Conditions: Multiple Myeloma Non-Hodgkin's Lymphoma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 38
Healthy volunteers: no

Brief summary:
The trial is an open label Simon optimal two-stage Phase II trial of fixed doses of oral meloxicam and subcutaneous filgrastim to assess the safety and efficacy in mobilizing autologous peripheral blood stem cells (PBSC) from multiple myeloma (MM) and non-Hodgkin's lymphoma (NHL) patients planning to undergo high-dose chemotherapy with stem cell support. Clinical data regarding the cellular composition and function of the graft mobilized by this combination will be obtained.

Detailed description:

Arms:
arm 1: Meloxicam and Filgrastim will be administered in fixed doses to each patient enrolled on this study. The treatments will be administered in a staggered dose schedule for a total treatment duration of 7 days prior to apheresis.

15 mg tablets of Meloxicam will be taken orally for 5 consecutive days.

10 µg/kg of Filgrastim will be subcutaneously injected for 5 consecutive days. Filgrastim may be subcutaneously injected for an additional 3 days if patients do not meet the primary endpoint for cell collection.

Interventions: intervention 1: Meloxicam intervention 2: Filgrastim
Intervention descriptions: intervention 1: 15 mg tablets of Meloxicam will be taken orally in the morning, with or without food. intervention 2: Filgrastim will be subcutaneously injected in one or two sites at home.

Protocol document:
Prot_SAP_000.pdf: 
Protocol Version Date: 12/21/2016
Page | 1 
A Phase II Trial of Prostaglandin E2 Inhibition, using Meloxicam, plus 
Filgrastim for Mobilization of Autologous Peripheral Blood Stem Cells in 
Patients with Multiple Myeloma, Hodgkin’s Disease and Non-Hodgkin’s 
Lymphoma 
IUCRO-0419 
Coordinating Center: 
Indiana University Simon Cancer Center 
Principal Investigator: 
Sherif S. Farag, MD, PhD 
Professor of Medicine 
Indiana University School of Medicine 
R-3 Walther Hall, C414
980 W. Walnut Street
Indianapolis, IN 46202
Phone: (317) 278-0460
Fax: (317) 274-2262
ssfarag@iu.edu
Co-Investigators: 
Rafat Abonour, MD 
Robert Nelson, MD  
Michael Robertson, MD 
Jennifer Schwartz, MD 
Louis Pelus, PhD 
Rebecca Silberman, MD 
Attaya Suvannasankha, MD 
Mohammad Abu Zaid, MD 
Research Nurse:  
Carol Huntley, RN 
Study Statistician: 
Susan Perkins, PhD 
Protocol Version: 
December 21, 2016  
NCT02078102 


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Protocol Version Date: 12/21/2016                                                                               Page | 2  
 
 
Table of Contents 
1.0  
BACKGROUND AND STUDY RATIONALE ........................................................................... 5 
1.1  Importance of CD34 cell dose for engraftment kinetics .................................................................. 5 
1.2 NSAIDs mobilize hematopoietic progenitor cells ........................................................................... 6 
1.3 Mobilization of hematopoietic progenitors by NSAIDs .................................................................. 7 
1.4 Schedule of meloxicam and G-CSF administration ......................................................................... 8 
1.5 Meloxicam mobilizes hematopoietic progenitors in healthy human volunteers .............................. 9 
1.6 Mobilization of autologous PBSC at Indiana University  .............................................................. 10 
1.7 Study and Dose Rationale .............................................................................................................. 11 
1.8 Inclusion of Women and Minorities  ............................................................................................. 11 
2.0  
STUDY OBJECTIVES ................................................................................................................ 11 
2.1 Study Overview  ............................................................................................................................ 11 
2.2 Primary Objectives......................................................................................................................... 11 
2.3 Secondary Objectives..................................................................................................................... 12 
3.0  
ELIGIBILITY CRITERIA  ................................................................................................ 12 
3.1Inclusion Criteria ................................................................................................................... 11 
3.2 Exclusion Criteria  ......................................................................................................................... 13 
4.0  
REGISTRATION PROCEDURES AND INFORMED CONSENT ....................................... 13 
5.0  
TREATMENT PLAN  ................................................................................................................. 14 
 
5.1 Mobilization and collection of peripheral blood stem cells  .......................................................... 14 
 
 
5.1.1 
Medication schedule  ........................................................................................................ 14 
5.1.2 
MM patients  ..................................................................................................................... 15 
 
 
5.1.3 
NHL and HD patients  ...................................................................................................... 15 
 
 
5.1.4 
Proton Pump ..................................................................................................................... 15 
 
 
5.1.5 
PBSC Collection  .............................................................................................................. 15 
 
5.2 Transplantation of patients  ............................................................................................................ 15 
 
 
5.2.1 
Mobilization ...................................................................................................................... 15 
 
 
5.2.2 
Planned regimen ............................................................................................................... 16 
 
 
5.3.3 
Infusion of PBMC ............................................................................................................. 16 
6.0 DEFINITIONS  ................................................................................................................................... 16 
 
6.1 Toxicity .......................................................................................................................................... 16 
 
6.2 Time to engraftment, neutrophils  .................................................................................................. 16 
 
6.3 Time to engraftment, platelets  ...................................................................................................... 16 
 
6.4 Primary graft failures  .................................................................................................................... 16 


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7.0 STOPPING RULE  ............................................................................................................................. 16 
8.0 FOLLOW-UP  ..................................................................................................................................... 16 
9.0 STUDY SCHEDULE  ......................................................................................................................... 17 
10.0 DOSE MODIFICATION AND MANAGEMENT OF TOXICITY  ............................................ 18 
11.0 DRUG FORMULATION, AVAILABILITY, PREPERATION .................................................. 18 
11.1 Meloxicam  ................................................................................................................................... 18 
 
11.1.1 Availability  ........................................................................................................................ 18 
 
11.1.1 Storage and Stability  .......................................................................................................... 18 
 
11.1.3 Administration  ................................................................................................................... 18 
 
11.1.4 Accountability  .................................................................................................................... 18 
 
11.1.5 Toxicities  ........................................................................................................................... 18 
 
 
11.1.5.1 Contraindications  ...................................................................................................... 19 
11.1.6 Drug interactions  ................................................................................................................ 20 
 
11.2 Filgrastim ...................................................................................................................................... 20 
 
 
11.2.1 Availability  ........................................................................................................................ 20 
 
 
11.2.2 Storage and Stability  .......................................................................................................... 20 
 
 
11.2.3 Administration  ................................................................................................................... 20 
 
 
11.2.4 Toxicity  .............................................................................................................................. 20 
12.0 BIOLOGICAL CORRELATIVE STUDIES AND SAMPLE SUBMISSION ............................ 20 
 
12.1 Laboratory correlative studies  ..................................................................................................... 20 
 
 
12.1.1 Peripheral blood CD34 cells  .............................................................................................. 20 
 
 
12.1.2 Expression of CXR4 on CD34 cells  .................................................................................. 20 
 
 
12.1.3 Colony forming units  ......................................................................................................... 21 
 
 
12.1.4 Peripheral blood SCID repopulating cell assays  ................................................................ 21 
 
 
12.1.5 Gene microarray analysis  ................................................................................................... 21 
12.1.6 PBSC apheresis product  ..................................................................................................... 21 
 
 
12.1.7 Cellular composition of apheresis product  ......................................................................... 21 
 
12.2 Sample procurement  .................................................................................................................... 22 
 
 
12.2.1Peripheral blood CD34 cells ................................................................................................ 22 
 
 
12.2.2 Assessment of CXR4 on CD34 cells mobilized ................................................................. 22 
 
 
12.2.3 Assessment of colony forming units  .................................................................................. 22 
 
 
12.2.4 Assessment of SCID repopulating cell assays  ................................................................... 22 
 
 
12.2.5 Assessment of CD34 in PBSC product  .............................................................................. 22 
 
 
12.2.6 Assessment of CXCR4 on CD34 PBSC product  ............................................................... 23 
 
 
12.2.7 Immune cell composition  ................................................................................................... 23 
 
 
12.2.8 Gene expression .................................................................................................................. 23 
13.0 STATISTICAL CONSIDERATION  .............................................................................................. 23 
 
13.1 General considerations  ................................................................................................................ 23 


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13.2 Study design  ................................................................................................................................ 23 
 
13.3 Criteria for stopping study  ........................................................................................................... 24 
 
13.4 Analysis datasets  ......................................................................................................................... 24 
 
13.5 Sample size ................................................................................................................................... 24 
 
13.6 Patient characteristics and significant protocol violations............................................................ 25 
 
 
13.6.1 Patient characteristics  ......................................................................................................... 25 
 
 
13.6.2 Significant protocol violations  ........................................................................................... 25 
 
13.7 Patient disposition ........................................................................................................................ 25 
 
13.8 Treatment exposure  ..................................................................................................................... 25 
 
13.9 Analysis plan  ............................................................................................................................... 25 
 
 
13.9.1 Safety and Tolerability  ....................................................................................................... 25 
 
 
13.9.2 Concomitant medication  .................................................................................................... 25 
 
 
13.9.3 Analysis of primary objectives ........................................................................................... 26 
 
 
13.9.4 Analysis of secondary objectives ........................................................................................ 26 
14.0 ADVERSE EVENT REPORTING  ................................................................................................. 27 
 
14.1 Definition of adverse events  ................................................................................................... 27 
 
 
14.1.1 Adverse event ..................................................................................................................... 27 
 
 
14.1.2 Suspected adverse reaction  ................................................................................................ 27 
 
 
14.1.3 Adverse reaction  ................................................................................................................ 28 
 
 
14.1.4 Serious adverse event  ......................................................................................................... 28 
 
 
14.1.5 Unexpected adverse event  .................................................................................................. 28 
 
 
14.1.6 Pregnancy  ........................................................................................................................... 28
 
 
14.1.7 Determining attribution to investigational agent ................................................................ 29 
 
14.2 Adverse event reporting criteria  ............................................................................................. 29 
 
 
14.2.1 Reporting to the IRB  .......................................................................................................... 29 
 
 
14.2.2 Reporting to DSMC  ........................................................................................................... 29 
15.0 DATA AND SAFETY MONITORING PLAN .............................................................................. 30 
 
15.1 Oversight and study progress  ...................................................................................................... 30 
 
 
15.1.1 Accrual  ............................................................................................................................... 30 
 
 
15.1.2 Protocol deviations  ............................................................................................................. 31 
 
15.2 Unanticipated problems  ............................................................................................................... 31 
 
15.3 Data quality control  ..................................................................................................................... 31 
 
 
15.3.1 Data collection  ................................................................................................................... 31 
16.0 REFERENCES  ................................................................................................................................. 32 


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1. BACKGROUND AND STUDY RATIONALE 
1.1 Importance of CD34 cell dose for engraftment kinetics following autologous PBSC 
transplantation 
High-dose chemotherapy with autologous stem cell transplantation (ASCT) remains an important 
treatment modality for patients with non-Hodgkin’s lymphoma (NHL) and multiple myeloma 
(MM). For the majority of patients with aggressive NHL (mostly diffuse large B cell lymphoma) 
who relapse, ASCT remains the best curative option; particularly for those with chemotherapy-
sensitive disease where up to 40-50% of patients remain disease free.1-3 For patients with MM, 
while not curative, ASCT is associated with the highest complete remission rate, improved 
progression-free and overall survival compared with conventional chemotherapy.4-6 Further, for 
MM patients even in the era of novel agents (such immunomodulatory drugs and proteasome 
inhibitors), the best reported results are with tandem cycles of high-dose chemotherapy with 
ASCT.7,8 Today, MM and NHL remain the most common indications for high-dose chemotherapy 
with ASCT.9 
Studies have shown a significant correlation between CD34 cell dose in PBSC products and the 
time to engraftment following ASCT. It is generally accepted that 2x106 CD34 cells/kg is the 
minimum threshold dose below which complete and rapid hematopoietic recovery may not 
consistently occur.10,11 However, several studies suggest that a CD34 cell dose ≥5x106/kg should 
be regarded as the “optimal” target for a single ASCT, particularly for platelet recovery, which 
appears to depend more greatly on higher CD34 cell doses than neutrophil recovery.12-16 Beyond 
CD34 dose, however, qualitative differences in CD34 cells collected may also be important, as 
patients who require two apheresis procedures to collect >2.5x106 CD34 cells/kg have slower 
platelet engraftment independent of the CD34 cell dose.13 Interestingly, there is also evidence that 
very high doses of CD34 cells (>15x106/kg) can reduce or eliminate severe thrombocytopenia and 
requirements for platelet transfusions,17,18 although such doses may not be obtainable in most 
patients. Therefore, higher CD34 cell doses, obtained with the least number of aphereses, appear 
to result in improved engraftment kinetics. 
G-CSF, alone or in combination with chemotherapy, is the most commonly used agent for 
mobilizing autologous PBSC. However, in published studies, up to 40% of patients fail to mobilize 
an “optimal” CD34 cell dose using G-CSF, even with up to 4 days of apheresis.19-23 Plerixafor, a 
small molecule CXCR4 antagonist, has been shown to significantly increase the number of CD34+ 
cells mobilized compared to G-CSF alone,24,25 and is now approved by the FDA for mobilization 
of PBSC in patients with NHL and MM. While significantly improving CD34 cell yield, a 
significant disadvantage of plerixafor is cost.11 While still meeting accepted standards of cost-
effectiveness, a recent economic evaluation of the cost utility of plerixafor + G-CSF as first-line 
treatment for mobilization of autologous PBSC in NHL patients estimated an additional lifetime 
cost of $25,576/patient compared to G-CSF alone.26 While risk-adapted strategies administering 
plerixafor only to patients with low blood CD34 cell counts after 4 days of G-CSF (before first 
apheresis) may reduce expense, mobilization costs remain significantly higher.27-29 Furthermore, 
14-24% of MM and NHL patients receiving upfront plerixafor + G-CSF still failed to collect 
≥2x106 CD34+ cells/kg despite 4 days of apheresis in large reported trials.33,34 The search for 
additional novel mobilizing agents and strategies remains an area of active clinical 
investigation.11,30    


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Protocol Version Date: 12/21/2016                                                                               Page | 6  
 
As reviewed below, our preliminary data shows that prostaglandin E2 (PGE2) inhibition using 
common, inexpensive non-steroidal anti-inflammatory drugs (NSAID) act synergistically with G-
CSF to mobilize higher numbers of HS/PC with good engraftment potential. Our long-term goal 
is to develop a novel, inexpensive and efficacious mobilization regimen of meloxicam plus G-CSF. 
The cost of a 4-day regimen of meloxicam, as proposed here, is $3.80 (www.drugstore.com). 
While comparative studies will be eventually required, this trial is a first step in clinical translation 
of our laboratory findings with the immediate goal of determining feasibility and safety, as well 
as evaluating for preliminary signs of efficacy to determine if larger randomized trials are justified 
to compare meloxicam plus G-CSF with currently used standard mobilization regimens (G-CSF 
alone, plerixafor plus G-CSF). The results of this trial have the potential scientific and clinical 
significance of:    
 Clinical confirmation of the importance of the PGE2 pathway in modulating human HS/PC 
egress marrow niche.  
 Enhancing the ability to collect greater CD34 cells in a PBSC product with the potential of 
improving engraftment kinetics as reviewed above. 
 Developing a simple and inexpensive alternative mobilization regimen to plerixafor and      G-
CSF, which would be more cost-effective for PBSC mobilization, with significantly less 
expense for transplant centers and an already financially-stretched health system.31   
 Our results will also lay the foundation for future testing of NSAID together with other existing 
mobilization regimens, including plerixafor plus G-CSF, in the subset of patients who remain 
difficult to mobilize despite the latter combination.  
1.2 NSAIDs mobilize hematopoietic progenitor cells from bone marrow and enhance 
mobilizing effect of G-CSF. 
We, and others, have demonstrated important regulatory roles for PGE2 in hematopoiesis.32-39 
Relevant to this trial, PGE2 inhibits growth of human and murine colony-forming units 
granulocyte/macrophage (CFU-GM) and CFU-M in vitro40 and myelopoiesis in vivo.32,33,38 More 
recently, short-term exposure of bone marrow cells to PGE2 has been shown to enhance 
hematopoietic cell engraftment 
in 
murine 
transplantation 
models.41-44 
Therefore, 
the 
underlying hypothesis of this 
trial is that inhibition of PGE2 
would increase myelopoiesis, 
making more hematopoietic 
stem 
and 
progenitor 
cells 
(HS/PC) 
available 
for 
mobilization, 
as 
well 
as 
increase the egress of HS/PC 
from the bone marrow into the 
blood and potentially synergize 
with G-CSF in PBSC mobilization.  
In mouse models, we have shown that NSAID mobilize HS/PC from bone marrow of treated mice, 
and enhanced the mobilizing effect of G-CSF. As shown in Fig 1a (left panel), treatment of 
Figure 1. Mobilization of hematopoietic progenitors (CFU-GM) in 
mice treated for 4 day with NSAID. (a) Mobilization of CFU-GM by 
indomethacin, G-CSF and combination treatment. (b) Fold increase in 
CFU-GM over G-CSF mobilization with NSAID with varying COX-1 and 
COX-2 selectivity; SC-560 (SC), valeryl salicylate (V), indomethacin 
(IN), aspirin (A), ibuprofen (IB), meloxicam (M), licofelone (L), celecoxib 


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Protocol Version Date: 12/21/2016                                                                               Page | 7  
 
C57Bl/6 mice with the prototypical NSAID indomethacin (50 µg/mouse) for 4 days resulted in a 
significant increase (~ 4 fold) in hematopoietic progenitor cell (CFU-GM) in peripheral blood that 
was not accompanied by an increase in total white blood cell count. Similarly, indomethacin 
significantly enhanced (~ 2 fold) the mobilization of CFU-GM when co-administered with G-CSF 
(Fig 1a right panel). 
1.3 Mobilization of hematopoietic progenitors by NSAIDs depends on inhibition of 
cyclooxygenase (COX)-1 and COX-2 enzymes.  
As shown in Fig 1a, treatment with the lipoxygenase inhibitor bailcalein, failed to mobilize CFU-
GM, either alone or when 
combined 
with 
G-CSF, 
indicating that the effect on 
mobilization 
of 
hematopoietic progenitors 
was 
specific 
to 
the 
cyclooxygenase 
pathway 
and not general eicosanoid 
inhibition. In addition, as 
shown in Fig 1b, the effect 
on 
hematopoietic 
progenitor cell mobilization 
was 
dependent 
on 
co-
inhibition of COX-1 and -2 
enzymes, 
with 
no 
significant effect seen with 
the pure COX-1 inhibitor 
SC-560 (SC), the pure COX-2 inhibitor NS-398 (NS), or the relatively selective COX-2 inhibitors 
licofelone (L), celecoxib (C) and valdecoxib (VC). The 
most pronounced and significant effect on mobilization of 
CFU-GM (above that seen with G-CSF alone) was 
observed with the dual COX-1 and -2 inhibitors aspirin, 
indomethacin (IN), ibuprofen (IB) and meloxicam (M). As 
we were interested in developing a clinical mobilization 
regimen of NSAID with G-CSF, we chose meloxicam for 
further investigation because of its better side effect profile 
compared to other dual COX inhibitors tested; specifically 
meloxicam is associated with reduced incidence of 
gastrointestinal discomfort45 and reduced inhibition of 
platelet aggregation.46 As shown in Fig 2, meloxicam 0.5 
mg/kg administered for 4 days to C57Bl/6 enhanced 
mobilization of hematopoietic progenitor cells (HPC) (Fig 
2a) as well as the phenotypic hematopoietic stem cell 
(HSC)-enriched populations Sca-1+ c-kit+ lineage- (SKL) or the highly purified CD150+ CD48- 
(SLAM) SKL populations (Fig 2b) to the blood (and spleen; not shown). Furthermore, meloxicam 
acted synergistically with G-CSF to mobilize HPC and HSC into blood (and spleen; not shown).  
Figure 2. Meloxicam (0.5 mg/kg) mobilizes hematopoietic progenitor 
cells (a) and stem cells (b) in C57Bl/6 mice, and synergistically 
enhances mobilization by G-CSF. Data are mean ± SEM of 5 mice per 
group, each assayed individually. ***P<0.001  
 
 
  
0.0
0.5
1.0
1.5
2.0
2.5
G-
G-CSF + 
N
S
CRU per 2 x 
10 PBMC 
Figure 
3. 
Competitive 
repopulating 
units 
(CRU) 
assayed 
at 
3 
months 
post-
transplant of G-CSF and G-
CSF+MXC 
(concurrently 
administered) mobilized 
cells. 
Data represent mean ± SEM of 2 


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Protocol Version Date: 12/21/2016                                                                               Page | 8  
 
1.4 Schedule of meloxicam and G-CSF administration is important for the engraftment 
potential of mobilized hematopoietic progenitors and stem cells.  
While administration of meloxicam (and other NSAID tested) concurrently with G-CSF appeared 
to enhance mobilization as shown above, we found an important influence of dose scheduling of 
the two agents when considering engraftment potential of mobilized cells using competitive 
transplantation assays.47 Meloxicam (MXC) + G-CSF or G-CSF alone (control) were administered 
for 4 days to BoyJ mice (CD45.1). On day 5, peripheral blood mononuclear cells were acquired 
and transplanted (intravenously) at a 2:1 ratio with C57Bl/6J (CD45.2) competitor whole bone 
marrow cells into lethally irradiated (1.1 Gy) C57Bl/6J recipient mice. Donor chimerism as 
assessed by the relative percentage of CD45.2 cells in peripheral blood by flow-cytometry. At 3 
months, the frequency of colony repopulating units (CRU) per test cells was assayed as previously 
described.47  As shown in Fig 3, there was no significant difference in engraftment, as assessed by 
CRUs between G-CSF and G-CSF + MXC mobilized grafts, despite higher HS/PC in the G-CSF 
+ MXC cells (data not shown). 
PGE2 up-regulates CXCR4, important for homing of HSC to the niche, on hematopoietic 
progenitors.43 Conversely, inhibition of PGE2 synthesis results in down-regulation of CXCR4 
expression, which might have accounted for the observed apparent lack of enhancement in 
engraftment in shown in Fig 3. As CXCR4 down-regulation is transient, we tested a modification 
of the G-CSF and meloxicam schedule by staggering the administration of meloxicam and G-CSF 
(allowing a 2 day break in meloxicam) to allow for hematopoietic mobilization and restoration 
endogenous PGE2 synthesis and of CXCR4 expression, as shown schematically in Fig 4a. As 
shown in Figure 4b, CXCR4 expression was significantly reduced following on phenotypically 
defined HSC (SKL cells) in blood of BoyJ mice treated with concurrent administration of 4 days 
of G-CSF+MXC or with one-staggering of the two agents as in Fig 4a, with full recovery to control 
levels after a two-stagger in the administration of MXC and G-CSF. The two-day stagger schedule 
of MXC+G-CSF mobilization resulted in enhanced engraftment of mobilized cells in competitive 
transplantation assays, as demonstrated by enhanced donor chimerism and CRU recovery 
compared to G-CSF alone and G-CSF+MXC without stagger (Fig 4c).  


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In non-competitive transplants, using two-day staggered mobilization schedule of G-CSF and 
meloxicam, both neutrophil and platelet recovery were significantly faster compared with G-CSF 
mobilized grafts in lethally irradiated mice (Fig 5). Based on these results, the proposed clinical 
trial will use a two-day stagger of meloxicam and G-CSF for mobilization of PBSC.   
 
 
1.5 Meloxicam mobilizes hematopoietic progenitors in healthy human volunteers. 
G-CSF
G-CSF + MXC
0
1
2
3
4
5
6
0
4
8
12 16 20 24 28
Neutrophils (K/µl)
90
P<0.05
Days Post-Transplant
50%
100%
0
200
400
600
800
1000
1200
0
4
8
12 16 20 24 28
Platelets (K/µl)
90
P<0.05
Days Post-Transplant
50%
100%
Figure 5. Recovery of neutrophils (left) and platelets (right) in lethally irradiated
C57Bl/6J mice following non-competitive transplantation of G-CSF or G-
CSF+MXC (given in a two-day stagger schedule) mobilized peripheral blood
mononuclear cells from BoyJ mice.


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Protocol Version Date: 12/21/2016                                                                               Page | 10  
 
 We investigated the effect of meloxicam on mobilizing hematopoietic progenitor cells in 7 human 
volunteers to validate the effect observed. Blood was collected at baseline and after a      4-day 
course of oral meloxicam (15 mg/day) for assessment of CD34+ cells, CFU-GM,           CFU-
GEMM, and BFU-E. As shown in Fig 6, meloxicam alone resulted in a significant mean two-fold 
mobilization of CD34+ cells in peripheral blood, as well as significant increases in CFU-GM and 
CFU-GEMM (but not BFU-E). It should be noted that the level of increase in hematopoietic 
progenitors observed following meloxicam alone in human volunteers is very similar to that 
observed in mice (see Fig 1), indicating a is strong likelihood that the overall preliminary data in 
animal models will hold up clinically. 
 
1.6 Mobilization of autologous PBSC at Indiana University  
Due to the high cost of plerixafor, we do not use plerixafor up-front on all MM and NHL patients 
undergoing mobilization of autologous PBSC at our institution. To similarly save cost associated 
with the use of plerixafor, a number of centers have advocated a risk-adapted approach whereby 
plerixafor is added after 4 days of filgrastim only in those patients who show evidence of 
“suboptimal” mobilization based on assessment of peripheral blood CD34 measurement,29,48,49 or 
alternatively on the basis of the CD34 dose collected on the first day’s apheresis.29 However, as 
the target or “acceptable” CD34 dose, as well as the “acceptable” number of aphereses in which 
this achieved, vary somewhat by institution, precise recommendations also vary; currently no 
standard algorithm exists. At Indiana University, we target minimum CD34 doses of 10x106/kg 
for MM (for potentially tandem or second late transplantation), and 5x106/kg for NHL patients, 
respectively. To minimize utilization of apheresis resources, we also attempt to collect the target 
dose in only 1-2 aphereses if possible. Therefore, patients begin mobilization with G-CSF       (10 
μg/kg/day) for 4 days. If the first day’s collection on day 5 is less than half of the target, plerixafor 
is added on the evening of day 5 (G-CSF continued), and apheresis performed the next day. 
We have analyzed our mobilization and collection yields in consecutive MM and NHL patients 
treated at our institution between January 2010 and August 2012. For 202 MM patients mobilized 
during this period, 42% achieved a CD34 collection of ≥5x106/kg (half of target) with the first 
apheresis (G-CSF alone), with a median collection on day 1 of 4.4 (range, 0.1-21.6) x106/kg. 
Similarly, for 71 NHL patients, 49% collected a CD34 dose of ≥2.5x106/kg (half of target) with 
the first apheresis (G-CSF alone), with a median collection on day 1 of 2.4 (range, 0.1-11.4) 
x106/kg. It is possible that our higher yields with G-CSF alone on day 1 of apheresis, compared 
with those of G-CSF (plus placebo) arms in the randomized trials of plerixafor + G-CSF versus G-
Figure 6. Mobilization of hematopoietic progenitor cells in normal human volunteers.


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CSF and placebo in MM and NHL patients,24,25 might reflect a less heavily pre-treated patient 
population at our institution and/or the greater volume of blood processed at our institution (5 
blood volumes versus 3 blood volumes in the published trials) during apheresis.  Based our 
institution’s algorithm, over half of our MM and NHL patients require plerixafor.   
1.7 Study and Dose Rationale 
Our preliminary data clearly demonstrate a novel and highly efficacious mobilizing regimen that 
combines administration of filgrastim with NSAID treatment to block PGE2 biosynthesis. Also, 
cells mobilized with this combination show stable long-term engraftment in vivo, which may also 
be enhanced compared to filgrastim only-mobilized grafts.  However, any enhancement of 
engraftment appears to be dependent on staggering the dosing of filgrastim and meloxicam, rather 
than absolute concurrent administration.  We, therefore, propose a phase II trial to clinically test 
this regimen in MM and NHL patients collecting autologous PBSC for myeloablative high-dose 
chemotherapy with stem cell support. 
1.8 Inclusion of Women and Minorities 
Patients who meet eligibility criteria will be included on this study without regard to gender, race, 
or ethnicity. 
2. STUDY OBJECTIVES 
2.1  
Study Overview 
The trial is an open label Simon optimal two-stage Phase II trial of fixed doses of oral meloxicam 
and subcutaneous filgrastim to assess the safety and efficacy in mobilizing autologous peripheral 
blood stem cells (PBSC) from multiple myeloma (MM) and Hodgkin’s Disease (HD) or non-
Hodgkin’s lymphoma (NHL) patients planning to undergo high-dose chemotherapy with stem cell 
support. Clinical data regarding the cellular composition and function of the graft mobilized by 
this combination will be obtained. 
2.2 
Primary Objective 
The objective of this study is to investigate whether meloxicam and filgrastim can result in a 20% 
increase in the proportion of patients who mobilize and collect at least half of the total target 
CD34+ cell dose in the first apheresis.  As the total target CD34 dose varies with disease, the 
primary objective will be as follows according to disease:  
• Multiple myeloma patients: 
Investigate if meloxicam and filgrastim can result in an increase in the proportion of patients 
who mobilize and collect ≥5x106 CD34 cells/kg in the first day’s apheresis, from a historical 
40% to at least 60%.   
• Hodgkin’s and Non-Hodgkin’s lymphoma patients: 
Investigate if meloxicam and filgrastim can result in an increase in the proportion of patients 
who mobilize and collect ≥2.5x106 CD34 cells/kg in the first day’s apheresis, from a historical 
50% to at least 70%. 


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2.3 
Secondary Objectives 
• Describe the toxicity profile of the combination of Meloxicam and Filgrastim 
• Describe the graft composition of PBSC collected using Meloxicam and Filgrastim 
including hematopoietic and immune cell subsets.  
• Describe the engraftment kinetics of Meloxicam and Filgrastim mobilized PBSC in MM, 
HD and NHL patients undergoing myeloablative autologous PBSC transplantation 
3. ELIGIBILITY CRITERIA 
3.1 Inclusion Criteria  
A patient must meet all of the following inclusion criteria to be eligible for enrollment in 
this study: 
1. Has provided written informed consent prior to completing any study procedures. 
2. Patients must have a previously documented histologic diagnosis of multiple myeloma 
(MM) Hodgkin’s Disease (HD) or non-Hodgkin’s lymphoma (NHL), and be eligible to 
undergo autologous PBSC transplantation on institutional protocols. 
a. Multiple myeloma should be in first or second partial response or better, as 
defined by International Myeloma Working Group criteria.50 
b. Hodgkin’s Disease should be primary refractory or relapsed (either 
chemosensitive or refractory) 
c. Non-Hodgkin’s lymphoma must be in either first or second partial response or 
better and have any one of the following histologies: 
• Diffuse large B cell lymphoma 
• Transformed lymphoma 
• Mantle cell lymphoma 
• Follicular lymphoma (any grade) 
• Peripheral T cell lymphoma 
 
3. Age ≥18 to ≤75 years at time of consent. 
4. Karnofsky performance status of at least 70% 
5. Patients must have the following baseline laboratory values: 
a. Serum bilirubin, AST and ALT ≤ twice the upper limit of normal 
b. Serum creatinine ≤2.0 mg/dl 
c. Urine M-Protein ≤1 g/24 hours (MM Patients only) 
6. One of the following must be satisfied: 
a. The patient is undergoing mobilization to collect and store for an autologous 
PBSC transplant in the future 
b. The patient is eligible to undergo autologous PBSC transplantation on 
institutional protocols in the future and has adequate organ function as defined as: 
i. Left ventricular ejection fraction ≥45% 
ii. Corrected LDCO ≥ 50% 


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7. No prior attempt at mobilizing PBSC. 
8. Patients must be at least 4 weeks from last cytotoxic chemotherapy (including alkylating, 
anthracyclines, epipodophylatoxins, and platinum drugs), or immunomodulatory drugs 
(including lenalidomide or pomalidomide, or related derivatives) at time of treatment on 
this protocol. 
9.  Patients must be at least 2 weeks from last treatment with a proteasome inhibitor (e.g., 
bortezomib, carfilzomib) at time of treatment on this protocol. 
10. Patients must be negative for HIV. 
11. Women of childbearing potential must have a negative pregnancy test (urine or serum) 
and must not be lactating at the time of informed consent.  
a. Women and men must use adequate birth control while taking part in this study 
(such as a condom or diaphragm with contraceptive cream/jelly, birth control 
pills, Norplant, abstinence (no sexual intercourse) or surgical sterilization. 
3.2 Exclusion Criteria 
Exclude a patient if any of the following conditions are observed: 
1. Patients must not have received radiation therapy within the past 4 weeks 
2. Patients must not have received radiation therapy to more than 20% of hematopoiesis 
forming bones (spine, pelvis and proximal long bones) during lifetime. 
3. Patients must not have active central nervous system involvement. 
4. Patients must not have a prior autologous, syngeneic or allogeneic hematopoietic stem 
cell transplant. 
5. Patients must not have received prior bone seeking radionuclides. 
6. Patients must not have received myeloid growth factors within 2 weeks before 
mobilization attempt on this study. 
7. Patients must not have taken NSAID in the past 14 days before treatment on this 
protocol. 
8. Patients must not have nor had active or recent peptic ulcer disease within the past 6 
months. 
a. Patients with active significant symptoms of dyspepsia will be excluded. 
9. Patients with a history of asthma will be excluded because of the potential for NSAID to 
precipitate asthma in these patients.   
4. REGISTRATION PROCEDURES AND INFORMED CONSENT 
Patients must be willing and component to consent after being informed of the procedures to be 
followed, the experimental nature of the therapy, alternatives, potential benefits, side-effects, 
risks, and discomforts. All patients will be registered with the Indiana University Cancer Center 
Clinical Research Office. Regulatory files will be maintained by the Clinical Research Office 
and applicable regulatory documents must be completed and on file prior to registration of any 
patients. Potential patients will be identified in the Oncology outpatient clinics or by referrals 
from outside physicians. Patients who appear to be eligible for this trial will be screened for 
eligibility utilizing the Eligibility Criteria. The original signed IRB approved Informed Consent 
Document and completed eligibility checklist will be forwarded to the Clinical Research Office 
designee for eligibility verification and registration in the OnCore® database. Notification will be 


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sent to the principal investigator, treating physician and research nurse when registration is 
complete. Registration must occur prior to initiation of therapy.   
5. TREATMENT PLAN 
This is an open label Phase II trial that will use fixed doses of meloxicam and filgrastim in a 
staggered dose schedule for a total treatment duration of 7 days prior to apheresis. Patients must 
have adequate blood counts within 30 days prior to mobilization to proceed. Patients will be given 
a pill diary to record their administration and compliance with meloxicam. 
Patients who fail to mobilize and collect half of the target cell collection on the first day of 
collection will be considered as failing the primary endpoint. Those who fail to meet the primary 
endpoint for collection on the first day of apheresis may be given plerixafor as rescue per 
institutional guidelines. Patients who receive cells that are mobilized with plerixafor (i.e., who 
have failed the primary endpoint) may receive the collected cells, and their engraftment kinetics 
will be analyzed separately.    
Patients who meet the primary endpoint will continue to receive filgrastim at the starting dose until 
the total target CD34 dose is collected. Those who do not receive plerixafor (i.e., mobilized only 
with meloxicam plus filgrastim) will proceed to transplantation when appropriate using the 
collected PBSC, and will be analyzed for the secondary endpoint of engraftment kinetics 
separately from those who receive rescue plerixafor.   
5.1 Mobilization and collection of Peripheral Blood Stem Cells (PBSC)  
5.1.1 Eligible patients will be treated with meloxicam and filgrastim in the following 
schedule: 
Within 30 days prior to the time of mobilization: 
Patients must have all of the following blood counts to proceed forward with 
mobilization 
• Total white blood cell count (WBC) ≥2.5x109/l  
• Absolute neutrophil count (ANC) ≥1.5x109/l  
• Platelet count (PLT) ≥100x109/l. 
Days 1-5: 
• Meloxicam 15 mg PO daily in the morning. 
Days 4-7:   
• Filgrastim 10 µg/kg/day SC (may be rounded to nearest vial size). 
Day 1 Apheresis:  
• Apheresis 20-25 L of blood or 5 blood volumes 
• Filgrastim 10 µg/kg/day SC (may be rounded to nearest vial size) 
 
 


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Day 2-4 Apheresis (If Required):  
The following will be completed for patients who do not meet the primary end point 
for collection  
• Apheresis (20-25 L of blood or 5 blood volumes) if required (see sections 
5.1.2 and 5.1.3 below) 
• Filgrastim 10 µg/kg/day SC  
• Plerixafor (to be determined by treating physician) 
 
5.1.2 For MM patients: 
If the collection on day 1 of apheresis is <5x106 CD34 cells/kg, this is considered a 
treatment failure for the purposes of this protocol. The patient may continue 
additional collections, continuing mobilization with either filgrastim alone or 
plerixafor may be added at the discretion of the treating physician. 
If the collection on day 1 of apheresis is ≥5x106 CD34 cells/kg, patients continue with 
filgrastim at 10 μg/kg/day until collection of the target dose is achieved. Additional 
mobilizing agents are not added. Patients will continue with daily apheresis until the 
target dose of ≥10x106 CD34 cells/kg is collected or a maximum of four aphereses 
are performed.   
 
5.1.3 For HD and NHL patients:                                                              
If the collection on day 1 of apheresis is <2.5x106 CD34 cells/kg, this is considered a 
treatment failure for the purposes of this protocol. The patient may continue 
additional collections. Continuing mobilization with either filgrastim alone or 
plerixafor may be added at the discretion of the treating physician. 
If the collection on day 1 of apheresis is ≥2.5x106 CD34 cells/kg, patients continue 
with filgrastim at 10 μg/kg/day until collection of the target dose is achieved. 
Additional mobilizing agents are not added. Patients will continue with daily 
apheresis until the target dose of ≥5x106 CD34 cells/kg is collected if possible (or a 
maximum of four aphereses are performed). 
NOTE:  Optimally it is suggested that the target CD34+ cell dose for MM, HD and 
NHL patients be obtained, although this is not required to proceed with 
transplantation. A minimum of 2.5x106 CD34 cells/kg per transplant is required on this 
protocol.  
5.1.4 A proton pump inhibitor may be administered to mitigate the gastrointestinal effect of 
meloxicam according to physician discretion. 
5.1.5 PBSC collected will be cryopreserved in DMSO per institutional protocol until 
transplantation. 
5.2  
Transplantation of patients 
5.2.1 All patients who mobilize sufficient numbers of CD34 cells will proceed to 
transplantation if clinically appropriate.  


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5.2.2 Recipient patients should receive the planned preparative regimen appropriate for their 
disease according to institutional protocols for autologous PBSC transplantation.  
5.2.3 PBSC will be infused on day 0 per institutional protocols.  A minimum of 2.5x106 
CD34 cells/kg will be infused per transplant. 
6. DEFINITIONS  
 
6.1  
Toxicity.  The National Cancer Institute Common Terminology Criteria for Adverse 
events (CTCAE) version 4.0 (http://ctep.cancer.gov) will be used to characterize toxicities. 
Toxicity is assessed as definitely related, possibly, probably related, unlikely or unrelated to 
meloxicam + filgrastim. See Section 14. 
6.2    Time to engraftment of neutrophils.  The time to engraftment of neutrophils is 
defined as the time from day 0 to the date of the first of three consecutive days after 
transplantation during which the absolute neutrophils count (ANC) is at least 0.5 x109/l.  
Patients surviving at least 14 days will be evaluable for this endpoint. 
6.3  
Time to engraftment of platelets.  The time to engraftment of platelets is defined as 
the time from day 0 to the first of seven days post transfusion, when the platelet count is    ≥20 
x109/l, verified by three consecutive CBCs.  
6.4  
Primary graft failure. Primary graft failure is defined as lack of neutrophil 
engraftment by day +30 in patients surviving a minimum of 30 days. 
7. STOPPING RULE 
It is not expected that any engraftment failure will be observed for PBSC mobilized with the 
combination of meloxicam and filgrastim.  Therefore, if 4 or more patients fail to engraft using 
meloxicam 
plus 
filgrastim 
mobilized 
PBSC 
(minimum 
CD34 
cell 
dose 
infused 
2.5x106/kg/transplant), in the absence of another obvious cause (e.g., poor viability after thaw, 
severe sepsis), the study will be terminated for lack of feasibility. 
8. FOLLOW-UP PERIOD 
Patients will be followed until 100 days post-transplant at which time they will go off study. Date 
of disease progression, date of death and cause of death will be collected if the event occurs prior 
to Day 100.  
 
 
 
 
 
 


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9. STUDY SCHEDULE 
 
PRE-
MOBILIZA
-TION 
MOBILIZATION DAYS 
APHERESIS 
POST-
APHERESIS 
 Day  
1 
Day  
2 
Day  
3 
Day  
4 
Day 
 5 
Day  
6 
Day  
7 
Day  
1 
 Day 
2* 
Day  
3* 
Day  
4* 
One week 
after last day 
of apheresis 
As needed 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Baseline medical history 
XE 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
medicationsA 
XE 
 
 
 
 
 
 
 
 
 
 
 
 
Provide patient with 
medication diary 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteriaB 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment 
Meloxicam 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
Filgrastim 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
PlerixaforF 
 
 
 
 
 
 
 
 
 
X 
X 
X 
 
Laboratory studies 
CBC and differential 
Basic metabolic 
panel 
 
XE 
XE 
 
 
 
 
 
 
 
 
X+ 
X+ 
 
X+ 
 
 
X+ 
 
 
X+ 
 
Special studies 
 
 
 
 
 
 
 
 
 
 
 
 
 
Peripheral blood 
(PB):  
CD34 cells 
CXCR4 on PB 
CD34 cells 
PB CFUs 
Gene microarray 
 
 
X 
X 
 
X 
X 
 
 
 
 
 
 
XC 
 
 
 
 
 
 
 
 
X+ 
X+ 
 
X+ 
 
 
 
X+ 
X+ 
 
 
 
X+ 
X+ 
 
 
 
X+ 
X+ 
 
 


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Apheresis Product: 
CD34 cells 
CXCR4 on CD34 
cells 
Immune cells 
Gene microarray  
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
 
 
X 
X 
 
X 
 
X 
X 
 
X 
 
Adverse eventsD 
 
 
 
 
 
 
 
 
X (Last day of apheresis) 
X 
Patient return of 
medication diary 
 
 
 
 
 
 
 
 
X (Last day of apheresis) 
 
AInclude the stop date for aspirin or other NSAIDs if applicable (at least two weeks prior to starting Meloxicam) 
BIf apheresis is rescheduled after the patient is found to be eligible, document that the new timeline fits eligibility criteria 
CThe correlative CXC3 on PB CD34 cells is optional on day 4 of mobilization. Collection will be determined by the treating physician. 
DRecorded from mobilization day 1 through the last day of apheresis with a follow-up one week later 
EMust be completed within 30 days prior to mobilization 
FPlerixafor is only administered if the subject is a treatment failure on day 1 of apheresis and even then it is at the treating physician's discretion.  
Treatment failure for MM = collection on day 1 of apheresis is <5x106 CD34 cells/kg.  Treatment failure for HD/NHL = collection on day 1 of 
apheresis is <2.5x106 CD34 cells/kg. 
*If required based on CD34 cells collected in apheresis product (Note: Patients who are not treatment failures at day 1 of apheresis continue with 
apheresis without the addition of plerixafor until the target dose is achieved or a maximum of four aphereses are performed.  Patients who are 
treatment failures at day 1 of apheresis may or may not continue apheresis with or without the addition of plerixafor at the treating physician's 
discretion.)  
+Test to be done on peripheral blood drawn BEFORE apheresis  
 
 


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10. DOSE MODIFICATIONS AND MANAGEMENT OF TOXICITY 
Toxicity will be managed according to the discretion of the treating physician and Institutional 
guidelines. No dose modification of the drugs used in the mobilization regimen will be made. 
11. DRUG FORMULATION, AVAILABILITY, AND PREPARATION 
11.1 
Meloxicam (Mobic®) 
11.1.1   
Availability 
Meloxicam is an oral non-steroidal anti-inflammatory drug with reversible COX-1 and -2 
inhibitory activities.  It is available as 7.5 mg and 15 mg tablets, as well as a 7.5 mg/5 ml 
suspension.  In this protocol, meloxicam will be purchased from commercial sources and 
provided to subjects free of charge through Investigation Drug Services.  
11.1.2  
Storage & Stability 
Meloxicam should be stored in a dry place at room temperature, 15-30°C (59-86°F).  
11.1.3  
Administration 
Meloxicam may be taken with or without food.  However, it may be administered with food 
or milk to minimize gastrointestinal irritation.  In this protocol, meloxicam will be used at the 
standard dose of 15 mg/day. 
 
 
11.1.4  
Accountability 
Meloxicam will be stored and dispensed through Indiana University Investigational Drug 
Services. The medication will be given to or mailed to the patient’s home by the study nurse 
prior to the beginning of study treatment. The patient will be given a drug diary to record 
medication administration and accountability. 
11.1.5  
Toxicities 
The most common side effects and toxicities of meloxicam with reported frequencies are as 
follows: 
Frequencies 2% to 10%:  
• Cardiovascular: Edema (≤5%)  
• Central nervous system: Headache (2% to 8%), pain (1% to 5%), dizziness 
(≤4%), insomnia (≤4%)  
• Dermatologic: Pruritus (≤2%), rash (≤3%)  
• Gastrointestinal: Dyspepsia (4% to 10%), diarrhea (2% to 8%), nausea (2% to 
7%), abdominal pain (2% to 5%), constipation (≤3%), flatulence (≤3%), vomiting 
(≤3%) 
• Genitourinary: Urinary tract infection (≤7%), micturition (≤2%) 
• Hematologic: Anemia (≤4%)  
• Neuromuscular & skeletal: Arthralgia (≤5%), back pain (≤3%) 
• Respiratory: Upper respiratory infection (≤8%), cough (≤2%), pharyngitis (≤3%)  


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• Miscellaneous: Flu-like syndrome (2% to 6%), falls (≤3%)  
Frequencies <2% (Limited to important or life-threatening):  
 
Abnormal dreams, abnormal vision, agranulocytosis, albuminuria, allergic reaction, 
alopecia, anaphylactoid reactions, angina, angioedema, anxiety, appetite increased, 
arrhythmia, asthma, bilirubinemia, bronchospasm, bullous eruption, BUN increased, 
cardiac failure, colitis, confusion, conjunctivitis, creatinine increased, dehydration, 
depression, diaphoresis, duodenal perforation, duodenal ulcer, dyspnea, edema (facial), 
eructation, erythema multiforme, esophagitis, exfoliative dermatitis, fatigue, fever, gastric 
perforation, gastric ulcer, gastritis, gastroesophageal reflux, gastrointestinal hemorrhage, 
GGT increased, hematemesis, hematuria, hepatic failure, hepatitis, hot flushes, hyper-
/hypotension, interstitial nephritis, intestinal perforation, jaundice, leukopenia, malaise, 
melena, MI, mood alterations, nervousness, palpitation, pancreatitis, paresthesia, 
photosensitivity reaction, pruritus, purpura, renal failure, seizure, shock, somnolence, 
Stevens-Johnson syndrome, syncope, tachycardia, taste perversion, thrombocytopenia, 
tinnitus, toxic epidermal necrolysis, transaminases increased, tremor, ulcerative stomatitis, 
urinary retention (acute), urticaria, vasculitis, vertigo, xerostomia, weight gain/loss  
11.1.5.1 
Contraindications:  
Hypersensitivity (eg, asthma, urticaria, allergic-type reactions) to meloxicam, aspirin, 
other NSAIDs, or any component of the formulation; perioperative pain in the setting of 
coronary artery bypass graft (CABG) surgery.  
11.1.6 Drug Interactions: 
In studies where meloxicam was administered with cimetidine, digoxin, and methotrexate, 
there were no drug interactions.  Meloxicam may interfere with angiotensin convertase 
(ACE) inhibitors or with furosemide, which may lead to an increase in blood pressure in 
patients taking these drugs for treatment of hypertension. As a result, the dose of ACE 
inhibitor or Lasix may need to be changed when starting or stopping meloxicam.  
Meloxicam should be avoided by patients with a history of asthma, hives or other allergic 
reactions to aspirin or other NSAIDs.  
If aspirin is taken with meloxicam there may be an increased risk for developing an ulcer.  
Persons who have more than 3 alcoholic beverages per day may be at increased risk of 
developing stomach ulcers when taking meloxicam or other NSAIDs.  
Cholestyramine, colestipol, and colesevelam may decrease the effectiveness of meloxicam 
by preventing its absorption from the intestine.  
Lithium blood levels may increase or decrease after meloxicam therapy starts or stops. 
Therefore, both the patient taking lithium and the blood level of lithium need to be 
evaluated when starting or stopping meloxicam.  
Meloxicam should be used with caution in combination with anticoagulants (e.g., warfarin) 
because of an increased risk of bleeding.  
 


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11.2  Filgrastim (Granulocyte Colony-Stimulating Factor; Neupogen®; recombinant-
methionyl human granulocyte-colony stimulating factor; r-methHuG-CSF) 
11.2.1  
Availability 
G-CSF is commercially available in vials containing 1 ml (300 µg/ml) or 1.6 ml at (300 
µg/ml) for a total of 480 µg; and in pre-filled syringes containing 300 µg/0.5 mL and 480 
µg/0.8 ml. This medication is part of standard of care. The patient and/or a third party payer 
will be responsible for the cost of this medication. 
11.2.2  
Storage & Stability 
Intact vials and pre-filled syringes should be stored under refrigeration. Do not allow the 
drug to freeze. Each vial should be entered only once, or syringe used for only one dose, 
and the remainder discarded. Filgrastim may be further diluted in D5W to a concentration 
≥ 15 µg/mL for IV administration. 
11.2.3  
Administration 
The daily dose should be injected subcutaneously in one or two sites at home by the patient.  
11.2.4  
Toxicity 
Chills, nausea, anorexia, myalgia, bone pain, local injection site pain. Rare reports of 
splenic rupture in donors who have received filgrastim for mobilization of PBSC have 
occurred. Please refer to the package insert for a comprehensive list of adverse events. 
12. BIOLOGICAL CORRELATIVE STUDIES AND SAMPLE SUBMISSION 
12.1 
Laboratory Correlative studies   
12.1.1  Peripheral blood CD34 cells: CD34 cell count in peripheral blood will be estimated 
by flow-cytometry using the ISHAGE protocol, as currently performed in the IU Health 
Cellular Therapy Laboratory at baseline and on each day of apheresis before the 
procedure. 
12.1.2 Assessment of expression of CXCR4 on CD34+ cells mobilized: Peripheral blood 
CD34+ cells will also be assessed for CXCR4 surface expression at baseline, on day 4 
(at the investigator’s discretion) and on each day of apheresis before the procedure. 
CXCR4 surface expression on blood CD34+ cells will be assessed by flow-cytometry 
and quantified using the QuantiBRITE method.51 This is to investigate whether the 
changes in CXCR4 expression with meloxicam, and after staggering, observed in our 
preclinical studies also occur clinically 
12.1.3 Colony forming units (CFU) in peripheral blood: Peripheral blood will be assessed 
for hematopoietic progenitors (CFUs) at baseline and on day 1 of apheresis before the 
procedure. Hematopoietic progenitors (CFU-GM, CFU-GEMM and BFU-E) assays 
will be performed using methylcellose media with 30% HI-FCS, 1 U/ml Epo, 50 ng 
rhSCF and 10 ng rhGM-CSF, and CFU-GM, BFU-E and CFU-GEMM quantified after 
7 days incubation at 37oC, in 5% CO2, 5% O2 in humidified air, as previously 
described.36 


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12.1.4 Gene microarray analysis in CD34 cells:  While exploratory, the intent of the gene 
expression profiling is to define gene changes/pathways responsible for the effects of NSAIDs 
on myeloid progenitor cell potential as a means to identify new potential targets for further 
investigation. We believe this approach will provide important information on pathways 
associated with NSAID-mediated change in HPC proliferative potential and define new targets 
to enhance functional efficiency of HS/PC for transplant that may be used directly on the graft 
ex vivo rather than in the patient. Changes in gene expression in sorted CD34 cells 
following meloxicam and filgrastim mobilization will be assessed at baseline (prior to 
meloxicam), and on day 1 of apheresis.   
12.1.5 PBSC apheresis product CD34 cell yield and CXCR4 expression:  The CD34+ cell 
yield per kg of recipient weight will be determined in each PBSC product using the 
ISHAGE method as used in the Cellular Therapy Laboratory. In addition, CXCR4 
expression on CD34 cells in each collection will be assessed on each day of apheresis. 
12.1.6 Cellular composition of the apheresis product: In addition, we will also estimate the 
immune cellular composition of the product including the following on each day of 
apheresis: 
 CD3+T cells (CD3+CD4+, and CD3+CD8+)  
 Treg cells (CD3+CD4+CD25+FOXP3+)  
 CD4+ T cell subsets (CD45RA+CD27+, CD45RA+CD27-CD62L+, 
CD45RA-CD27+CD62L+, CD45RA-CD27+CD62L-, CD45RA-CD27-) 
 CD8+ T cell subsets (CD45RA+CD27+, CD45RA+CD27-CD62L+, 
CD45RA-CD27+CD62L+, CD45RA-CD27+CD62L-, CD45RA-CD27-) 
 B cells (CD19) 
 NK cells (CD3-CD56+) 
 NKT cells (CD3+CD56+CD1d+TCRVβ11+) 
 
12.2  Sample Procurement 
12.2.1  Peripheral blood CD34+ cells:  
Collect 5 ml of peripheral blood in heparin tubes (green top) from patient at the 
following time points: 
• Baseline (prior to administration of meloxicam).  This may be done at any time 
before protocol treatment is started. 
• Before each apheresis on days 1-4 (as performed). 
Samples will be sent to IU Health Cellular Therapy Laboratory and assayed per 
institutional practice. 
12.2.2 Assessment of expression of CXCR4 on CD34+ cells mobilized:  
Collect 5 ml of peripheral blood in heparin tubes (green top) from patient at the 
following time points: 


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• Baseline (prior to administration of meloxicam). This may be done at any time 
before protocol treatment is started. 
• Day 4 of mobilization. Sample collection is optional at the discretion of the 
treating physician. 
• Before each apheresis on days 1-4 (as performed). 
Samples will be sent to Dr. Farag’s Laboratory, Center of Immunobiology, Walther 
Hall-R3, C440, 980 W. Walnut Street, Indianapolis, IN.  
12.2.3 Assessment of colony forming units (CFUs): 
Collect 5 ml of peripheral blood in heparin tubes (green top) from patient at the 
following time points: 
• Baseline (prior to administration of meloxicam).  This may be done at any time 
before protocol treatment is started. 
• Day 1 of apheresis (prior to apheresis) 
Samples will be sent to Dr. Farag’s Laboratory, Center of Immunobiology, Walther 
Hall-R3, C440, 980 W. Walnut Street, Indianapolis, IN.  
12.2.4 Assessment of CD34 cells in PBSC product 
The apheresis product will be delivered to the Cellular Therapy Laboratory following 
apheresis according to institutional standard operating procedures. CD34+ cell counts 
will be assayed on samples of the apheresis product per Laboratory standard operating 
procedures. 
12.2.5 Assessment of CXCR4 expression on CD34 cells in PBSC product 
The apheresis product will be delivered to the Cellular Therapy Laboratory (CTL) 
following apheresis according to institutional standard operating procedures.  A 1.0 ml 
sample will be processed for immune cell composition, and will be picked up from the 
CTL by a member of the Farag lab for processing. 
12.2.5 Immune cell composition of PBSC product 
The apheresis product will be delivered to the Cellular Therapy Laboratory (CTL) 
following apheresis according to institutional standard operating procedures.  A 1.0 ml 
sample in a green top tube will be picked up from the CTL by a member of the Farag 
lab for processing.  Note: Testing will be performed on the same 1.0 ml sample taken 
for CXCR testing (section 12.2.6); no additional sampling is required for this 
assessment. 
12.2.5 Gene expression microarray studies on CD34 cells in PBSC product 
 
The apheresis product will be delivered to the Cellular Therapy Laboratory (CTL) 
following apheresis according to institutional standard operating procedures.  This will 
also be performed at baseline. A 0.5 ml sample in EDTA (purple top tube) will be 
picked up from the CTL by a member of the Farag lab for processing. 


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13. STATISTICAL CONSIDERATIONS 
13.1  General considerations 
Statistical analysis of this study will be the responsibility of Biostatistics and Data 
Management Core at IUSCC. Parameter estimates and relevant summary statistics will be 
reported where appropriate. For continuous variables, summary statistics will include 
number of patients, mean, median, standard deviation, minimum and maximum. 
Categorical endpoints will be summarized using number of patients, frequency, and 
percentages. Missing data will not be imputed. 
Additional exploratory analyses of the data will be conducted as deemed appropriate. 
Changes from this analysis plan will not require an amendment to the protocol unless it 
changes a significant feature of the protocol. 
13.2  Study Design 
The trial is an open label Simon optimal two-stage Phase II trial of fixed doses of oral 
meloxicam and subcutaneous filgrastim to assess the safety and efficacy in mobilizing 
autologous peripheral blood stem cells (PBSC) from multiple myeloma (MM) and 
Hodgkin’s or non-Hodgkin’s lymphoma (NHL) patients planned to undergo high-dose 
chemotherapy with stem cell support. 
CTCAE Version 4.0 will be used to summarize adverse events in the assessment of safety 
and tolerability of the combination therapy.  
13.3  Criteria for Stopping Study 
• If 4 or more patients fail to engraft using meloxicam plus filgrastim mobilized 
PBSC (min CD34 cell dose infused 2.5x106/kg/transplant), in the absence of 
another obvious cause (e.g., poor viability after thaw, severe sepsis), the study 
will be terminated for lack of feasibility. 
• For MM patients: After testing meloxicam + filgrastim on 25 patients in the first 
stage, the trial will be terminated if ≤11 succeed in collecting ≥5x106 CD34/kg in 
the first apheresis.  
• For HD and NHL patients: After testing meloxicam + filgrastim on 24 patients in 
the first stage, the trial will be terminated if ≤13 succeed in collecting ≥2.5x106 
CD34/kg in the first apheresis.  
13.4  Analysis Datasets 
The following datasets will be considered for analysis purposes: 
a) All Enrolled: All patients who signed informed consent 
b) Evaluable: All patients who received at least one dose of Meloxicam+Filgrastim. 
 
13.5  Sample Size 
This study uses a Simon optimal two-stage design.52 In statistical terms: 


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 For MM patients (about 40% of whom collect ≥5x106 CD34/kg in the first apheresis 
with filgrastim alone at our institution; see above), we will test the null hypothesis H0: 
p0 ≤0.4 vs the alternative hypothesis H1: p1 ≥0.6, where p is the probability of a 
successful collection of ≥5x106 CD34/kg in the first apheresis, with type I error (α) set 
at 0.05 and type II error (β) set at 0.1. After testing meloxicam + filgrastim on 25 
patients in the first stage, the trial will be terminated if ≤11 succeed in collecting ≥5x106 
CD34/kg in the first apheresis. If >11 succeed, the trial will proceed to the second stage 
and an additional 41 patients treated to a total of 66. If >32 patients succeed in 
collecting ≥5x106 CD34/kg in first apheresis, we will conclude that the regimen is 
worthy of further study. 
 For HD and NHL patients (about 50% of whom collect ≥2.5x106 CD34/kg in the first 
apheresis with filgrastim alone at our institution; see above), we will test the null 
hypothesis H0: p0 ≤0.5 vs the alternative hypothesis H1: p1 ≥0.7, where p is the 
probability of a successful collection ≥2.5x106 CD34/kg in the first apheresis (α = 0.05; 
β = 0.1). After testing meloxicam + filgrastim on 24 patients in the first stage, the trial 
will be terminated if ≤13 succeed in collecting ≥2.5x106 CD34/kg in the first apheresis. 
If >13 succeed, the trial will proceed to the second stage and an additional 37 patients 
treated to a total of 61. If > 36 patients succeed in collecting ≥2.5x106 CD34/kg in the 
first apheresis, we will that the regimen is worthy of further study. 
We therefore plan to enroll a maximum of 127 patients (66 MM; 61 HD and NHL) over 
four-five years. Based on the size of our program, where >90 MM and >40 HD and NHL 
patients are transplanted annually, we believe that this accrual goal is feasible. 
 
13.6  Patient Characteristics and Significant Protocol Violations 
13.6.1 Patient Characteristics 
Patient demographics and patient baseline characteristics will be listed and summarized 
for all patients enrolled, including age, gender, and race. Counts, means, medians, 
standard deviation, minimum and maximum values will be presented. 
13.6.2 Significant Protocol Violations 
The IUSCC will closely monitor study IUCRO-0419 to identify and evaluate any 
violation of good clinical practices (GCP) or clinically important protocol violations. 
Clinically important protocol violation will be defined as those deviations from the 
protocol that could affect patient safety, data integrity, or the conclusions drawn from the 
study. Important protocol violations and any actions to be taken regarding the exclusion 
of patients or affected data from specific analyses will be summarized and listed. This 
information will be submitted to the IRB at the time of continuing review. 
 
 
13.7  Patient Disposition 


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Patient disposition will be tabulated and will show the number of patients enrolled, and 
the number of patients completing the each stage of the study. All reasons for 
discontinuation will be listed and summarized. 
13.8  Treatment Exposure/Compliance 
Treatment exposure and compliance will be summarized using descriptive statistics for 
all enrolled patients. 
13.9  Analysis Plan 
13.9.1 Safety and Tolerability 
To evaluate the safety and tolerability of the combination of Meloxicam and Filgrastim, 
summaries of treatment related adverse events in the Evaluable population will be 
tabulated. All adverse events (AEs) will be presented in incidence tables coded by 
CTCAE term. An adverse event will be considered treatment related if it occurred on or 
after date of first dose of Meloxicam+Filgrastim and was possibly, probably, or definitely 
related to treatment. All adverse events will be recorded beginning at study enrollment. 
Events occurring prior to the first dose of Meloxicam will be considered medical history. 
Adverse events will be recorded at the first dose of Meloxicam until at least one week 
after the last day of apheresis. If there is a graft failure, AEs will be captured during 
mobilization and the post-mobilization phases. 
All deaths recorded in this study will be listed and summarized for the evaluable 
population. 
13.9.2 Concomitant Medication 
Summaries and listing of all concomitant medication will be produced for the 
mobilization phase. 
 
 
13.9.3  Analysis of Primary Objectives 
The primary objective is to investigate if meloxicam and filgrastim can result in a 20% 
increase in the proportion of patients who mobilize and collect at least half of the total 
target CD34+ cell dose in the first apheresis. As the total target CD34 dose varies with 
disease, the primary objective will be as follows according to disease:  
o Multiple myeloma patients: 
Investigate if meloxicam and filgrastim can result in an increase in the proportion 
of patients who mobilize and collect ≥5x106 CD34 cells/kg in the first day’s 
apheresis, from a historical 40% to at least 60%.   
o Hodgkin’s or Non-Hodgkin’s lymphoma patients: 
Investigate if meloxicam and filgrastim can result in an increase in the proportion 
of patients who mobilize and collect ≥2.5x106 CD34 cells/kg in the first day’s 
apheresis, from a historical 50% to at least 70%. 
Two-sided 95% confidence intervals (calculated using the Jennison-Turnbull 
method) will be calculated to estimate the proportion of patients who mobilize 


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and collect the appropriate cells/kg in the first day’s apheresis for each patient 
group. 
13.9.4  Analysis of Secondary Objectives 
For the secondary objectives, non-hematological toxicity will be graded and described 
according to The National Cancer Institute Common Terminology Criteria for Adverse 
events (CTCAE) version 4.0 (http://ctep.cancer.gov), and will be described in terms of 
frequency.  
CD34+, CFUs and immune cell subset counts, in peripheral blood and in apheresis 
products, respectively, at each dose level will be described in terms of median, mean and 
standard deviation. In peripheral blood the fold difference for cell types following 
meloxicam alone, and following meloxicam + plerixafor, relative to baseline will be 
described and compared for each dose level in each patient by the paired t-test, with a p-
value <0.05 considered significant.  
Subjects who receive plerixafor (in addition to meloxicam and filgrastim) will be described 
separately with respect to engraftment. No statistical comparison is planned for the 
engraftment of meloxicam and filgrastim with those receiving additional plerixafor. The 
time to engraftment of neutrophils will be defined as the time from day 0 of transplant to 
the first of three consecutive days after transplantation during which the ANC is ≥0.5 
x109/l. The time to engraftment of platelets will be defined as the time from day 0 to the 
first of seven of transplant to the first seven days after transplantation during which date 
the platelet count is at least 20 x109/l, seven days post transfusion, verified by three 
consecutive CBCs. In addition, we will also describe the times to platelet recovery to 
≥50x109/l and 100x109/l. The times to count recovery will be plotted using the method of 
Kaplan-Meier.  
 
14. ADVERSE EVENT REPORTING 
 
14.1 
Definitions of Adverse Events 
 
14.1.1 
Adverse Event (AE) 
An adverse event is defined as any untoward medical occurrence associated with the use 
of a drug in humans, whether or not considered drug related. An adverse event (also 
referred to as an adverse experience) can be any unfavorable and unintended sign (e.g. an 
abnormal laboratory finding), symptom, or disease temporarily associated with the use of 
a drug, without any judgment about causality.  An adverse event can arise with any use of 
the drug (e.g., off-label use, use in combination with another drug) and with any route of 
administration, formulation, or dose, including an overdose. Adverse events will be graded 
according to the NCI Common Toxicity Criteria, Version 4.0. 
 
AEs will be reported from the time of first dose of Meloxicam through one week after the 
last day of apheresis. Events occurring prior to the first dose of Meloxicam will be 
considered medical history. An adverse event will be considered treatment related if it 
occurred on or after the date of the first dose of Meloxicam+Filgrastim and was possibly, 


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probably, or definitely related to treatment. Documentation should be obtained for all AEs 
and consist of onset and resolution dates, severity/grade, relationship to medications (see 
section 14.1.6) and outcome of the event. Engraftment failure will not be considered an 
adverse event. Failure to engraft will be recorded separately and will be considered a 
“stopping rule” (see section 7 and 13.3). 
 
14.1.2 
Suspected Adverse Reaction (SAR) 
Suspected adverse reaction is any adverse event for which there is a reasonable possibility 
that the drug caused the adverse event. ‘Reasonable possibility’ means there is evidence to 
suggest a causal relationship between the drug and the adverse event. A suspected adverse 
reaction implies a lesser degree of certainty about causality than adverse reaction, which 
means any adverse event caused by a drug. Suspected adverse reactions are the subset of 
all adverse events for which there is a reasonable possibility that the drug caused the event. 
 
Examples of types of evidence that would suggest a causal relationship between the drug 
and the adverse event: 
• A single occurrence of an event that is uncommon and known to be strongly 
associated with drug exposure (e.g., angioedema, hepatic injury, Stevens-Johnson 
Syndrome). 
• One or more occurrences of an event that is not commonly associated with drug 
exposure, but is otherwise uncommon in the population exposed to the drug (e.g., 
tendon rupture). 
• An aggregate analysis of specific events observed in a clinical trial (such as known 
consequences of the underlying disease or condition under investigation or other 
events that commonly occur in the study population independent of drug therapy) that 
indicates those events occur more frequently in the drug treatment group than in a 
concurrent or historical control group. 
 
14.1.3 
Adverse Reaction (AR) 
An adverse reaction is any adverse event caused by a drug. Adverse reactions are a subset 
of all suspected adverse reactions where there is reason to conclude that the drug caused 
the event. 
 
14.1.4 
Serious Adverse Event (SAE) 
An adverse event or suspected adverse reaction is considered “serious” if it results in any 
of the following outcomes: 
• 
Results in death  
• 
Is life-threatening. Life-threatening is defined as an adverse event or suspected 
adverse reaction that places the subject at immediate risk of death. It does not 
include an adverse event or suspected adverse reaction that, had it occurred in a 
more severe form, might have caused death.  
• 
Requires inpatient hospitalization or prolongation of existing hospitalization 
NOTE: Hospitalizations that are not considered SAEs are:  
 Hospitalization planned prior to first administration of study drug 


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 Hospitalization for elective treatment of a pre-existing condition 
unrelated to the study medication 
• 
Results in persistent or significant disability/incapacity 
• 
Is a congenital anomaly or birth defect 
• 
Is an important medical event (defined as a medical event(s) that may not be 
immediately life-threatening or result in death or hospitalization but, based upon 
appropriate medical and scientific judgment, may jeopardize the patient or may 
require intervention (e.g., medical, surgical) to prevent one of the other serious 
outcomes listed in the definition above). 
 
14.1.5 
Unexpected Adverse Event 
Any adverse event or suspected adverse reaction in which the specificity or severity is not 
listed in the study protocol, product inserts or the informed consent document is 
considered “unexpected”. 
 
14.1.6 
Pregnancy 
If a patient becomes pregnant while on this study, the investigator, sub-investigator or site 
personnel must be notified immediately. Study staff will ensure the patient is not allowed to 
proceed in the study or to transplantation per institutional guidelines. Pregnancy should be 
recorded as an adverse event and followed through the outcome of the pregnancy. If the outcome 
of the pregnancy meets the criterion for classification of an SAE (see section 14.1.4) it must be 
reported within 24 hours of notification through the OnCore® system. 
 
14.1.7 
Determining Attribution to the Investigational Agent(s) 
Attribution: An assessment of the relationship between the AE and the medical 
intervention. CTCAE does not define an AE as necessarily “caused by a therapeutic 
intervention”. After naming and grading the event, the clinical investigator must assign 
an attribution to the AE using the following attribution categories: 
 
Relationship 
Attribution 
Description 
Unrelated to investigational 
agent/intervention 
Unrelated 
The AE is clearly NOT related 
Unlikely 
The AE is doubtfully related 
Related to investigational 
agent/intervention 
Possible 
The AE may be related 
Probable 
The AE is likely related 
Definite 
The AE is clearly related 
 
14.2 
Adverse Event (AE) Reporting Requirements: 
 
Adverse events (AEs) deemed clinically significant by the principle investigator or     
sub-investigators will be recorded from the time of first study drug administration and for 
at least two weeks after the last day of mobilization, regardless of whether or not the 
event(s) are considered related to trial medications.  All AEs considered related to trial 


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medication will be followed until resolution, return to baseline, or deemed clinically 
insignificant, even if this occurs post-trial. 
 
14.2.1 
Reporting to the IRB:  
1. Unanticipated problems involving risks to subjects or others will be reported promptly 
to the IRB if they:  
• caused harm;  
• were unexpected;  
• were related or possibly related to the research intervention; AND  
• required revision to the informed consent document. 
 
If the adverse event does not meet all four (4) criteria listed above, the event does not 
have to be promptly reported to the Indiana University IRB.  However, it should be 
reported at the time of continuing review. 
 
2. Prompt reporting of unanticipated problems to the IRB is defined as within 5 days 
from becoming aware of the event. 
 
14.2.2 
Reporting to the DSMC: 
Regardless of study sponsorship, the Data Safety Monitoring Committee (DSMC) chair 
and/or coordinator will review all expedited SAE reports through OnCore®. Expedited 
reports are completed per IRB guidelines and may include the IRB Prompt Reporting form 
and/or non-compliance form. When follow-up information is received, a follow up report 
should also be created in OnCore®.  The DSMC chair and/or coordinator will review 
expedited SAE reports weekly, and report findings to the DSMC quarterly.  
15.    DATA SAFETY MONITORING PLAN (DSMP) 
Investigators will conduct continuous review of data and patient safety.  Monthly review 
meetings for Phase I/II and Phase II trials are required and will include the principal investigator, 
clinical research specialist and/or research nurse (other members per principal investigator’s 
discretion).  Monthly meeting summaries should include review of data, the number of patients, 
significant toxicities as described in the protocol, and responses observed.  Summaries will be 
submitted monthly and reviewed quarterly by the DSMC. 
Study Auditing and Monitoring 
All trials conducted at the IUSCC are subject to auditing and/or monitoring.  Reports will be 
reviewed quarterly by the full DSMC (Reference Risk Table in full DSMC Charter). 
Early Study Closure 
At any time during the conduct of the trial, if it is the opinion of the investigators that the risks (or 
benefits) to the patient warrant early closure of the study, this recommendation should be made in 
writing to the Data Safety Monitoring Committee.  Alternatively, the DSMC may initiate 
suspension or early closure of the study based on its quarterly review of the investigator reports. 
 


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Reporting Guidelines 
The DSMC has streamlined the reporting process by utilizing reports from OnCore®. This has 
allowed direct view of reports within the Clinical Trials Management System (CTMS); thus 
discontinuing paper reports. SAE reports are entered into OnCore® monthly and reviewed by the 
DSMC chair and/or coordinator monthly. Findings will be reported to the full DSMC quarterly.  
Reporting Death:  
Death will be reported per local IRB reporting guidelines (Section 5.8 of the Unanticipated 
Problems and Noncompliance SOP).  The DSMC will review all reported deaths monthly. 
 
Study Accrual Oversight 
Accrual data will be entered into the IU Simon Cancer Center OnCore® system on a monthly basis. 
The Protocol Accrual Committee (PAC) reviews study accrual twice per year while the PAC 
coordinator reviews accrual quarterly 
 
15.1 
Oversight of Study Progress  
15.1.1 
Accrual 
Accrual data will be entered into the IU Simon Cancer Center OnCore® system in real time. 
The Protocol Accrual Committee (PAC) reviews study accrual twice per year while the PAC 
coordinator reviews accrual quarterly. 
   15.1.2 
Protocol Deviations 
Protocol deviations are entered into the IU Simon Cancer Center OnCore® system monthly and 
reviewed by the DSMC chair and/or coordinator. Findings will be reported to the full DSMC 
quarterly. 
15.2  Unanticipated Problems 
Investigators are required to submit unanticipated problems to the DSMC (through OnCore®) 
concurrent with their submission of them to the IRB.  Prompt reporting of unanticipated 
problems to the IRB is defined as within 5 days of discovery. 
Unanticipated problems that will be reported promptly to the IRB include: 
• Major protocol deviation/violation 
• Change to the protocol taken without prior IRB review to eliminate apparent immediate 
hazard to a research subject (e.g. purposeful and for subject safety)  
• Complaint of a subject that indicates unexpected risks, or complaint that cannot be 
resolved by the research team 
• Publication in the literature, safety monitoring report, interim result or other finding that 
indicates an unexpected change to the risks or potential benefits of the research, in terms 
of severity or frequency 
• Change in FDA labeling or withdrawal from marketing of a drug, device, or biologic 
used in a research study 
• Investigator- or sponsor-initiated suspension or hold 
• Serious or continuing non-compliance 


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• Adverse events (See section 14) 
15.3 
Data Quality Control 
 
 
15.3.1 Data Collection 
Study data will be collected and stored in OnCore® (www.forteresearch.com, Forte Research 
Systems, Madison Wisconsin). OnCore® is a web based comprehensive cancer clinical trial 
software system which uses an Oracle database to store all study data (ex. patient registration 
forms, electronic Case Report Forms, calendar of events). Access to data through OnCore® is 
restricted by user accounts and assigned roles. OnCore® properly used is compliant with Title 21 
CFR Part 11.  
All participating institutions will enter study data into the IUSCC OnCore® database. Clinical trial 
data in OnCore® are periodically monitored by the IU Simon Cancer Center Data Safety 
Monitoring Coordinator and the Clinical Research Office Education and Quality Manager. 
 
 
 
 
 
 


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