the 
patient.  
• Unacceptable treatment related toxicity, NCI CTC AE version 4.0. Grade 3 or 4 that 
fails to recover to baseline or < Grade 3 in the absence of treatment within 4 weeks]  
• General or specific changes in the patient’s condition render the patient unacceptable 
for further treatment in the judgment of the investigator,  
• Patient decision to withdraw from treatment (partial consent) or from the study (full 
consent), 
• Pregnancy during the course of the study for a child-bearing participant 
• Death 


 
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The date and reason for discontinuation must be documented.  Every effort should be 
made to complete the appropriate assessments.  
 
6.4 
Duration of Follow Up 
 
30-Day Follow-Up: Patients will be followed for toxicity for 30 days after treatment has 
been discontinued or until death, whichever occurs first.  
 
Long term Follow-Up: Patients will be followed, every 3-6 months (as clinically indicated), 
for 2 years after discontinuation of study medications for long-term outcomes. 
 
The clinical course of each event will be followed until resolution, stabilization, or until it 
has been determined that the study treatment or participation is not the cause.  
 
Serious adverse events that are still ongoing at the end of the study period will necessitate 
follow-up to determine the final outcome. Any serious adverse event that occurs after the 
study period and is considered to be possibly related to the study treatment or study 
participation will be recorded and reported immediately. 
 
 
7.0   
DOSING DELAYS / DOSE MODIFICATIONS 
As both agents are well-tolerated with no expected grade 3-4 toxicities, no dose 
modifications are planned for this study. No hematological toxicities are expected with either 
agent. 
 
Event 
Name 
Nausea and/or vomiting 
Grade of 
Event 
Management/Next 
Dose for curcumin 
Management/Next 
Dose for vitamin D3 
≤ Grade 1 
No change in dose 
No change in dose 
Grade 2 
Hold until ≤ Grade 1.  
Resume at same dose 
level. 
Hold until ≤ Grade 1.  
Resume at same dose 
level. 
Grade 3 
Off protocol therapy 
Hold * until < Grade 
Off protocol therapy 
Grade 4 
Off protocol therapy 
Off protocol therapy 
*Patients requiring a delay of >2 weeks should go off protocol therapy. 
Recommended management:  anti-emetics. 
 
 
Event 
Name 
Diarrhea 
Grade of 
Event 
Management/Next 
Dose for curcumin 
Management/Next 
Dose for vitamin D3 


 
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≤ Grade 1 
No change in dose 
No change in dose 
Grade 2 
Hold until ≤ Grade 1.  
Resume at same dose 
level. 
Hold until ≤ Grade 1.  
Resume at same dose 
level. 
Grade 3 
Decrease the dose to 
4 g PO daily 
Off protocol therapy 
Grade 4 
Off protocol therapy 
Off protocol therapy 
*Patients requiring a delay of >2 weeks should go off protocol therapy. 
Recommended management:  Loperamide antidiarrheal therapy 
Dosage schedule:  4 mg at first onset, followed by 2 mg with each loose 
motion until diarrhea-free for 12 hours (maximum dosage:  16 mg/24 
hours) 
Adjunct anti-diarrheal therapy is permitted and should be recorded when 
used. 
 
Event 
Name 
Hypercalcemia 
Grade of 
Event 
Management/Next 
Dose for curcumin 
Management/Next 
Dose for vitamin D3 
≤ Grade 1 
No change in dose 
No change in dose 
Grade 2 
Hold until ≤ Grade 1.  
Resume at same dose 
level. 
Hold until ≤ Grade 1.  
Resume at same dose 
level. 
Grade 3 
Off protocol therapy 
Off protocol therapy 
Grade 4 
Off protocol therapy 
Off protocol therapy 
*Patients requiring a delay of >2 weeks should go off protocol therapy. 
Recommended management:  workup for hypercalcemia as per standard 
of care 
 
Event 
Name 
Other Unexpected toxicity 
Grade of 
Event 
Management/Next 
Dose for curcumin 
Management/Next 
Dose for vitamin D3 
≤ Grade 1 
No change in dose 
No change in dose 
Grade 2 
Hold until ≤ Grade 1.  
Resume at same dose 
level. 
Hold until ≤ Grade 1.  
Resume at same dose 
level. 
Grade 3 
Off protocol therapy 
Off protocol therapy 
Grade 4 
Off protocol therapy 
Off protocol therapy 
*Patients requiring a delay of >2 weeks should go off protocol therapy. 
Recommended management:  per standard of care 
 
8.0 
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS 
The following is a list of AEs (Section 8.1) and the reporting requirements associated with 
observed AEs (Sections 8.3 and 8.4).  


 
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The clinical course of each event will be followed until resolution, stabilization, or until it has 
been determined that the study treatment or participation is not the cause.  
 
Serious adverse events that are still ongoing at the end of the study period will necessitate 
follow-up to determine the final outcome. Any serious adverse event that occurs after the study 
period and is considered to be possibly related to the study treatment or study participation will 
be recorded and reported immediately. 
8.1 
Adverse Events and Potential Risks  
 
8.1.1 Curcumin 
The most common side effects (occurs in more than 10 of 100 people) reported in clinical 
trials are: 
• mild nausea 
• vomiting 
• diarrhea 
• reflux 
• bloating 
 
All resolved with discontinuation of therapy. 
 
8.1.1 Vitamin D3 
Vitamin D3 is well-tolerated and no serious AEs are expected.  
 
A rare side effect that may be expected (occurs in less than 1 of 100 people) is:  
 
• Hypercalcemia is unusual but is recognized AEs of high-dose vitamin D3 therapy 
especially in individuals with unrecognized hyperparathyroidism. Hypercalcemia 
related to vitamin D3 resolves with discontinuation of therapy. Typical symptoms of 
hypercalcemia include poor appetite, nausea and vomiting, abdominal pain, 
generalized weakness, and frequent urination. If we observe calcium level greater 
than 11 mg/dL, corrected to serum albumin by as follows: corrected calcium = (0.8 x 
(4 - patient albumin)) + serum Ca, we plan to hold vitamin D3 and order vitamin D 
25(OH) level in the clinical lab to establish such diagnosis. It is generally accepted 
that vitamin D 25(OH) levels greater than 80 ng/ml are considered toxic but the level 
on itself doesn't establish toxicity in the absence of hypercalcemia. 
 
8.2 
Definitions  
 
8.2.1 
Adverse Events   
An adverse event (AE) is any unfavorable or unintended event, physical or psychological, 
associated with a research study, which causes harm or injury to a research participant as a result 
of the participant’s involvement in a research study. The event can include abnormal laboratory 
findings, symptoms, or disease associated with the research study. The event does not necessarily 


 
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have to have a causal relationship with the research, any risk associated with the research, the 
research intervention, or the research assessments.  
 
Adverse events may be the result of the interventions and interactions used in the research; 
the collection of identifiable private information in the research; an underlying disease, 
disorder, or condition of the subject; and/or other circumstances unrelated to the research or 
any underlying disease, disorder, or condition of the subject. In general, adverse events that 
are at least partially the result of (a) or (b) would be considered related to the research, 
whereas adverse events solely related to (c) or (d) would be considered unrelated to the 
research.  
 
8.2.2 The significance of an adverse event is used to describe the patient/event outcome or 
action criteria associated with events that pose a threat to a patient’s life or functioning (i.e., 
moderate, severe or life threatening).  Based on the National Cancer Institute Guidelines for 
the Cancer Therapy Evaluation Program, severity can be defined by the following grades of 
events: 
 
Grades 1 are mild adverse events. (e.g., minor event requiring no specific medical 
intervention; asymptomatic laboratory findings only; marginal clinical relevance) 
 
Grades 2 are moderate adverse events (e.g., minimal intervention; local intervention; 
non-invasive intervention; transfusion; elective interventional radiological procedure; 
therapeutic endoscopy or operation). 
 
Grades 3 are severe and undesirable adverse events (e.g., significant symptoms 
requiring hospitalization or invasive intervention; transfusion; elective interventional 
radiological procedure; therapeutic endoscopy or operation). 
 
Grades 4 are life threatening or disabling adverse events (e.g., complicated by acute, 
life-threatening metabolic or cardiovascular complications such as circulatory failure, 
hemorrhage, sepsis; life–threatening physiologic consequences; need for intensive 
care or emergent invasive procedure; emergent interventional radiological procedure, 
therapeutic endoscopy or operation). 
 
Grades 5 are fatal adverse event resulting in death.     
 
8.2.3   Serious Adverse Events  
A serious adverse event (SAE) is any adverse experience occurring at any dose that results 
in any of the following outcomes:  
• Results in death.  
• Is a life-threatening adverse experience.  The term life-threatening in the definition 
of serious refers to an adverse event in which the subject was at risk of death at the 
time of the event.  It does not refer to an adverse event which hypothetically might 
have caused death if it were more severe.  


 
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• Requires inpatient hospitalization or prolongation of existing hospitalization.  
Any adverse event leading to hospitalization or prolongation of hospitalization will be 
considered as Serious, UNLESS at least one of the following expectations is met: 
o The admission results in a hospital stay of less than 12 hours OR 
o The admission is pre-planned (i.e., elective or scheduled surgery arranged 
prior to the start of the study) OR 
o The admission is not associated with an adverse event (e.g., social 
hospitalization for purposes of respite care. 
However it should be noted that invasive treatment during any hospitalization may 
fulfill the criteria of “medically important” and as such may be reportable as a serious 
adverse event dependant on clinical judgment.  In addition where local regulatory 
authorities specifically require a more stringent definition, the local regulation takes 
precedent.  
• Results in persistent or significant disability/incapacity.  The definition of 
disability is a substantial disruption of a person’s ability to conduct normal life’s 
functions. 
• Is a congenital anomaly/birth defect.  
• Is an important medical event.  Important medical events that may not result death, 
be life-threatening, or require hospitalization may be considered a serious adverse 
experience when, based upon appropriate medical judgment, they may jeopardize the 
patient or subject and may require medical or surgical intervention to prevent one of 
the outcomes listed in this definition.  Examples of such medical events include 
allergic bronchospasm requiring intensive treatment in an emergency room or at 
home, blood disease or disorders, or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse. 
 
8.2.4 Expectedness 
Adverse Events can be Expected or Unexpected. 
 
An expected adverse event is an event previously known or anticipated to result from 
participation in the research study or any underlying disease, disorder, or condition of the 
subject. The event is usually listed in the Investigator Brochure, consent form or research 
protocol.  
 
An unexpected adverse event is an adverse event not previously known or anticipated to result 
from the research study or any underlying disease, disorder, or condition of the subject.  
 
8.2.5 Attribution 
Attribution is the relationship between an adverse event or serious adverse event and the study 
drug.  Attribution will be assigned as follows: 


 
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• Definite – The AE is clearly related to the study drug. 
• Probable – The AE is likely related to the study drug. 
• Possible – The AE may be related to the study drug. 
• Unlikely – The AE is doubtfully related to the study drug. 
• Unrelated – The AE is clearly NOT related to the study drug. 
 
8.3  
Reporting Procedures for All Adverse Events 
 
All participating investigators will assess the occurrence of AEs throughout the subject’s 
participation in the study.  Subjects will be followed for toxicity for 30 days after treatment has 
been discontinued or until death, whichever occurs first.  The clinical course of each event will 
be followed until resolution, stabilization, or until it has been determined that the study treatment 
or participation is not the cause.   
 
The investigator is responsible for ensuring that all adverse events observed by the investigator 
or reported by the subject which occur after the subject has signed the informed consent are fully 
recorded in the subject’s case report form, subject’s medical records, and/or any other 
institutional requirement. Source documentation must be available to support all adverse events.  
 
A laboratory test abnormality considered clinically relevant (e.g., causing the subject to 
withdraw from the study), requiring treatment or causing apparent clinical manifestations, or 
judged relevant by the investigator, should be reported as an adverse event.   
The investigator will provide the following for all adverse events: 
• Description of the event 
• Date of onset and resolution 
• Grade of toxicity  
• Attribution of relatedness to the investigational agent 
• Action taken as a result of the event 
• Outcome of event 
 
In this study, descriptions and grading scales found in the NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.0 available at http://ctep.cancer.gov will be utilized for 
AE reporting.  
 
8.4  
Serious Adverse Event Reporting Procedures 
 
8.4.1 Reporting 
Serious adverse events that occur, beginning with the signing of the informed consent form, 
during treatment, or within 30 days of the last dose of treatment must be reported to Paolo 
Caimi, MD (Principal Investigator). 
 
8.4.2 FDA Reporting 
The University Hospitals Principal Investigator, Paolo Caimi, M.D., as holder of the IND, will 
be responsible for all communication with the FDA.  In accordance with 21 CFR 312.32, the 


 
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University Hospitals Principal Investigator is responsible for notifying the FDA of SAEs that are 
serious, unexpected (not listed in the Investigator Brochure) and judged to be related (i.e., 
possible, probable, definite) to the study drug.  Events meeting the following criteria need to be 
submitted to the FDA as Expedited IND Safety Reports.    
 
7 Calendar Day IND Safety Report 
Any unexpected fatal or life-threatening suspected adverse event represent especially important 
safety information and, therefore, must be reported more rapidly to FDA (21 CFR 312.32(c)(2)).  
Any unexpected fatal or life-threatening suspected adverse event must be reported to FDA no 
later than 7 calendar days after the University Hospitals Principal Investigator initial receipt of 
the information (21 CFR 312.32(c)(2)).  University Hospitals Principal Investigator will 
complete a Medwatch Form FDA 3500A and notify the FDA by telephone or facsimile 
transmission. 
 
15 Calendar Day IND Safety Report 
The timeframe for submitting an IND safety report to FDA and all participating investigators is 
no later than 15 calendar days after the University Hospitals Principal Investigator determines 
that the suspected adverse event or other information qualifies for reporting (21 CFR 
312.32(c)(1)).  This includes any serious, unexpected adverse events considered reasonably or 
possibly related to the investigational agent.  University Hospitals Principal Investigator will 
complete a Medwatch Form FDA 3500A and notify the FDA by telephone or facsimile 
transmission.  If FDA requests any additional data or information, the University Hospitals 
Principal Investigator must submit it to FDA as soon as possible, but no later than 15 calendar 
days after receiving the request (21 CFR 312.32(c)(1)(v)).    
 
Follow-up IND Safety Report 
Any relevant additional information that the University Hospitals Principal Investigator obtains 
that pertains to a previously submitted IND safety report must be submitted to FDA as a Follow-
up IND Safety Report without delay, as soon as the information is available (21 CFR 
312.32(d)(2)).  The University Hospitals Principal Investigator will maintain records of its efforts 
to obtain additional information. 
 
 
 
 
IND Annual Reports 
IND Annual Reports 
 
 
 
 
IND Annual Reports 
A summary of all IND safety reports submitting during the previous year will be reported to the 
FDA in the annual report by the University Hospitals Principal investigator, as holder of the 
IND. 
 
Reporting Serious Problems to FDA 
Medwatch Form FDA 3500A: 
http://www.fda.gov/Safety/MedWatch/HowToReport/DownloadForms/default.htm 
Telephone: 1-800-332-1088 
Fax: 1-800-FDA-0178 
 


 
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8.5  
Data Safety Toxicity Committee 
It is the Case Comprehensive Cancer Center’s Principal Investigator’s responsibility to ensure 
that ALL serious adverse events are reported to the Case Comprehensive Cancer Center’s Data 
Safety Toxicity Committee. This submission is simultaneous with their submission to the 
Sponsor or other Regulatory body.  
 
 
9.0 
 
PHARMACEUTICAL INFORMATION    
 
A list of the adverse events and potential risks associated with the investigational or 
commercial agents administered in this study can be found in Section 8.0.   Both curcumin 
and vitamin D3 are available commercially as food supplements; both of which will be 
provided to study subjects free of charge. 
 
 
9.1    Curcumin 
 Chemical Name:  (1E,6E)-1,7-Bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-
3,5-dione  
 
Other Names:  iferuloylmethane; C.I. 75300; Natural Yellow 3 
 
Classification:  Polyphenol 
 
Molecular Formula:  C21H20O6 
 
 
Mode of Action:  Affects multiple and complex pathways but the main mode of 
action is interference with activity of the transcription 
factor NF-κB 
 
Metabolism:  In the gastrointestinal tract and liver. 
 
Product description:  Curcumin will be provided as 1g tablets (tablet size 20 x 7 x 7 
mm).  
 
Storage requirements:  Tablets can be stored at room temperature. 
 
Stability:   Tablets are stable at room temperature. 
 
Route of administration:  A total of 8 tablets (total dose 8g) would be given by 
mouth daily without regard to food intake. 
 
Drug Procurement:  Pharmaceutical grade curcumin will be provided by from 
Sabinsa Corporation (contact information below) free of charge.  
 
Dr. Kalyanam Nagabhushanam Ph.D., 
President (R&D) 


 
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SABINSA CORPORATION 
20 Lake Drive  
East Windsor, NJ 08520 
Ph: 732-777-1111 Ext 35 
www.sabinsa.com 
email: kalyanam@sabinsa.com 
Drug will be distributed to study subjects through investigational drug services. 
 
Drug Accountability: The investigator or designated study personnel are responsible for 
maintaining accurate dispensing records of the study drug.  All study drugs must be accounted 
for, including study drug accidentally or deliberately destroyed.  Under no circumstances will the 
investigator allow the investigational drug to be used other than as directed by the protocol.  If 
appropriate, drug storage, drug dispensing, and drug accountability may be delegated to the 
pharmacy section of the investigative site.   
 
Drug Destruction: At the completion of the study, there will be a final reconciliation of drug 
shipped, drug consumed, and drug remaining. This reconciliation will be logged on the drug 
reconciliation form, signed and dated. Any discrepancies noted will be investigated, resolved, and 
documented prior to return or destruction of unused study drug. Drug destroyed on site will be 
documented in the study files. 
 
9.2    Vitamin D3 
Chemical Name:  (3β,5Z,7E)-9,10-secocholesta-5,7,10(19)-trien-3-ol 
 
Other Names:  Cholecalciferol, activated 7-dehydrocholesterol. 
 
Classification:  Steroid 
 
Molecular Formula:  C27H44O 
 
 
Mode of Action:  Calcitriol, activated form of vitamin D3, binds to VDR in the nucleus 
andaffects multiple pathways to inhibit cellular proliferation among other mechanisms.  
 
Metabolism:  In the liver and kidneys.  
 
Product description:  Pharmaceutical grade vitamin D3 is commercially available from 
multiple vendors as 2000, 5000, or 10,000 IU tablets or capsules. 
 
Storage requirements:  Tablets can be stored at room temperature. 
 
Stability:  Tablets are stable at room temperature. Vitamin D3 is very sensitive to UV light 
and will be dispensed in appropriate UV-light blocking containers.  
 


 
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Route of administration:  A total of 10,000 IU would be given by mouth daily without 
regard to food intake. 
 
Drug Procurement:  Pharmaceutical grade vitamin D3 will be obtained from a commercial 
vendor (as tablets or capsules). A single batch will be purchased and provided to study 
subjects free of charge. Drug will be dispensed to study subjects through investigational 
pharmacy . 
 
For vitamin D 
Dr James Grote 
BTR Group, Inc.  
PO Box 501  
Pittsfield, Il. 62363  
FAX (217) 285-6454 
Phone  (217) 320-1594 
Email grotejames@hotmail.com 
http://www.vitd3.com/healthcare_professionals.php 
 
Drug Accountability: The investigator or designated study personnel are responsible for 
maintaining accurate dispensing records of the study drug.  All study drugs must be accounted 
for, including study drug accidentally or deliberately destroyed.  Under no circumstances will the 
investigator allow the investigational drug to be used other than as directed by the protocol.  If 
appropriate, drug storage, drug dispensing, and drug accountability may be delegated to the 
pharmacy section of the investigative site.   
 
Drug Destruction: At the completion of the study, there will be a final reconciliation of drug 
shipped, drug consumed, and drug remaining. This reconciliation will be logged on the drug 
reconciliation form, signed and dated. Any discrepancies noted will be investigated, resolved, and 
documented prior to return or destruction of unused study drug. Drug destroyed on site will be 
documented in the study files. 
 
 
10.0 CORRELATIVE / SPECIAL STUDIES 
All correlative studies are mandatory. 
 
10.1 
Vitamin D receptor expression in CLL cells 
The purpose of this correlative study is to measure intracellular vitamin D receptor (VDR) 
levels in CLL cells compared to normal T-cells. There is preclinical evidence that curcumin 
increases intracellular VDR cells in clonal lymphoid cells (23). 
 
10.1.1 Background  
We hypothesize that the synergistic effect of curcumin and vitamin D3 on CLL cells is due to 
increased intracellular VDR levels with curcumin pretreatment (23). 
 
10.1.2   Rationale for Analysis 


 
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We plan to assess VDR at baseline and on D8, after 1 week of treatment with curcumin, and 
prior to starting vitamin D3 treatment to prove this. Quantitative intracellular measurement of 
VDR by flow cytometry, in peripheral blood mononuclear cells, has been performed, and 
validated, by other investigators before (86). The purpose of this analysis is exploratory/proof 
of concept. Subjects with SLL with no peripheral blood lymphocytosis will be excluded from 
this analysis. 
 
10.1.3   Collection of Specimens 
About 4-5 ml of blood will be drawn into 1 green-topped tube (containing heparin).  The tube 
will be kept at ambient temperature and will be delivered to the TRPC laboratory within 3 
hours of venipuncture. Blood samples will be drawn at the following 3 times points:  
 
1.  Cycle 1, Day 1: 
pre treatment 
2.  Cycle 1, Day 8: 
prior to starting vitamin D3 
3.  Cycle 2, Day 1: 
after treatment with both curcumin and vitamin D3  
 
10.1.4 
Handling of Specimens  
All specimens are to be shipped to the TRPC at the address below.   
 
Translational Research & Pharmacology Core 
ATTN  Erin Hohler 
University Hospitals of Cleveland 
11100 Euclid Avenue 
Seidman Cancer Center, Room 3608 
Cleveland, OH 44106 
Telephone: 216-286-3889/216-386-3890 
Fax: 216-286-5772 
Pager: 33471 
E-mail: emh14@case.edu 
 
TRPC Personnel will log the specimen information into the OnCore database and de-identify 
the specimen using a code specific for this trial.  
 
PBMCs will be isolated by standard Ficoll-Hypaque methods, counted and re-suspended in 
90% fetal bovine serum, 10% DMSO at 10 million cells/ml. Cells will be aliquoted into 3 
equal portions into cryopreservation tubes and labeled with identifier, cell number, and 
volume. Cells will be frozen using a controlled rate freezing container and stored at -70 C (in 
liquid nitrogen) until analyzed.   
 
Specimens will be transported to the Case Comprehensive Cancer Center Cytometry Core 
Facility Laboratory for analysis upon request of the Principle Investigator.  
 
If the sample is collected at an outside laboratory then it should be transported at room 
temperature as soon as possible to the TRPC by the rapid hospital courier service.   
 
10.1.5  
Analytical Laboratory 


 
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The specimens will be analyzed in the Case Comprehensive Cancer Center Cytometry Core 
Facility, under the direction of Dr. James Jacobberger. Dr. Jacobberger will provide overall 
guidance on experimental design and interpretation of results. Personnel in the Cytometry 
Core Facility will perform all staining, cytometry and analysis. 
 
Case Comprehensive Cancer Center Cytometry Core Facility 
2103 Cornell Rd, WRB-3517 
Cleveland, OH 44106  
 
Contact: R. Michael Sramkoski 
Telephone: (216)368-1021 
Email: rms19@case.edu 
10.1.6   Correlative Methods  
Cells will be rapidly thawed and re-suspended in FBS. 
 
Cells will be processed and stained using the Woost modifications of the Chow protocol 
without methanol. 
  
Surface staining for CD19 will be performed to identify CLL cells. (86).  
 
Cells will be analyzed using the following antibodies: 
 
1. Vitamin D receptor: Cell Signaling Technology #12550 (Rabbit mab D2K6W) 
2.  PE-CD3 
3.  PerCp or V500-CD19 
4.  PerCp or Krome Orange CD45 
 
10.2 
Pharmacodynamic analysis of NF-κB and bcl-2 in CLL cells  
 
10.2.1 
Background 
The purpose of this study is to evaluate the effect of curcumin and curcumin/vitamin D 
combination on NF-κB signaling in CLL cells. NF-κB is the main target of curcumin in 
cancer cells and curcumin was shown to downregulate NF-κB levels in CLL cells (25-28). 
Both curcumin and vitamin D3 were shown to induce apoptosis in CLL cell lines.  The 
purpose of this analysis is exploratory/proof of concept. 
 
10.2.2.   Rationale for Analysis  
Inhibition of NF-κB signaling was validated as a pharmacodynamic endpoint for curcumin 
treatment in prior clinical investigations (32). Bcl-2 is a master regulator of apoptosis in CLL 
cells (87) and would be of interest to quantitate bcl-2 expression with curcumin +/- vitamin 
D3 treatment as both agents may be synergistic in inducing apoptosis in CLL cells. Curcumin 
and 1,25-dihydroxyvitamin D3  were already shown to downregulate bcl-2 in other cellular 
systems leading to apoptosis (88-90). Quantitative intracellular measurement of NF-κB and 
bcl-2 by flow cytometry, in peripheral blood mononuclear cells, has been performed and 
validated by other investigators before (91, 92). This purpose of this analysis is 


 
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exploratory/proof of concept. Subjects with SLL with no peripheral blood lymphocytosis will 
be excluded from this analysis. 
 
10.2.3   Collection of Specimens 
About 4-5 ml of blood will be drawn into 1 green-topped tube (containing heparin).  The tube 
will be kept at ambient temperature and will be delivered to the TRPC laboratory within 3 
hours of venipuncture. Blood samples will be drawn at the following 3 times points:  
 
1.  Cycle 1, Day 1: 
pre treatment 
2.  Cycle 1, Day 8: 
prior to starting vitamin D3 
3.  Cycle 2, Day 1: 
after treatment with both curcumin and vitamin D3  
 
10.1.4 
Handling of Specimens  
All specimens are to be shipped to the TRPC at the address below.   
 
 
Translational Research & Pharmacology Core 
ATTN  Erin Hohler 
University Hospitals of Cleveland 
11100 Euclid Avenue 
Seidman Cancer Center, Room 3608 
Cleveland, OH 44106 
Telephone: 216-286-3889/216-386-3890 
Fax: 216-286-5772 
Pager: 33471 
E-mail: emh14@case.edu 
 
TRPC Personnel will log the specimen information into the OnCore database and de-identify 
the specimen using a code specific for this trial.  
 
PBMCs will be isolated by standard Ficoll-Hypaque methods, counted and re-suspended in 
90% fetal bovine serum, 10% DMSO at 10 million cells/ml. Cells will be frozen using a 
controlled rate freezing container and stored at -70 C until analysis.   
 
Specimens will be transported to the Case Comprehensive Cancer Center Cytometry Core 
Facility Laboratory for analysis upon request of the Principle Investigator.  
 
If the sample is collected at an outside laboratory then it should be transported at room 
temperature as soon as possible to the TRPC by the rapid hospital courier service.   
 
10.1.5  
Analytical Laboratory 
The specimens will be analyzed in the Case Comprehensive Cancer Center Cytometry Core 
Facility, under the direction of Dr. James Jacobberger. Dr. Jacobberger will provide overall 
guidance on experimental design and interpretation of results. Personnel in the Cytometry 
Core Facility will perform all staining, cytometry and analysis. 
 


 
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Case Comprehensive Cancer Center Cytometry Core Facility 
2103 Cornell Rd, WRB-3517 
Cleveland, OH 44106  
 
Contact: R. Michael Sramkoski 
Telephone: (216)368-1021 
Email: rms19@case.edu 
 
10.1.6   Correlative Methods  
Cells will be rapidly thawed and re-suspended in FBS. 
 
Cells will be processed and stained using the Woost modifications of the Chow protocol 
without methanol (93) 
Surface staining for CD19 will be performed to identify CLL cells. (86).  
  
Cells will be washed then analyzed by flow cytometer for quantitative estimation of for 
intracellular NF-κB and bcl-2 (91, 92).  
 
Cells will be analyzed using the following antibodies: 
 
1.  NF-kB, Depending on assay need: 
a.  Biolegend 616704 (A488 mouse mab) for p50 
b.  CST #4886 (A488 rabbit mab) for phospho-S536-p65 
c.  BD Biosci #558421 (A488 mouse mab) for phospho-S529-p65 
d.  BD Biosci #610868 (mouse mab) for p65  
2. Bcl2: Depending on assay: 
a. BD Biosci #610539 (mouse mab, clone 7) 
b. BD Biosci #560637 (V450 mouse mab, clone 100) 
c. Biolegend #BCL/10C4 (A647 mouse mab, clone 10C4) 
 
3.  PE-CD3 
4.  PerCp or V500-CD19 
5.  PerCp or Krome Orange CD45 
 
10.3 
Curcumin and vitamin D3 pharmacokinetics 
 The purpose of this study is to measure standard pharmacokinetic parameters of curcumin 
and vitamin D in blood in all study subjects. For subjects with CLL, this data will also be 
integrated with pharmacodynamic parameters described above to determine the relationship 
between circulating drug levels and effects on VDR, NF-κB, and bcl-2. The purpose of this 
analysis is exploratory/proof of concept. 
 
10.3.1 
Background 
Despite the use of doses of curcumin as high as 8 g/d in humans, very little free curcumin is 
typically found in patient plasma samples (43, 94). Rather, curcumin is present in plasma in 
conjugated (glucuronide and sulfate) forms, thereby necessitating appropriate enzymatic 
hydrolysis of the plasma before detection of free curcumin (95). 


 
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10.3.2.   Rationale for Analysis  
Pharmacokinetic analysis of free curcumin with mass spectroscopy in human plasma, post 
oral administration, after appropriate enzymatic hydrolysis of the plasma has performed and 
validated before by different investigators (32, 43, 94). Since there is little or no correlation 
between plasma levels and effect (32, 96), there is little utility in performing intensive 
pharmacokinetic analysis. Vitamin D3 25OH (25-hydroxycholecalciferol) levels will be 
measured by liquid chromatography tandem-mass spectrometry (97). Serum levels of 25-
hydroxycholecalciferol has been validated as reflective of whole-body vitamin D stores and 
are used clinically to define vitamin D adequacy, deficiency, and toxicity (98). As we don’t 
know how curcumin influences vitamin D metabolism, and vice versa, will assess curcumin 
and 25-hydroxycholecalciferol levels in plasma before treatment, one week after treatment 
with curcumin and before starting vitamin D3, and 3 weeks after treatment with both agents. 
No adjustment in dose or stopping of vitamin D is planned based on vitamin D OH level for 
3 reasons: (1) The assay used to monitor vitamin D level is for research purposes and isn't a 
CLIA-certified assay; (2) We are not running samples in real time to make such clinical 
decisions; samples will be batch-assayed; (3) There is very little correlation between vitamin 
D levels and actual toxicity. Vitamin D toxicity is a clinical diagnosis and a normal serum 
calcium level excludes the diagnosis of vitamin D toxicity (please refer to section 8.1.1 for 
further details). 
 
10.3.3 
Collection of Specimens 
About 4-5 ml of blood will be drawn into 1 green-topped tube (containing heparin).  The tube 
will be kept at ambient temperature and will be delivered to the TRPC laboratory within 3 
hours of venipuncture. Blood samples will be drawn at the following 3 times points:  
 
1.  Cycle 1, Day 1: 
pre treatment 
2.  Cycle 1, Day 8: 
prior to starting vitamin D3 
3.  Cycle 2, Day 1: 
after treatment with both curcumin and vitamin D3  
 
10.3.4 
Handling of Specimens  
All specimens are to be shipped to the TRPC at the address below.   
 
Translational Research & Pharmacology Core 
ATTN  Erin Hohler 
University Hospitals of Cleveland 
11100 Euclid Avenue 
Seidman Cancer Center, Room 3608 
Cleveland, OH 44106 
Telephone: 216-286-3889/216-386-3890 
Fax: 216-286-5772 
Pager: 33471 
E-mail: emh14@case.edu 
 
TRPC Personnel will log the specimen information into the OnCore database and de-identify 
the specimen using a code specific for this trial.  


 
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Plasma will be isolated by standard methods, aliquoted into cryovials (0.5ml/tube) and frozen 
at -70 C until analysis.   
 
Specimens will be transported to the Case Comprehensive Cancer Center Pharmacology 
Core Facility Laboratory for analysis upon request of the Principle Investigator.  
 
If the sample is collected at an outside laboratory then it should be transported at room 
temperature as soon as possible to the TRPC by the rapid hospital courier service.   
 
10.3.5  
Analytical Laboratory 
All pharmacokinetic studies will be performed by the Case Comprehensive Cancer Center 
Pharmacology Core Facility Laboratory. Pharmacokinetic analysis of free curcumin with 
mass spectroscopy in human plasma, post oral administration, after appropriate enzymatic 
hydrolysis of the plasma has performed and validated before by different investigators (32, 
43, 94). The Case Comprehensive Cancer Center Pharmacology Core Facility Laboratory has 
already developed, and validated, a method for analysis of 25-hydroxycholecalciferol (Yan 
Xu, Ph.D. personal communication) 
 
The Case Cancer Pharmacology Core  
11001 Cedar Avenue, Suite 200  
Cleveland, OH  44106 
Contact: Yan Xu Ph.D. 
Telephone: (216) 832-0010 
Email: y.xu@csuohio.edu 
 
10.4 
Quality of Life Assessments  
The purpose of this correlative study is to measure the impact of curcumin and 
curcumin/vitamin D combination on quality of life (QOL) of patients with early stage CLL.  
 
10.4.1 
Background and Rationale 
Shanafelt et al. has demonstrated that CLL, at all stages, has a negative impact on QOL; the 
emotional well-being scores of CLL patients were dramatically lower than that of both the 
general population and patients with other types of cancer in analysis of 1482 patients (99). 
There is no intervention that has been shown to improve QOL in CLL patients. There is 
anecdotal evidence that curcumin and vitamin D improve QOL in cancer patients (100-103). 
Patients enrolled on the trial so far have reported improvement in their fatigue and overall 
sense of well-being. 
 
10.4.2 Measurement 
We propose using the Functional assessment of chronic illness therapy- Lymphoma (FACT-
Lym) questionnaire to assess QOL at baseline (within 2 weeks before starting C1 D1) and at 
end of treatment (within 2 weeks of discontinuation of study medication). Patients who are 
responding and will go on the 2 year continuation phase will take the FACT-Lym 
questionnaire within 2 weeks before starting C7 D1 and at the end of treatment. The FACT-
Lym (appendix G) is a short, well-validated QOL measure has a general module (FACT-G) 


 
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with four subscales: physical, social/family, emotional and functional (104). The FACT-Lym 
was validated in indolent non-Hodgkin's lymphoma (which has a biology similar to 
CLL/SLL) and in CLL (105). Each of the four different subscales will be analyzed 
individually and the composite scale with 10% improvement after treatment considered 
significant based on prior published literature (106) 
 
10.5 
Additional Correlative Studies 
Study has been closed to accrual on 4/12/2016 at University Hospitals. Frozen plasma/serum 
and peripheral blood mononuclear cells will be shipped to Dr Basem William at the Ohio 
State University, former PI on the trial, to undertake further analysis of inflammatory 
cytokines and exosomes, under a material transfer agreement (MTA). Dr William will have 
no access to patient identifying information and the generated research data set will be linked 
to clinical dataset through a unique patient number. They key linking datasets will be 
maintained at University Hospitals. The planned studies do not include any genetic analysis. 
Samples would be shipped to: 
 
Leukemia Tissue Bank Shared Resource 
334 Tzagournis Research Facility 
420 W. 12th Ave. 
Columbus, Ohio 43210 
 
 
11.0  STUDY PARAMETERS AND CALENDAR  
 
11.1 
Study Parameters 
 
11.1.1 Screening Evaluation   
Screening studies and evaluations will be used to determine the eligibility of each subject for 
study inclusion. All evaluations must be completed < 30 days prior to administration of 
protocol therapy. Bone marrow biopsy, flow cytometry, cytoegenetics, and interphase FISH 
performed up to 5 years prior to enrollment are acceptable. 
 
• Informed Consent 
• Demographics 
• Medical History  
• Complete physical examination including lymph node measurements (all palpable 
lymph nodes will be measured in greatest dimension and documented)  
• Height 
• Weight 
• Vital signs including: blood pressure, pulse, temperature, and respiratory rate 
• Concomitant Medications Assessment including prescription medications, OTC, and 
nutritional/herbal supplements.  
• ECOG Performance status < 2 
  
• Baseline Symptoms Assessment 
• Laboratory Studies: 


 
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• Complete Blood Count (CBC) with differential and platelets. Absolute 
lymphocyte count (ALC) will be calculated from CBC and differential 
• Serum 
Chemistries: 
albumin, 
alkaline 
phosphatase, 
total 
bilirubin, 
bicarbonate, BUN, calcium, chloride, creatinine, glucose,  potassium, total 
protein, SGOT [AST], SGPT [ALT], sodium 
• Vitamin D 25(OH) level; standard of care test (63).  
• Calculated creatinine clearance will be done if creatinine and/or BUN are 
abnormal.    
• ß-HCG for women of childbearing potential 
• CT scan of chest, abdomen, and pelvis (with and without contrast) will be performed 
in subjects with SLL who don’t have ALC<5000 and non-measurable peripheral 
adenopathy. MRI may be performed if subject has allergy to iodinated contrast media 
• Bone Marrow Biopsy is optional and not required prior to enrollment in study 
• Peripheral blood flow cytometry (unless already performed on bone marrow biopsy) 
• Peripheral blood cytogenetics including interphase FISH analysis for chromosome 11, 
12, 13, and 17 abnormalities (unless already performed on bone marrow biopsy) 
 
11.1.2 Treatment Period 
Treatment cycles are 28 days long.  
A visit window of + 3 days is allowed for chemistry and hematology labs  
A visit window of + 7 days is allowed for 3 month and long term follow-up visits.  
A visit window of + 3 days is allowed for physical exams.  
 
Cycle 1, Day 1 
Cycle 1, Day 1 evaluations do not need to be repeated if screening evaluations were 
conducted within 2 weeks prior to administration of protocol therapy.   
 
• Physical Examination including lymph node measurements (all palpable lymph nodes 
will be measured in greatest dimension and documented)  
• Weight 
• Vital signs including: blood pressure, pulse, temperature, and respiratory rate 
• Concomitant Medications Assessment including prescription medications, OTC, and 
nutritional/herbal supplements.  
• ECOG Performance status < 2 
• Baseline Symptoms Assessment  
• Laboratory Studies: 
o Complete Blood Count (CBC) with differential and platelets. ALC will be 
calculated from CBC and differential 
o Serum 
Chemistries: 
albumin, 
alkaline 
phosphatase, 
total 
bilirubin, 
bicarbonate, BUN, calcium, chloride, creatinine, glucose,  potassium, total 
protein, SGOT [AST], SGPT [ALT], sodium 
o Calculated creatinine clearance will be done if creatinine and/or BUN are 
abnormal.    
o ß-HCG for women of childbearing potential 
o Vitamin D 25(OH) level.  


 
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• Correlative Studies: 
o Vitamin D receptor (VDR); by flow cytometry  (only in subjects with CLL) 
o NF-κB; by flow cytometry (only in subjects with CLL) 
o bcl-2; by flow cytometry (only in subjects with CLL) 
o Curcumin and vitamin D 25(OH) plasma level [PK] 
• Curcumin dispensed to start on Day 1 
• Pill diary distributed on Day 1 
 
Cycle 1, Day 8 
• Weight 
• Vital signs including: blood pressure, pulse, temperature, and respiratory rate 
• ECOG Performance status < 2 
 
• Adverse events assessment 
• Laboratory Studies: 
o Complete Blood Count (CBC) with differential and platelets. ALC will be 
calculated from CBC and differential 
o Serum 
Chemistries: 
albumin, 
alkaline 
phosphatase, 
total 
bilirubin, 
bicarbonate, BUN, calcium, chloride, creatinine, glucose,  potassium, total 
protein, SGOT [AST], SGPT [ALT], sodium 
o Calculated creatinine clearance will be done if creatinine and/or BUN are 
abnormal.    
• Correlative Studies: 
o Vitamin D receptor (VDR); by flow cytometry (only in subjects with CLL) 
o NF-κB; by flow cytometry (only in subjects with CLL) 
o bcl-2; by flow cytometry (only in subjects with CLL) 
o Curcumin and vitamin D 25(OH) plasma level [PK] 
• Vitamin D3 dispensed to start on Day 8 
 
Cycle 2, Day 1 
• Physical Examination including lymph node measurements (all palpable lymph nodes 
will be measured in greatest dimension and documented) 
• Weight 
• Vital signs including: blood pressure, pulse, temperature, and respiratory rate 
• Concomitant Medications Assessment including prescription medications, OTC, and 
nutritional/herbal supplements.  
• ECOG Performance status < 2 
 
• Adverse events assessment 
• Laboratory Studies: 
o Complete Blood Count (CBC) with differential and platelets. ALC will be 
calculated from CBC and differential 
o Serum 
Chemistries: 
albumin, 
alkaline 
phosphatase, 
total 
bilirubin, 
bicarbonate, BUN, calcium, chloride, creatinine, glucose,  potassium, total 
protein, SGOT [AST], SGPT [ALT], sodium 


 
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o Vitamin D 25(OH) level (as clinically indicated if there are signs of vitamin D 
toxicity or if calcium level, corrected to serum albumin, is >11 mg/dL) 
o Calculated creatinine clearance will be done if creatinine and/or BUN are 
abnormal.    
• Correlative Studies: 
o Vitamin D receptor (VDR); by flow cytometry (only in subjects with CLL) 
o NF-κB; by flow cytometry (only in subjects with CLL) 
o bcl-2; by flow cytometry (only in subjects with CLL) 
o Curcumin and vitamin D 25(OH) plasma level [PK] 
• Curcumin and vitamin D3 [4 week supply dispensed to start on Day 1] 
• Pill diary collected and new diary distributed 
 
Cycles 3-6, Day 1 
• Physical Examination including lymph node measurements (all palpable lymph nodes 
will be measured in greatest dimension and documented) 
• Weight 
• Vital signs including: blood pressure, pulse, temperature, and respiratory rate 
• Concomitant Medications Assessment including prescription medications, OTC, and 
nutritional/herbal supplements.  
• ECOG Performance status < 2 
 
• Adverse events assessment 
• On cycle 3 D1 only (+/- 3 days for flexibility of scheduling): CT scan of chest, 
abdomen, and pelvis (with and without contrast) will be performed in subjects with 
SLL who don’t have ALC<5000 and non-measurable peripheral adenopathy. MRI 
may be performed if subject has allergy to iodinated contrast media. Purpose of this 
study is to assess response to treatment. 
• Laboratory Studies: 
o Complete Blood Count (CBC) with differential and platelets. ALC will be 
calculated from CBC and differential 
o Serum 
Chemistries: 
albumin, 
alkaline 
phosphatase, 
total 
bilirubin, 
bicarbonate, BUN, calcium, chloride, creatinine, glucose,  potassium, total 
protein, SGOT [AST], SGPT [ALT], sodium 
o Calculated creatinine clearance will be done if creatinine and/or BUN are 
abnormal.    
o Vitamin D 25(OH) level (as clinically indicated if there are signs of vitamin D 
toxicity or if calcium level, corrected to serum albumin, is >11 mg/dL) 
• Curcumin and vitamin D3 [4 week supply dispensed to start on Day 1] 
• Pill diary collected and new diary distributed 
 
Cycles ≥7 up to 2 years, Day 1 (for patients attaining a partial response or better) 
• Physical Examination including lymph node measurements (all palpable lymph nodes 
will be measured in greatest dimension and documented) 
• Weight 
• Vital signs including: blood pressure, pulse, temperature, and respiratory rate 


 
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• Concomitant Medications Assessment including prescription medications, OTC, and 
nutritional/herbal supplements.  
• ECOG Performance status < 2 
 
• Adverse events assessment 
• Laboratory Studies: 
o Complete Blood Count (CBC) with differential and platelets. ALC will be 
calculated from CBC and differential 
o Serum 
Chemistries: 
albumin, 
alkaline 
phosphatase, 
total 
bilirubin, 
bicarbonate, BUN, calcium, chloride, creatinine, glucose,  potassium, total 
protein, SGOT [AST], SGPT [ALT], sodium 
o Vitamin D 25(OH) level (as clinically indicated if there are signs of vitamin D 
toxicity or if calcium level, corrected to serum albumin, is >11 mg/dL) 
o Calculated creatinine clearance will be done if creatinine and/or BUN are 
abnormal.    
• Curcumin and vitamin D3 [4 week supply dispensed to start on Day 1] 
• Pill diary collected and new diary distributed 
 
End of Treatment Visit (within 1 week of discontinuation of study medications) 
• Physical Examination including lymph node measurements (all palpable lymph nodes 
will be measured in greatest dimension and documented) 
• Weight 
• Vital signs including: blood pressure, pulse, temperature, and respiratory rate 
• Concomitant Medications Assessment including prescription medications, OTC, and 
nutritional/herbal supplements.  
• ECOG Performance status < 2 
 
• Adverse events assessment 
• Pill diary collected 
• Laboratory Studies: 
o Complete Blood Count (CBC) with differential and platelets. ALC will be 
calculated from CBC and differential 
o Serum 
Chemistries: 
albumin, 
alkaline 
phosphatase, 
total 
bilirubin, 
bicarbonate, BUN, calcium, chloride, creatinine, glucose,  potassium, total 
protein, SGOT [AST], SGPT [ALT], sodium 
o Calculated creatinine clearance will be done if creatinine and/or BUN are 
abnormal.    
o ß-HCG for women of childbearing potential 
o Vitamin D 25(OH) level (as clinically indicated if there are signs of vitamin D 
toxicity or if calcium level, corrected to serum albumin, is >11 mg/dL) 
 
30 Day Follow-Up 
• Physical Examination including lymph node measurements (all palpable lymph nodes 
will be measured in greatest dimension and documented) 
• Weight 
• Vital signs including: blood pressure, pulse, temperature, and respiratory rate 


 
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• Concomitant Medications Assessment including prescription medications, OTC, and 
nutritional/herbal supplements.  
• ECOG Performance status < 2 
 
• Adverse events assessment 
• Laboratory Studies: 
o Complete Blood Count (CBC) with differential and platelets. ALC will be 
calculated from CBC and differential 
o Serum 
Chemistries: 
albumin, 
alkaline 
phosphatase, 
total 
bilirubin, 
bicarbonate, BUN, calcium, chloride, creatinine, glucose,  potassium, total 
protein, SGOT [AST], SGPT [ALT], sodium 
o Calculated creatinine clearance will be done if creatinine and/or BUN are 
abnormal.    
o Vitamin D 25(OH) level (as clinically indicated if there are signs of vitamin D 
toxicity or if calcium level, corrected to serum albumin, is >11 mg/dL) 
 
Long Term Follow-Up (for 2 years after discontinuation of study medications, every 3-6 
months as clinically indicated) 
 
• Physical Examination including lymph node measurements (all palpable lymph nodes 
will be measured in greatest dimension and documented) 
• Weight 
• Vital signs including: blood pressure, pulse, temperature, and respiratory rate 
• ECOG Performance status < 2 
• Adverse Events Assessment  
• Laboratory Studies: 
o Complete Blood Count (CBC) with differential and platelets 
o Serum 
Chemistries: 
albumin, 
alkaline 
phosphatase, 
total 
bilirubin, 
bicarbonate, BUN, calcium, chloride, creatinine, glucose,  potassium, total 
protein, SGOT [AST], SGPT [ALT], sodium 
o Calculated creatinine clearance will be done if creatinine and/or BUN are 
abnormal.    
 
11.2 
Calendar 
Screening studies will studies are to be conducted within 30 days prior to administration of 
protocol therapy. Exception: Bone marrow biopsy, flow cytometry, cytometry, cytoegenetics, 
and interphase FISH performed up to 5 years prior to enrollment 
 
 
 
 
Study Days 
Pre-
Study 
Cycle 1
Day 
1b 
Cycle 
1 
Day 8
Cycle 
2 Day 
1 
Cycles 3-
6 
Day 1 
Cycles 
7+ 
Day 1 f
End of 
Treatment
30 Day 
Follow 
Upi 
Long 
term 
Follow-
Upg,i
REQUIRED 
ASSESSMENTS
 
 
 
 
 
 
 
 
 


 
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Informed Consent
X
 
 
 
 
 
 
 
 
Demographics
X
 
 
 
 
 
 
 
 
Medical History
X
 
 
 
 
 
 
 
 
Height 
X
 
 
 
 
 
 
 
 
Weight 
X
X
X
X
X
X
X
X
X
Vitals (blood pressure, 
pulse, temperature, and 
respiratory rate)
X
X
X
X
X
X
X
X
X
Physical Examinationi
X
X
 
X
X
X
X
X
X
Concomitant 
Medication 
Assessment
X
X
 
X
X
X
X
X
 
ECOG PS
X
X
X
X
X
X
X
X
X
Baseline Symptoms
X
X
 
 
 
 
 
 
 
Adverse Event 
Assessment
 
 
X
X
X
X
X
X
X
Peripheral blood flow 
cytometry
X
 
 
 
 
 
 
 
 
Peripheral blood 
cytogenetics and FISH  
X
 
 
 
 
 
 
 
 
CBC / diff / plateletsi 
X
X
X
X
X
X
X
X
X
Serum Chemistry a, i
X
X
X
X
X
X
X
X
X
ß-HCG,  women of 
childbearing potential
X
X
 
 
 
 
X
 
 
Vitamin D 25(OH) 
level
X
X*
 
X*
X*
X*
X*
X
 
DISEASE 
ASSESSMENT
 
 
 
 
 
 
 
 
 
Lymph node 
measurement
X
X
 
X
X
X
X
X
X
CT 
chest/abdomen/pelvisc
X
 
 
 
X
 
 
 
 
Bone marrow biopsy 
(optional)
X
 
 
 
 
 
 
 
 
MISC ITEMS
 
 
 
 
 
 
 
 
 
Pill Diary
 
X
 
X
X
X
X
 
 
TREATMENT
 
 
 
 
 
 
 
 
 
Curcumin
 
 
 
 
 
 
 
 
 
Vitamin D3
 
 
 
 
 
 
 
 
 
CORRELATIVE 
STUDIES
 
 
 
 
 
 
 
 
 
Pharmacokinetic 
Samplingd
 
X
X
X
 
 
 
 
 
Flow cytometrye
 
X
X
X
 
 
 
 
 
Quality of life 
questionnaire 
Xh
 
 
 
 
 
Xh
 
 


 
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a:  Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, 
potassium, total protein, SGOT [AST], SGPT [ALT], sodium.  Calculated creatinine clearance will be done if 
creatinine and/or BUN are abnormal.   [UH: Order COMP2]   
b: Cycle 1, Day 1 evaluations do not need to be repeated if screening evaluations were conducted within 2 
weeks prior to administration of protocol therapy 
c: In subjects with SLL who have ALC<5000 and non-measurable peripheral adenopathy 
d: Plasma level of curcumin and vitamin D 25(OH) 
e: For vitamin D receptor, NF-κB, and bcl-2, CLL patients only 
f: For patients attaining a partial response or better 
g: Every 3-6 months as clinically indicated 
h: Utilizing FACT-Lym questionnaire (appendix G) within 2 weeks prior to start of treatment and within 2 
weeks of discontinuation of study medications. Patients who are responding and will go on the 2 year 
continuation phase will take the FACT-Lym questionnaire within 2 weeks before starting C7 D1 and at the 
end of treatment. 
i. +/- 3 day window 
*: As clinically indicated if there are signs of vitamin D toxicity or if calcium level, corrected to serum 
albumin, is >11 mg/dL
 
 
MEASUREMENT OF EFFECT   
 
12.1 
Response Criteria for CLL; based on NCI-WG (107) 
Complete response requires all of the following for a period of at least two months from 
completion of therapy:  
• Peripheral blood lymphocytes (evaluated by blood and differential count) below 4 x 
109/L (4000/_L). 
• Absence of significant lymphadenopathy (eg, lymph nodes >1.5 cm in diameter) by 
physical examination. 
• No hepatomegaly or splenomegaly on physical exam;  
• Absence of constitutional symptoms;  
• Normal CBC as exhibited by polymorphonuclear leukocytes > 1500/µL, platelets > 
100,000/µL, hemoglobin > 11.0 g/dl (untransfused) 
• Bone marrow aspirate and biopsy must be at least normocellular for age, with less 
than 30% of nucleated cells being lymphocytes. Lymphoid nodules should be absent. 
If the marrow is hypocellular, a repeat determination should be performed after 4 
weeks, or until peripheral blood counts have recovered. However, this time interval 
should not exceed 6 months after the last treatment. 
• Patients who fulfill the criteria for CR after induction with the exception of a 
persistent cytopenia that is believed to be treatment related will be considered a 
partial response. Additionally, patients who fulfill the criteria of CR with exception of 
having bone marrow lymphoid nodules will be considered a partial response. Patients 
who fulfill the criteria of CR but declined having a bone marrow biopsy will be 
considered be in PR. 
 
Partial response requires a > 50% decrease in peripheral lymphocyte count from pre-
treatment value, > 50% reduction in lymphadenopathy, and/or > 50% reduction in 


 
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splenomegaly/ hepatomegaly for a period of at least two months from completion of 
therapy. All lymph nodes will be measured bi-dimensionally and the sums of these added 
to determine if 50% or greater reduction has occurred.  
 
Additionally, these patients must have one of the following:  
• 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 (untransfused) or 50% improvement from pretreatment 
value.  
 
Progressive Disease is characterized by any one of the following events:  
• >50% increase in the products of at least two lymph nodes (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.  
• >50% increase in the absolute number of circulating lymphocytes to at least 
5,000/µL.  
• Transformation to a more aggressive histology (i.e., Richter’s syndrome or 
prolymphocytic leukemia with > 55% prolymphocytes).  
• 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 and of underlying CLL. A bone marrow biopsy in such 
settings is strongly encouraged.  
 
Stable Disease includes 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. 
 
 


 
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12. 2 
Definitions for SLL with radiographically measurable lesions 
 
• Measurable disease: the presence of at least one measurable lesion. If the 
measurable disease is restricted to a solitary lesion, its neoplastic nature should be 
confirmed by cytology/histology.  
 
• Measurable lesions - defined as those that can be accurately measured in at least one 
dimension (longest diameter to be recorded) as >20 mm with conventional techniques 
(PET, CT,) or as >10 mm with spiral CT scan.  All tumor measurements must be 
recorded in millimeters (or decimal fractions of centimeters). 
 
• Non-measurable lesions - all other lesions, including small lesions (longest diameter 
<20 mm with conventional techniques or <10 mm with spiral CT scan), i.e., bone 
lesions, leptomeningeal disease, ascites, pleural/pericardial effusion, inflammatory 
breast disease, lymphangitis cutis/pulmonis, cystic lesions, and also abdominal 
masses that are not confirmed and followed by imaging techniques. 
 
• Baseline documentation of “Target” lesions - all measurable lesions up to a 
maximum of five lesions per organ and 10 lesions in total, representative of all 
involved organs should be identified as target lesions and recorded and measured at 
baseline. Target lesions should be selected on the basis of their size (determining the 
product obtained from the longest diameter of two perpendicular measurements) and 
their suitability for accurate repeated measurements (either by imaging techniques or 
clinically).  A sum of the products of the longest perpendicular dimensions (LD) for 
all target lesions will be calculated and reported as the baseline sum LD.  The 
baseline sum LD will be used as reference by which to characterize the objective 
tumor response. 
 
• Non-target lesions - All other lesions (or sites of disease) should be identified as 


 
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non-target lesions and should also be recorded at baseline.  Non-target lesions include 
measurable lesions that exceed the maximum numbers per organ or total of all 
involved organs as well as non-measurable lesions.  Measurements of these lesions 
are not required, but the presence or absence of each should be noted throughout 
follow-up.   
 
12.3    Response Criteria for SLL; based on Cheson criteria (108) 
The criteria for NHL are as follows (GTD = Greatest Transverse Diameter; SPD = Sum 
of the Products of the Greatest Diameter): 
 
Complete Remission (CR): 
• Disappearance of all evidence of disease. 
• No disease related symptoms. 
• Lymph nodes, nodal masses regressed to “normal” size: 
o If >1.5 cm before treatment, regressed to ≤ 1.5 cm in GTD. 
o If 1.1 to 1.5 cm before treatment, regressed to ≤ 1 cm in GTD (or 
>75% in SPD). If PET scan was positive before therapy, a post-
treatment residual mass of any size is permitted as long as it is PET 
negative. 
• Spleen and all previously enlarged organs decreased to normal in size.   
• If the Bone marrow was involved prior to treatment, it is clear on repeat 
aspirate and biopsy at the same site. 
 
Partial Remission (PR) 
• ≥ 50% decrease in SPD of six largest dominant nodes/nodal masses. 
• No increase in size of other nodes, liver or spleen. 
• Splenic and hepatic nodes regressed at least 50% in SPD 
• No new sites of disease. 
• If the PET scan was positive before therapy, the post-treatment PET is 
positive in at least one previously involved site.  
• Patients who achieve a CR by the above criteria, but who have persistent bone 
marrow involvement (or those in whom pre-treatment bone marrow was 
involved and post-treatment bone marrow involvement was not assessed). 
 
Relapsed Disease (RD) 
• In patients previously CR or CRu: 
• New lesion > 1.5 cm in any axis 
• Size of previously involved site has increase ≥ 50% in GTD. 
• ≥ 50% in either: 
o GTD of any previously identified node that was >1 cm in its short 
axis, or  
o SPD of any node or other lesion. 
 
Stable Disease (SD) 
• Patients who have achieved less than a partial remission but who have not 


 
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developed findings consistent with progressive disease. 
 
Progressive Disease (PD) 
• In patients previously PR or SD. 
• ≥ 50% increase from nadir or baseline in SPD or any node or lesion 
• ≥ 50% increase from nadir in GTD of any node previously >1cm in shortest 
diameter 
• Appearance of any new lesion during or at the end of therapy. 
 
Evaluation of best overall response 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started).  The patient’s best response assignment 
will depend on the achievement of both measurement and confirmation criteria. 
 
 
Target 
Lesions 
 
Non-Target 
Lesions 
 
New 
Lesions 
 
Overall 
Response 
 
CR 
 
CR 
 
No 
 
CR 
 
CR 
 
Incomplete 
response/S
D 
 
No 
 
PR 
 
PR 
 
Non-PD 
 
No 
 
PR 
 
SD 
 
Non-PD 
 
No 
 
SD 
 
PD 
 
Any 
 
Yes or No 
 
PD 
 
Any 
 
PD 
 
Yes or No 
 
PD 
 
Any 
 
Any 
 
Yes 
 
PD 
 
Note: Patients with a global deterioration of their health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be classified 
as having “symptomatic deterioration.”  Every effort should be made to document objective 
progression, even after discontinuation of treatment. 
 
In some circumstances, it may be difficult to distinguish residual disease from normal tissue.  
When the evaluation of complete response depends on this determination, it is recommended 
that the residual lesion be investigated (fine needle aspirate/biopsy) before confirming the 
complete response status. 


 
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12.4 
Biologic response criteria CLL and SLL (78) 
Given the favorable toxicity profile of curcumin and vitamin D3 in healthy adults and the 
intention to evaluate the efficacy of both agent to delay or prevent PD in patients with 
CLL/SLL, we also evaluated an additional response category termed ‘‘biologic response’’ 
among patients who did not meet standard NCI-WG criteria for CR and PR. The criteria for a 
biologic response were prospectively defined in a recent study of Polyphenon E, after 
discussion and approval of the NCI. Polyphenon E, very much like curcumin and vitamin 
D3, is the most active ingredient in green tea extract and it works through unique, 
noncytotoxic mechanisms. Biologic response was defined as a reduction in the absolute 
lymphocyte count (ALC) of > 20% from the pretreatment level that was sustained for at least 
2 months or a ≥ 30% reduction in all palpable lymphadenopathy (78).  
 
 
12.5 
Duration of Response 
 
Duration of overall response:   
The duration of overall response is measured from the time measurement criteria are met for 
CR or PR (whichever is first recorded) until the first date that recurrent or progressive 
disease is objectively documented (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started). 
The duration of overall CR is measured from the time measurement criteria are first met for 
CR until the first date that progressive disease is objectively documented.  
Duration of stable disease:   
Stable disease is measured from the start of the treatment until the criteria for progression are 
met, taking as reference the smallest measurements recorded since the treatment started, 
including the baseline measurements.  
 
12.6 
Progression-free survival (PFS) 
Progression-free Survival (PFS) is defined as the time from entry onto study until CLL/SLL 
progression or death from any cause. PFS is often considered the preferable endpoint in 
lymphoma clinical trials, especially those involving incurable histologic subtypes (e.g., 
follicular and low grade, mantle cell lymphoma). PFS reflects tumor growth and, therefore, 
occurs prior to the endpoint of overall survival. In addition, PFS is not confounded by the 
administration of subsequent therapy. Whether a prolongation of PFS represents direct 
clinical benefit or a surrogate for clinical benefit depends on the magnitude of the effect and 
the risk-benefit ratio of the therapy under investigation. Unlike survival, the precise date of 
progression is generally unknown. It may be defined as the first date of documentation of a 
new lesion or enlargement of a previous lesion, or the date of the scheduled clinic visit 
immediately after radiologic assessment has been completed. Where there is missing 
information, censoring of the data may be defined as the last date at which progression status 
was adequately assessed. 
 
12.7 
Time to first cytotoxic treatment (TFCT) 


 
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Time to first cytotoxic treatment (TFCT) is defined as the time from entry onto study until 
initiation of treatment with cytotoxic agents because of disease progression. As curcumin and 
vitamin D3 combination has the potential for delaying disease progression, or maintaining 
stable disease, TFCT is a clinically meaningful end-point of these patients. 
 
 
13.0 
RECORDS TO BE KEPT / REGULATORY CONSIDERATIONS  
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 8.0 
(Adverse Events: List and Reporting Requirements). 
 
13.1 
Data Reporting  
The OnCore Database will be utilized, as required by the Case Comprehensive Cancer 
Center, to provide data collection for both accrual entry and trial data management.  OnCore 
is a Clinical Trials Management System housed on secure servers maintained at Case 
Western Reserve University.  OnCore properly used is compliant with Title 21 CFR Part 11.  
Access to data through OnCore is restricted by user accounts and assigned roles.  Once 
logged into the OnCore system with a user ID and password, OnCore defines roles for each 
user which limits access to appropriate data. User information and password can be obtained 
by contacting the OnCore Administrator at oncore-registration@case.edu. 
 
This study will utilize electronic Case Report Form completion in the OnCore database.  A 
calendar of events and required forms are available in OnCore. 
 
13.2 
Regulatory Considerations 
The study will be conducted in compliance with ICH guidelines and with all applicable federal 
(including 21 CFR parts 56 & 50), state or local laws.  
 
13.2.1 Written Informed consent 
Provision of written informed consent must be obtained prior to any study-related procedures.  
The Principal Investigator will ensure that the subject is given full and adequate oral and written 
information about the nature, purpose, possible risks and benefits of the study as well as the 
subject’s financial responsibility.  Subjects must also be notified that they are free to discontinue 
from the study at any time.  The subject should be given the opportunity to ask questions and 
allowed time to consider the information provided.  
The original, signed written Informed Consent Form must be kept with the Research Chart in 
conformance with the institution’s standard operating procedures. A copy of the signed written 
Informed Consent Form must be given to the subject. 
13.2.2 Subject Data Protection 
In accordance with the Health Information Portability and Accountability Act (HIPAA), a 
subject must sign an authorization to release medical information to the sponsor and/or allow the 
sponsor, a regulatory authority, or Institutional Review Board access to subject’s medical 


 
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information that includes all hospital records relevant to the study, including subjects’ medical 
history. 
 
13.2.3 Accessing Electronic Medical Records for University Hospitals Health System   
This study will access electronic medical records systems to obtain medical information for the 
subjects enrolled to this study.  
 
In order to insure patient safety, investigators and study personnel must have up-to-the-minute 
health information for subjects enrolled to this study.  Therefore, electronic medical records must 
be utilized to obtain medical information in a timely manner.   
 
The following electronic systems will be used:  Athena program to access scheduling 
information; UH Physician Portal to access lab results and physician notes; PCOSS LITE as 
necessary to locate archived medical records; COPATH to locate archived pathology records; 
PACS to access radiological imaging results; and MySecureCare (Sunrise Clinical Manager) to 
access some or all of the above information when this application is fully functional.   
 
Access to these systems is required for the life of this research study.   
 
Information obtained from electronic systems will be copied into the Seidman Cancer Center 
Clinical Trials Unit research chart and/or printed (lab results, physician notes, etc.) and stored in 
the research chart.  Research charts are kept secure and destroyed according to UH policy.   
 
Study data will be obtained by the PI, co-investigators, study coordinator, and/or data manager 
for this study via password-protected login.  
 
13.2.4  Retention of records 
The Principal Investigator of The Case Comprehensive Cancer Center supervises the retention of 
all documentation of adverse events, records of study drug receipt and dispensation, and all IRB 
correspondence for as long as needed to comply with national and international regulations. No 
records will be destroyed until the Principal Investigator confirms destruction is permitted.  
 
13.2.5  Audits and inspections  
Authorized representatives of the sponsor, a regulatory authority, an Independent Ethics 
Committee (IEC) or an Institutional Review Board (IRB) may visit the Center to perform audits 
or inspections, including source data verification.  The purpose of an audit or inspection is to 
systematically and independently examine all study-related activities and documents to 
determine whether these activities were conducted, and data were recorded, analysed, and 
accurately reported according to the protocol, Good Clinical Practice (GCP), guidelines of the 
International Conference on Harmonization (ICH), and any applicable regulatory requirements.   
13.2.6 Data Safety and Monitoring Plan 
This protocol will adhere to the policies of the Case Comprehensive Cancer Center Data and 
Safety Monitoring Plan in accordance with NCI regulations.  
 
 


 
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14.0 
STATISTICAL CONSIDERATIONS 
 
14.1 
Study Design/Endpoints 
The primary endpoint of this trial will be the overall response rate (biologic response rate+CR + 
PR; CR/PR are based on NCI-WG (for CLL) and Cheson criteria (for SLL). The point estimate 
of the overall response rate and biologic response rate along with 95% confidence intervals will 
be calculated using binomial distribution theory.  The secondary efficacy variables of:  Time to 
first cytotoxic treatment (TFCT), progression free survival (PFS) and overall survival (OS) will 
be estimated using Kaplan-Meier method and displayed graphically.  Duration of response will 
also be calculated as a secondary variable of efficacy. 
 
14.2 
Sample Size/Accrual Rate 
The sample size is calculated for a single arm, Simon optimal 2-stagephase II deign. The design 
to test the null hypothesis that P ≤ 0.1 versus the alternative that P ≥ 0.3 has a sample size of 29 
and a probability of early termination of 0.74 under the null. The power is 0.8 with statistical 
significance declared at an alpha level of 0.05. An accrual goal of 35 patients will be enrolled in 
this study to allow 20% ineligibility or drop outs. According to the Simon 2-stage method, 10 
patients will be accrued initially during stage I. If there is evidence of clinical benefit, the 
remaining 25 patients will be enrolled during stage II. For the purpose of stopping the trial for 
futility, clinical benefit is defined as biologic response or better (please refer to section 12.4 for 
the definition of biologic response). 
 
In the planned Simon 2-Stage analysis, 10 patients will be enrolled in stage I. An interim analysis 
will be performed after the 10th patient completes the induction therapy period. If 1 or fewer 
patients exhibit clinical benefit (biologic response or better), the trial will be stopped. If 2 or 
more patients demonstrate clinical benefit, the study will proceed to stage II and an additional 19 
patients will be enrolled and treated. If the trial goes on to the second stage, a total of 29 eligible 
patients will be studied. If the total number responding is less than or equal to 5, the drug 
combination is considered not worth further exploration. The entire study group of 35 patients 
will be evaluated in the final analysis. 
 
 
14.3 
Analysis of Secondary Endpoints 
The secondary endpoints include Time to first cytotoxic treatment (TFCT), progression free 
survival (PFS) and overall survival (OS). For those time-to-event endpoints, Kaplan-Meier 
method and Cox proportional hazard model will be used for the data analysis.  Potential 
prognostic factors will be correlated with conversion status by Fisher’s exact test or Chi-square 
test, logistic regression will be used to assess the effect on conversion from the combination of 
multiple factors.  
 
 
14.4 
Reporting and Exclusions 
 
14.4.1 Evaluation of toxicity:  
All patients will be evaluable for toxicity from the time of their first treatment. All patients 
treated with curcumin and vitamin D3 will be included in safety summaries and analyses from 
the time of first treatment.  The safety and tolerability of curcumin and vitamin D3 will be 


 
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examined by:  extent of exposure to treatment (dose, duration, and number of patients), and a 
detailed examination of adverse events, laboratory test results, vital signs, and physical findings. 
 
Our planned sample number is 35 evaluable patients, but if there is evidence of toxicity as high 
as 20% DLTs the study will be terminated within the first 20 patient cohort. If ever 2 of the 
initial 10 patients exhibit DLT the study will be terminated. If ever 5 of the entire 35 patients 
exhibit DLT the treatment will be considered too toxic. These rules imply 84% power with 9.9% 
type I error to distinguish a 20% DLT rate from one not over 8%.  The chance of early 
termination under the hypothesis of 20% DLT is 37%. The chance of early termination in error is 
1.8%. 
 
14.4.2 Evaluation of response:   
Subjects need to have received 2 or more cycles of treatment to be evaluable for response. Each 
patient will be assigned one of the following categories:  1) complete response, 2) partial 
response, 3) stable disease, 4) progressive disease, 5) early death from malignant disease, 6) 
early death from toxicity, 7) early death because of other cause, or 9) unknown (not assessable, 
insufficient data).  [Note:  By arbitrary convention, category 9 usually designates the “unknown” 
status of any type of data in a clinical database.] 
 
All of the patients who met the eligibility criteria (with the possible exception of those who 
received no study medication) should be included in the main analysis of the response rate.  
Patients in response categories 4-9 should be considered to have a treatment failure (disease 
progression).  Thus, an incorrect treatment schedule or drug administration does not result in 
exclusion from the analysis of the response rate.   
 
14.4.3 Expected Accrual   
Those patients are typically managed by watchful waiting and are typically under-represented in 
clinical trials as they are perceived to have good prognosis. We expect to enroll 10-15 patients 
per year on this study. 
 


 
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 15.0 
References 
 
1. 
Shanafelt TD, Byrd JC, Call TG, Zent CS, Kay NE. Narrative review: initial 
management of newly diagnosed, early-stage chronic lymphocytic leukemia. Annals of 
internal medicine. 2006;145(6):435-47. 
2. 
Chemotherapeutic options in chronic lymphocytic leukemia: a meta-analysis of the 
randomized trials. CLL Trialists' Collaborative Group. Journal of the National Cancer 
Institute. 1999;91(10):861-8. 
3. 
Dighiero G, Maloum K, Desablens B, Cazin B, Navarro M, Leblay R, et al. 
Chlorambucil in indolent chronic lymphocytic leukemia. French Cooperative Group on 
Chronic Lymphocytic Leukemia. The New England journal of medicine. 1998;338(21):1506-
14. 
4. 
Irving GR, Karmokar A, Berry DP, Brown K, Steward WP. Curcumin: the potential 
for efficacy in gastrointestinal diseases. Best practice & research Clinical gastroenterology. 
2011;25(4-5):519-34. 
5. 
Balasubramanian K. Molecular orbital basis for yellow curry spice curcumin's 
prevention of Alzheimer's disease. Journal of agricultural and food chemistry. 
2006;54(10):3512-20. 
6. 
Priyadarsini KI, Maity DK, Naik GH, Kumar MS, Unnikrishnan MK, Satav JG, et al. 
Role of phenolic O-H and methylene hydrogen on the free radical reactions and antioxidant 
activity of curcumin. Free radical biology & medicine. 2003;35(5):475-84. 
7. 
Weber WM, Hunsaker LA, Abcouwer SF, Deck LM, Vander Jagt DL. Anti-oxidant 
activities of curcumin and related enones. Bioorganic & medicinal chemistry. 
2005;13(11):3811-20. 
8. 
Barclay LR, Vinqvist MR, Mukai K, Goto H, Hashimoto Y, Tokunaga A, et al. On 
the antioxidant mechanism of curcumin: classical methods are needed to determine 
antioxidant mechanism and activity. Organic letters. 2000;2(18):2841-3. 
9. 
Lin JK, Pan MH, Lin-Shiau SY. Recent studies on the biofunctions and 
biotransformations of curcumin. Biofactors. 2000;13(1-4):153-8. 
10. 
Wang YJ, Pan MH, Cheng AL, Lin LI, Ho YS, Hsieh CY, et al. Stability of curcumin 
in buffer solutions and characterization of its degradation products. Journal of pharmaceutical 
and biomedical analysis. 1997;15(12):1867-76. 
11. 
Jaiswal AS, Marlow BP, Gupta N, Narayan S. Beta-catenin-mediated transactivation 
and cell-cell adhesion pathways are important in curcumin (diferuylmethane)-induced growth 
arrest and apoptosis in colon cancer cells. Oncogene. 2002;21(55):8414-27. 
12. 
Kunnumakkara AB, Diagaradjane P, Anand P, Harikumar KB, Deorukhkar A, 
Gelovani J, et al. Curcumin sensitizes human colorectal cancer to capecitabine by modulation 
of cyclin D1, COX-2, MMP-9, VEGF and CXCR4 expression in an orthotopic mouse model. 
International journal of cancer Journal international du cancer. 2009;125(9):2187-97. 
13. 
Howells LM, Mitra A, Manson MM. Comparison of oxaliplatin- and curcumin-
mediated antiproliferative effects in colorectal cell lines. International journal of cancer 
Journal international du cancer. 2007;121(1):175-83. 
14. 
Notarbartolo M, Poma P, Perri D, Dusonchet L, Cervello M, D'Alessandro N. 
Antitumor effects of curcumin, alone or in combination with cisplatin or doxorubicin, on 
human hepatic cancer cells. Analysis of their possible relationship to changes in NF-kB 
activation levels and in IAP gene expression. Cancer letters. 2005;224(1):53-65. 


 
CASE 5913  
Protocol Version 7 Dated 10/2/2018 
 
 
58 of 74 
15. 
Milacic V, Banerjee S, Landis-Piwowar KR, Sarkar FH, Majumdar AP, Dou QP. 
Curcumin inhibits the proteasome activity in human colon cancer cells in vitro and in vivo. 
Cancer research. 2008;68(18):7283-92. 
16. 
Anto 
RJ, 
Mukhopadhyay 
A, 
Denning 
K, 
Aggarwal 
BB. 
Curcumin 
(diferuloylmethane) induces apoptosis through activation of caspase-8, BID cleavage and 
cytochrome c release: its suppression by ectopic expression of Bcl-2 and Bcl-xl. 
Carcinogenesis. 2002;23(1):143-50. 
17. 
Basile V, Ferrari E, Lazzari S, Belluti S, Pignedoli F, Imbriano C. Curcumin 
derivatives: molecular basis of their anti-cancer activity. Biochemical pharmacology. 
2009;78(10):1305-15. 
18. 
Li L, Aggarwal BB, Shishodia S, Abbruzzese J, Kurzrock R. Nuclear factor-kappaB 
and IkappaB kinase are constitutively active in human pancreatic cells, and their down-
regulation by curcumin (diferuloylmethane) is associated with the suppression of 
proliferation and the induction of apoptosis. Cancer. 2004;101(10):2351-62. 
19. 
Choudhuri T, Pal S, Agwarwal ML, Das T, Sa G. Curcumin induces apoptosis in 
human breast cancer cells through p53-dependent Bax induction. FEBS letters. 2002;512(1-
3):334-40. 
20. 
Weir NM, Selvendiran K, Kutala VK, Tong L, Vishwanath S, Rajaram M, et al. 
Curcumin induces G2/M arrest and apoptosis in cisplatin-resistant human ovarian cancer 
cells by modulating Akt and p38 MAPK. Cancer biology & therapy. 2007;6(2):178-84. 
21. 
Squires MS, Hudson EA, Howells L, Sale S, Houghton CE, Jones JL, et al. Relevance 
of mitogen activated protein kinase (MAPK) and phosphotidylinositol-3-kinase/protein 
kinase B (PI3K/PKB) pathways to induction of apoptosis by curcumin in breast cells. 
Biochemical pharmacology. 2003;65(3):361-76. 
22. 
Chiu TL, Su CC. Curcumin inhibits proliferation and migration by increasing the Bax 
to Bcl-2 ratio and decreasing NF-kappaBp65 expression in breast cancer MDA-MB-231 
cells. International journal of molecular medicine. 2009;23(4):469-75. 
23. 
William BM, Goodrich A, Peng C, Li S. Curcumin inhibits proliferation and induces 
apoptosis of leukemic cells expressing wild-type or T315I-BCR-ABL and prolongs survival 
of mice with acute lymphoblastic leukemia. Hematology. 2008;13(6):333-43. 
24. 
Furman RR, Asgary Z, Mascarenhas JO, Liou HC, Schattner EJ. Modulation of NF-
kappa B activity and apoptosis in chronic lymphocytic leukemia B cells. Journal of 
immunology. 2000;164(4):2200-6. 
25. 
Everett PC, Meyers JA, Makkinje A, Rabbi M, Lerner A. Preclinical assessment of 
curcumin as a potential therapy for B-CLL. American journal of hematology. 2007;82(1):23-
30. 
26. 
Ghosh AK, Kay NE, Secreto CR, Shanafelt TD. Curcumin inhibits prosurvival 
pathways in chronic lymphocytic leukemia B cells and may overcome their stromal 
protection in combination with EGCG. Clinical cancer research : an official journal of the 
American Association for Cancer Research. 2009;15(4):1250-8. 
27. 
Qiao Q, Jiang Y, Li G. Curcumin improves the antitumor effect of X-ray irradiation 
by blocking the NF-kappaB pathway: an in-vitro study of lymphoma. Anti-cancer drugs. 
2012;23(6):597-605. 
28. 
Qiao Q, Jiang Y, Li G. Curcumin enhances the response of non-Hodgkin's lymphoma 
cells to ionizing radiation through further induction of cell cycle arrest at the G2/M phase and 
inhibition of mTOR phosphorylation. Oncology reports. 2013;29(1):380-6. 


 
CASE 5913  
Protocol Version 7 Dated 10/2/2018 
 
 
59 of 74 
29. 
Gururajan M, Dasu T, Shahidain S, Jennings CD, Robertson DA, Rangnekar VM, et 
al. Spleen tyrosine kinase (Syk), a novel target of curcumin, is required for B lymphoma 
growth. Journal of immunology. 2007;178(1):111-21. 
30. 
Ghosh SS, Krieg R, Massey HD, Sica DA, Fakhry I, Ghosh S, et al. Curcumin and 
enalapril ameliorate renal failure by antagonizing inflammation in 5/6 nephrectomized rats: 
role of phospholipase and cyclooxygenase. American journal of physiology Renal 
physiology. 2012;302(4):F439-54. 
31. 
Dohner H, Fischer K, Bentz M, Hansen K, Benner A, Cabot G, et al. p53 gene 
deletion predicts for poor survival and non-response to therapy with purine analogs in 
chronic B-cell leukemias. Blood. 1995;85(6):1580-9. 
32. 
Dhillon N, Aggarwal BB, Newman RA, Wolff RA, Kunnumakkara AB, Abbruzzese 
JL, et al. Phase II trial of curcumin in patients with advanced pancreatic cancer. Clinical 
cancer research : an official journal of the American Association for Cancer Research. 
2008;14(14):4491-9. 
33. 
Golombick T, Diamond TH, Manoharan A, Ramakrishna R. Monoclonal 
gammopathy of undetermined significance, smoldering multiple myeloma, and curcumin: a 
randomized, double-blind placebo-controlled cross-over 4g study and an open-label 8g 
extension study. American journal of hematology. 2012;87(5):455-60. 
34. 
Ravindranath V, Chandrasekhara N. Metabolism of curcumin--studies with 
[3H]curcumin. Toxicology. 1981;22(4):337-44. 
35. 
Wahlstrom B, Blennow G. A study on the fate of curcumin in the rat. Acta 
pharmacologica et toxicologica. 1978;43(2):86-92. 
36. 
Holder GM, Plummer JL, Ryan AJ. The metabolism and excretion of curcumin (1,7-
bis-(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione) in the rat. Xenobiotica; the fate 
of foreign compounds in biological systems. 1978;8(12):761-8. 
37. 
Ravindranath V, Chandrasekhara N. Absorption and tissue distribution of curcumin in 
rats. Toxicology. 1980;16(3):259-65. 
38. 
Garcea G, Berry DP, Jones DJ, Singh R, Dennison AR, Farmer PB, et al. 
Consumption of the putative chemopreventive agent curcumin by cancer patients: assessment 
of curcumin levels in the colorectum and their pharmacodynamic consequences. Cancer 
epidemiology, biomarkers & prevention : a publication of the American Association for 
Cancer Research, cosponsored by the American Society of Preventive Oncology. 
2005;14(1):120-5. 
39. 
Sharma RA, Ireson CR, Verschoyle RD, Hill KA, Williams ML, Leuratti C, et al. 
Effects of dietary curcumin on glutathione S-transferase and malondialdehyde-DNA adducts 
in rat liver and colon mucosa: relationship with drug levels. Clinical cancer research : an 
official journal of the American Association for Cancer Research. 2001;7(5):1452-8. 
40. 
Shoba G, Joy D, Joseph T, Majeed M, Rajendran R, Srinivas PS. Influence of 
piperine on the pharmacokinetics of curcumin in animals and human volunteers. Planta 
medica. 1998;64(4):353-6. 
41. 
Perkins S, Verschoyle RD, Hill K, Parveen I, Threadgill MD, Sharma RA, et al. 
Chemopreventive efficacy and pharmacokinetics of curcumin in the min/+ mouse, a model of 
familial adenomatous polyposis. Cancer epidemiology, biomarkers & prevention : a 
publication of the American Association for Cancer Research, cosponsored by the American 
Society of Preventive Oncology. 2002;11(6):535-40. 


 
CASE 5913  
Protocol Version 7 Dated 10/2/2018 
 
 
60 of 74 
42. 
Shpitz B, Giladi N, Sagiv E, Lev-Ari S, Liberman E, Kazanov D, et al. Celecoxib and 
curcumin additively inhibit the growth of colorectal cancer in a rat model. Digestion. 
2006;74(3-4):140-4. 
43. 
Sharma RA, Euden SA, Platton SL, Cooke DN, Shafayat A, Hewitt HR, et al. Phase I 
clinical trial of oral curcumin: biomarkers of systemic activity and compliance. Clinical 
cancer research : an official journal of the American Association for Cancer Research. 
2004;10(20):6847-54. 
44. 
Ireson CR, Jones DJ, Orr S, Coughtrie MW, Boocock DJ, Williams ML, et al. 
Metabolism of the cancer chemopreventive agent curcumin in human and rat intestine. 
Cancer epidemiology, biomarkers & prevention : a publication of the American Association 
for Cancer Research, cosponsored by the American Society of Preventive Oncology. 
2002;11(1):105-11. 
45. 
Cheng AL, Hsu CH, Lin JK, Hsu MM, Ho YF, Shen TS, et al. Phase I clinical trial of 
curcumin, a chemopreventive agent, in patients with high-risk or pre-malignant lesions. 
Anticancer research. 2001;21(4B):2895-900. 
46. 
Garcea G, Jones DJ, Singh R, Dennison AR, Farmer PB, Sharma RA, et al. Detection 
of curcumin and its metabolites in hepatic tissue and portal blood of patients following oral 
administration. British journal of cancer. 2004;90(5):1011-5. 
47. 
Shoskes D, Lapierre C, Cruz-Correa M, Muruve N, Rosario R, Fromkin B, et al. 
Beneficial effects of the bioflavonoids curcumin and quercetin on early function in cadaveric 
renal 
transplantation: 
a 
randomized 
placebo 
controlled 
trial. 
Transplantation. 
2005;80(11):1556-9. 
48. 
Aggarwal BB, Kumar A, Bharti AC. Anticancer potential of curcumin: preclinical 
and clinical studies. Anticancer research. 2003;23(1A):363-98. 
49. 
Miller JW. Vitamin D and cognitive function in older adults: are we concerned about 
vitamin D-mentia? Neurology. 2010;74(1):13-5. 
50. 
Baeke F, Gysemans C, Korf H, Mathieu C. Vitamin D insufficiency: implications for 
the immune system. Pediatr Nephrol. 2010;25(9):1597-606. 
51. 
Giovannucci E, Liu Y, Rimm EB, Hollis BW, Fuchs CS, Stampfer MJ, et al. 
Prospective study of predictors of vitamin D status and cancer incidence and mortality in 
men. Journal of the National Cancer Institute. 2006;98(7):451-9. 
52. 
Kim M, Mirandola L, Pandey A, Nguyen DD, Jenkins MR, Turcel M, et al. 
Application of vitamin D and derivatives in hematological malignancies. Cancer letters. 
2012;319(1):8-22. 
53. 
Porojnicu AC, Robsahm TE, Ree AH, Moan J. Season of diagnosis is a prognostic 
factor in Hodgkin's lymphoma: a possible role of sun-induced vitamin D. British journal of 
cancer. 2005;93(5):571-4. 
54. 
Hughes AM, Armstrong BK, Vajdic CM, Turner J, Grulich AE, Fritschi L, et al. Sun 
exposure may protect against non-Hodgkin lymphoma: a case-control study. International 
journal of cancer Journal international du cancer. 2004;112(5):865-71. 
55. 
Kricker A, Armstrong BK, Hughes AM, Goumas C, Smedby KE, Zheng T, et al. 
Personal sun exposure and risk of non Hodgkin lymphoma: a pooled analysis from the 
Interlymph Consortium. International journal of cancer Journal international du cancer. 
2008;122(1):144-54. 


 
CASE 5913  
Protocol Version 7 Dated 10/2/2018 
 
 
61 of 74 
56. 
Lim U, Freedman DM, Hollis BW, Horst RL, Purdue MP, Chatterjee N, et al. A 
prospective investigation of serum 25-hydroxyvitamin D and risk of lymphoid cancers. 
International journal of cancer Journal international du cancer. 2009;124(4):979-86. 
57. 
Purdue MP, Hartge P, Davis S, Cerhan JR, Colt JS, Cozen W, et al. Sun exposure, 
vitamin D receptor gene polymorphisms and risk of non-Hodgkin lymphoma. Cancer causes 
& control : CCC. 2007;18(9):989-99. 
58. 
Raimondi S, Johansson H, Maisonneuve P, Gandini S. Review and meta-analysis on 
vitamin D receptor polymorphisms and cancer risk. Carcinogenesis. 2009;30(7):1170-80. 
59. 
Hickish T, Cunningham D, Colston K, Millar BC, Sandle J, Mackay AG, et al. The 
effect of 1,25-dihydroxyvitamin D3 on lymphoma cell lines and expression of vitamin D 
receptor in lymphoma. British journal of cancer. 1993;68(4):668-72. 
60. 
Chen S, Sims GP, Chen XX, Gu YY, Lipsky PE. Modulatory effects of 1,25-
dihydroxyvitamin D3 on human B cell differentiation. J Immunol. 2007;179(3):1634-47. 
61. 
Consolini R, Pala S, Legitimo A, Crimaldi G, Ferrari S. Effects of vitamin D on the 
growth of normal and malignant B-cell progenitors. Clinical and experimental immunology. 
2001;126(2):214-9. 
62. 
Pepper C, Thomas A, Hoy T, Milligan D, Bentley P, Fegan C. The vitamin D3 analog 
EB1089 induces apoptosis via a p53-independent mechanism involving p38 MAP kinase 
activation and suppression of ERK activity in B-cell chronic lymphocytic leukemia cells in 
vitro. Blood. 2003;101(7):2454-60. 
63. 
Shanafelt TD, Drake MT, Maurer MJ, Allmer C, Rabe KG, Slager SL, et al. Vitamin 
D insufficiency and prognosis in chronic lymphocytic leukemia. Blood. 2011;117(5):1492-8. 
64. 
Politzer WM. Long-term clinical remission of a patient with chronic lymphocytic 
leukemia using alternative treatment option: cottonseed oil (gossypol). Phytomedicine : 
international journal of phytotherapy and phytopharmacology. 2008;15(8):563-5. 
65. 
Amir E, Simmons CE, Freedman OC, Dranitsaris G, Cole DE, Vieth R, et al. A phase 
2 trial exploring the effects of high-dose (10,000 IU/day) vitamin D(3) in breast cancer 
patients with bone metastases. Cancer. 2010;116(2):284-91. 
66. 
Gallagher JC. Metabolic effects of synthetic calcitriol (Rocaltrol) in the treatment of 
postmenopausal osteoporosis. Metabolism: clinical and experimental. 1990;39(4 Suppl 1):27-
9. 
67. 
Gallagher JC, Goldgar D. Treatment of postmenopausal osteoporosis with high doses 
of synthetic calcitriol. A randomized controlled study. Annals of internal medicine. 
1990;113(9):649-55. 
68. 
Gross C, Stamey T, Hancock S, Feldman D. Treatment of early recurrent prostate 
cancer 
with 
1,25-dihydroxyvitamin 
D3 
(calcitriol). 
The 
Journal 
of 
urology. 
1998;159(6):2035-9; discussion 9-40. 
69. 
Osborn JL, Schwartz GG, Smith DC, Bahnson R, Day R, Trump DL. Phase II trial of 
oral 1,25-dihydroxyvitamin D (calcitriol) in hormone refractory prostate cancer. Urologic 
oncology. 1995;1(5):195-8. 
70. 
Muindi JR, Peng Y, Potter DM, Hershberger PA, Tauch JS, Capozzoli MJ, et al. 
Pharmacokinetics of high-dose oral calcitriol: results from a phase 1 trial of calcitriol and 
paclitaxel. Clinical pharmacology and therapeutics. 2002;72(6):648-59. 
71. 
Fakih MG, Trump DL, Muindi JR, Black JD, Bernardi RJ, Creaven PJ, et al. A phase 
I pharmacokinetic and pharmacodynamic study of intravenous calcitriol in combination with 


 
CASE 5913  
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62 of 74 
oral gefitinib in patients with advanced solid tumors. Clinical cancer research : an official 
journal of the American Association for Cancer Research. 2007;13(4):1216-23. 
72. 
Muindi JR, Johnson CS, Trump DL, Christy R, Engler KL, Fakih MG. A phase I and 
pharmacokinetics study of intravenous calcitriol in combination with oral dexamethasone and 
gefitinib in patients with advanced solid tumors. Cancer chemotherapy and pharmacology. 
2009;65(1):33-40. 
73. 
Muindi JR, Modzelewski RA, Peng Y, Trump DL, Johnson CS. Pharmacokinetics of 
1alpha,25-dihydroxyvitamin D3 in normal mice after systemic exposure to effective and safe 
antitumor doses. Oncology. 2004;66(1):62-6. 
74. 
Beer TM, Munar M, Henner WD. A Phase I trial of pulse calcitriol in patients with 
refractory malignancies: pulse dosing permits substantial dose escalation. Cancer. 
2001;91(12):2431-9. 
75. 
Beer TM, Javle MM, Ryan CW, Garzotto M, Lam GN, Wong A, et al. Phase I study 
of weekly DN-101, a new formulation of calcitriol, in patients with cancer. Cancer 
chemotherapy and pharmacology. 2007;59(5):581-7. 
76. 
Mosieniak G, Sliwinska M, Piwocka K, Sikora E. Curcumin abolishes apoptosis 
resistance of calcitriol-differentiated HL-60 cells. FEBS letters. 2006;580(19):4653-60. 
77. 
Bartik L, Whitfield GK, Kaczmarska M, Lowmiller CL, Moffet EW, Furmick JK, et 
al. Curcumin: a novel nutritionally derived ligand of the vitamin D receptor with implications 
for 
colon 
cancer 
chemoprevention. 
The 
Journal 
of 
nutritional 
biochemistry. 
2010;21(12):1153-61. 
78. 
Shanafelt TD, Call TG, Zent CS, Leis JF, LaPlant B, Bowen DA, et al. Phase 2 trial 
of daily, oral Polyphenon E in patients with asymptomatic, Rai stage 0 to II chronic 
lymphocytic leukemia. Cancer. 2013;119(2):363-70. 
79. 
Gribben JG. How I treat CLL up front. Blood. 2010;115(2):187-97. 
80. 
Chel VG, Ooms ME, Popp-Snijders C, Pavel S, Schothorst AA, Meulemans CC, et al. 
Ultraviolet irradiation corrects vitamin D deficiency and suppresses secondary 
hyperparathyroidism in the elderly. Journal of bone and mineral research : the official journal 
of the American Society for Bone and Mineral Research. 1998;13(8):1238-42. 
81. 
Davie MW, Lawson DE, Emberson C, Barnes JL, Roberts GE, Barnes ND. Vitamin 
D from skin: contribution to vitamin D status compared with oral vitamin D in normal and 
anticonvulsant-treated subjects. Clinical science. 1982;63(5):461-72. 
82. 
Holick MF. Environmental factors that influence the cutaneous production of vitamin 
D. The American journal of clinical nutrition. 1995;61(3 Suppl):638S-45S. 
83. 
Stamp TC. Factors in human vitamin D nutrition and in the production and cure of 
classical rickets. The Proceedings of the Nutrition Society. 1975;34(2):119-30. 
84. 
Hathcock JN, Shao A, Vieth R, Heaney R. Risk assessment for vitamin D. The 
American journal of clinical nutrition. 2007;85(1):6-18. 
85. 
Chen Y, Liu WH, Chen BL, Fan L, Han Y, Wang G, et al. Plant polyphenol curcumin 
significantly affects CYP1A2 and CYP2A6 activity in healthy, male Chinese volunteers. The 
Annals of pharmacotherapy. 2010;44(6):1038-45. 
86. 
Joseph RW, Bayraktar UD, Kim TK, St John LS, Popat U, Khalili J, et al. Vitamin D 
receptor upregulation in alloreactive human T cells. Human immunology. 2012;73(7):693-8. 
87. 
Rogalinska M, Kilianska ZM. Targeting Bcl-2 in CLL. Current medicinal chemistry. 
2012;19(30):5109-15. 


 
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63 of 74 
88. 
Rao J, Xu DR, Zheng FM, Long ZJ, Huang SS, Wu X, et al. Curcumin reduces 
expression of Bcl-2, leading to apoptosis in daunorubicin-insensitive CD34+ acute myeloid 
leukemia cell lines and primary sorted CD34+ acute myeloid leukemia cells. Journal of 
translational medicine. 2011;9:71. 
89. 
Yu J, Zhou X, He X, Dai M, Zhang Q. Curcumin induces apoptosis involving 
bax/bcl-2 in human hepatoma SMMC-7721 cells. Asian Pacific journal of cancer prevention 
: APJCP. 2011;12(8):1925-9. 
90. 
Kizildag S, Ates H, Kizildag S. Treatment of K562 cells with 1,25-dihydroxyvitamin 
D3 induces distinct alterations in the expression of apoptosis-related genes BCL2, BAX, 
BCLXL, and p21. Annals of hematology. 2010;89(1):1-7. 
91. 
Degheidy HA, Gadalla SM, Farooqui MZ, Abbasi F, Arthur DC, Bauer SR, et al. Bcl-
2 level as a biomarker for 13q14 deletion in CLL. Cytometry Part B, Clinical cytometry. 
2013;84(4):237-47. 
92. 
Lafarge S, Hamzeh-Cognasse H, Chavarin P, Genin C, Garraud O, Cognasse F. A 
flow cytometry technique to study intracellular signals NF-kappaB and STAT3 in peripheral 
blood mononuclear cells. BMC molecular biology. 2007;8:64. 
93. 
Woost PG, Solchaga LA, Meyerson HJ, Shankey TV, Goolsby CL, Jacobberger JW. 
High-resolution kinetics of cytokine signaling in human CD34/CD117-positive cells in 
unfractionated bone marrow. Blood. 2011;117(15):e131-41. 
94. 
Sharma RA, McLelland HR, Hill KA, Ireson CR, Euden SA, Manson MM, et al. 
Pharmacodynamic and pharmacokinetic study of oral Curcuma extract in patients with 
colorectal cancer. Clinical cancer research : an official journal of the American Association 
for Cancer Research. 2001;7(7):1894-900. 
95. 
Asai A, Miyazawa T. Occurrence of orally administered curcuminoid as glucuronide 
and glucuronide/sulfate conjugates in rat plasma. Life sciences. 2000;67(23):2785-93. 
96. 
Basnet P, Skalko-Basnet N. Curcumin: an anti-inflammatory molecule from a curry 
spice on the path to cancer treatment. Molecules. 2011;16(6):4567-98. 
97. 
van den Ouweland JM, Beijers AM, Demacker PN, van Daal H. Measurement of 25-
OH-vitamin D in human serum using liquid chromatography tandem-mass spectrometry with 
comparison to radioimmunoassay and automated immunoassay. Journal of chromatography 
B, Analytical technologies in the biomedical and life sciences. 2010;878(15-16):1163-8. 
98. 
Holick MF. Vitamin D deficiency. The New England journal of medicine. 
2007;357(3):266-81. 
99. 
Shanafelt TD, Bowen D, Venkat C, Slager SL, Zent CS, Kay NE, et al. Quality of life 
in chronic lymphocytic leukemia: an international survey of 1482 patients. British journal of 
haematology. 2007;139(2):255-64. 
100. 
Panahi Y, Sahebkar A, Amiri M, Davoudi SM, Beiraghdar F, Hoseininejad SL, et al. 
Improvement of sulphur mustard-induced chronic pruritus, quality of life and antioxidant 
status by curcumin: results of a randomised, double-blind, placebo-controlled trial. The 
British journal of nutrition. 2012;108(7):1272-9. 
101. 
Kanai M. Therapeutic applications of curcumin for patients with pancreatic cancer. 
World journal of gastroenterology : WJG. 2014;20(28):9384-91. 
102. 
Martinez-Alonso M, Dusso A, Ariza G, Nabal M. The effect on quality of life of 
vitamin D administration for advanced cancer treatment (VIDAFACT study): protocol of a 
randomised controlled trial. BMJ open. 2014;4(12):e006128. 


 
CASE 5913  
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103. 
Miller CW, Marino A, Moukharskaya J, Peiris AN. High vitamin D levels and 
improved quality of life in a patient with metastatic colorectal cancer: case report. Tennessee 
medicine : journal of the Tennessee Medical Association. 2009;102(10):37-8. 
104. 
Georgakopoulos A, Kontodimopoulos N, Chatziioannou S, Niakas D. EORTC QLQ-
C30 and FACT-Lym for the assessment of health-related quality of life of newly diagnosed 
lymphoma patients undergoing chemotherapy. European journal of oncology nursing : the 
official journal of European Oncology Nursing Society. 2013;17(6):849-55. 
105. 
Levin TT, Li Y, Riskind J, Rai K. Depression, anxiety and quality of life in a chronic 
lymphocytic leukemia cohort. General hospital psychiatry. 2007;29(3):251-6. 
106. 
Harrison CN, Mesa RA, Kiladjian JJ, Al-Ali HK, Gisslinger H, Knoops L, et al. 
Health-related quality of life and symptoms in patients with myelofibrosis treated with 
ruxolitinib versus best available therapy. British journal of haematology. 2013;162(2):229-
39. 
107. 
Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Dohner H, 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):5446-56. 
108. 
Cheson BD. New staging and response criteria for non-Hodgkin lymphoma and 
Hodgkin lymphoma. Radiologic clinics of North America. 2008;46(2):213-23, vii. 


 
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APPENDIX A 
 
EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG) PERFORMANCE 
STATUS CRITERIA 
 
 
 
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. 
 
 
 
 


 
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APPENDIX B 
 
INDICATIONS FOR TREATMENT PER NCI-WG CRITERIA FOR CLL (107) 
 
1. A minimum of any one of the following disease-related symptoms must be 
present: 
a. Weight loss >= 10% within the previous 6 months. 
b. Extreme fatigue (ie, ECOG PS 2 or worse; cannot work or unable to 
perform usual activities). 
c. Fevers of greater than 100.5°F for >= 2 weeks without evidence of 
infection. 
d. Night sweats without evidence of infection 
2. Evidence of progressive marrow failure as manifested by the development of, or 
worsening of, anemia and/ or thrombocytopenia 
3. Autoimmune anemia and/or thrombocytopenia poorly responsive to corticosteroid 
therapy 
4. Massive (ie, >6 cm below the left costal margin) or progressive splenomegaly 
5. Massive nodes or clusters (ie, >10 cm in longest diameter) or progressive 
lymphadenopathy 
6. Progressive lymphocytosis with an increase of >50% over a 2-month period, or 
an anticipated doubling time of less than 6 months 
7. Marked hypogammaglobulinemia or the development of a monoclonal protein in 
the absence of any of the above criteria for active disease is not sufficient for 
protocol therapy 
 
 
 
 
 
 


 
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APPENDIX C 
PATIENT PILL DIARY FOR CYCLE 1  
Patient Name ________________________Protocol #________________ Patient Study ID __________  
Cycle #: _______    
       Month #: _______     
INSTRUCTIONS FOR THE PATIENT: 
   1.  You will take 8 tablets of 1000 mg curcumin pills each day with or without food with a full glass (8 oz of water). 
   2.  You will take 1 tablet of 10,000 IU vitamin D3 pills each day with or without food with a full glass (8 oz of water) starting 
1 week after you start taking curcumin and continuously thereafter. 
   3.  Record the date, the number of tablets you took, and what time you took them. 
   4.  If you have any comments please record them in the “Comments” column below. 
   5.  Please bring your pill bottle and this form to your physician when you come for your next appointment.   
   6.  Please sign your name at the bottom of the diary.
Date 
 
Day 
8 tablets of 1000 mg 
curcumin pills and time 
taken 
1 tablet of 10,000 IU vitamin 
D3 pills and time taken 
 
Comments 
 
1 
 
 
 
 
2 
 
 
 
3 
 
 
 
4 
 
 
 
5 
 
 
 
6 
 
 
 
7 
 
 
 
8 
 
 
 
 
9 
 
 
 
 
10 
 
 
 
 
11 
 
 
 
 
12 
 
 
 
 
13 
 
 
 
 
14 
 
 
 
 
15 
 
 
 
 
16 
 
 
 
 
17 
 
 
 
 
18 
 
 
 
 
19 
 
 
 
 
20 
 
 
 
 
21 
 
 
 
 
22 
 
 
 
 
23 
 
 
 
 
24 
 
 
 
 
25 
 
 
 
 
26 
 
 
 
 
27 
 
 
 
 
28 
 
 
 
 


 
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Patient’s Signature: ________________________________________ Date: ___________ 
APPENDIX D 
PATIENT PILL DIARY FOR CYCLES 2-6  
Patient Name ________________________Protocol #________________ Patient Study ID __________  
Cycle #: _______    
       Month #: _______     
INSTRUCTIONS FOR THE PATIENT: 
   1.  You will take 8 tablets of 1000 mg curcumin pills each day with or without food with a full glass (8 oz of water). 
   2.  You will take 1 tablet of 10,000 IU vitamin D3 pills each day with or without food with a full glass (8 oz of water)   3.  
Record the date, the number of tablets you took, and what time you took them. 
   4.  If you have any comments please record them in the “Comments” column below. 
   5.  Please bring your pill bottle and this form to your physician when you come for your next appointment.   
   6.  Please sign your name at the bottom of the diary.
Date 
 
Day 
8 tablets of 1000 mg 
curcumin pills and time 
taken 
1 tablet of 10,000 IU vitamin 
D3 pills and time taken 
 
Comments 
 
1 
 
 
 
 
2 
 
 
 
 
3 
 
 
 
 
4 
 
 
 
 
5 
 
 
 
 
6 
 
 
 
 
7 
 
 
 
 
8 
 
 
 
 
9 
 
 
 
 
10 
 
 
 
 
11 
 
 
 
 
12 
 
 
 
 
13 
 
 
 
 
14 
 
 
 
 
15 
 
 
 
 
16 
 
 
 
 
17 
 
 
 
 
18 
 
 
 
 
19 
 
 
 
 
20 
 
 
 
 
21 
 
 
 
 
22 
 
 
 
 
23 
 
 
 
 
24 
 
 
 
 
25 
 
 
 
 
26 
 
 
 
 
27 
 
 
 
 
28 
 
 
 
 
Patient’s Signature: ________________________________________ Date: ___________ 
 


 
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APPENDIX E 
POTENTIAL CYP3A4 AND CYP2A6 INTERACTIONS 
 
CYP1A2 Substrates 
 
Alosetron  
Caffeine  
Clozapine  
Flutamide  
Frovatriptan  
Melatonin  
Mexiletine  
Mirtazapine 
Olanzapine  
Ramelteon  
Rasagiline 
Ropinirole  
Tacrine  
Theophylline  
Tizanidine  
Triamterene 
Zolmitriptan  
 
 
CYP2A6 Substrates 
 
Halothane 
Losigamone 
Methoxyflurane 
Cotinine 
Nicotine 
Valproic acid  
 
CYP1A2 Inducers 
 
Barbiturates 
Carbamazepine 
Primidone  
Rifampin  
Nicotine 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CYP2A6 Inducers 
 
Grapefruit juice  
Ketoconazole  
Methoxsalen  
Pilocarpine  
Tranylcypromine  
Isoniazid 
CYP1A2 Inhibitors 
 
Artemisinin  
Atazanavir  
Cimetidine  
Ciprofloxacin  
Enoxacin  
Ethinyl Estradiol  
Fluvoxamine  
Mexiletine  
Tacrine  
Thiabendazole  
Zileuton  
 
 
 
 
 
 
 
 
CYP2A6 Inhibitors 
 
Phenobarbital  
Rifampicin 
 


 
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 APPENDIX F  
 
POTENTIAL CYP3A4 INTERACTIONS 
 
 
CYP3A4 Inhibitors 
Acetaminophen 
Acetazolamide 
Amiodarone 
Amlodipine 
Amprenavir 
Anastrozole 
Aprepitant 
Atazanavir 
Atorvastatin 
Azelastine 
Azithromycin 
Betamethasone 
Bortezomib 
Bromocriptine 
Caffeine 
Cerivastatin 
Chloramphenicol 
Chlorzoxazone 
Cimetidine 
Ciprofloxacin 
Cisapride 
Clarithromycin 
Clemastine 
Clofazimine 
Clotrimazole 
Clozapine 
Cocaine 
Conivaptan 
Cyclophosphamide 
Cyclosporine 
Danazol 
Dasatinib (1) 
Delvirdine 
Desipramine 
Dexmedetomidine 
Diazepam 
 
Diclofenac 
Dihydroergotamine 
Diltiazem 
Disulfiram 
Docetaxel 
Doxorubicin 
Doxycycline 
Drospirenone 
Efavirenz 
Enoxacin 
Entacapone 
Ergotamine 
Erythromycin 
Ethinyl estradiol 
Etoposide 
Felodipine 
Fentanyl 
Fluconazole 
Fluoxetine 
Fluvastatin 
Fluvoxamine 
Fosamprenavir 
Glyburide 
Grapefruit Juice(2) 
Haloperidol 
Hydralazine 
Ifosfamide 
Imatinib 
Indinavair 
Irbesartan 
Isoniazid 
Isradipine 
Itraconazole 
Ketoconazole 
Lansoprazole 
Lidocaine 
 
Lomustine 
Losartan 
Lovastatin 
Mefloquine 
Mestranol 
Methadone 
Methimazole 
Methoxsalen 
Methylprednisolone 
Metronidazole 
Miconazole 
Midazolam 
Mifepristone 
Mirtazapine 
Mitoxantrone 
Modafinil 
Nefazodone 
Nelfinavir 
Nevirapine 
Nicardipine 
Nifedipine 
Nisoldipine 
Nizatidine 
Norfloxacin 
Olanzapine 
Omeprazole 
Orphenadrine 
Oxybutynin 
Paroxetine 
Pentamidine 
Pergolide 
Phencyclidine 
Pilocarapine 
Pimozide 
Pravastatin 
Prednisolone 
 
 
Primaquine 
Progesterone 
Propofol 
Propoxyphene 
Quinidine 
Quinine 
Quinupristin 
Rabeprazole 
Ranolazine 
Risperidone 
Ritonavir 
Saquinavir 
Selegiline 
Sertraline 
Sildenafil 
Sirolimus 
Sulconazole 
Tacrolimus 
Tamoxifen 
Telithromycin 
Teniposide 
Testosterone 
Tetracycline 
Ticlopidine 
Tranylcypromine 
Trazodone 
Troleandomycin 
Valproic Acid 
Venlafaxine 
Verapamil 
Vinblastine 
Vincristine 
Vinorelbine 
Voriconazole 
Zafirlukast 
Ziprasidone 
 


 
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APPENDIX F (continued) 
 
POTENTIAL CYP3A4 INTERACTIONS 
 
 
CYP3A4 Inducers 
Aminoglutethimide 
Carbamazepine 
Fosphenytoin 
Nafcillin 
Nevirapine 
Oxcarbazepine 
Pentobarbital 
Phenobarbital 
Phenytoin 
Primidone 
Rifabutin 
Rifampin 
Rifapentine 
St. John’s Wort (3) 
 
When drugs classified as ‘substrates’ are co-administered with (Study Agent), there is the potential for higher 
concentrations of the ‘substrate’. When (Study Agent)  is co-administered with compounds classified as 
‘inhibitors’, increased plasma concentrations of (Study Agent) is the potential outcome. The co-administration of 
‘inducers’ would potentially lower plasma (Study Agent) concentrations. 
 
Note: Adapted from Cytochrome P450 Enzymes: Substrates, Inhibitors, and Inducers. In: Lacy CF, Armstrong 
LL, Goldman MP, Lance LL eds. Drug Information Handbook 15TH ed. Hudson, OH; LexiComp Inc. 2007: 
1899-1912.   
Only major substrates and effective inducers are listed.   
Additional information for drug interactions with cytochrome P450 isoenzymes can be found at 
http://medicine.iupui.edu/flockhart/. 
 
(1)   Investigator’s Brochure: Dasatinib (BMS 354825). Bristol-Myers Squibb. October 2006. 
 
(2)  Malhotra et al. (2001). Clin Pharmacol Ther. 69:14-23. 
 
(3)  Mathijssen et al. (2002). J Natl Cancer Inst. 94:1247-1249. 
 
(4) Frye et al. (2004). Clin Pharmacol Ther. 76:323-329. 
 
 
 
 
Updated on May 1, 2007 


 
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APPENDIX G 
FACT-Lym (Version 4) 
English (Universal) 
 
16 November 2007 
Copyright  1987, 1997 
 
Page 1 of 3 
 
 
Below is a list of statements that other people with your illness have said are important. Please circle 
or mark one number per line to indicate your response as it applies to the past 7 days. 
 
 
 
 
 
PHYSICAL WELL-BEING 
 
Not 
at all 
A little 
bit 
Some-
what 
Quite
a bit 
Very 
much 
GP1 
I have a lack of energy .......................................................
0 
1 
2 
3 
4 
GP2 
I have nausea......................................................................
0 
1 
2 
3 
4 
GP3 
Because of my physical condition, I have trouble 
meeting the needs of my family.........................................
 
0 
 
1 
 
2 
 
3 
 
4 
GP4 
I have pain..........................................................................
0 
1 
2 
3 
4 
GP5 
I am bothered by side effects of treatment .........................
0 
1 
2 
3 
4 
GP6 
I feel ill ...............................................................................
0 
1 
2 
3 
4 
GP7 
I am forced to spend time in bed........................................
0 
1 
2 
3 
4 
 
 
 
SOCIAL/FAMILY WELL-BEING 
 
Not 
at all 
A little 
bit 
Some-
what 
Quite
a bit 
Very 
much 
GS1 
I feel close to my friends....................................................
0 
1 
2 
3 
4 
GS2 
I get emotional support from my family ............................
0 
1 
2 
3 
4 
GS3 
I get support from my friends.............................................
0 
1 
2 
3 
4 
GS4 
My family has accepted my illness ....................................
0 
1 
2 
3 
4 
GS5 
I am satisfied with family communication about my 
illness..................................................................................
 
0 
 
1 
 
2 
 
3 
 
4 
GS6 
I feel close to my partner (or the person who is my main 
support) ..............................................................................
 
0 
 
1 
 
2 
 
3 
 
4 
Q1 
Regardless of your current level of sexual activity, please 
answer the following question. If you prefer not to answer it, 
please mark this box           and go to the next section. 
 
 
 
 
 
GS7 
I am satisfied with my sex life ............................................
0 
1 
2 
3 
4 
 


 
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APPENDIX G (continued) 
FACT-Lym (Version 4) 
English (Universal) 
 
16 November 2007 
Copyright  1987, 1997 
 
Page 2 of 3 
 
 
Please circle or mark one number per line to indicate your response as it applies to the past 7 
days. 
 
 
 
 
EMOTIONAL WELL-BEING 
Not 
at all 
A little 
bit 
Some-
what 
Quite
a bit 
Very 
much 
GE1 
I feel sad ..............................................................................
0 
1 
2 
3 
4 
GE2 
I am satisfied with how I am coping with my illness..........
0 
1 
2 
3 
4 
GE3 
I am losing hope in the fight against my illness..................
0 
1 
2 
3 
4 
GE4 
I feel nervous.......................................................................
0 
1 
2 
3 
4 
GE5 
I worry about dying.............................................................
0 
1 
2 
3 
4 
GE6 
I worry that my condition will get worse............................
0 
1 
2 
3 
4 
 
 
 
 
 
FUNCTIONAL WELL-BEING 
 
Not 
at all 
A little 
bit 
Some-
what 
Quite
a bit 
Very 
much 
GF1 
I am able to work (include work at home) ..........................
0 
1 
2 
3 
4 
GF2 
My work (include work at home) is fulfilling.....................
0 
1 
2 
3 
4 
GF3 
I am able to enjoy life..........................................................
0 
1 
2 
3 
4 
GF4 
I have accepted my illness...................................................
0 
1 
2 
3 
4 
GF5 
I am sleeping well ...............................................................
0 
1 
2 
3 
4 
GF6 
I am enjoying the things I usually do for fun ......................
0 
1 
2 
3 
4 
GF7 
I am content with the quality of my life right now..............
0 
1 
2 
3 
4 
 
 


 
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APPENDIX G (continued) 
FACT-Lym (Version 4) 
English (Universal) 
 
16 November 2007 
Copyright  1987, 1997 
 
Page 3 of 3 
 
 
Please circle or mark one number per line to indicate your response as it applies to the past 7 
days. 
 
 
 
ADDITIONAL CONCERNS 
 
Not 
at all 
A little 
bit 
Some-
what 
Quite 
a bit 
Very 
much 
P2 
I have certain parts of my body where I experience pain....
0 
1 
2 
3 
4 
LEU1 
I am bothered by lumps or swelling in certain parts of 
my body (e.g., neck, armpits, or groin)...............................
 
0 
 
1 
 
2 
 
3 
 
4 
BRM3 
I am bothered by fevers (episodes of high body 
temperature) ........................................................................
 
0 
 
1 
 
2 
 
3 
 
4 
ES3 
I have night sweats..............................................................
0 
1 
2 
3 
4 
LYM1 
I am bothered by itching .....................................................
0 
1 
2 
3 
4 
LYM2 
I have trouble sleeping at night ...........................................
0 
1 
2 
3 
4 
BMT6 
I get tired easily...................................................................
0 
1 
2 
3 
4 
C2 
I am losing weight...............................................................
0 
1 
2 
3 
4 
Ga1 
I have a loss of appetite.......................................................
0 
1 
2 
3 
4 
HI8 
I have trouble concentrating................................................
0 
1 
2 
3 
4 
N3 
I worry about getting infections ..........................................
0 
1 
2 
3 
4 
LEU6 
I worry that I might get new symptoms of my illness.........
0 
1 
2 
3 
4 
LEU7 
I feel isolated from others because of my illness or 
treatment..............................................................................
 
0 
 
1 
 
2 
 
3 
 
4 
BRM9 
I have emotional ups and downs .........................................
0 
1 
2 
3 
4 
LEU4 
Because of my illness, I have difficulty planning for the 
future ...................................................................................
 
0 
 
1 
 
2 
 
3 
 
4