Clinical trial NCT00445341
Conditions: Lymphoma
Keywords: Microarray Proteomics Hybrid Schedule Tumor Lysis Syndrome Cyclin D1 Lymphoma Mantle Cell Lymphoma MCL Diffuse Large B-Cell Lymphoma DLBCL
Sponsor: National Cancer Institute (NCI)
Start date: 2006-11-27; Completion date: 2012-10-18
Enrollment: 28 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Background:

Mantle cell lymphoma (MCL) and diffuse large B-cell lymphoma (DLBCL) are aggressive subtypes of non-Hodgkin lymphoma.

Flavopiridol is an investigational drug that works differently from standard chemotherapy and may target abnormalities in MCL and DLBCL cells, such as a protein excess that prevents tumor cells from dying.

A challenge in developing flavopiridol for treatment has been determining its optimal dosing schedule. The schedule used for this study is effective in a type of leukemia called chronic lymphocytic leukemia (CLL) and may benefit patients with MCL and DLBCL also.

Objectives:

To determine the highest dose of flavopiridol that can be given safely to patients with relapsed MCL and DLBCL at the dosing schedule detailed below

To assess the response of the tumor to flavopiridol given at the test dosing schedule

Eligibility:

Patients 18 years of age and older with relapsed MCL or DLBCL

Design:

Flavopiridol is given at four different dose levels, starting with the lowest dose for the first group of three to six patients and increasing with subsequent groups, depending on side effects at the preceding dose. The drug is given weekly for 4 weeks followed by a 2-week break (one cycle) for up to six cycles. It is given through a vein as a 30-minute infusion followed by a 4-hour infusion.

Patients undergo the following procedures for research studies and to evaluate the effect of treatment on the tumor:

* Blood tests
* Lymph node, bone marrow and tumor biopsies
* Lymphapheresis to collect blood cells for research
* Disease staging with imaging studies (computed tomography (CT), positron emission tomography (PET) and/or magnetic resonance imaging (MRI) after every 2 cycles

Detailed description:
Background:

Flavopiridol is a synthetic N-methylpiperidinyl, chlorophenyl flavone compound that targets a number of different cellular pathways and processes.

It works through several different mechanisms that include inhibition of cyclin dependent kinases and the cyclin D-1 complex which is over-expressed in mantle cell lymphoma. Flavopiridol also has demonstrated activity in activated B-like diffuse large B-cell lymphoma cell lines.

One of the great challenges in developing flavopiridol and applying it clinically has been determining its optimal dosing schedule. Following several different dosing schedules, one strategy that has been very promising in chronic lymphocytic leukemia (CLL) is the application of so-called hybrid schedules of the drug (an infusion for an intermediate time following a bolus dose).

Objectives:

Assess the toxicity and safety of administration of this hybrid schedule.

Assess the response rate of the hybrid schedule of flavopiridol in relapsed mantle cell lymphoma (MCL) and diffuse large B-cell lymphoma (DLBCL).

Eligibility:

Relapsed MCL or DLBCL.

Eastern Cooperative Oncology Group (ECOG) performance status(P.S.) less than or equal to 2.

Age greater than or equal to 18 years.

Human immunodeficiency virus (HIV) serology negative

Design:

Phase I/II.

Phase I portion consists of 3-4 dose levels of 3-6 patients each.

Administer weekly times 4 and then 2 weeks off (1 cycle). Restage after every 2 cycles. Continue if complete response (CR), partial response (PR) or stable disease (SD) for up to 6 cycles. Dose reductions for toxicity will be addressed in the protocol.

Phase II portion of the study will be a Simon optimal two-stage design: designed to rule out 20% response rate (p0=0.20) in favor of a 45% response rate (p1=0.45).

The maximum sample size to be accrued for this study will be 71 patients.

Arms: arm 1: Flavopiridol 30 mg/m\^2 is given weekly for 4 weeks followed by a 2 week break for up to 6 cycles. It is given through a vein as a 30 minute infusion followed by a 4 hour infusion.
Interventions: intervention 1: Flavopiridol
Intervention descriptions: intervention 1: Flavopiridol 30 mg/m\^2 is given weekly for 4 weeks followed by a 2 week break for up to 6 cycles. It is given through a vein as a 30 minute infusion followed by a 4 hour infusion.

Protocol documents:
Prot_SAP_001.pdf: 
Amendment
Protocol Number:
07C0081-L
Principal Investigator: Mark Roschewski 
NCI 
LYMB 
301.451.9021 
mark.roschewski@nih.gov
(NIH Employee Name, Institute/Branch, Telephone and e-mail)
Reference Number:
373915
Protocol Title:
A Phase I/II Study of Flavopiridol in Relapsed or Refractory Mantle Cell Lymphoma (MCL) and Diffuse Large B-cell Lymphoma (DLBCL)
SIGNATURES
Principal Investigator (*): 
James L Gulley,  MD PhD - applied signature on 09/28/2017 4:53 PM EDT 
Mark Roschewski - applied signature on 09/28/2017 6:12 PM EDT
Accountable Investigator:
PI is the Accountable Investigator
Branch Chief/CC Department Head (**):
Thomas Waldmann - applied signature on 09/29/2017 7:52 AM EDT
Medical Advisory Investigator (if applicable):
N/A
Lead Associate Investigator signature:
N/A
Referral Contact signatures:
N/A
Associate Investigators signatures:
N/A
For Institute/Center Scientific Review Committee:
N/A
Other IC Clinical Director signatures:
N/A
APPROVALS
IRB Chair:
Michael Hamilton - applied signature on 10/07/2017 2:50 AM EDT
Clinical Director:
N/A
CONCURRENCE
OPS Protocol Specialist:
Signature
Print Name
Date
* Signature signifies that investigators on this protocol have been informed that the collection and use of personally identifiable information at
the NIH are maintained in a system of record governed under provisions of the Privacy Act of 1974. The information provided is mandatory for
employees of the NIH to perform their assigned duties as related to the administration and reporting of intramural research protocols and
used solely for those purposes.  Questions may be addressed to the Protrak System Owner.
** I have reviewed this research project and considered the NIH Policy for Inclusion of Women and Minorities in Clinical Research. Taking into 
account the overall impact that the project could have on the research field involved, I feel the current plans adequately includes both sex/
gender, minorities, children, and special populations, as appropriate. The current enrollment is in line with the planned enrollment report for 
inclusion of individuals on the basis of their sex/gender, race, and ethnicity and is appropriate and of scientific and technical merit. 
IRB Meeting Date:
Expedited
DEC Clearance Date:
NA
Protocol Version Date:09/28/2017
Lemuel Clayborn                                                                                AM L                                                   10/16/2017


Abbreviated Title:  Flavo in relapsed lymphomas 
Version Date:  09/28/2017 
 
1 
 Abbreviated Title:  Flavo in relapsed lymphomas 
 
CC Protocol #:   07C0081 L 
 CTEP Protocol #: #7844 (NOTE: Completed with CTEP; Amendment J, dated 01/16/2015)  
 
Version Date:  09/28/2017 
 
NCT Number: NCT00445341 
 
A Phase I/II Study of Flavopiridol in Relapsed or Refractory Mantle Cell lymphoma 
(MCL) and Diffuse Large B-cell Lymphoma (DLBCL) 
 
 
Principal Investigator: Mark Roschewski, MD, LYMB, CCR, NCI A-F 
Lymphoid Malignancies Branch (LYMB), CCR, NCI 
Building 10, Room 4N115 
National Institutes of Health 
Bethesda, MD 20892 
Phone: 240-760-6183  
Email:  mark.roschewski@nih.gov 
 
 
Lead Associate Investigator:   Adrian Wiestner M.D., Ph.D. NHLBIA-F 
 
 Hematology Branch, NHLBI 
 
 Building 10, Room 3-5140 
 
 National Institutes of Health 
 
 Bethesda, MD 20892 
 
 Phone:  301-594-6855 
 
 Email:  wiestnea@nhlbi.nih.gov  
 
 
Associate Investigators:   Wyndham Wilson, M.D., Ph.D. LYMB, CCR, NCIA-F 
Margaret Shovlin, R.N. OCD, CCR, NCI A-D 
Andrea Nicole Lucas, RN, OCD, CCR, NCI A-D 
Maryalice Stetler-Stevenson, M.D., LP, CCR, NCIE-F 
Seth Steinberg, Ph.D., OCD, CCR, NCI E-F 
 
 
Non-NIH Associate Investigator: Geoffrey Shapiro, M.D., Ph.D.  
Dana Farber Cancer Institute F-G 
 
 
 
Study Coordinator/ 
 
 
Referral Contact: Margaret Shovlin, R.N. OCD, CCR, NCI 
 
  Phone:  240-760-6089 
 
  Email:  mshovlin@mail.nih.gov 
 
 
Accountable Investigator: Wyndham H. Wilson, M.D., Ph.D. 
 
 
 
 


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Version Date:  09/28/2017 
 
2 
Investigator Roles: 
A. Obtain information by intervening or interacting with living individuals for research purposes 
B. Obtaining identifiable private information about living individuals 
C. Obtaining the voluntary informed consent of individuals to be subjects 
D. Makes decisions about subject eligibility 
E. Studying, interpreting, or analyzing identifiable private information or data/specimens for 
research purposes 
F. Studying, interpreting, or analyzing de-identified data or specimens for research purposes 
G. Some/all research activities performed outside NIH 
 
Investigational Agents:   
Drug Name: 
Flavopiridol 
IND Number: 
IND #46211 
Sponsor: 
CTEP 
Manufacturer: 
Sanofi-Aventis Pharmaceuticals, Inc. 
 
NOTE:  The protocol has been completed with CTEP effective Amendment J (version date 
01/16/2015). 
Commercial Agents:  None 


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PRÉCIS 
 
Background:  
• Flavopiridol is a synthetic N-methylpiperidinyl, chlorophenyl flavone compound that 
targets a number of different cellular pathways and processes.  
• It works through several different mechanisms that include inhibition of cyclin dependent 
kinases and the cyclin D-1 complex which is over-expressed in mantle cell lymphoma. 
Flavopiridol also has demonstrated activity in activated B-like diffuse large B-cell 
lymphoma cell lines.  
• One of the great challenges in developing flavopiridol and applying it clinically has been 
determining its optimal dosing schedule. Following several different dosing schedules, one 
strategy that has been very promising in CLL is the application of so-called hybrid 
schedules of the drug (an infusion for an intermediate time following a bolus dose).  
 
Objectives:  
• Assess the toxicity and safety of administration of this hybrid schedule 
• Assess the response rate of the hybrid schedule of flavopiridol in relapsed MCL and 
DLBCL 
 
Eligibility: 
• Relapsed MCL or DLBCL 
• ECOG P.S. ≤ 2 
• Age ≥ 18 years 
• HIV serology negative 
 
Design: 
• Phase I/II 
• Phase I portion consists of 3-4 dose levels of 3-6 patients each 
• Administer weekly X 4 and then 2 weeks off (1 cycle). Restage after every 2 cycles. 
Continue if CR, PR or SD for up to 6 cycles. Dose reductions for toxicity will be 
addressed in the protocol. 
• Phase II portion of the study will be a Simon optimal two-stage design: designed to rule 
out 20% response rate (p0=0.20) in favor of a 45% response rate (p1=0.45) 
• The maximum sample size to be accrued for this study will be 71 patients. 
 
 
 


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TABLE OF CONTENTS 
PRÉCIS ........................................................................................................................................... 3 
TABLE OF CONTENTS ................................................................................................................ 4 
1 
INTRODUCTION ................................................................................................................... 6 
1.1 
Study Objectives .............................................................................................................. 6 
1.2 
Background and Rationale ............................................................................................... 6 
2 
ELIGIBILITY ASSESSMENT AND ENROLLMENT ....................................................... 11 
2.1 
Eligibility Criteria .......................................................................................................... 11 
2.2 
Research Eligibility Evaluation ...................................................................................... 11 
2.3 
Patient Registration ........................................................................................................ 12 
3 
STUDY IMPLEMENTATION ............................................................................................. 12 
3.1 
Study Design: ................................................................................................................. 12 
3.2 
Drug Administration ...................................................................................................... 13 
3.3 
Treatment Modifications: ............................................................................................... 15 
3.4 
Study Calendar ............................................................................................................... 19 
3.5 
Off Study Criteria ........................................................................................................... 21 
3.6 
Post Treatment Evaluation ............................................................................................. 21 
4 
SUPPORTIVE CARE ........................................................................................................... 21 
4.1 
Tumor Lysis Syndrome .................................................................................................. 21 
4.2 
Anti-emesis ..................................................................................................................... 22 
4.3 
Neutropenia .................................................................................................................... 22 
5 
DATA COLLECTION AND EVALUATION ..................................................................... 22 
5.1 
Data collection ................................................................................................................ 22 
5.2 
Data reporting ................................................................................................................. 22 
5.3 
Response criteria ............................................................................................................ 22 
5.4 
Toxicity Criteria ............................................................................................................. 23 
6 
STATISTICAL CONSIDERATIONS .................................................................................. 23 
6.1 
Data, Safety and Monitoring Board ............................................................................... 24 
7 
HUMAN SUBJECTS PROTECTIONS ................................................................................ 24 
7.1 
Rationale for subject selection ....................................................................................... 24 
7.2 
Evaluation of benefits and risks/discomforts ................................................................. 25 
7.3 
Risk/Benefit Analysis ..................................................................................................... 25 


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7.4 
Consent and assent ......................................................................................................... 25 
8 
SAFETY REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING PLAN
 
25 
8.1 
Definitions ...................................................................................................................... 25 
8.2 
NCI-IRB and Clinical Director Reporting ..................................................................... 25 
8.3 
CTEP Adverse Event Reporting Requirements ............................................................. 26 
8.4 
The Comprehensive Adverse Event and Potential Risks list (CAEPR) ......................... 26 
8.5 
Adverse Event Characteristics ....................................................................................... 29 
8.6 
Expedited Adverse Event Reporting .............................................................................. 29 
8.7 
Routine Adverse Event Reporting .................................................................................. 31 
8.8 
Secondary AML/MDS ................................................................................................... 31 
9 
REGULATORY CONSIDERATIONS ................................................................................ 31 
10 PHARMACEUTICAL INFORMATION ............................................................................. 32 
10.1 
CTEP-Supplied Agent ................................................................................................ 32 
10.2 
Other Agent(s) ............................................................................................................ 34 
11 REFERENCES ...................................................................................................................... 34 
12 APPENDIX A:  Specimen Collection and Storage ............................................................... 36 
12.1 
Pharmacokinetic Samples ........................................................................................... 36 
12.2 
Protocol Completion/Sample Destruction .................................................................. 36 
12.3 
Procedures for stored serum specimens...................................................................... 36 
12.4 
Procedures for Peripheral Blood Cells ....................................................................... 38 
12.5 
Procedures for lymph node biopsies sent to Dana Farber Cancer Institute ................ 39 
 
 
 


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1 
INTRODUCTION 
1.1 STUDY OBJECTIVES 
 Primary 
• Assess the response rate of flavopiridol in patients with relapsed mantle cell lymphoma 
(MCL) and diffuse large B-cell lymphoma (DLBCL) when administered as a 30 minute 
loading dose followed by a 4-hour infusion once weekly for 4 consecutive weeks every 6 
weeks 
• Assess the toxicity profile, dose-limiting toxicity and maximum tolerated dose of 
flavopiridol administered in the hybrid schedule of a 30 minute loading dose followed by 
a 4-hour infusion once weekly for 4 consecutive weeks every 6 weeks in patients with 
relapsed MCL and DLBCL.  
 Secondary 
• Determine the pharmacokinetics of flavopiridol when administered by hybrid schedules, 
correlating this with toxicity and Tumor Lysis Syndrome (TLS).  
• Assess tissue from tumor biopsies (where possible before and after flavopiridol) by 
microarray and protein analysis.    
 
1.2 BACKGROUND AND RATIONALE 
 Flavopiridol Background 
Flavopiridol is a synthetic flavone compound with a novel structure, compared to 
polyhydroxylated flavones such as quercetin and genistein.  
 
 
 
 
 
 
 
 
Flavopiridol is obtained from a synthetic process, but its chemical structure is identical to a product 
obtained from an indigenous plant in India called Dysoxylum binectariferum. When flavopiridol 
was first discovered, it was considered to be a tyrosine kinase antagonist but subsequently, it was 
shown to reversibly inhibit growth via inhibition of cyclin-dependent kinase (CDK)1 and CDK2[1, 
2].  Flavopiridol induced cell cycle inhibition by altering phosphorylation of tyrosine residues as 
well as antagonizing CDK1 and CDK2 activity as a result of competitive inhibition with ATP[3].  
Based on these initial observations, investigators hypothesized that flavopiridol would be effective 
in rapidly dividing tumor systems where a minimum volume of tumor exists. We now know that 
flavopiridol has a number of additional targets that include the cyclin D-1 complex over-expressed 
in mantle cell lymphoma and cyclin H. In addition, studies in lymphoma cell lines have 
demonstrated activity against activated B-cell (ABC) type cell lines and NF-kappa B down-
regulation[4, 5].  


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   Dose Scheduling of Flavopiridol 
One of the great challenges in developing flavopiridol and applying it in clinical trials has been its 
dose scheduling. Initial in vitro work performed at the NCI evaluated a long continuous infusion 
administration (72 hours: 50 mg/m2/day every 2 weeks)[6]. 72 hours exposure resulted in growth 
inhibition with little cell recovery over the next 3 days. These experiments provided support for a 
72 hour infusion schedule that was subsequently utilized in later phase I studies.  Although patients 
achieved steady state concentrations that had been shown to be cytotoxic in vitro, the response rate 
in solid tumor and lymphoma patients in the initial Phase I studies was disappointing. This is likely 
explained by the fact that the effects of flavopiridol are far more potent in fetal calf serum (used 
for most in vitro experiments) than in human plasma because of high protein binding in human 
(95-98%) compared to bovine (0%) serum. thus, much higher concentrations appear to be needed 
in vivo to achieve adequate free drug levels.   
Following this realization, alternative schedules of administration were investigated. In leukemia 
and lymphoma models, bolus schedules that achieved high concentrations resulted in potent anti-
tumor effects. A marked in vivo dose response curve with bolus administration of flavopiridol, 
compared to 72 hour continuous exposure was observed by Sausville and colleagues[7]. Trials in 
mantle cell lymphoma and CLL demonstrated that daily bolus schedules induced partial responses 
compared to long continuous infusions[8-10]. However, the half-life of flavopiridol is short 
following 1-hour administrations (3-4 hours) and brief exposure to this high concentration is 
probably inadequate to inhibit cellular targets. One strategy that could potentially produce high 
concentrations of drug for a relatively prolonged period of time is an infusion of flavopiridol for 
an intermediate time following a bolus loading dose.  
There has been much interest in investigating these so-called ‘hybrid’ schedules and at present, 
Byrd and colleagues are conducting a phase I/II study of the hybrid schedule 30 minute bolus (30 
mg/m2) followed by a 4 hour infusion (30 mg/m2 on cycle 1 with dose increase to 50 mg/m2 on 
subsequent cycles) in patients with previously treated CLL/SLL. To recap, both 24-hour and 72-
hour continuous infusion schedules in CLL were associated with 0 response rate and a bolus 
schedule produced a partial response rate of merely 11%[8]. Thus far, the response rate to the 
hybrid flavopiridol schedule has been 52% with some dramatic responses in lymph node reduction 
(Byrd: personal communications). This “step” schedule was adopted to reduce the incidence of 
severe TLS on cycle 1, which appears to be dose related. The development of TLS has only been 
seen in patients with CLL who have very high white cell counts (> 100,000). Therefore, given the 
very different biologies of the tumor types that we will be treating - as the patient population will 
consist of relapsed mantle cell and diffuse large B-cell lymphoma - we do not expect that TLS will 
be a significant problem or complication.  
 Results of Phase I studies of Flavopiridol 
The dose limiting toxicity for flavopiridol as a 72-hour continuous infusion schedule repeated 
every two weeks was secretory diarrhea[6].  Other toxicities included a proinflammatory syndrome 
with alterations in acute-phase reactants. Additional toxic effects included malaise, fever, 
hypoalbuminemia, tumor pain, hypotension, pericardial/pleural effusions, fatigue, anorexia, 
dysgeusia, lightheadedness, minimal nausea and vomiting, and elevated transaminases. The MTD 
was 50mg/m2/day for 3 days.  


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8 
A phase I trial of flavopiridol administered as a 1-hour bolus daily for 3 consecutive days has also 
been reported[11].  This regimen was repeated every 3 weeks.  The dose limiting toxicity occurred 
at 62.5 mg/m2 and included short duration neutropenia, diarrhea, nausea and vomiting.  
Several phase I combination studies of flavopiridol with other chemotherapy agents have been 
initiated.  Limited data are available from a flavopiridol + paclitaxel combination study utilizing 
paclitaxel (175 mg/m2 over 3 hours) followed on day 2 by flavopiridol (as 24 hour infusion) based 
upon in vitro synergy data from solid tumor cell lines[12].  This study included an escalation of 
flavopiridol to 80 mg/m2 without demonstrable fatigue or diarrhea[13].  At higher concentrations, 
reversible pulmonary toxicity was observed that was dose limiting.  It is uncertain if dose 
escalation above 80 mg/m2 will be possible with the exclusion of paclitaxel.  
The hybrid schedule that is being tested by Byrd and colleagues (personal communication) has 
been very effective in patients with relapsed CLL and SLL. Responses have been rapid with the 
development of acute tumor lysis syndrome (TLS) in some patients at higher doses with very high 
white cell counts. Thus far, 23 patients have been treated. The PR rate is 43% with a median 
response duration of 12 months. 2 patients developed tumor lysis syndrome (these patients had a 
high white cell count or bulky disease). Since the occurrence of these cases of TLS, patients with 
very high white cell counts are ineligible for treatment. All patients receive TLS prophylaxis and 
careful in-patient monitoring. Other grade 3 or 4 toxicities that have been encountered thus far 
include neutropenia, anemia, thrombocytopenia, hypokalemia, syncope, diarrhea, arthralgia, 
anemia and fatigue.  
 Pharmacokinetics of Flavopiridol  
As discussed above, the high plasma protein binding of flavopiridol explains its very low free 
concentration in human plasma compared to media containing fetal calf serum and explains the 
lack of clinical responses with various schedules. Studies that have assessed the pharmacokinetics 
of flavopiridol have shown a very wide variability in clearance and volume of distribution due to 
plasma protein binding.  
The elimination half-life of flavopiridol varies based on the infusion duration: 
a) 72 hour infusion: 10-27 hours[11] [14, 15] 
b) 24 hour infusion : 22 hours[16] 
c) 1 hour infusion: 3.5 to 5 hours[11] 
The total body clearance ranges from 11-16 L/hr/m 
Simulations of the plasma-concentration time curves at the proposed dose-schedules (courtesy of 
John Byrd): 


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9 
 
 
We plan to assess and investigate the pharmacokinetics of flavopiridol in this study. We will collect 
samples at 0.5 , 4.5  and 6 hours following the start of the bolus dose of flavopiridol on doses 1 
and 2 of cycle 1. These time-points are based on results from Byrd and colleagues who investigated 
this hybrid schedule of flavopiridol in patients with CLL.[17] 
 Rationale for Flavopiridol in MCL and DLBCL 
1.2.5.1 MCL 
Mantle cell lymphoma (MCL) is an aggressive non-Hodgkin lymphoma (NHL) and constitutes 
approximately 5-8 % of all NHLs. It usually presents with advanced stage disease, has a median 
age at diagnosis of approximately 65 years and is considered incurable with chemotherapy and 
antibody treatment. MCL is characterized by a distinct biologic profile and pathogenesis. The 
t(11;14) chromosomal translocation and over-expression of the cell cycle regulatory protein cyclin 
D1 are characteristic molecular findings. Recent advances have identified distinct intracellular 
pathways that likely play an important role in the pathobiology of MCL. This elucidation has led 
to the testing of agents that specifically target abnormal pathways in MCL cells. One of the most 
attractive therapeutic targets for MCL is the cyclin D1 complex which is associated with cell cycle 
deregulation. Flavopiridol targets a number of different cellular pathways and processes. It induces 
cell cycle arrest by cyclin dependent kinase (cdk) inhibition and its actions include the inhibition 
of cdk7 and cyclin H, and the down-regulation of cyclin D1 and D3 expression leading to G1 
arrest. Exposure of mantle cell lymphoma cell lines to flavopiridol-induced apoptosis has been 
associated with decreased levels of cyclin D1 expression.  Therefore, investigating flavopiridol in 
patients with MCL is a very interesting strategy. In MCL, flavopiridol at a dose of 50 mg/m2/day 
has been tested both as a 72 hour continuous infusion every 2 weeks and as a 1 hour infusion daily 
X 3, every 3 weeks[9, 10]. No patients (0/10) responded to the continuous infusion schedule but 3 
of 27 patients had a partial response to the bolus schedule (12% PR) – there is no statistical 


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10 
difference between these two portions (Fisher’s exact test, p=0.55). These results suggest that the 
continuous infusion schedule achieved inadequate steady state levels of drug to induce cytotoxicity 
and that the bolus schedule probably induced adequate drug levels but for too short a time to 
achieve significant tumor kill. Thus, our hope is that the hybrid schedule of flavopiridol will 
achieve high enough and adequate cytotoxic drug levels (bolus) that are maintained for enough 
time (infusion) to effectively kill tumor cells.  
1.2.5.2 DLBCL 
DLBCL is also an aggressive disease and the most common subtype of NHL. Gene expression 
profiling has revealed that there are at least 3 distinct sub-types of DLBCL and one of these, the 
activated B-cell like (ABC) type, is associated with a worse prognosis and patients who relapse 
after initial therapy are more likely to have this type. It is particularly worthwhile investigating 
and developing therapies that can target the ABC type. Studies of flavopiridol lymphoma cell lines 
have demonstrated strong activity of flavopiridol on OCI-Ly3 lymphoma cell lines which are an 
excellent model of the ABC type of DLBCL[4]. Flavopiridol inhibits the NF-kappa B pathway 
which is constitutively activated in the ABC type of DLBCL. Thus, the ABC type of DLBCL may 
be a particularly attractive target for flavopiridol and therefore our interest in investigating the drug 
in DLBCL[5].  
1.2.5.3 Hybrid schedule in MCL and DLBCL 
We propose to evaluate the safety of the hybrid schedule of flavopiridol which is administered as 
a 30 minute bolus followed by a 4 hour infusion weekly x 4 consecutive weeks, followed by 2 
weeks without flavopiridol treatment for a cycle duration of 6 weeks in patients with relapsed or 
refractory MCL and DLBCL.  To determine the safe tolerated dose of the hybrid schedule, a phase 
I dose escalation will be performed to determine the MTD. To determine the efficacy of the hybrid 
schedule at the MTD, a phase II study will be performed in MCL and DLBCL.  
There are distinct molecular targets amenable to flavopiridol in both MCL and DLBCL, which we 
plan to evaluate. Among these are the cyclin D-1 complex, NF-kappa B, various cyclin dependent 
kinases and various specific genes. The rationale for studying these markers is as follows: In 
mantle cell lymphoma cells, we wish to investigate if markers such as cyclin D-1 and certain cyclin 
dependent kinases are down-regulated by flavopiridol and if there are any patterns of association 
between levels of certain markers and outcome. In DLBCL, we will assess in an exploratory 
manner if flavopiridol is more effective in the ABC versus GCB subtype of DLBCL.  Because 
these studies are exploratory and hypothesis generating, the study will not be powered to answer 
a specific biological question.   
Given the activity of flavopiridol when administered as a bolus schedule, we are interested in 
investigating the hybrid schedule of Byrd and colleagues that has yielded very promising results 
in CLL/SLL. We aim to both assess the efficacy of the hybrid schedule in MCL and DLBC and in 
addition determine if tumor lysis syndrome, which has been reported in approximately 15% of 
CLL/SLL patients treated with this schedule, occurs in MCL and DLBCL patients. 
 
 
 
 
 


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2 
ELIGIBILITY ASSESSMENT AND ENROLLMENT 
2.1 ELIGIBILITY CRITERIA 
 Previously treated mantle cell lymphoma or diffuse large B-cell lymphoma (to include 
mediastinal (thymic) large B-cell lymphoma; transformed large B-cell lymphoma; 
follicular grade IIIB large B-cell lymphoma; intravascular large B-cell lymphoma) 
 Confirmed pathological diagnosis at the National Cancer Institute, NIH. 
 Recurrent measurable disease (measurable disease in 2 dimensions or leukemic disease 
which can be quantified and followed) 
 Prior anthracycline-based treatment for patients with DLBCL 
 Age > 18years 
 ECOG performance 2 or better 
 Major organ function:  ANC > 1000/mcL, Platelet > 50,000/mcL, Creatinine < 1.5 mg/dL 
or creatinine clearance > 60 mL/min; SGPT < 5 x upper limit of normal; bilirubin < 2 
mg/dL (total) except < 5 mg/dL in patients with Gilbert’s syndrome as defined by > 80% 
unconjugated. ANC and platelet requirements must be met independent of transfusion.  
 Informed consent and willingness to use contraception by both men and women.  
 Both male and female patients must be willing to use adequate contraception (to include 
effective barrier methods of contraception) or to completely abstain from heterosexual 
intercourse while on protocol treatment.   
  Not pregnant or nursing because of an unknown potential for teratogenic or abortifacient 
effects 
 HIV serology negative. HIV positive patients receiving combination anti-retroviral 
therapy are excluded from the study because of possible pharmacokinetic interactions 
with flavopiridol.  Additionally, the biology of HIV associated DLBCL’s is often quite 
different from HIV negative disease due to involvement of EBV. 
 Hepatitis B surface antigen negative. 
 No active CNS lymphoma.  These patients have a poor prognosis and because they 
frequently develop progressive neurological dysfunction that would confound the 
evaluation of neurological and other adverse events. 
 No history of inflammatory bowel disease unless this has been inactive for a period of 2 
or more years. 
 Recovery from toxicity of prior therapy to a grade 1 or less.  
 No systemic cytotoxic or experimental treatments within 4 weeks of treatment. 
 No WBC > 100,000 cells/mcL 
2.2 RESEARCH ELIGIBILITY EVALUATION  
Blood tests (except serologies) and pregnancy test to be done within one week of study entry, 
other studies to be done within 4 weeks before study entry: 


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• Complete History and Physical examination. 
• CBC, differential, PT, PTT, SGOT, SGPT, LDH, alkaline phosphatase, bilirubin, 
albumin, calcium, phosphate, uric acid, creatinine (24 hour creatinine clearance if serum 
creatinine > 1.5 mg/dL), electrolytes, urinalysis, HIV serology, hepatitis B surface 
antigen and Anti Hepatitis B core antibody.  
• Unilateral bone marrow aspirate and biopsy if not performed within 1 month. 
• HCG (urine) in women of childbearing potential. 
• Electrocardiogram.  
• Staging: CT scans of chest, abdomen and pelvis.  
• PET as clinically indicated.  
• Head CT or Brain MRI and lumbar puncture with flow and cytology as clinically 
indicated.  
2.3 PATIENT REGISTRATION 
Authorized staff must register an eligible candidate with NCI Central Registration Office (CRO) 
within 24 hours of signing consent.  A registration Eligibility Checklist from the web site 
(http://camp.nci.nih.gov/ccr/welcome.htm) must be completed and faxed to 301-480-0757.  After 
confirmation of eligibility at Central Registration Office, CRO staff will call pharmacy to advise 
them of the acceptance of the patient on the protocol prior to the release of any investigational 
agents.  Verification of Registration will be forwarded electronically via e-mail to the research 
team. A recorder is available during non-working hours.  
3 
STUDY IMPLEMENTATION 
3.1 STUDY DESIGN:  
 Phase I Design 
There will be 3-4 defined dose levels, with 3-6 patients treated at each dose level. The Phase I 
dose escalation will follow one of two different escalation rates shown in Tables 1 and 2. If DLT 
is observed in 0-1/6 patients on dose level 1, escalation will proceed according to Table 1. If 
DLT is observed in 2 of up to 6 patients on dose level 1, escalation will proceed according to 
Table 2. Escalation decision rules are shown below: 
 
 
Number of Patients with DLT 
at a Given Dose Level 
 
Escalation Decision Rule 
 
0 out of 3 
 
Enter 3 patients at the next dose level 
 
> 2 
 
Dose escalation will be stopped.  This dose level will be 
declared the maximally administered dose (highest dose 
administered).  Three (3) additional patients will be 
entered at the next lowest dose level if only 3 patients 
were treated previously at that dose.  


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1 out of 3 
 
Enter at least 3 more patients at this dose level. 
• 
If 0 of these 3 patients experience DLT, proceed to 
the next dose level. 
• 
If 1 or more of this group suffer DLT, then dose 
escalation is stopped, and this dose is declared the 
maximally administered dose.  Three (3) additional 
patients will be entered at the next lowest dose level if 
only 3 patients were treated previously at that dose. 
This rule does not apply to dose level one.  Please see 
section 4.2 
 
<1 out of 6 at highest dose level below 
the maximally administered dose 
 
This is the recommended phase 2 dose.  At least 6 patients 
must be entered at the recommended phase 2 dose. 
 
Entry onto a new dose level cannot occur until all patients on the previous dose level have 
completed cycle 1. The PI or his designee must be consulted regarding the proper dose level for 
all new patients. The definition of DLT is described in section 4.2.  
 Phase 2 Design 
The Phase 2 dose and schedule will be determined by the MTD in the Phase 1 portion. Please 
contact the PI or Study Chair for appropriate dose. 
3.2 DRUG ADMINISTRATION 
 Phase 1 Dosing and Schedule 
The Phase I dose escalation will follow one of two different escalation rates shown in Tables 1 and 
2 below. If DLT is observed in 0/3 or 1/6 patients on dose level 1, subsequent patients will be 
enrolled according to the paradigm described in Table 1 below. If DLT is observed in 2/6 patients 
on dose level 1, subsequent patients will be enrolled according to the paradigm described in Table 
2 below.  
Flavopiridol dose levels 
 
Table 1  
Cycle 1, Week 1 
Cycle 1, Weeks 2–4, AND 
All weeks During All Subsequent Cycles 
Dose 
level 
Bolus x30 
minutes IV 
Continuous 
infusion x 4 hrs 
Bolus x30 
minutes IV 
Continuous infusion x 4 
hrs 
1 
30mg/m2  
30mg/m2 
30mg/m2  
50mg/m2 
2 
30mg/m2  
50mg/m2 
30mg/m2  
50mg/m2 
3 
30mg/m2 
50mg/m2 
40mg/m2 
60mg/m2  
4 
40mg/m2 
60mg/m2 
40mg/m2  
60mg/m2 
 
 
Table 2 
Cycle 1, Week 1 
Cycle 1, Weeks 2–4, AND 
All weeks During All Subsequent 
Cycles 


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Dose 
level 
Bolus x30 
minutes IV 
Continuous 
infusion x 4 hrs 
Bolus x30 
minutes IV 
Continuous infusion x 
4 hrs 
1 
30mg/m2  
30mg/m2 
30mg/m2  
50mg/m2 
1A 
25mg/m2  
25mg/m2 
30mg/m2  
50mg/m2 
1B 
25mg/m2 
25mg/m2 
40mg/m2 
60mg/m2  
 
• Administer weekly x 4 consecutive weeks, followed by 2 weeks without flavopiridol 
treatment for a cycle duration of 6 weeks (1 cycle).  
• For cycles 2-6, administer the doses given during cycle 1, weeks 2-4 for all doses.  
• Administer up to 6 cycles if no disease progression.   
• Restage all positive sites of disease after every 2 cycles, except bone marrow which should 
be repeated after other sites have achieved a CR.  
• Administer flavopiridol in the inpatient unit on cycle 1, dose 1 (bolus and infusion). 
• Unless medically contraindicated, all patients will receive allopurinol 300 mg per day on 
cycle 1 x 5 days. All patients should receive at least 200 mL/hr 0.9% Sodium Chloride 
Injection for 6 hours prior to the first flavopiridol dose. Detailed required guidelines for 
Tumor Lysis Syndrome prevention is shown in section 4.3. 
• If cycle 1, dose 1 is tolerated without TLS, subsequent doses may be administered 
outpatient. 
• For patients who develop grade 4 neutropenia, G-CSF at a dose of 300 mcg/day SC  will 
be instituted. Flavopiridol can be administered when the ANC is above 500. If grade 4 
neutropenia persists for more than 7 days on G-CSF this will constitute a DLT and 
warrant a dose reduction in drug by 20%. Once G-CSF is instituted, it will be continued 
as prophylaxis from day 2 through day 6 of each week of treatment. G-CSF should be 
stopped the day prior to each flavopiridol dose. 
 
 Phase 2 Dosing 
 
• Dose will be the MTD from the phase I portion. 
• Administer weekly x 4 consecutive weeks, followed by 2 weeks without flavopiridol 
treatment for a cycle duration of 6 weeks (1 cycle).  
• For all weeks of all cycles after cycle 1, patients will receive the dose administered on cycle 
1, weeks 2-4.  
• Administer up to 6 cycles if no disease progression.   
• Restage all positive sites of disease after every 2 cycles, except bone marrow which should 
be repeated after other sites have achieved a CR.  
 Definition of Dose Limiting Toxicity: 
Dose-limiting toxicity will be determined during the first cycle of treatment and is defined as: 
• any grade 3 or greater non-hematologic toxicity excluding transient liver function 
abnormalities that resolve spontaneously within 10 days and/or transient electrolyte 
abnormalities that are not life-threatening, or fatigue 
• grade 4 thrombocytopenia (< 25,000/mcL) persisting for  4 or more days 


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15 
• grade 4 neutropenia ANC < 500/mcL persisting for 7 or more days despite the institution 
of G-CSF 
• inability to continue with cycle 2 by 3 weeks after the end of cycle 1.  Exceptions to this 
(i.e. accidents, family emergencies, etc) will be evaluated on a case-by-case basis. 
• irreversible > grade 2 non-hematologic toxicity  
• irreversible grade 3 thrombocytopenia at least possibly due to flavopiridol.   
• And is a drug related event with an attribution of possible, probable or definite.  
 
Patients with compromised bone marrow function from lymphoma will not be evaluable for 
hematologic related DLT.  Irreversible is defined as lasting > 3 weeks.  All toxicity will be 
evaluated and scored using NCI Common Terminology Criteria for Adverse Events (CTCAE) 
version 3.0 until December 31, 2010.  CTCAE version 4.0 will be utilized beginning January 1, 
2011.   
3.3 TREATMENT MODIFICATIONS: 
Patients should have recovered toxicities that are clinically significant and attributable to 
flavopiridol to grade 1 or baseline before beginning another cycle.  If toxicity has not resolved to 
this level within 3 weeks from the end of the previous cycle, flavopiridol will be discontinued. 
 Hematological Toxicity 
Dose modifications of flavopiridol should be made according to the following schema: 
 
Hematological toxicity on Day 1 of Cycle:  
Platelets (at start of cycle) 
Flavopiridol Dose 
< 50,000 
Delay up to 2 weeks until Plts ≥ 50,000 and reduce dose 20%. 
Neutrophil count (at start 
of cycle) 
 
< 500 
Start G-CSF. Administer flavopiridol when ANC is > 500. Once 
G-CSF is instituted, continue to administer it prophylactically for 
subsequent  (days 2-6 each week) doses 
< 500 despite G-CSF for 7 or 
more days 
Reduce dose of flavopiridol by 20% and repeat dose only when 
ANC is >500 
 
Hematological Toxicity During the Cycle:  
Platelets  
Flavopiridol Dose 
< 50,000 
Delay up to 2 weeks until Plts ≥ 50,000 and reduce dose 20%. 
Neutrophil count  
 
< 500 
Start G-CSF. Administer flavopiridol when ANC is > 500. Once 
G-CSF is instituted, continue to administer it prophylactically for 
subsequent  (days 2-6 each week) doses 
< 500 for 7 or more days 
despite G-CSF 
Reduce dose of flavopiridol by 20% and repeat dose only when 
ANC is >500 
If grade 4 neutropenia lasting for 7 or more days on G-CSF or grade 3 thrombocytopenia develops 
during treatment, hold the next dose until recovery below this toxicity and reduce dose by 20% for 
subsequent doses and cycles as instructed in above tables.  


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16 
 Diarrhea Toxicity 
 
Diarrhea treatment during cycle:  At first loose stool:  Start loperamide 2 mg p.o. q 2 h while 
awake and q 4 h while sleeping.  Continue around the clock until 12 h diarrhea free.  If diarrhea 
free > 12 h, stop loperamide.  Lomotil may also be given for diarrhea in addition to or as an 
alternative to loperamide. Please note the manufacturer’s recommended maximum daily dose 
of loperamide is 16 mg. If grade 3 diarrhea or diarrhea is accompanied by mucus or 
dehydration, hold doses of flavopiridol (if applicable) and hydrate.   
 
Diarrhea Toxicity on Previous Cycle:  
Diarrhea on previous cycle  
Flavopiridol dose  
< Grade 3 
No change 
Grade 3 or associated  
with mucus or dehydration 
Reduce dose by 20% on 
all subsequent cycles.  
Grade 4 
Hold until diarrhea 
grade < 3 and reduce 
dose 20% 
 
Diarrhea Toxicity During the Cycle:  
Diarrhea on  previous week  
Flavopiridol dose  
< Grade 3 
No change 
   Grade 3  
Reduce dose by 20%.  If 
toxicity persists for > 7 
days after reduction, hold 
dose.  . 
Grade 4 
Hold until diarrhea 
grade < 3 and reduce 
dose 20% 
 
If grade 3 diarrhea on previous cycle, reduce dose 20% on subsequent cycles. If grade 4 
diarrhea on previous cycle, hold until diarrhea < grade 3 and reduce dose 20%.  
 Deep Venous Thrombosis 
If deep venous thrombosis (DVT) or pulmonary embolus (PE) or other grade 3 or 4 clotting 
event occurs, at the discretion of the treating investigator, therapy will be initiated with full dose 
Low Molecular Weight Heparin or other anticoagulants as indicated.. If recurrent DVT or PE 
occurs despite full and therapeutic anticoagulation, therapy with flavopiridol must be terminated 
and the patient will be removed from the protocol.  
 Pulmonary Reactions 
Patients who develop grade 2 or 3 dyspnea with or without chest pain, temporally related to 
flavopiridol, will be monitored closely. Oxygen saturation and a chest x-ray should be checked. 
These patients may be retreated without dose reduction if the toxicity resolves completely. 
Patients who develop dyspnea that is temporally related to flavopiridol and is severe (at rest 
grade 4) or associated with tachypnea, hypoxemia, bronchospasm or pulmonary 


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17 
edema/pneumonitis will be considered to have had grade 4 toxicity and will be removed from the 
protocol. Appropriate supportive measures including steroids and diuretics should be instituted at 
the discretion of the treating investigator.  
 Liver Function Tests 
Liver tests, including AST, ALT and total bilirubin will be checked weekly during therapy.  
• In order to initiate a cycle, liver function tests must be at grade ≤ 2.  
• Within 24 hours prior to each dose, LFTs must be ≤ 2 in order for therapy to be 
administered.  
• If liver function tests demonstrate ≥ grade 3 elevation, flavopiridol will be held until 
resolution to ≤ 2.  
• If  ≥ grade 3 elevation occurred flavopiridol will be reduced by one dose level (except for 
patients at dose level 1 in which case flavopiridol will be discontinued).  
 Tumor Lysis Syndrome 
Tumor lysis syndrome is a term given to a group of metabolic complications that occur after 
treatment of neoplasms. These disorders include hyperkalemia, hyperphosphatemia, 
hyperuricemia, hypocalcemia and acute renal failure.  Due to cases of tumor lysis syndrome 
encountered by Byrd et al, that have included two early fatal events associated with uncontrolled 
hyperkalemia, the following supportive care issues are required for patients on cycle 1 dose 1 
who are participating on this trial. These serve as guidelines for management that can be 
modified to facilitate good patient care based upon the individual being treated. 
 
1) Primary decisions regarding management of tumor lysis syndrome and cytokine release 
syndrome will be made by the principal investigator or designees.  Only one patient will 
be initiated on flavopiridol per day to assure adequate monitoring and intervention can be 
provided.  
2) Patients will be admitted to the in-patient service the evening prior to scheduled doses of 
flavopiridol, for a minimum of the first treatment (cycle 1 dose 1).  Patients who do not 
have significant tumor lysis may receive cycle 1 doses 2-4 as well as all subsequent cycles 
as outpatients. This will allow inpatient monitoring of patients during the most critical 
window of vulnerability to tumor lysis, yet allow patients who tolerate flavopiridol to 
eventually be treated in the outpatient setting.   
3) The Renal consult service will be made aware of all inpatient admissions for treatment on 
this study.  Administer flavopiridol only during hours of the day when the renal service has 
been notified and is prepared to perform dialysis within 1 hour of notification.  
4) Patients will receive IV hydration with 5% dextrose infusion with 200 mEq (200 mmol) 
sodium bicarbonate per Liter at 200 mL/hr for at least 10 hours prior to initiation of 
flavopiridol dose.  This alkaline infusion will continue throughout the course of therapy 
and for at least 10 hours after completion of infusion. 
5) Patients will begin allopurinol 300 mg orally per day at least 24 hours before cycle 1 dose 
1 and continuing for at least 1 week.  Rasburicase may be administered at the discretion of 
the treating physician but should be reserved for patients whose uric acid rises to 10 or 
above despite prophylaxis with allopurinol and hydration. If rasburicase is used, uric acid 
measurements must be drawn in a heparinized tube, placed on ice immediately and 
transported for rapid analysis to avoid spuriously low results. 


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18 
6) Patients will receive an oral phosphate binder (Calcium Acetate 1334 mg or equivalent) 
the evening prior to and in the morning prior to initiation of the flavopiridol bolus. 
7) Patients will have potassium levels drawn the morning within 3 hours prior to initiation of 
flavopiridol (with the investigator knowing the value prior to starting therapy); at the end 
of the bolus infusion, hourly during administration of flavopiridol; and 1, 2 and 3 hours 
after completion of flavopiridol dose. These tests will be performed STAT.  Patients with 
serum potassium ≥ 4.0 will receive a 30 gm dose of sodium polystyrene sulfonate P.O. 
prior to initiation of the flavopiridol bolus. 
8) Patients will continue to receive Flavopiridol as outlined in the protocol (Section 4.2).   
9) Patients who develop clinical evidence of cytokine release syndrome or who have 
hyperkalemia requiring dialysis will receive immediate steroid therapy with an equivalent 
of at least 20 mg of IV dexamethasone.  Cytokine syndrome is described in the CTCAE 
Version 3.0. It occurs during or shortly after drug infusion and generally resolves within 
24 hours after completing the infusion.  The signs and symptoms of cytokine syndrome 
include allergic reaction (including drug fever), arthralgia, bronchospasm, cough, 
dizziness, dyspnea, fatigue, headache, hyper- or hypotension, myalgia, nausea, pruritis, 
rash, rigors, chills, sweating, tachycardia, tumor pain, or urticaria.  
10) Patients who develop a rise in their serum potassium to more than 4.5 mmol/L should 
immediately receive a 30 gm dose of sodium polystyrene sulfonate P.O.. 
11) Patients who develop a rise in their serum potassium to more than 5.0 mmol/L will receive 
a 10 unit dose of IV insulin and 50mL of 50% dextrose injection.  (Prior to this intervention, 
it is permissible to repeat this measurement if hyperkalemia is suspected to be due to 
specimen hemolysis).  If there is true hyperkalemia, drug administration should be 
discontinued. 
12) Patients who develop a rise in their serum potassium to more than 5.5 will be considered 
for emergent intermittent or continuous hemodialysis.  Prior to this intervention, it is 
permissible to repeat this measurement if hyperkalemia is suspected to be due to specimen 
hemolysis. 
13) Patients who develop cytokine release (defined in 9) or who require dialysis for 
hyperkalemia and/or other symptoms of tumor lysis will be administered prophylactic 
antibiotics for Gram negative organisms (piperacillin sodium 4 gm + tazobactam sodium 
0.5 gm Q8 hours or equivalent) and Gram positive organisms (vancomycin 1 gm IV Q12 
hours or equivalent) until dialysis is discontinued. 
14) Patients may be discharged home the day after the flavopiridol dose has been given, and  
their chemistry laboratory results have been reviewed by the treating physician. 
15) For patients who have been initially treated for TLS, the decision about when it is safe and 
feasible to move them to the outpatient setting will be made by the responsible investigator. 
If during outpatient therapy severe tumor lysis develops requiring hemodialysis, the patient 
will not be retreated with flavopiridol. 
16) Patients receiving flavopiridol in the outpatient clinic will begin alkaline IV hydration 
(similar to point 4) beginning at least 1 hour prior to initiation of the study drug.  This 
alkaline infusion will continue throughout the course of therapy and for at least 2 hours 
following completion of infusion. 
17) For patients who have been treated for TLS during the first cycle, a single dose of 
dexamethasone 20 mg PO should be administered for all further doses at the discretion of 
the investigator to diminish risk of cytokine release syndrome. 


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19 
18) Patients will continue to take allopurinol and an oral phosphate binder, as above unless 
they become intolerant to it. 
19) During dose 2, the potassium levels will be obtained as outlined in item 7  of section 4.3.6. 
Following completion of dose 2, patients will have potassium levels drawn prior to, every 
2 hours during, and after completion of the flavopiridol dose in the outpatient setting.  
Intervention with sodium polystyrene sulfonate and/or IV insulin will be as above.  Patients 
will not be discharged from the outpatient unit with an elevated serum potassium; if 
necessary, patients must be admitted overnight for observation. 
20) Telemetry monitoring will be performed at the discretion of the PI or his designee. 
 Other Clinically Significant (determined by PI or AI) Non-Hematological Toxicity  
These are adverse events that are felt to be at least possibly related to flavopiridol administration 
and in the opinion of the PI or AI do not have serious medical consequences (i.e. replaced easily) 
such as low phosphorus , low albumin or low calcium. 
 
Symptom grade 
Management 
 grade 2 
Treat symptomatically 
 grade 3 
Hold next dose until grade 1 or baseline and resume 
flavopiridol if further therapy is indicated 
  
 
3.4 STUDY CALENDAR  
Studies 
Pre-
therapyA 
Day -1 or 
day 
1 
of 
each cycle 
Weekly 
during 
therapy 
Every 
second 
cycle 
Follow-upB 
Hx; PE; VS; PS   
x 
x 
 
 
x 
Tumor Measurement 
x 
 
 
x 
x 
CBC/diff 
xF 
x 
x 
 
x 
Electrolytes, Creatinine/BUN 
ALT, AST,  
Bilirubin, LDH, Ca++, Phos, Mg 
xF 
 
x 
 
X 
 
 
x 
 
10 mL red top for serum storage 
x 
x 
 
 
x 
Clinical PET scan D 
x 
 
 
 
 
CT chest/abdomen/pelvis C 
x 
 
 
x 
x 
Bone marrow  biopsy & aspirate and 
peripheral blood for flow cytometry 
where indicated E  
x 
 
 
xE 
 
Tumor biopsy, timed blood collections 
and/or apheresis G 
X 
 
 
 
 
Tumor Lysis Syndrome monitoring 
 
XH 
 
 
 
A- Initial assessment may be performed within 4 weeks prior to starting treatment.  
B- Follow-up to occur every 3-4 months until disease progression requiring initiation of non-protocol 
therapy. 
C- Extent of CT scans may be limited to assess sites of prior disease.   
D- PET scans will be performed pre-therapy if clinically indicated. PET may be obtained at the first post-
treatment restaging in patients in CRu.   
E- Obtain pre-treatment and after patients achieve CR by other staging.  


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F- These laboratory tests must be obtained within one week of initial treatment.   
G- Where possible, tumor biopsies will be obtained by core needle biopsy or surgery pre-treatment. In 
select patients a repeat core biopsy of superficial nodes may be carried out within 24 hours from the 
end of the first flavopiridol infusion. Snap freeze and store tissue biopsies for translational studies at -
80°C. Lymphapheresis may be performed pre-treatment in patients with leukemic MCL and may be 
repeated after the completion of the flavopiridol infusion. Timed blood samples of 20-40 mL each, 
typically pre-treatment, at 1 hour, 3hours, 6hours and 24hours may be obtained in selected patients 
during the first flavopiridol infusion. In patients with leukemic disease this may be repeated during 
the second flavopiridol infusion. Research blood collections will be limited to less than 450 mL in any 
6 week period. 
H- Please refer to section 4.3.6 on TLS monitoring for details of what is required.  
 
• 
Pharmacokinetics:  Collect one 6 mL sodium heparin tube at the following time points on dose 1 
and 2 of cycle 1 only: 30 minutes after the start of the bolus infusion, 4.5 hours and 6 hours after 
the start of the bolus infusion. All PKs should be placed directly on ice and then refrigerated until 
specimen is picked up. 
• 
Microarray analysis: The pretreatment lymph node biopsy, apheresis or blood sample (in the case 
of leukemic disease) will be used to perform all standard diagnostic tests. In addition we will extract 
RNA and protein for research studies. The second apheresis or the timed blood samples following 
the first treatment of flavopiridol will be used for research studies only. Timed blood samples may 
be subjected to microarray analysis to assess the effects of flavopiridol on the gene expression in 
normal and malignant cells.  
• 
Proteomic analysis: In protein extracts of tumor cells pre and during therapy we aim to determine 
activity of key regulatory proteins such as components of the NF-kappa B signal transduction 
pathway, the levels of cell cycle inhibitors such as p21cip and p27kip-1 and the p53 stress response. 
Where possible we may initiate studies that aim at characterizing changes in protein levels on a 
global scale. 
• 
Tissue immunohistochemistry: Tumor tissue will be analyzed by immunohistochemistry and may 
include among other antigens, bcl-2, p53, MUM-1, bcl-6, MIB-1, and CD-10. Antibodies for 
assessment of cdk2 and cdk4 inhibition will include as many of the following as possible:  anti-
total Rb, anti-Rb [pT356], anti-Rb [pS249/T252], anti-Rb [pS807/811], anti-Rb [pS780], anti-Rb 
[pS795], anti-total p27Kip1, and anti-p27Kip1 [pT187].  Samples will also be analyzed for expression 
of cdk2, cdk4 and p16INK4A, Ki67 and TUNEL staining. Assessment of cdk9 inhibition will be 
performed with anti-cyclin D1 and anti-Mcl-1, as well as anti-total RNA polymerase II, anti-RNA 
polymerase II [pSer2] and anti-RNA polymerase II [pSer5], (if RNA polymerase II antibodies can 
be optimized for immunohistochemistry).  
• 
Tumor tissue may be stored for future research assays which are related to this study and do not 
pose an increase in patient risk.   
• 
Serum storage: Collect one 10 mL red top tube for serum storage pre treatment and prior to each 
cycle. 
 
Biopsy Procedure: 
Standard techniques will be used for pre-treatment percutaneous biopsies which may include CT 
and / or ultrasound guided biopsy. In some cases, such biopsies may be expedited and facilitated 
with the use of navigation tools such as an automated laser angle selector connected to CT scan, 
or a standard needle guide connected to a protractor to determine which exact angle the biopsy 
needle will be inserted. 
These guiding techniques may occur as maneuvers to facilitate the biopsy, which will take place 
in the usual conventional fashion, with standard, disposable, conventional spring-loaded biopsy 


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21 
equipment. Such guiding techniques may add to the reliability of tissue acquisition from specific 
spatial coordinates of a tumor target. Accurate spatial tissue acquisition may lead to more reliable, 
accurate and precise tissue characterization, which in turn should be more reproducible. When 
performing sequential biopsies, the knowledge of sampling location within a tumor may actually 
help avoid multiple needle punctures or repeat procedures, as might occur when samples are 
obtained from necrotic regions or regions without high quality mRNA (cDNA) for microarrays or 
sufficient protein for proteomics analysis.  
Sequential biopsy has been used routinely at the NCI as a research and prognostic tool, as well as 
pathway to surrogate biological markers for tumor response, prognosis, or susceptibility to specific 
targeted agents. Sequential biopsies are usually performed under the assumption that all tumor is 
created equal (mRNA and proteins) at a given time point, which is clearly an oversimplification 
with broad ramifications. Precision biopsy techniques might normalize some of the spatial 
heterogeneity inherent to tumors. Such normalization (as occurs when repeat biopsies are taken 
from precisely the same location of tumors) could minimize the added noise from the interpretation 
of already voluminous and noisy data (as in the case of the gene microarrays).  
From the CT-guided biopsy, patients will receive (from two CT scans) a total of 8.0 rem to their 
kidneys and 5.2 rem each to their stomach, gallbladder wall and lower large intestine.  All other 
organs will receive smaller amounts of radiation.  Although each organ will receive a different 
dose, the amount of radiation exposure patients will receive from these procedures is equal to a 
uniform whole-body exposure of 1.2 rem. This calculated value is known as the “effective dose” 
and is used to relate the dose received by each organ to a single value.  The amount of radiation 
received in this study is within the dose guideline established by the NIH Radiation Safety 
Committee for research subjects.  The guideline is for an effective dose not to exceed 5 rem 
received per year in adults. The NIH Radiation Safety Committee has reviewed the use of radiation 
in adults in this research study and has approved this use as involving acceptable risk and necessary 
to obtain the research information desired. 
In patients with leukemic disease, apheresis (lymphapheresis) will be performed for research 
purposes only in lieu of a tissue biopsy.  
3.5 OFF STUDY CRITERIA 
• Voluntary withdrawal.   
• Institution of non-protocol treatment. 
• Non-compliance which affects safety or endpoints of the study. 
• Physician’s determination that withdrawal is in the patient’s best interest.    
3.6 POST TREATMENT EVALUATION 
Follow-up to occur every 3-4 months until disease progression that requires institution of non-
protocol treatment. Adverse event data that occurs during the follow-up period that is unrelated to 
study treatment will not be reported. Patients who are taken off-protocol will continue to be 
followed for survival.  
4 
SUPPORTIVE CARE  
4.1 TUMOR LYSIS SYNDROME 
See section 4.3 in Treatment Modification Section 


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4.2 ANTI-EMESIS 
Patients may receive prophylactic anti-emetics with ondansetron or granisetron.  
4.3 NEUTROPENIA 
If patients develop grade 4 neutropenia, begin treatment with G-CSF.  Administer 300 mcg for 
all patients. Once G-CSF is instituted, continue to administer it prophylactically for subsequent 
(days 2-6 each week) doses on all cycles.  Give G-CSF for days 2-6 each week, stopping it the 
day before the next dose.  On dose 4, give G-CSF for days 2-6 after the dose.  
5 
DATA COLLECTION AND EVALUATION  
5.1 DATA COLLECTION   
Data will be collected and entered into the NCI C3D clinical trials database. Complete records 
must be maintained on each patient including supplementary information obtained from outside 
laboratories, radiology reports, or physician’s records. These records will serve as the primary 
source material that forms the basis for the research record. The primary source documentation 
will assure the following:  
• The patient satisfied each eligibility criterion.  
• Signed informed consent was obtained prior to registration and treatment.  
• Treatment was given according to protocol or any protocol violations documented and 
justified.   
• Toxicity and response were assessed according to protocol. 
• Drug accountability records were kept on each patient.  
5.2 DATA REPORTING 
This study will be monitored by the Clinical Data Update System (CDUS) version 3.0. 
Cumulative CDUS data will be submitted quarterly to CTEP by electronic means.  Reports are 
due January 31, April 30, July 31 and October 31.  Instructions for submitting data using the 
CDUS can be found on the CTEP web site (http://ctep.cancer.gov/reporting/cdus.html). 
Effective Amendment J (version date 01/16/2015), the protocol has been completed with CTEP. 
5.3 RESPONSE CRITERIA 
Response criteria for lymphomas as per Cheson criteria. [18] with modifications as described 
below. Responses must last for at least 4 weeks off treatment.  
• Complete response (CR): Complete disappearance of all detectable clinical and 
radiographic evidence of disease and disappearance of all disease-related symptoms if 
present before therapy, and normalization of those biochemical abnormalities (e.g. LDH) 
definitely assignable to the lymphoma.  All lymph nodes must have regressed to normal 
size ( 1.5 cm in greatest diameter if > 1.5 cm before therapy).  Previously involved 
nodes that were 1.1 to 1.5 cm in greatest diameter must have decreased to  1 cm or by 
more than 75% in the sum of the products of the greatest diameters (SPD). Spleen, if 
considered to be enlarge before therapy, must have regressed in size and not be palpable 
on physical examination.  The bone marrow must show no evidence of disease by 


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23 
histology.  Flow cytometric, molecular or cytogenetic studies will not be used to 
determine response.  
• Complete response unconfirmed (CRu): As per CR criteria except that if a residual node 
is > 1.5 cm, it must have regressed by > 75% in SPD.  Lymphocyte aggregates within the 
bone marrow must be negative for B-cell markers (e.g. L26). 
• Partial response:  50% decreased in SPD of 6 largest dominant nodes or nodal masses. 
No increase in size of nodes, liver or spleen and no new sites of disease.  Splenic and 
hepatic nodules must regress by  50% in the SPD.  Bone marrow is irrelevant for 
determination of a PR.   
• Definition of progressive disease (PD):  Defined by at least one of the following: >25% 
increase in the sum of the products of at least two lymph nodes, appearance of new lymph 
nodes, >50% increase in the size of the liver and/or spleen as determined by measurement 
below the respective costal margin, appearance of new palpable hepatomegaly or 
splenomegaly that was not previously present, >50% increase in the absolute number of 
circulating lymphocytes.  
• Definition of stable disease:  (SD) will be characterized by not meeting any of the criteria 
outlined above.  
5.4 TOXICITY CRITERIA  
NCI Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 will be utilized for 
AE reporting until December 31, 2010.  CTCAE version 4.0 will be utilized beginning January 
1, 2011. 
All appropriate treatment areas should have access to a copy of the CTCAE version 3.0 and 
CTCAE version 4.0.  A copy of the CTCAE version 3.0 and CTCAE version 4.0 can be 
downloaded from the CTEP web site (http://ctep.cancer.gov) .  Dose limiting toxicity is defined 
in section 4.2.  
6 
STATISTICAL CONSIDERATIONS 
This will be a Phase I/II study.  
• The Phase I portion of the study will have three to four treatment dose levels.  Three to six 
patients will be accrued on each of the dose levels. Enrollment will proceed on the next 
dose level if 0 of 3 or 1 of 6 patients experience DLT. MTD will be defined as the highest 
dose level in which 0-1/6 patients experience DLT.    
• The Phase II portion of the study will use a Simon optimal two-stage design in each of the 
two histology cohorts, MCL and DLBCL. For each of these two, the trial will be designed 
to rule out a 20% response rate (p0=0.20) in favor of a 45% response rate (p1=0.45).  The 
justification for this is that other regimens could be associated with a 20% response rate 
and the objective is to demonstrate if this agent is superior to that level. With 
alpha=beta=0.10, the first stage for each histology would accrue 14 patients (28 total for 
the first stage, but by performing response evaluation on the 6 patients treated at the MTD 
in the phase I portion of the study and by counting them in each phase II arm according to 
their histology, this would only require 22 newly enrolled patients in the first stage). If 0-


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24 
3 of the 14 in a given arm have a PR or CR, then no further patients would be accrued. If 
4 or more of the 14 patients in an arm have a CR or PR, then accrual would proceed to a 
total of 25 patients in that arm (11 more patients beyond the 14 in the first stage). If 4 to 7 
have a PR or CR, then this is insufficient activity to warrant further investigation while 8 
or more responses in 25 would be adequate to justify further development. Under the null 
hypothesis, 20%, the probability of early termination would be 70%.  
• With up to 24 patients enrolled in the phase I portion, and 50 - 6 (6 are used for response 
evaluation from the phase I portion)=44 new patients potentially required for the phase II 
portion, a total of 24+44=68 total evaluable patients may be required if both arms need to 
go to the second stage. To allow for a small number of   non evaluable patients, the accrual 
ceiling will be set at 71.  
• To determine if patients have responded, they will be assessed every 8 weeks. The latest 
time for determining a response will be after 16 weeks or 4 cycles of therapy.  
• It is expected that up to 3 years may be required to accrue up to 71 total patients permitted 
to enroll onto this trial.  
• At this time, regarding correlative studies that will be performed such as microarray and 
proteomic analysis, we have not as yet identified how these markers and values are 
modified and changed by flavopiridol therapy. Hence, we do not plan a defined statistical 
analysis as this research is exploratory at this time.  
6.1 DATA, SAFETY AND MONITORING BOARD 
All data will be collected in a timely manner and reviewed by the PI and/or study chairman for 
toxicity.  In the event that unacceptable toxicity occurs, the IRB and IND holders will be 
informed and appropriate measures as outlined in the study will be taken.  The monitoring of this 
study will be done by the PI/Study Chairman and CTEP on an ongoing manner so a DSMB will 
not be used.  
7 
HUMAN SUBJECTS PROTECTIONS  
7.1 RATIONALE FOR SUBJECT SELECTION 
Mantle cell lymphoma affects all races and genders but predominantly affects older patients and 
there is a male preponderance. This will be reflected in the distribution of cases of mantle cell 
lymphoma. Diffuse large B-cell lymphoma affects all races and genders. Males are more likely 
than females to be affected and this will be reflected in the gender distribution of our cases.  This 
trial is directed at assessing the new drug, flavopiridol, administered by a hybrid schedule in 
patients with relapsed mantle cell and diffuse large B-cell lymphoma. We have selected patients 
with relapsed disease and have developed the trial design to recognize that some may be 
potentially curable and others are not.  Patients under the age of 18 are excluded because 
inclusion of an occasional younger patient will not provide generalizable information that would 
justify their inclusion on this study; pediatric patients with recurrent mantle cell lymphoma or 
diffuse large B cell lymphoma are extremely rare and are treated on pediatric studies.  
Additionally, pregnant or nursing mothers are excluded because of the potential teratogenic 
effects of therapy. 


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25 
7.2 EVALUATION OF BENEFITS AND RISKS/DISCOMFORTS 
Patients may obtain direct benefit from treatment with flavopiridol. Results from phase I and II 
studies of flavopiridol show tolerable side effects. This hybrid schedule has been associated with 
tumor lysis syndrome in patients with CLL who have very high white cell counts but we do not 
anticipate this toxicity in this patient population due to very different tumor biology than CLL.  
7.3 RISK/BENEFIT ANALYSIS 
Patients may derive direct benefit from flavopiridol. There is in vitro evidence that demonstrates 
good activity of flavopiridol in patients with mantle cell lymphoma and diffuse large B-cell 
lymphoma. These diseases appear to have several molecular targets that are amenable to 
flavopiridol. The hybrid schedule of flavopiridol has been associated with excellent responses in 
patients with CLL and will potentially be very effective in patients with MCL and DLBCL.  
7.4 
 CONSENT AND ASSENT 
Informed written consent will be obtained in all patients on this trial.  There will be no minors 
enrolled < 18 years old so that assent is unnecessary.  The attached informed consent contains all 
elements required for consent.  In addition, the Principal Investigator or associate investigator 
will provide oral consent and will be available to answer all patient questions. 
8 
SAFETY REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING 
PLAN 
8.1 DEFINITIONS 
 Protocol Deviation (NIH Definition) 
Any change, divergence, or departure from the IRB-approved research protocol.  
 Unanticipated Problem 
Any incident, experience, or outcome that: 
• Is unexpected in terms of nature, severity, or frequency in relation to  
(a) the research risks that are described in the IRB-approved research protocol and 
informed consent document; Investigator’s Brochure or other study documents, and 
(b) the characteristics of the subject population being studied; AND 
• Is related or possibly related to participation in the research; AND 
• Suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was previously 
known or recognized. 
8.2 NCI-IRB AND CLINICAL DIRECTOR REPORTING 
 NCI-IRB and NCI CD Expedited Reporting of Unanticipated Problems and Deaths 
The Protocol PI will report in the NIH Problem Form to the NCI-IRB and NCI Clinical Director: 
• All deaths, except deaths due to progressive disease  


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26 
• All Protocol Deviations 
• All Unanticipated Problems 
• All non-compliance 
Reports must be received within 7 days of PI awareness via iRIS. 
 NCI-IRB Requirements for PI Reporting at Continuing Review 
The protocol PI will report to the NCI-IRB:  
1. A summary of all protocol deviations in a tabular format to include the date the 
deviation occurred, a brief description of the deviation and any corrective action. 
2. A summary of any instances of non-compliance. 
3. A tabular summary of the following adverse events: 
• All Grade 2 unexpected events that are possibly, probably or definitely related to 
the research;  
• All Grade 3 and 4 events that are possibly, probably or definitely related to the 
research;  
• All Grade 5 events regardless of attribution;  
• All Serious Events regardless of attribution.  
NOTE: Grade 1 events are not required to be reported.  
 NCI-IRB Reporting of IND Safety Reports 
Only IND Safety Reports that require a sponsor recommended change to the protocol or the 
consent form or in the opinion of the PI increases risks to study participants will need to be 
reported to the NCI IRB. 
8.3 CTEP ADVERSE EVENT REPORTING REQUIREMENTS  
NOTE:  Effective Amendment J (version date 01/16/2015), the protocol has been completed 
with CTEP. 
 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The following 
list of AEs (Section 8.2) and the characteristics of an observed AE (Section 8.3) will determine 
whether the event requires expedited (via AdEERS) reporting in addition to routine (via CDUS) 
reporting. 
8.4 THE COMPREHENSIVE ADVERSE EVENT AND POTENTIAL RISKS LIST (CAEPR)  
Comprehensive Adverse Events and Potential Risks List (CAEPR) for Flavopiridol (NSC 
#649890) 
 
The Comprehensive Adverse Event and Potential Risks list (CAEPR) provides a single list of 
reported and/or potential adverse events (AE) associated with an agent using a uniform 
presentation of events by body system. In addition to the comprehensive list, a subset, the Agent 
Specific Adverse Event List (ASAEL), appears in a separate column and is identified with bold 
and italicized text. This subset of AEs (ASAEL) contains events that are considered 'expected' 
for expedited reporting purposes only. Refer to the 'CTEP, NCI Guidelines: Adverse Event 


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27 
Reporting Requirements' 
http://ctep.info.nih.gov/protocolDevelopment/default.htm#adverse_events_adeers for further 
clarification. Frequency is provided based on 852 patients. Below is the CAEPR for flavopiridol 
(Alvocidib). 
1 
Version 2.2, January 11, 2010 
 
 Adverse Events with Possible  
 Relationship to Flavopiridol (Alvocidib) 
 (CTCAE 4.0 Term) 
[n= 852] 
 
 
 
 EXPECTED AEs FOR 
ADEERS REPORTING  
Agent Specific Adverse 
Event List 
(ASAEL) 
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious 
(<3%) 
 
Expected 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
Anemia 
 
 
 Anemia 
 
Febrile neutropenia 
 
 Febrile neutropenia 
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
  
Diarrhea 
 
 
 Diarrhea 
Nausea 
 
 
 Nausea 
Vomiting 
 
 
 Vomiting 
GENERAL DISORDERS AND ADMINISTRATION SITE 
CONDITIONS 
  
 
Chills 
 
 Chills 
Fatigue 
 
 
 Fatigue 
 
Fever 
 
 Fever 
 
Pain 
 
  
IMMUNE SYSTEM DISORDERS 
  
 
Cytokine release syndrome 
 
 Cytokine release syndrome 
INFECTIONS AND INFESTATIONS 
  
 
Infections and infestations - 
Other (Infection - Select) 
 
 Infections and infestations - Other 
(Infection - Select) 
INVESTIGATIONS 
  
 
Alanine aminotransferase 
increased 
 
 Alanine aminotransferase 
increased 
 
Aspartate aminotransferase 
increased 
 
 Aspartate aminotransferase 
increased 
 
Blood bilirubin increased 
 
 Blood bilirubin increased 
 
Lymphocyte count decreased 
 
 Lymphocyte count decreased 
Neutrophil count decreased  
 
 Neutrophil count decreased 
Platelet count decreased 
 
 
 Platelet count decreased 
White blood cell decreased  
 
 White blood cell decreased 
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
 Anorexia 
 
Hyperglycemia 
 
 Hyperglycemia 
 
Hypoalbuminemia 
 
  
 
Hypophosphatemia 
 
  
 
Tumor lysis syndrome 
 
 Tumor lysis syndrome 


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28 
MUSCULOSKELETAL AND CONNECTIVE TISSUE 
DISORDERS 
  
 
Myalgia 
 
  
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED 
(INCL CYSTS AND POLYPS) 
  
 
Tumor pain 
 
 Tumor pain 
NERVOUS SYSTEM DISORDERS 
  
 
Dysgeusia 
 
 Dysgeusia 
 
Intracranial hemorrhage 
 
  
RESPIRATORY, THORACIC AND MEDIASTINAL 
DISORDERS 
  
 
Dyspnea 
 
 Dyspnea 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Alopecia 
 
 Alopecia 
VASCULAR DISORDERS 
  
 
Hypotension 
 
 Hypotension 
 
Thromboembolic event 
 
 Thromboembolic event 
 
1 
 This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all 
Principal Investigators at the time of revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, the protocol and the agent should 
be included in the e-mail. 
 
Also reported on flavopiridol (Alvocidib) trials but with the relationship to flavopiridol (Alvocidib) 
still undetermined: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system disorders - Other 
(generalized edema); Bone marrow hypocellular 
CARDIAC DISORDERS - Atrial fibrillation; Atrial flutter; Myocardial infarction; Paroxysmal atrial 
tachycardia; Pericardial effusion; Pericardial tamponade; Pericarditis; Sinus bradycardia; Sinus 
tachycardia; Supraventricular tachycardia  
GASTROINTESTINAL DISORDERS - Constipation; Dry mouth; Dysphagia; Flatulence; Ileus; 
Mucositis oral; Rectal hemorrhage 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Non-cardiac chest pain 
IMMUNE SYSTEM DISORDERS - Allergic reaction 
INVESTIGATIONS - Alkaline phosphatase increased; Creatinine increased; INR increased; Weight loss 
METABOLISM AND NUTRITION DISORDERS - Dehydration; Hypercalcemia; Hyperkalemia; 
Hyperuricemia; Hypocalcemia; Hypokalemia; Hyponatremia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthralgia; Bone pain; 
Generalized muscle weakness 
NERVOUS SYSTEM DISORDERS - Dizziness; Dysphasia; Headache; Ischemia cerebrovascular; 
Neuralgia; Peripheral sensory neuropathy; Seizure; Syncope; Vasovagal reaction 
PSYCHIATRIC DISORDERS - Confusion 
RENAL AND URINARY DISORDERS - Acute kidney injury 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Cough; Hypoxia; Pleural 
effusion; Respiratory failure; Respiratory, thoracic and mediastinal disorders - Other (Hemorrhage, 
pulmonary/upper respiratory – Select) 


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29 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Hyperhidrosis; Pruritus; Rash maculo-papular 
VASCULAR DISORDERS - Phlebitis 
 
Note: Flavopiridol (Alvocidib) in combination with other agents could cause an exacerbation of any 
adverse event currently known to be caused by the other agent, or the combination may result in events 
never previously associated with either agent. 
8.5 ADVERSE EVENT CHARACTERISTICS  
• CTCAE term (AE description) and grade:  The descriptions and grading scales found in the 
revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 will be 
utilized until December 31, 2010 for AE reporting.  CTCAE version 4.0 will be utilized 
beginning January 1, 2011.  All appropriate treatment areas should have access to a copy of the 
CTCAE version 4.0.  A copy of the CTCAE version 4.0 can be downloaded from the CTEP 
web site (http://ctep.cancer.gov). 
• ‘Expectedness’:  AEs can be ‘Unexpected’ or ‘Expected’ (see Section 8.2 above) for expedited 
reporting purposes only.  ‘Expected’ AEs (the ASAEL) are bold and italicized in the CAEPR 
(Section 8.2). 
• Attribution of the AE: 
• Definite – The AE is clearly related to the study treatment. 
• Probable – The AE is likely related to the study treatment. 
• Possible – The AE may be related to the study treatment. 
• Unlikely – The AE is doubtfully related to the study treatment. 
• Unrelated – The AE is clearly NOT related to the study treatment. 
8.6 EXPEDITED ADVERSE EVENT REPORTING 
 Expedited AE reporting for this study must use AdEERS (Adverse Event Expedited 
Reporting System), accessed via the CTEP home page (http://ctep.cancer.gov).  The 
reporting procedures to be followed are presented in the “CTEP, NCI Guidelines: 
Adverse Event Reporting Requirements” which can be downloaded from the CTEP home 
page (http://ctep.cancer.gov).  These requirements are briefly outlined in the table below 
(Section 8.4.2). 
In the rare occurrence when Internet connectivity is lost, a 24-hour notification is to be 
made to CTEP by telephone at 301-897-7497.  Once Internet connectivity is restored, the 
24-hour notification phoned in must be entered electronically into AdEERS by the 
original submitter at the site. 
 Expedited Reporting Guidelines – AdEERS Reporting Requirements for Adverse    
Events That Occur Within 30 Days1 of the Last Dose of the Investigational Agent on 
Phase 1 Trials 
 
Phase 1 Trials 
 
 
Grade 1 
 
Grade 2 
 
Grade 2 
 
Grade 3 
 
Grade 3 
Grades 
4 & 52 
Unexpected  
and Expected 
 
Unex-
pected 
 
 
Expected 
Unexpected 
Expected 
Unexpected  
and 
Expected 
with  
Hospitali-
without 
Hospitali- 
with  
Hospitali- 
without 
Hospitali- 


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30 
zation 
zation 
zation 
zation 
Unrelated 
Unlikely 
Not 
Required 
Not 
Required 
Not 
Required 
10 
Calendar 
Days 
Not 
Required 
10 
Calendar 
Days 
Not 
Required 
24-Hour; 
5 Calendar 
Days 
Possible 
Probable 
Definite 
Not 
Required 
10 
Calendar 
Days 
Not 
Required 
24-Hour; 
5 Calendar 
Days 
24-Hour; 
5 Calendar 
Days 
10 
Calendar 
Days 
Not 
Required 
24-Hour; 
5 Calendar 
Days 
1 Adverse events with attribution of possible, probable, or definite that occur greater than 30 days after the last 
dose of treatment with an agent under a CTEP IND require reporting as follows: 
AdEERS 24-hour notification followed by complete report within 5 calendar days for: 
• 
Grade 3 unexpected events with hospitalization or prolongation of hospitalization 
• 
Grade 4 unexpected events  
• 
Grade 5 expected events and unexpected events 
 
2 Although an AdEERS 24-hour notification is not required for death clearly related to progressive disease, a full report is 
required as outlined in the table. 
December 15, 2004 
 
Note:  All deaths on study require both routine and expedited reporting regardless of 
causality.  Attribution to treatment or other cause must be provided. 
• Expedited AE reporting timelines defined: 
➢ “24 hours; 5 calendar days” – The investigator must initially report the AE via 
AdEERS within 24 hours of learning of the event followed by a complete 
AdEERS report within 5 calendar days of the initial 24-hour report. 
➢ “10 calendar days” - A complete AdEERS report on the AE must be submitted 
within 10 calendar days of the investigator learning of the event.  
• Any medical event equivalent to CTCAE grade 3, 4, or 5 that precipitates hospitalization 
(or prolongation of existing hospitalization) must be reported regardless of attribution 
and designation as expected or unexpected with the exception of any events identified as 
protocol-specific expedited adverse event reporting exclusions.   
• Any event that results in persistent or significant disabilities/incapacities, congenital 
anomalies, or birth defects must be reported via AdEERS if the event occurs following 
treatment with an agent under a CTEP IND. 
• Use the NCI protocol number and the protocol-specific patient ID assigned during trial 
registration on all reports. 
 Protocol-Specific Expedited Adverse Event Reporting Exclusions 
 
CTCAE Category 
Adverse Event 
Grade 
Hospitalization/ 
Prolongation of 
Hospitalization 
Attribution Comments 
gastrointestinal 
diarrhea 
3 
yes 
any 
 
blood/bone marrow 
neutrophils 
4 
no 
any 
 
blood/bone marrow 
lymphopenia 
4 
no 
any 
 
blood/bone marrow 
leukocytes 
 4 
no 
any 
 
metabolic 
phosphate, serum-low 
2-4 
no 
any 
 
metabolic 
Albumin, serum-low 
2-4 
no 
any 
 
metabolic 
calcium, serum-high 
2-3 
no 
any 
 
metabolic 
calcium, serum-low 
2-3 
no 
any 
 


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31 
8.7 ROUTINE ADVERSE EVENT REPORTING 
All Adverse Events must be reported in routine (CDUS) study data submissions.  AEs reported 
through AdEERS must also be reported in routine study data submissions. 
8.8 SECONDARY AML/MDS  
AML/MDS events must be reported via AdEERS (in addition to your routine AE reporting 
mechanisms).  In CTCAE v4.0, the event(s) may be reported as either: 1) Leukemia secondary to 
oncology chemotherapy, 2) Myelodysplastic syndrome, or 3) Treatment-related secondary 
malignancy.   
9 
REGULATORY CONSIDERATIONS 
Cooperative Research and Development Agreement (CRADA):  
“The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI 
under a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical 
Company(ies) (hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer 
Treatment and Diagnosis.  Therefore, the following obligations/guidelines, in addition to the 
provisions in the “Intellectual Property Option to Collaborator” (http:// ctep.cancer.gov/industry) 
contained within the terms of award, apply to the use of the Agent(s) in this study: 
1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor can 
Agent(s) be transferred or licensed to any party not participating in the clinical study.  
Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) and 
shall be maintained as such by the investigators. The protocol documents for studies 
utilizing investigational Agents contain confidential information and should not be shared 
or distributed without the permission of the NCI.  If a copy of this protocol is requested by 
a patient or patient’s family member participating on the study, the individual should sign 
a confidentiality agreement. A suitable model agreement can be downloaded from: 
http://ctep.cancer.gov. 
2. For a clinical protocol where there is an investigational Agent used in combination with 
(an)other investigational Agent(s), each the subject of different collaborative agreements , 
the access to and use of data by each Collaborator shall be as follows (data pertaining to 
such combination use shall hereinafter be referred to as "Multi-Party Data”.): 
a. NCI will provide all Collaborators with prior written notice regarding the existence and 
nature of any agreements governing their collaboration with NIH, the design of the 
proposed combination protocol, and the existence of any obligations that would tend to 
restrict NCI's participation in the proposed combination protocol. 
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical 
trial by any other Collaborator solely to the extent necessary to allow said other 
Collaborator to develop, obtain regulatory approval or commercialize its own 
investigational Agent. 
c. Any Collaborator having the right to use the Multi-Party Data from these trials must 
agree in writing prior to the commencement of the trials that it will use the Multi-Party 
Data solely for development, regulatory approval, and commercialization of its own 
investigational Agent. 


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32 
3. Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement 
will be made available exclusively to Collaborator(s), the NCI, and the FDA, as appropriate 
and unless additional disclosure is required by law or court order. Additionally, all Clinical 
Data and Results and Raw Data will be collected , used and disclosed consistent with all 
applicable federal statutes and regulations for the protection of human subjects, including, 
if applicable, the Standards for Privacy of Individually Identifiable Health Information set 
forth in 45 C.F.R. Part 164. 
4. When a Collaborator wishes to initiate a data request, the request should first be sent to the 
NCI, who will then notify the appropriate investigators (Group Chair for Cooperative 
Group studies, or PI for other studies) of Collaborator's wish to contact them. 
5. Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the 
guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is 
a DMC for this clinical trial. 
6. Any manuscripts reporting the results of this clinical trial must be provided to CTEP by 
the Group office for Cooperative Group studies or by the principal investigator for non-
Cooperative Group studies for immediate delivery to Collaborator(s) for advisory review 
and comment prior to submission for publication.  Collaborator(s) will have 30 days from 
the date of receipt for review.  Collaborator shall have the right to request that publication 
be delayed for up to an additional 30 days in order to ensure that Collaborator’s confidential 
and proprietary data, in addition to Collaborator(s)’s intellectual property rights, are 
protected.  Copies of abstracts must be provided to CTEP for forwarding to Collaborator(s) 
for courtesy review as soon as possible and preferably at least three (3) days prior to 
submission, but in any case, prior to presentation at the meeting or publication in the 
proceedings. Press releases and other media presentations must also be forwarded to CTEP 
prior to release. Copies of any manuscript, abstract and/or press release/ media presentation 
should be sent to: 
Regulatory Affairs Branch, CTEP, DCTD, NCI 
Executive Plaza North, Suite 7111 
Bethesda, Maryland  20892 
FAX 301-402-1584 
Email:  anshers@mail.nih.gov  
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No 
publication, manuscript or other form of public disclosure shall contain any of 
Collaborator’s confidential/ proprietary information. 
10 PHARMACEUTICAL INFORMATION 
10.1 CTEP-SUPPLIED AGENT 
 CTEP IND agent alvocidib (Flavopiridol), NSC #649890; IND #46211 
 
Chemical Name: 4H-1-benzopyran-4-one, 2-(2-chloropheynl)-5, 7-dihydroxy-8-[(3S-4R)-3-
hydroxy-1-methyl-4-piperidinyl]-hydrochloride 
Other Names:  HMR 1275, flavopiridol 


Abbreviated Title:  Flavo in relapsed lymphomas 
Version Date:  09/28/2017 
 
33 
CAS Registry Number: 131740-09-5 
Molecular Formula:  C21H20CINO5 • HCl; M.W.: 438.29 
Description:     Synthetic flavone 
How Supplied: Alvocidib is provided by Sanofi-Aventis Pharmaceuticals, Inc. and distributed by 
CTEP, NCI.  It is supplied as a sterile, yellow to greenish-colored 10 mg/mL 
solution in flint glass vials with elastomeric closures.  Each vial contains 54.5 mg 
of HMR 1275, which is equivalent to 50 mg of the free base, acetic acid and Water 
for Injection.  The pH of the solution is about 3. 
Preparation:  The contents of the vial must be diluted prior to infusion with 0.9% Sodium 
Chloride Injection USP or 5% Dextrose Injection USP to final concentrations 
ranging from 0.09 to 1.0 mg/mL alvocodib (free base equivalent).  The diluted 
solutions are iso-osmotic and the pH is about 3.5 to 4.1.  The company currently 
recommends using a final concentration of 0.09 to 1 mg/mL to decrease the risk 
of thrombotic complications. 
Storage:  Store the vials at room temperature (25oC to 30oC) and protect from sunlight. Store 
diluted alvocidib solutions at room temperature and administer within 12 huors from 
preparation to the end of the infusion. 
Stability: Shelf-life surveillance of the intact vials in on-going; intact vials have been found stable 
for up to 36 months at 25o C.  
Dilute solutions of alvocidib are specifically compatible with silicone elastomer tubing, 
Becton-Dickinson filter needles, polyurethane tubing, and Hospira's Gemstar®  
administration sets.  And they are generally compatible with IV bags composed of 
polyvinyl chloride (PVC) with diethylhexyl phthalate (DEHP), ethylene vinylacetate 
(EVA) copolymer, or low density polyethylene (LDPE) and with tubing composed of 
silicone elastomer, polyurethane, or PVC. 
Route of Administration: Intravenous. Flavopiridol may be given peripherally or via a 
central venous access device. 
Reported Adverse Events and Potential Risks:  A list of the AEs and potential risks 
associated with Flavopiridol can be found in Section 8.2. 
 Agent Ordering and Agent Accountability  
NCI supplied agents may be requested by the Principal Investigator (or their authorized designee).  
Pharmaceutical Management Branch (PMB) policy requires that agent be shipped directly to the 
NCI.  PMB does not permit the transfer of agents between institutions (unless prior approval from 
PMB is obtained.) The CTEP assigned protocol number must be used for ordering all CTEP 
supplied investigational agents.  The responsible investigator at NCI must be registered with 
CTEP, DCTD through an annual submission of FDA form 1572 (Statement of Investigator), 
Curriculum Vitae, Supplemental Investigator Data Form (IDF), and Financial Disclosure Form 
(FDF).  If there are several participating investigators, CTEP supplied investigational agents for 
the study should be ordered under the name of one lead investigator at that institution. 
Agent may be requested by completing a Clinical Drug Request (NIH-986) and mailing it to the 
Drug Management and Authorization Section, PMB, DCTD, NCI, 9000 Rockville Pike, EPN 


Abbreviated Title:  Flavo in relapsed lymphomas 
Version Date:  09/28/2017 
 
34 
Room 7149, Bethesda, MD 20892-7422 or faxing it to (301) 480-4612.  For questions call (301) 
496-5725. 
Agent Inventory Records - The investigator, or a responsible party designated by the investigator, 
must maintain a careful record of the inventory and disposition of all agents received from DCTD 
using the NCI Drug Accountability Record (DAR) Form.  (See the NCI Investigator’s Handbook 
for Procedures for Drug Accountability and Storage.) 
10.2 OTHER AGENT(S) 
 Allopurinol  
Supply:  Commercially available. 
Pharmacology:   Allopurinol reduces the production of uric acid by inhibiting xanthine oxidase, 
the enzyme responsible for conversion of hypoxanthine to xanthine and of xanthine to uric acid, 
resulting in reductions in plasma and urinary concentrations of uric acid. 
Product description: Allopurinol is available in 100mg tablets and 300mg tablets. Allopurinol 
sodium is also available as a powder for injection for intravenous administration. It is not 
anticipated that intravenous allopurinol will be utilized for the purpose of this protocol. 
Storage and Stability:  Oral tablets should be stored at 15o to 25oC (59o to 77oF).  
Route of administration:  Oral  
Dose: 300 mg given orally once daily if estimated creatinine clearance is greater than 20 mL/min. 
Follow product labeling guidelines for dose adjustment if estimated creatinine clearance is less 
than or equal to 20 mL/min. 
Toxicities:  Allopurinol hypersensitivity or allergic reactions manifest by varying kinds of skin 
rash in association with fever, chills, leukopenia or leukocytosis, eosinophilia, arthralgia and 
pruritus. Dermatological complications related to allopurinol therapy are common and may occur 
in up to 10% to 15% of cases particularly if allopurinol is used concurrently with ampicillin or 
amoxicillin. The most common side effect of allopurinol is a MACULOPAPULAR RASH, often 
preceded by pruritus, an important warning symptom and an indication to discontinue the drug to 
avoid progression to more severe reactions (Prod Info Zyloprim(R), 2000). Allopurinol has 
produced hepatotoxic effects ranging from an alteration in liver function tests to hepatitis, which 
may be a part of a generalized hypersensitivity reaction. 
11 REFERENCES  
 
1. Carlson, B.A., et al., Flavopiridol induces G1 arrest with inhibition of cyclin-dependent 
kinase (CDK) 2 and CDK4 in human breast carcinoma cells. Cancer Res, 1996. 56(13): p. 
2973-8. 
2. Kaur, G., et al., Growth inhibition with reversible cell cycle arrest of carcinoma cells by 
flavone L86-8275. J Natl Cancer Inst, 1992. 84(22): p. 1736-40. 
3. Worland, P.J., et al., Alteration of the phosphorylation state of p34cdc2 kinase by the flavone 
L86-8275 in breast carcinoma cells. Correlation with decreased H1 kinase activity. Biochem 
Pharmacol, 1993. 46(10): p. 1831-40. 


Abbreviated Title:  Flavo in relapsed lymphomas 
Version Date:  09/28/2017 
 
35 
4. Lam, L.T., et al., Genomic-scale measurement of mRNA turnover and the mechanisms of 
action of the anti-cancer drug flavopiridol. Genome Biol, 2001. 2(10): p. RESEARCH0041. 
5. Takada, Y. and B.B. Aggarwal, Flavopiridol inhibits NF-kappaB activation induced by 
various carcinogens and inflammatory agents through inhibition of IkappaBalpha kinase and 
p65 phosphorylation: abrogation of cyclin D1, cyclooxygenase-2, and matrix 
metalloprotease-9. J Biol Chem, 2004. 279(6): p. 4750-9. 
6. Senderowicz, A.M., et al., Phase I trial of continuous infusion flavopiridol, a novel cyclin-
dependent kinase inhibitor, in patients with refractory neoplasms. J Clin Oncol, 1998. 16(9): 
p. 2986-99. 
7. Arguello, F., et al., Flavopiridol induces apoptosis of normal lymphoid cells, causes 
immunosuppression, and has potent antitumor activity In vivo against human leukemia and 
lymphoma xenografts. Blood, 1998. 91(7): p. 2482-90. 
8. Byrd, J.C., et al., Treatment of relapsed chronic lymphocytic leukemia by 72-hour continuous 
infusion or 1-hour bolus infusion of flavopiridol: results from Cancer and Leukemia Group B 
study 19805. Clin Cancer Res, 2005. 11(11): p. 4176-81. 
9. Kouroukis, C.T., et al., Flavopiridol in untreated or relapsed mantle-cell lymphoma: results 
of a phase II study of the National Cancer Institute of Canada Clinical Trials Group. J Clin 
Oncol, 2003. 21(9): p. 1740-5. 
10. Lin, T.S., et al., Seventy-two hour continuous infusion flavopiridol in relapsed and refractory 
mantle cell lymphoma. Leuk Lymphoma, 2002. 43(4): p. 793-7. 
11. Tan, A.R., et al., Phase I clinical and pharmacokinetic study of flavopiridol administered as a 
daily 1-hour infusion in patients with advanced neoplasms. J Clin Oncol, 2002. 20(19): p. 
4074-82. 
12. Bible, K.C. and S.H. Kaufmann, Flavopiridol: a cytotoxic flavone that induces cell death in 
noncycling A549 human lung carcinoma cells. Cancer Res, 1996. 56(21): p. 4856-61. 
13. Schwartz, G., et al., Flavopiridol enhances the biologic effects of paclitaxel: A phase I trial in 
patients with advanced solid tumors. Proc Am Soc Clin Oncol 17: 188, 1998: 725, 1998. 
14. Thomas, J.P., et al., Phase I clinical and pharmacokinetic trial of the cyclin-dependent kinase 
inhibitor flavopiridol. Cancer Chemother Pharmacol, 2002. 50(6): p. 465-72. 
15. Zhai, S., et al., Flavopiridol, a novel cyclin-dependent kinase inhibitor, in clinical 
development. Ann Pharmacother, 2002. 36(5): p. 905-11. 
16. Schwartz, G.K., et al., Phase I study of the cyclin-dependent kinase inhibitor flavopiridol in 
combination with paclitaxel in patients with advanced solid tumors. J Clin Oncol, 2002. 
20(8): p. 2157-70. 
17. Byrd, J.C., et al., Flavopiridol administered using a pharmacologically derived schedule is 
associated with marked clinical efficacy in refractory, genetically high-risk chronic 
lymphocytic leukemia. Blood, 2006. 
18. Cheson, B.D., et al., Report of an international workshop to standardize response criteria for 
non-Hodgkin's lymphomas. J Clin Oncol, 1999. 17(4): p. 1244. 
 


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36 
12  APPENDIX A:  Specimen Collection and Storage 
All specimens obtained in the protocol are used as defined in the protocol.  Any specimens that 
are remaining at the completion of the protocol will be stored in the conditions described below 
for an indefinite amount of time. The PI will report any loss or destruction of samples to the NCI 
IRB as soon as he is made aware of such loss.  
12.1 PHARMACOKINETIC SAMPLES 
All data associated with samples sent to the Blood Processing Core (BPC) under the direction of 
Dr. Figg is entered into the Clinical Pharmacology Program’s LABrador database (aka 
LabSamples or, formerly, “Patient Sample Database Management System” (PSDMS)). This is a 
secure program that can only be accessed by authorized users in Dr. Figg’s lab. LABrador 
creates a unique barcode ID for every sample and sample box which cannot be traced back to 
patients without LABrador access. 
The data recorded for each sample includes the patient ID, name, trial name/protocol number, 
time drawn, cycle time point, dose, material type, as well as box and freezer location. There are 
patient demographics that can be obtained to correlate with the samples through the system.  For 
each samples, there are notice associate with processing method (delay in sample processing, 
storage conditions on the ward, etc.).  Bar-coded samples are stored in bar-coded boxes in a 
locked freezer at either -20 or -85C according to stability requirements.  These freezers are 
located onsite in Dr. Figg’s lab and offsite at NCI Frederick Central Repository Services in 
Frederick, MD. Samples will be stored until requested by the researcher assigned to the protocol 
(however, those requests must come from a member of Dr. Figg’s laboratory with LABrador 
access/clearance).  All requests are monitored and tracked in the system. All researchers are 
required to sign a form stating that the samples are only to be used for research purposes 
associated with this trial (as per the IRB approved protocol – that protocol is stored in the 
LABrador system) and that any unused samples must be returned to Dr. Figg’s laboratory. 
12.2 PROTOCOL COMPLETION/SAMPLE DESTRUCTION 
Once primary research objectives for the protocol are achieved, intramural researchers can 
request access to remaining samples providing they have an IRB approved protocol and patient 
consent. 
The PI will report destroyed samples to the IRB if samples become unsalvageable because of 
environmental factors (ex. broken freezer or lack of dry ice in a shipping container) or if a patient 
withdraws consent. Samples will also be reported as lost if they are lost in transit between 
facilities or misplaced by a researcher.  Dr. Figg’s laboratory will report any freezer problems, 
lost samples or other problems associated with samples to the IRB, the NCI Clinical Director, 
and the office of the CCR, NCI. 
12.3 PROCEDURES FOR STORED SERUM SPECIMENS  
The Clinical Support Laboratory, Leidos Biomedical Research, Inc.-Frederick, processes and 
cryopreserves samples in support of IRB-approved, NCI clinical trials.  All laboratory personnel 
with access to patient information annually complete the NIH online course in Protection of 
Human Subjects.  The laboratory is CLIA certified for CD4 immunophenotyping and all 
laboratory areas operate under a Quality Assurance Plan with documented Standard Operating 


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37 
Procedures that are reviewed annually.  Laboratory personnel are assessed for competency prior 
to being permitted to work with patient samples.  Efforts to ensure protection of patient 
information include: 
• The laboratory is located in a controlled access building and laboratory doors are kept 
locked at all times. Visitors to the laboratory are required to be accompanied by 
laboratory staff at all times.   
• Hard copy records or electronic copies of documents containing patient information are 
kept in the locked laboratory or other controlled access locations.    
• An electronic database is used to store information related to patient samples processed 
by the laboratory.   
o The database resides on a dedicated program server that is kept in a central, 
locked computer facility.   
o The facility is supported by two IT specialists who maintain up to date security 
features including virus and firewall protection.   
o Program access is limited to specified computers as designated by the laboratory 
director.  Each of these computers has a password restricted login screen.   
o The database sample entry program itself is accessed through a password 
protected entry screen.   
o The database program has different levels of access approval to limit 
unauthorized changes to specimen records and the program maintains a sample 
history.   
• Upon specimen receipt each sample is assigned a unique, sequential laboratory accession 
ID number.  All products generated by the laboratory that will be stored either in the 
laboratory freezers or at a central repository facility are identified by this accession ID. 
• Beginning October 1, 2006 inventory information will be stored at the vial level and each 
vial will be labeled with both a sample ID and a vial sequence number.   
• Vial labels do not contain any personal identifier information.    
• Samples are stored inventoried in locked laboratory freezers and are routinely transferred 
to the NCI-Frederick repository facilities for long term storage.  These facilities are 
operated by Fisher Bioservices, Inc. under subcontract to Leidos Biomedical Research, 
Inc.-Frederick.   
• Access to stored clinical samples is restricted.  Investigators establish sample collections 
under “Source Codes” and the investigator responsible for the collections, typically the 
protocol Principal Investigator, specifies who has access to the collection.  Beginning 
October 1, 2006 specific permissions will be required to view, input or withdraw samples 
from a collection.  Prior to that date sample input was not restricted and restrictions were 
limited to specimen withdrawal.   
• Sample withdrawal requests submitted to approved laboratory staff by anyone other than 
the repository source code owner are submitted to the source code owner for approval.  
Beginning October 1, 2006 the repository facility will also notify the Source Code holder 
of any submitted requests for sample withdrawal.   
• It is the responsibility of the Source Code holder (generally the NCI Principal 
Investigator) to ensure that samples requested and approved for withdrawal are being 
used in a manner consistent with IRB approval.   


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38 
o The Clinical Support Laboratory does perform testing services that may be 
requested by clinical investigators including, but not limited to, 
immunophenotyping by flow cytometry and cytokine testing using ELISA or 
multiplex platforms.   
• When requests are submitted by the NCI investigator for shipment of samples outside of 
the NIH it is the policy of the laboratory to request documentation that a Material 
Transfer Agreement is in place that covers the specimen transfer.  The laboratory does 
not provide patient identifier information as part of the transfer process but may, at the 
discretion of the NCI investigator, group samples from individual patients when that is 
critical to the testing process.    
• The NCI investigator responsible for the sample collection is responsible for ensuring 
appropriate IRB approvals are in place and that a Material Transfer Agreement has been 
executed prior to requesting the laboratory to ship samples outside of the NIH.   
12.4 PROCEDURES FOR PERIPHERAL BLOOD CELLS 
1. Orders for tumor biopsies, research blood samples and lymphapheresis collections should be 
placed in CRIS (Clinical Research Information System, Clinical Research Center, NIH, 
Bethesda, MD) 
2. Tumor biopsies will be submitted in native condition to the Department of Pathology, CRC, 
NIH and handled according to routine procedures. Material released for research studies will 
be documented on form NIH 2803-1. Initial processing of samples for research will depend on 
the size of the tumor biopsy. For core biopsies the research sample will typically consist of 2 
cores in a microcentrifuge vial snap frozen on dry ice. Surgical lymph node biopsies may in 
addition be processed for single cell suspension, additional vials of snap frozen tissue and OCT 
embedded tissue. 
3. Lymphapheresis is performed in the Department of Transfusion Medicine, and blood will be 
collected in the phlebotomy suite, on a clinical ward, or in an outpatient clinic of the CRC, 
NIH. Samples will be transferred to the research laboratory at room temperature. Cells will be 
separated by Ficoll density gradient centrifugation and only mononuclear cells will be 
harvested, processed, analyzed, and stored.  
4. Tumor and normal blood cells may be viably frozen, typically at concentrations of 20-
100x106/mL in FCS with 10% DMSO using a temperature controlled freezing process to 
optimize sample viability. Samples will be transferred to Nitrogen tanks for long term storage.  
5. Tumor and normal blood cells can be further processed. Additional purification may be carried 
out by selection with magnetic beads binding to appropriate surface molecules, typically 
CD19. For analysis cells may be lysed to obtain RNA (using Qiagen manufactured kits are 
similar) or proteins (salt and/or triton containing buffers with addition of protease and 
phosphatase inhibitors). Integrity of RNA is monitored by gel electrophoresis and 
concentration of RNA or protein is measured spectrophotometrically.  
6. Research sample inventory and storage. All research samples are assigned a unique number 
and cataloged. Viably frozen cells are stored in a temperature controlled, alarm secured 
Nitrogen tank. Tumor biopsies and processed biologic material (RNA, protein) is stored at -
80C in a temperature controlled, alarm secured -80C freezer.  


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39 
12.5 PROCEDURES FOR LYMPH NODE BIOPSIES SENT TO DANA FARBER CANCER INSTITUTE 
Procedures. Lymph node biopsies will be obtained within 1 week of the first Flavopiridol dose 
and at the conclusion of a Flavopiridol infusion.  Biopsies will be fixed in formalin and either 
shipped on the day of acquisition to the Dana-Farber/Harvard Cancer Center Pathology Core 
or processed at NIH. Formalin-fixed, paraffin-embedded 5-µM sections will be mounted on 
glass slides, and subjected to immunohistochemistry with an automated stainer (BioGenex, 
San Roman, CA). Antibodies for assessment of cdk2 and cdk4 inhibition will include as many 
of the following as possible:  anti-total Rb, anti-Rb [pT356], anti-Rb [pS249/T252], anti-Rb 
[pS807/811], anti-Rb [pS780], anti-Rb [pS795], anti-total p27Kip1, and anti-p27Kip1 [pT187].  
Samples will also be analyzed for expression of cdk2, cdk4 and p16INK4A, Ki67 and TUNEL 
staining. Assessment of cdk9 inhibition will be performed with anti-cyclin D1 and anti-Mcl-1, 
as well as anti-total RNA polymerase II, anti-RNA polymerase II [pSer2] and anti-RNA 
polymerase II [pSer5], (if RNA polymerase II antibodies can be optimized for 
immunohistochemistry).   
Scoring of immunohistochemical sections will be performed by Dr. Lucian Chirieac (Brigham 
and Women’s Hospital, Department of Pathology).  A minimum of 200 cells will be scored for 
nuclear staining and will be graded as 0, 1+ or 2+.  The percentage of all positive cells and 
strongly positive cells will be compared pre- and post treatment, so that for each pair of 
specimens, the percent change from baseline of these parameters will be calculated. 
We will also examine the association between objective response and stable disease and 
baseline levels of cyclin D1 and p16INK4A in tumor biopsies, as well as microarray analysis 
performed at the NCI, to assess the relationship between the initial proliferative signature and 
clinical outcome after Flavopiridol treatment. 
Statistical considerations.  The major objectives will be to demonstrate that Flavopiridol has 
inhibited cdk targets within lymphoma cells and to determine whether the modulation of cdk 
targets correlates with response. Statistical significance between levels of biomarkers pre- and 
post-treatment will be assessed by the Wilcoxon signed rank test.   The relationship between 
changes in phospho-Rb, p27Kip1, phospho-RNA polymerase II, cyclin D1, Mcl-1 and Ki67 and 
radiographic tumor response will be assessed using rank-based correlation methods for pairs 
of quantitative endpoints, and by the Wilcoxon rank-sum test for the association between 
quantitative endpoints and radiographic response.  
Samples were sent to:  
Geoffrey Shapiro, MD, PhD 
Dana Farber Cancer Institute 
Associate Professor of Medicine, Harvard Medical School 
44 Binney Street, Boston, MA 02115 
(617) 632-2096 
geoffrey_shapiro@dfci.harvard.edu  
 
 

ICF_000.pdf: 
 
 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
   MEDICAL RECORD  
               •  Adult Patient or     •  Parent, for Minor Patient 
 
 
INSTITUTE: 
National Cancer Institute 
 
 
STUDY NUMBER: 
07-C-0081 
PRINCIPAL INVESTIGATOR:  Kieron Dunleavy, M.D. 
 
 
STUDY TITLE: 
A  Phase  I/II  Study  of  Flavopiridol  
in  Relapsed  or  Refractory  Mantle  Cell  
lymphoma  (MCL)  and 
Diffuse Large B-cell Lymphoma (DLBCL) 
 
 
Continuing Review Approved by the IRB on 6/13/11 
Amendment Approved by IRB on 06/02/11 (I)    
  
  
 
Date Posted to Web:  06/10/11 
Standard 
 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL 
 
RESEARCH STUDY 
 
•   Adult Patient or    •   Parent, for Minor Patient 
 
NIH-2514-1 (07-09) 
 
P.A.: 09-25-0099 
 
File in Section 4:  Protocol Consent (1) 
 
 
INTRODUCTION 
 
We invite you to take part in a research study at the National Institutes of Health (NIH). 
 
First, we want you to know that: 
 
Taking part in NIH research is entirely voluntary. 
 
 
You may choose not to take part, or you may withdraw from the study at any time.  In either case, you will not 
lose any benefits to which you are otherwise entitled.  However, to receive care at the NIH, you must be taking 
part in a study or be under evaluation for study participation. 
 
 
You may receive no benefit from taking part.  The research may give us knowledge that may help people in the 
future. 
 
Second, some people have personal, religious or ethical beliefs that may limit the kinds of medical or research treatments 
they would want to receive (such as blood transfusions).  If you have such beliefs, please discuss them with your NIH 
doctors or research team before you agree to the study. 
 
Now we will describe this research study.  Before you decide to take part, please take as much time as you need to ask 
any questions and discuss this study with anyone at NIH, or with family, friends or your personal physician or other health 
professional. 
 
DESCRIPTION OF RESEARCH STUDY 
 
You have been invited to participate in this study because you have either relapsed mantle cell lymphoma (MCL) or diffuse 
large B-cell lymphoma (DLBCL).  This is a clinical research study using a drug called flavopiridol. Flavopiridol is an 
investigational drug that has been shown in the laboratory to work in a different way to standard chemotherapy. Its 
effectiveness may depend on the amount of drug (dose) and schedule (timing of drug dose). Earlier studies of flavopiridol 
given on a different schedule were not successful. The schedule that you will be receiving has been tested on patients 
with a different type of disease called chronic lymphocytic leukemia (CLL). Some of the patients with CLL who received 
flavopiridol developed a complication called tumor lysis syndrome (TLS) which is where there is a quick death of tumor 
cells which may cause the amount of potassium and other substances in the bloodstream to rise to dangerous levels. The 
dose was then lowered and certain patients with very high white cell counts most at risk for developing TLS were not 
treated with flavopiridol until their white count was lowered. Since these changes, the dose and schedule that you will be 


 
 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 
07-C-0081 
CONTINUATION:  page  2  of  10  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
 
receiving in this study has been given to at least 42 patients safely. In this study, we are trying to determine what the 
maximum dose of flavopiridol is that can be given safely to patients with your tumor type as a 30 minute initial infusion 
followed by a 4 hour infusion, given weekly for 4 consecutive weeks followed by a 2 week treatment break. There will be 
4 different dose levels of flavopiridol in this study and when you are enrolled, the dose level that you receive depends on 
when you are enrolled in relation to the other patients and the side effects that other patients on the study have had. Our 
goal is to enroll up to 71 patients on this study.  
 
There are several abnormalities in mantle cell and diffuse large B-cell lymphoma cells which may be targeted by 
flavopiridol. For example, a type of protein called cyclin D-1 has high expression in mantle cell lymphoma cells and 
probably prevents the tumor cells from dying. Cyclin D-1 is a target of flavopiridol and we hope that by targeting this it 
will cause tumor cells to die. There are several other proteins in both mantle cell and diffuse large B-cell lymphoma cells 
which may be targeted by flavopiridol. We hope that by using this new schedule, which is very effective in CLL, we will 
see good responses which will translate into clinical benefit in patients with mantle cell and diffuse large B-cell lymphoma.  
 
Study Design: Before being enrolled in the study, you will undergo a series of tests to determine if you are eligible for 
the study and to determine the extent (called stage) of your lymphoma.  If you are found not to be eligible for the study, 
you will be referred back to your home physician.  If you are eligible and decide to participate, we will ask you to undergo 
a lymph node biopsy before you start any treatment. As part of your clinical evaluation and follow up we will use CT scans 
to determine the extent of your disease and response to treatment. 
 
Administration of flavopiridol: Flavopiridol is given intravenously (IV—into a vein). It may be given in a little catheter 
inserted on the day of the infusion or through a venous access device (also called central venous catheter). If you already 
have a central venous catheter, a new one will not be placed.  If it is determined that you need a central venous catheter, 
you  will  be  given  an  appointment  
for  an  outpatient  surgical  procedure  to  place  the  catheter  
into  a  vein  
in  the  arm  or 
chest.  You  will  receive  further  information  about  the  procedure  and  the  catheter  from  the  clinic  that  performs  these 
procedures. 
You will be admitted to the hospital to receive flavopiridol for the first infusion.  Flavopiridol is given as a 4 and a half hour 
infusion.  Some of the drug dose is given over the first 30 minutes; the remainder is infused over 4 hours.  You will 
receive medications for nausea and diarrhea.  For the first treatment, you will be given the drug allopurinol by mouth and 
fluid into your veins to prevent an unlikely, but serious, side effect called tumor lysis syndrome (which occurs when cancer 
cells die too rapidly). The study doctor will decide if on subsequent cycles you need treatment to prevent tumor lysis 
syndrome.  If you do not have serious side effects, you will go home the following day. This treatment will be repeated 
weekly for 4 weeks in a row, followed by 2 weeks with no treatment.  This 6 week time period is called a “cycle.” 
After the first infusion, the remaining treatments will be in the outpatient clinic as long as you do not develop serious side 
effects. You may go home 2-3 hours after outpatient treatments.  If you have serious side effects as an outpatient, you 
will be hospitalized. Any further flavopiridol would then be given to you in the hospital.  
If  you  develop  
low  white  blood  counts  during  flavopiridol  treatment,  we  will  begin  treatment  with  Neupogen  (G-CSF) 
which can cause your neutrophil count to rise. Once we start Neupogen, we will continue it throughout the course of your 
treatment with flavopiridol. 
 
Research tests:  We would like to perform research studies on your blood, bone marrow, tumor tissue or other fluids to 
look at different genes and proteins that may be involved in the development of your lymphoma or the reaction of the 
immune system.  We will not examine mutations of normal genes from your tissue without obtaining additional permission 
from you.  We plan to do a tissue biopsy before you start treatment and in selected cases a second biopsy after treatment 


 
 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 
07-C-0081 
CONTINUATION:  page  3  of  10  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
 
has begun. These biopsies will give us important information about your tumor and the effects of flavopiridol on it. 
Biopsies requiring major surgery (e.g., in the chest or the abdomen) will not be performed for research purposes alone 
but only if absolutely necessary for your medical care.  Some of the research tissue and samples obtained may be sent to 
centers outside of the National Cancer Institute for tests to better understand how flavopiridol works in cancer cells. 
 
 Lymph node biopsy: 
The purpose of the lymph node biopsy is to identify biomarkers that may predict how a patient will respond to flavopiridol.  
Please clearly check the appropriate box below: 
 
  I am volunteering to take part in the optional lymph node biopsy  
 
  I am NOT volunteering to take part in the optional lymph node biopsy  
 
Some patients may also undergo up to two biopsies under CT guidance for research purposes. This radiation is for 
research purposes only and is not necessary for your medical care.  
 
Certain patients who have tumor cells in their blood stream may be asked to undergo a procedure called lymphapheresis 
or apheresis for research purposes. Lymphapheresis or apheresis is done by circulating your blood through the apheresis 
machine. To do this you must have two places where IV needles are placed. There are two ways to do this procedure. In 
the first method, a needle is placed into each of your arm veins. The second method uses a vascular access device. Both 
methods provide a route for your blood to be circulated through the apheresis machine. Your blood is removed from one 
IV site, and then flows through the tubing into the machine. The machine has a centrifuge that separates the part of the 
blood that is to be removed. Only a small portion of your blood is circulated through the machine at any one time. The 
blood then returns to you through the other IV site. The procedure takes 2 - 4 hours to complete. Once the procedure is 
done, all of your blood is returned to you. You will be taken off the machine by the nurse. The needles are then removed 
and pressure is put over where the needles were to be sure that bleeding stops. After a period of rest, you will be told 
when to come in for your next procedure. The procedure may be done more than once. 
 
You may have some discomfort when the nurse puts the needles into your veins. Keeping your arms in one position and 
staying still during a 2 - 4 hour procedure may also be a little uncomfortable. Some patients may feel dizzy, light-headed, 
nauseated, or cold during the procedure. Tell the staff right away if you feel any of these side effects. It is normal to feel 
tired for a short time after this procedure. 
 
What happens after treatment is completed:  This depends on how you have responded to the therapy.  If all 
evidence of disease has disappeared, we will schedule periodic visits to the Clinical Center for follow-up examination and 
tests.  If the disease does not disappear entirely or if it should recur after having disappeared for a period of time, then 
you may need further therapy.  At that time you will be given the opportunity of participating in additional research 
protocols that may be appropriate for you.  If no such protocols are available, you will be returned to the care of your 
local physician.  We will continue to contact you and/or your local physician to see how you are doing even after you have 
completed treatment on this protocol. It is important to stress that participation in this protocol does not constitute a 
promise of long-term medical care here at the Clinical Center.  It is conceivable that participation in this study may make 
you ineligible to participate in certain other research protocols because the requirements for entry onto these protocols 
may not allow patients who have already been treated with certain drugs or who have had certain side effects from 
previous treatment.  You may decide now not to receive treatment on this protocol, or you may choose at any point in 
time to stop the treatment and withdraw from the protocol; in either case you will be returned to the care of your 
referring physician.   


 
 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 
07-C-0081 
CONTINUATION:  page  4  of  10  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
 
ALTERNATIVE APPROACHES OR TREATMENTS  
 
Alternative procedures that could be used to treat your disease include: 
 
1.  
Combination drug regimens. There are several drugs which are very active in diffuse large B-cell lymphoma and 
mantle cell lymphoma.  
2.  
Treatment with single drugs.  
3.  
Radiation (X-ray) treatments.  This can stop tumor growth in particular locations, such as bone, abdomen, and 
other sites but is not successful in controlling the disease overall unless the disease is very localized at the start of 
therapy.  
4.  
Surgery.  As with radiation, surgery can be successful in removing tumor from particular locations but cannot be 
used successfully to remove all lymphoma cells from the body, since the disease is almost always present in 
multiple locations.  Also, surgery cannot be used against tumor in some of the organs most commonly involved by 
lymphoma, such as the liver or the lungs. 
5.   
Bone marrow transplantation may be an alternative type of treatment. This can be curable in some patients with 
relapsed or refractory mantle cell lymphoma or diffuse large B-cell lymphoma.  
6. 
Watching and waiting may be an option for select patients without symptoms. 
7.   
 Getting no treatment; getting comfort care, also called palliative care. This type of care helps reduce pain, 
tiredness, appetite problems, and other problems caused by cancer. It does not treat the cancer directly, but 
instead tries to improve how you feel. Comfort care tries to keep you as active and comfortable as possible. 
RISKS OR DISCOMFORTS OF PARTICIPATION 
 
In order to determine whether this study is suitable for you, a number of tests will have to be done.   Some or all of these 
tests will be repeated during and after the flavopiridol at different times.  Depending on the tests you had before coming 
here, these may include blood and urine tests, studies of lung function, CAT or MRI scans, radioisotope scans (for 
example a PET scan), colonoscopies, and biopsies of tumor tissue, bone marrow, liver, or other sites.  Biopsies will, when 
possible, be done under local anesthesia.  The risks associated with bone marrow biopsies include pain, bleeding, and 
local infection.  Risks of biopsies include pain, bleeding, infection, and the risks to the particular area undergoing surgery.  
General anesthesia itself is generally very safe but has a very small risk of major complications such as heart attack or 
stroke.  The surgical and anesthetic risks will be explained to you in more detail at the time of surgery, if this is needed.  
Risks of colonoscopy with biopsies include discomfort and bleeding from the rectum; rarely the colon may be punctured 
and if this occurs, it is serious and may require surgery.   A separate consent describing all of the complications and side 
effects of colonoscopy with biopsies will be obtained from you.  
 
In order to receive this therapy it is possible that you will need to have an intravenous catheter placed.  This catheter is 
usually placed in the arm, chest or neck area into a major vein inside your chest.  We usually remove the catheter after 
each cycle but on occasion it can be left in for several cycles.  The catheter may be necessary for infusion of flavopiridol 
and for the drawing of blood.  It is usually inserted under local anesthesia.  The risks associated with the procedure 
include pain, bleeding, infection, and puncture of the underlying lung.  Lung puncture can result in lung collapse, which 
might require that a chest tube be placed into the chest cavity (usually for a day or two) to help the lung re-inflate.  The 
long-term risks of the catheter include infection and clotting of the vein in which the catheter sits.  If these occur, it may 
be necessary to remove the catheter.  These risks will be explained to you in more detail at the time of the insertion.  


 
 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 
07-C-0081 
CONTINUATION:  page  5  of  10  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
 
Possible side effects of Flavopiridol: 
 
Likely: 
• Lack of enough red blood cells (anemia) 
• Diarrhea 
• Nausea or the urge to vomit 
• Vomiting 
• Fatigue or tiredness 
• Decreased number of a type of white blood cell (neutrophil/granulocyte) 
• Decreased number of a type of blood cell that help to clot blood (platelet) 
• Decrease in the total number of white blood cells (leukocytes) 
 
Less Likely: 
• Fever associated with dangerously low levels of a type of white blood cell (neutrophils) 
• Belly pain 
• Chills 
• Fever 
• Pain 
• Potentially life-threatening condition during a drug infusion which may cause low blood pressure, rash, fever, 
chills, difficulty breathing, rapid heartbeat, nausea, and kidney damage 
• Infection 
• Increased blood level of a liver enzyme (ALT/SGPT) 
• Increased blood level of a liver enzyme (AST/SGOT) 
• Increased blood level of a liver pigment (bilirubin) often a sign of liver problems 
• Decreased number of a type of white blood cell (lymphocyte) 
• Loss of appetite 
• High blood sugar level 
• Decreased levels of a blood protein called albumin 
• Decreased blood level of  phosphate 
• High or low blood calcium 
• Group of signs and symptoms due to rapid breakdown of tumor that can occur after treatment of cancer has 
started that causes increased levels of blood potassium, uric acid, and phosphate, decreased levels of blood 
calcium, and kidney failure 
• Increased creatinine (blood test that indicates kidney function) 
• Muscle pain 
• Pain in the area of the tumor 
• Taste changes 
• Bleeding from the brain 
• Shortness of breath 
• Hair loss 
• Low blood pressure 
• Fainting 
• Formation of a blood clot that breaks loose and is carried by the blood stream to plug another blood vessel 


 
 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 
07-C-0081 
CONTINUATION:  page  6  of  10  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
 
 
If you receive Neupogen, the possible side effects include:  
• 
Bony pain  
• 
Skin rash 
• 
Skin reddening around the injection site 
• 
Muscle cramps 
• 
Decreased platelets (not clinically significant) 
• 
Pain or numbness and tingling around the chin 
• 
Worsening of certain pre-existing inflammatory conditions (such as psoriasis eczema, or vasculitis) 
• 
Fever, body aches 
• 
Alterations in certain laboratory tests 
• 
With prolonged administration Neupogen has been associated with hair thinning and enlargement of the spleen.  
 
In addition to the above listed side effects, unforeseeable or unexpected risks, including death may be involved with this 
drug. Your physicians will watch you closely for side effects and will stop treatment if any side effects become a serious 
threat to your life or well-being.  Your physicians will also stop the treatments if it becomes clear that the treatment is not 
successfully controlling your disease. 
You should not become pregnant or father a baby while on this study because the drug in this study can affect an unborn 
baby. Women should not breastfeed a baby while on this study. It is important you understand that you need to use birth 
control while on this study. Check with your study doctor about what kind of birth control methods to use and how long to 
use them. Some methods might not be approved for use in this study.  Flavopiridol may be toxic to the cells in the ovary 
and testicle and may produce sterility.  Recovery of normal fertility is not well studied.  For this reason, men who are 
about to receive this treatment should, if they wish to have children in the future, consider sperm banking before start of 
the treatment.  Women of childbearing age will have a pregnancy test, which must be negative at the time of study entry.  
This test requires that a urine sample be obtained within one week prior to the study.  The results of the pregnancy test 
will be made available to you prior to the initiation of the study.  
Rarely, patients may develop a dangerous side effect from blood transfusions called graft versus host disease (GVH).  This 
disease is caused by white cells from the blood transfusion that can attack your normal tissues and cause death.  GVH is 
preventable by radiating the blood before you receive it.  It is important to emphasize that you will not receive any 
radiation from the blood and the radiation procedure done on the donated blood will not harm you.  If you require a blood 
transfusion at the NIH during this study, you will receive blood that has been radiated.  However, if your local physician 
gives you a blood transfusion, it is important that you make sure the blood has been radiated. 
This research study involves exposure to radiation from one to two CT scans. Please note that this radiation exposure is 
not necessary for your medical care and is for research purposes only. If you are an adult, the total amount of radiation 
you will receive in this study is from 1-2 CT scans.  
 
Using the standard way of describing radiation dose, from participating in this study, you will receive (from two CT scans) 
a total of 8.0 rem to your kidneys and 5.2 rem each to your stomach, gallbladder wall and lower large intestine.  All other 
organs  will  receive  smaller  amounts  of  radiation.    Although  each  organ  will  receive  a  different  dose,  the  amount  of 
radiation  exposure  you  will  receive  
from  
these  procedures  
is  equal  
to  a  uniform  whole-body  exposure  of 1.2 rem.  This 
calculated value is known as the “effective dose” and is used to relate the dose received by each organ to a single value.  
The  amount  of  radiation  received  in  this  study  is within the  dose  guideline  established  by  the  NIH  Radiation  Safety 
Committee for research subjects.  The guideline is for an effective dose not to exceed 5 rem received per year in adults. 


 
 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 
07-C-0081 
CONTINUATION:  page  7  of  10  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
 
The NIH Radiation Safety Committee, a group of experts in radiation matters, has reviewed the use of radiation in adults 
in  this  research  study  and  has  approved  this  use  as  involving  acceptable risk  and  necessary  to  obtain  the  research 
information desired. 
 
For comparison, the average person in the United States receives a radiation exposure of 0.3 rem per year from natural 
background sources, such as from the sun, outer space, and from radioactive materials that are found naturally in the 
earths air and soil.  The dose that you will receive from two CT scans is about the same amount you would normally 
receive in 4 years from these natural sources.   If you would like more information about radiation and examples of 
exposure levels from other sources, please ask the investigator for a copy of the pamphlet called, An Introduction to 
Radiation for NIH Research Subjects. 
 
The effects of radiation exposure on humans have been studied for over 60 years.  In fact, these studies are the most 
extensive ever done of any potentially harmful agent that could affect humans.  In all these studies, no harmful effect to 
humans has been observed from the levels of radiation you will receive by taking part in this research study.   However, 
scientists disagree on whether radiation doses at these levels are harmful.  Even though no effects have been observed, 
some scientists believe that radiation can be harmful at any dose - even low doses such as those received during this 
research. 
 
One possible effect that could occur at these doses is a slight increase in the risk of cancer. Please be aware that the 
natural chance of a person getting a fatal cancer during his/her lifetime is about 1 out of 4 (or 25 percent). The increase 
in the chance of getting a fatal cancer, as a result of the radiation exposure received from this research study, is 
estimated at 0.05 percent. Therefore, the total risk of fatal cancer may be estimated to increase from 25 percent to up to 
25.05 percent. This change in risk is small and cannot be measured directly.  Compared with other everyday risks, such as 
flying in an airplane or driving a car, this increase is considered slight.  
 
Please tell your doctor if you have taken part in other research studies or received any medical care at the NIH or other 
places/hospitals that used radiation.  This way we can make sure that you will not receive too much radiation.  Consider 
x-rays taken in radiology departments, cardiac catheterization, and fluoroscopy as well as nuclear medicine scans in which 
radioactive materials were injected into your body. 
 
If you would like more information about radiation and examples of exposure levels from other sources, please ask the 
investigator for a copy of the pamphlet called, An Introduction to Radiation for NIH Research Subjects. 
 
If  you  are  pregnant  you  may  not  participate  
in  this  research  study.    It  
is  best  to  avoid  radiation  exposure  to  unborn 
children since they are more sensitive to radiation than adults.  
POTENTIAL BENEFITS OF PARTICIPATION 
We hope that some patients will have tumor shrinkage with flavopiridol. However, it is possible that you may not respond 
to any of this treatment. 
RESEARCH SUBJECT’S RIGHTS 
 
Any complication arising from this treatment will receive full and prompt medical attention.  However, the National Cancer 
Institute, Federal Government, and the Clinical Center do not provide financial compensation for injury or long-term 


 
 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 
07-C-0081 
CONTINUATION:  page  8  of  10  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
 
medical treatment for such injuries, except as may be provided by remedies available under law. The study drug 
flavopiridol will be provided by CTEP. You will not be paid for taking part in this study.  Your participation in this research 
study may contribute to the development of commercial products from which Sanofi Aventis Pharmaceuticals, Inc. or 
others may derive an economic benefit.  You will have no rights to any patents or discoveries arising from this research, 
and you will receive no economic benefit. Your medical care and the costs of the laboratory and radiographic studies done 
at the Clinical Center, NIH will be at no expense to you.  If the blood tests needed to monitor the effects of treatment are 
to be done by your local physician, you can be reimbursed for the costs if your insurance does not cover this expense; 
permission for this must be obtained by your NIH physician in advance.  The NIH cannot, however, reimburse you for the 
costs of other types of medical care delivered outside the NIH, even if you are seeking medical attention as a result of 
side effects from treatment given here, unless permission is granted in advance by the principal investigator of this study.  
Similarly, we do not ordinarily reimburse the costs of diagnostic radiology tests (such as CT scans, MRI, or chest X-rays) 
done outside the NIH, even if they are done for the purposes of this study.  
 
NEW INFORMATION 
 
You will be informed of any new findings related to the development or safety of flavopiridol that may affect your 
willingness to continue to take part in this study. 
 
EARLY TERMINATION 
 
You will be discontinued from this study for any of the following reasons: 
 
• You may be withdrawn from the study if you do not comply with the study requirements. 
• Your doctors do not feel it is in your medical best interests to be continued on this study. 
• You have had unacceptable toxicity which does not permit safe continuation on the study 
• You require another treatment. 
 
MAKING YOUR CHOICE 
 
We would like to keep some of the blood/tissue that is left over for future research.  These specimens will be identified by 
a number and not your name.  The use of your specimens will be for research purposes only and will not benefit you.  It 
is also possible that the stored specimens may never be used.  Results of the research done on your specimens will not be 
available to you or your doctor.  It might help people who have cancer and other diseases in the future.  
 
If you decide now that your blood/tissue can be kept for future research, you can change you mind at any time.  Just 
contact us and let us know that you do not want us to use your blood/tissue.  Then any remaining blood/tissue that 
remains will be destroyed.  
 
Please read each sentence below and think about you choice.  After reading each sentence, circle and initial the answer 
that is right for you.  If you have any questions, please talk to your doctor or nurse.  No matter what you decide to do, it 
will not affect your care. 
 
 
1. My blood/tissue may be kept for use in research to learn about, prevent or treat cancer.  
 
Yes  
  
  
  
 
No  
  
Initials_____________ 


 
 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 
07-C-0081 
CONTINUATION:  page  9  of  10  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
 
 
2. My blood/tissue may be kept for use in research to learn about, prevent or treat other health problems (for example: 
diabetes, Alzheimer’s disease, or heart disease). 
 
Yes  
  
  
  
 
No  
  
Initials_____________ 
 
3. Someone may contact me in the future to ask permission to use my specimen(s) in new research at the NIH not 
included in this consent.  
 
Yes  
  
  
  
 
No  
  
Initials_____________ 
 


 
  
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
   MEDICAL RECORD 
•  Adult Patient or    •  Parent, for Minor Patient 
 
STUDY NUMBER: 
07-C-0081 
CONTINUATION:  page  10  of  10  pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL 
 
RESEARCH STUDY (Continuation Sheet) 
 
•  Adult Patient or   •  Parent, for Minor Patient 
 
NIH-2514-1 (07-09) 
 
P.A.: 09-25-0099 
 
File in Section 4:  Protocol Consent 
 
 
OTHER PERTINENT INFORMATION 
1. Confidentiality.  When results of an NIH research study are reported in medical journals or at scientific meetings, 
the people who take part are not named and identified.  In most cases, the NIH will not release any information about 
your research involvement without your written permission.  However, if you sign a release of information form, for 
example, for an insurance company, the NIH will give the insurance company information from your medical record.  This 
information might affect (either favorably or unfavorably) the willingness of the insurance company to sell you insurance. 
 
The Federal Privacy Act protects the confidentiality of your NIH medical records.  However, you should know that the Act 
allows release of some information from your medical record without your permission, for example, if it is required by the 
Food and Drug Administration (FDA), members of Congress, law enforcement officials, or authorized hospital accreditation 
organizations. 
 
2. Policy Regarding Research-Related Injuries.  The Clinical Center will provide short-term medical care for any 
injury resulting from your participation in research here.  In general, no long-term medical care or financial compensation 
for research-related injuries will be provided by the National Institutes of Health, the Clinical Center, or the Federal 
Government.  However, you have the right to pursue legal remedy if you believe that your injury justifies such action. 
 
3. Payments.  The amount of payment to research volunteers is guided by the National Institutes of Health policies.  In 
general, patients are not paid for taking part in research studies at the National Institutes of Health.  Reimbursement of 
travel and subsistence will be offered consistent with NIH guidelines. 
 
4. Problems or Questions. If you have any problems or questions about this study, or about your rights as a research 
participant, or about any research-related injury, contact the Principal Investigator, Kieron Dunleavy, M.D.; Building 10, 
Room 4N115, Telephone:  301-435-1007.   
 
You may also call the Clinical Center Patient Representative at 301-496-2626. 
 
5. Consent Document.  Please keep a copy of this document in case you want to read it again. 
COMPLETE APPROPRIATE ITEM(S) BELOW: 
 
A. Adult Patient’s Consent 
B. Parent’s Permission for Minor Patient. 
I  have  read  the  explanation  about  this  study  and  have  been  given  the 
opportunity to discuss it and to ask questions.  I hereby consent to take 
part in this study. 
I  have  
read  
the  explanation  about  
this  study  and  have  been  given  
the 
opportunity to discuss it and to ask questions.  I hereby give permission 
for my child to take part in this study.   
(Attach NIH 2514-2, Minor’s Assent, if applicable.) 
 
  
 
 
  
 
Signature of Adult Patient/Legal Representative 
Date 
 
 
 
Print Name 
Signature of Parent(s)/Guardian 
Date 
 
 
 
Print Name 
C. Child’s Verbal Assent (If Applicable) 
The information in the above consent was described to my child and my child agrees to participate in the study. 
 
 
 
  
 
 
 
 
Signature of Parent(s)/Guardian 
Date 
 
Print Name 
THIS CONSENT DOCUMENT HAS BEEN APPROVED FOR USE  
FROM JUNE 13, 2011 THROUGH JUNE 12, 2012.  
 
 
 
  
 
 
  
 
Signature of Investigator 
Date 
 
 
 
Print Name 
Signature of Witness 
Date 
 
 
 
Print Name