Clinical trial NCT00397579
Conditions: Leukemia Myelodysplastic Syndromes Blastic Plasmacytoid Dendritic Cell Neoplasm
Keywords: adult acute myeloid leukemia with 11q23 (MLL) abnormalities adult acute myeloid leukemia with inv(16)(p13;q22) adult acute myeloid leukemia with t(15;17)(q22;q12) adult acute myeloid leukemia with t(16;16)(p13;q22) adult acute myeloid leukemia with t(8;21)(q22;q22) recurrent adult acute myeloid leukemia secondary acute myeloid leukemia untreated adult acute myeloid leukemia de novo myelodysplastic syndromes previously treated myelodysplastic syndromes secondary myelodysplastic syndromes blastic plasmacytoid dendritic cell neoplasm plasmacytoid dendritic cell leukemia CD123+
Sponsor: University of Texas Southwestern Medical Center
Start date: 2013-05-01; Completion date: 2017-07-27
Enrollment: 11 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
RATIONALE: Combinations of biological substances in DT388IL3 fusion protein may be able to carry cancer killing substances directly to the cancer cells.

PURPOSE: This phase I/II trial is studying the side effects and best dose of DT388IL3 fusion protein and to see how well it works in treating patients with acute myeloid leukemia or myelodysplastic syndromes.

Detailed description:
OBJECTIVES:

* Determine the maximum tolerated dose of DT\_388IL3 fusion protein in patients with refractory or relapsed or poor-risk acute myeloid leukemia (AML) or high-risk myelodysplastic syndromes (MDS).
* Define the dose-limiting toxicities of this regimen in these patients.
* Measure the pharmacokinetics of this regimen in these patients.
* Measure the immune responses in patients treated with this regimen.
* Evaluate response and correlate with disease type (relapsed/refractory or poor-risk de novo AML or high-risk MDS), pretreatment marrow blast percentage, and leukemia blast interleukin-3 receptor density.

OUTLINE: This is a phase I, multicenter, dose-escalation study followed by a phase II, open-label study.

* Phase I: Patients receive DT\_388IL3 IV over 15 minutes daily for 5 days in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of DT\_388IL3 until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.

* Phase II: An additional 15 patients receive DT\_388IL3 at the MTD as in phase I. Patients undergo serum and blast collection periodically for laboratory studies, including analysis of expression of interleukin-3 receptors and anti-DT\_388IL3 antibodies at baseline. Samples are also analyzed by immunoenzyme assays and flow cytometry.

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

PROJECTED ACCRUAL: A total of 50 patients will be accrued for this study.

Arms: arm 1: Patients will be treated with a maximum of five doses of approximately 15min IV infusions of DT388IL3/SL-401 over a ten day period at a maximum of once daily.
Interventions: intervention 1: DT388IL3
Intervention descriptions: intervention 1: Intravenously via a 3 cc plastic syringe as a 15 minute bolus infusion daily for five days.

Protocol documents:
Prot_SAP_000.pdf: 
 
University of Texas Southwestern Medical Center Protocol 01913 – Amendment 40 
 
 
 
 
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Therapy Targeting the Interleukin-3 Receptor (IL3R) for Patients with Relapsed or Refractory and 
Elderly Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN) with DT388IL3 -SL-401 (IND# 11314): 
a Phase IB Clinical Trial 
 
 
Investigators:  
 
 
Arthur E. Frankel, MD 
University of Texas Southwestern Medical Center 
Dallas, TX  
Telephone:  (214) 648-1579 
FAX: (214) 6481578 
 
Co-Investigators: 
 
 
Robert Collins, MD 
 
 
 
University of Texas Southwestern Medical Center 
 
 
 
Dallas, TX 
 
 
 
Telephone: (214) 648-4155 
 
 
 
 
Larry Anderson, MD 
 
 
 
University of Texas Southwestern Medical Center 
 
 
 
Dallas, TX 
 
 
 
Telephone: (214) 648- 4155 
 
 
 
 
Prapti Patel, MD 
 
 
 
University of Texas Southwestern Medical Center 
 
 
 
Dallas, TX 
 
 
 
Telephone: (214) 648-4155 
 
 
 
 
Madhuri Vusirikala, MD 
 
 
 
University of Texas Southwestern Medical Center 
 
 
 
Dallas, TX 
 
 
 
Telephone: (214) 648-4155 
 
 
 
 
 
Group Statisticians: 
 
 
Chul Ahn, PhD/Song Zhang, PhD/Xian-Jin Xie, PhD 
 
 
 
 
 
University of Texas Southwestern Medical Center 
 
 
 
 
 
 
Dallas, TX  
 
 
 
 
 
Telephone:  (214) 648-4017 
 
 
 
 
 
 
 
Study Drug:  
 
 
 
DT388IL3 (also known as SL-401) 
 
IND Number:  
 
 
11314 
 
IND Holder Name: 
 
 
Arthur Frankel, MD 
 
Funding Source:  
 
 
Stemline Therapeutics, Inc.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Original Version: 
June 23, 2004  
Revised: 
 
February 11, 2013 
 
Amendment 1:  
February 9, 2005 
Amendment 2:  
February 23, 2005 
Amendment 3:  
June 22, 2005  
Amendment 4:  
July 25, 2005 
Amendment 5:  
September 28, 2005 
Amendment 6:  
December 5, 2005 
Amendment 7:  
February 16, 2006 
Amendment 8:  
June 20, 2006 
Amendment 9:  
August 8, 2006 
Amendment 10: 
October 26, 2006 
Amendment 11: 
January 2, 2007 
Amendment 12: 
April 2, 2007 
Amendment 13: 
June 28, 2007 
Amendment 14:  
July 2, 2007 
Amendment 15: 
October 12, 2007 
Amendment 16: 
October 30, 2007 
Amendment 17: 
December 13, 2007 
 
Amendment 18: 
June 27, 2008 
Amendment 19: 
July 29, 2008 
Amendment 20:        
November 11, 2008 
Amendment 21: 
November 14, 2008 
Amendment 22: 
December 15, 2008 
Amendment 23: 
December 23, 2008 
Amendment 24:  
January 8, 2009 
Amendment 25:  
February 18, 2009 
Amendment 26: 
June 22, 2009 
Amendment 27: 
July 6, 2009 
Amendment 28: 
December 2, 2009 
Amendment 29: 
December 16, 2009 
Amendment 30: 
January 19, 2010 
Amendment 31:  
March 31, 2010 
Amendment 32 
June 4, 2010 
Amendment 33: 
October 7, 2010 
Amendment 34: 
January 25, 2011 
Amendment 35:  
February 11, 2013 
Amendment 36: 
May 31, 2013 
Amendment 37:  
September 17, 2013 
Amendment 38:  
September 19, 2014 
Amendment 39: 
December 18, 2014 
Amendment 40: 
November 22, 2016 
 
 
 
UT Southwestern Medical Center at Dallas 
Harold C. Simmons Cancer Center 
Attn: Clinical Research Office 
5323 Harry Hines Blvd.  MC 9179 
Dallas, TX 75390-9179 
 


 
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CONFIDENTIAL 
This material is the property of the UTSW Simmons Cancer Center. Do not disclose or use except as authorized in writing by the study 
sponsor. 
 
TABLE OF CONTENTS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TITLE PAGE 
 
 
 
 
 
 
 
 
 
1 
TABLE OF CONTENTS 
 
 
 
 
 
 
 
3 
SCHEMA 
 
 
 
 
 
 
 
 
 
4 
1.0 
BACKGROUND AND RATIONALE 
 
 
 
 
 
 
5 
2.0 
OBJECTIVES  
 
 
 
 
 
 
 
 
9 
3.0 
PATIENT SELECTION CRITERIA 
 
 
 
 
 
 
9 
3.1 
ELIGIBILITY 
 
 
 
 
 
 
 
 
9 
3.2 
INELIGIBILITY  
 
 
 
 
 
 
 
9 
4.0 
TREATMENT PLAN 
 
 
 
 
 
 
 
 
10 
4.1 
STUDY DESIGN 
 
 
 
 
 
 
 
10 
 
4.2 
TREATMENT SCHEDULE 
 
 
 
 
 
 
11 
 
4.3 
CNS LEUKEMIA 
 
 
 
 
 
 
 
13 
 
4.4 
CONCOMITANT TREATMENT 
 
 
 
 
 
13 
5.0 
STUDY PARAMETERS 
 
 
 
 
 
 
 
13 
 
5.1 
STUDY TABLE  
 
 
 
 
 
 
 
14 
 
5.5 
CORRELATIVE STUDIES 
 
 
 
 
 
 
15 
6.0 
TREATMENT MODIFICATIONS 
 
 
 
 
 
 
16 
 
6.1 
REASON FOR STUDY DISCONTINUATION  
 
 
 
16 
6.2 
TREATMENT MODIFICATION  
 
 
 
 
 
17 
6.3 
TOXICITY CRITERIA  
 
 
 
 
 
 
18 
 
6.4 
TOXICITY REPORTING 
 
 
 
 
 
 
18 
7.0 
 
ADVERSE EVENTS 
 
 
 
 
 
 
 
18 
8.0 
DRUG FORMULATION 
 
 
 
 
 
 
 
22 
9.0 
REGISTRATION  PROCEDURES 
 
 
 
 
 
 
23 
9.1 
REGISTRATION 
 
 
 
 
 
 
 
23 
 
9.2 
DATA MANAGEMENT  
 
 
 
 
 
 
23 
10.0 
STATISTICAL CONSIDERATIONS 
 
 
 
 
 
 
23 
11.0 
STUDY MANAGEMENT 
 
 
 
 
 
 
 
24 
12.0 
REFERENCES  
 
 
 
 
 
 
 
 
27 
 


 
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Schema 
 
I. 
Only patients with BPDCN will be screened for eligibility and, after eligibility is 
confirmed and informed consent obtained, pretreatment labs will be done and the 
patients will be admitted to University of Texas Southwestern Hospital and Clinics 
(see Section 4.1.2.1).   
 
Patients will begin on prophylactic medications on day 1 continuing throughout the 
treatment period to prevent side effects including: 
 
 
1 liter normal saline IV qd to maintain hydration for days of DT388IL3/SL-401 
treatment.  
 
Patients will be treated in-hospital, on a schedule of five daily doses with delays 
permitted between doses for a total maximum treatment period of ten days.  No more 
than one dose may be given daily and no more than five total doses. One hour prior 
to drug administration, patients will receive: 
 
 
acetaminophen 325 mg po 
 
diphenhydramine 25 mg IV 
 
solumedrol 40 mg IV  
 
famotidine 20 mg IV 
 
II. 
SL-401 will be administered into a free flowing normal saline IV over a period of 
approximately 15 minutes. Vital signs including blood pressure, pulse, temperature, 
respirations, and pulse oximetry will be measured post infusion, 30, 60, 180 minutes, 
and then every four hours thereafter. Strict Intake/Output and daily weights will be 
obtained during dosing days and the days following dosing. Blood draws (2cc) for 
pharmacokinetics (PK) will be done pretreatment and 5, 30, and 90 minutes post 
infusion on day 1 and identically for the fifth dose. Patients will be monitored closely 
for toxicities.  Toxicities that were observed previously with DT388IL3/SL-401 include 
fever, hypotension, dyspnea, hypoalbuminemia, weight gain, edema, and 
transaminasemia. 
 
 
Patients will have serum albumin monitored daily and will be given 25 grams 
of albumin each day the albumin is <3.0 gm/dL. 
 
Patients with >10% weight gain and no hypotension will receive furosemide 
IV as needed to prevent fluid overload.   
 
Patients with grade 3 respiratory compromise or grade 4 vascular leak 
toxicity will no longer receive the study drug and will be transferred (or 
admitted) to an ICU setting for monitoring and treatment at the physician’s 
discretion.  
 
Chills associated with the administration of the study drug may be treated 
with meperidine 12.5-50 mg IV or morphine sulphate 1-2 mg IV as needed.   
 
Anaphylaxis and cytokine release syndrome associated with rash, fever, 
urticaria, bronchospasm, and angioedema will be treated with 100 mg IV 
methylprednisolone (or dexamethasone, or hydrocortisone at equipotent 
doses), diphenhydramine 25-50 mg IV.  More severe symptoms will also be 
treated with 0.3cc epinephrine (1:1000) IV once only.  Patients will be 
transferred to an ICU setting for monitoring.   
 
Patients with fever ≥ 100.5 degrees F will be cultured, given antibiotics and 
given acetaminophen 325mg po every 6 hours at the discretion of treating 
physician. 
 
Patients with mild to moderate dyspnea and hypoxia will receive 


 
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supplemental oxygen and furosemide as needed. 
 
Patients with hypotension (SBP < 90mmHg) will receive normal saline fluid 
bolus IV in volumes as needed to restore blood pressure. 
 
III. 
The SL-401 dose is 12.5 µg/kg/day every day for five consecutive days.  Delays 
between doses are permitted for recovery from toxicities as long as all doses are 
administered within 10 days.  This 12.5 µg/kg/day dose corresponds to one dose 
level below the MTD determined for AML patients and is the recommended phase 2 
dose level (RP2D). See Section 1.3 for details.  If two patients experience drug-
related dose limiting toxicity, the MTD for BPDCN patients has been exceeded, 
enrollment to that dose will stop, and the next lower dose from the AML phase 1 
study--10g/kg may be tested on additional patients after consultation with the 
DSMC, IRB and FDA.  If 2 patients in the lower dose cohort experience dose-limiting 
toxicity (drug related grade 3 or 4 with the exceptions described 4.1.10), study 
accrual will be halted.  
 
IV. 
 
Dose-limiting toxicity (DLT) is defined as any drug-related grade 4 hematologic 
toxicity (unrelated to persistent leukemia) lasting > 28 days after the last day of 
therapy or non-hematologic toxicity of grade 3 toxicity except for transient (2weeks) 
asymptomatic transaminase or CPK elevations.  
 
V. 
Additional BPDCN patients will be treated until a total of 11 patients have been 
treated at the RP2D or BPDCN MTD—the lowest between these.  Response will be 
determined based on previous recommendations for response criteria for BPDCN [1, 
2]. 
 
VI. 
Correlative studies include the evaluation of response and toxicity in relation to 
pretreatment marrow blast index (product of percent blasts x marrow cellularity), 
presence of skin disease, presence of nodal disease or organomegaly by 
PET/CTscan, presence of circulating blasts, age, gender, prior therapies, and blast 
surface density of CD123.  
 
1.0 
Background of BPDCN and Rationale 
 
BPDCN is a rare hematologic malignancy of plasmacytoid dendritic cells with an incidence of 
approximately 50 patients/y in the United States.  The median age at diagnosis is 65 years and most 
patients are male.  Patients may present with involvement of skin, marrow, and blood, and, less 
frequently, node, liver and spleen.  Diagnosis entails immunohistochemical evidence of malignant 
CD4+CD56+CD123+TCL1+CD303+ blasts [3].  Treatment consists of combination chemotherapy 
and allogeneic bone marrow transplantation [1, 4].  Median survival is 12-18 months.  While 
preclinical data suggests anti-BPDCN activity of lenalidomide [5], no clinical trials have been 
reported with lenalidomide for relapsed BPDCN.  Patients frequently die from leukemic progression.  
 
 
1.1 
Fusion Protein Therapy of BPDCN 
 
One set of agents designed for extreme potency is fusion proteins consisting of protein synthesis 
inactivating peptide toxins fused to leukemia cell selective ligands.  Our laboratory has used 
diphtheria toxin (DT), a 535 amino acid residue protein with three domains--a catalytic domain 
(amino acid residues 1-186) connected by a arginine-rich disulfide loop to a translocation domain 
(amino acids 187-388) followed by a cell binding domain (amino acids 389-535) [6].  DT binds to a 
heparin-binding epidermal growth factor precursor on the cell surface and undergoes receptor-
mediated endocytosis [7].  In the early endosomes, DT is cleaved by furin, and, in the acidic 
environment, the translocation domain helices insert into the vesicle membrane.  Cytosolic beta-


 
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COP, Hsp90 and thioredoxin reductase facilitate the escape of the DT A fragment containing the 
catalytic domain to the cytosol [8].  In the cytosol, the A fragment ADP-ribosylates elongation factor 2 
leading to inhibition of protein synthesis and programmed cell death or necrosis [9]. 
 
We constructed the fusion protein DT388GMCSF composed of the catalytic and translocation 
domains of DT fused via a Met-His linker to human granulocyte-macrophage colony-stimulating 
factor [10].  The fusion protein was selectively toxic to AML cell lines and patient progenitors [11, 12] 
and showed in vivo anti-leukemic efficacy in SCID mice bearing human leukemias [13].  A clinical 
batch of drug was prepared and 38 patients with relapsed or refractory AML were treated with up to 
five daily bolus infusions [14].  Remissions were observed in four patients lasting up to one year, but 
liver injury, presumably due to hepatic Kupffer cell expression of the GM-CSF receptor, was 
observed which prevented dose escalation.  Because of the toxicity of DT388GMCSF, our laboratory 
sought to design and produce an alternative fusion protein that was not only more potent but which, 
by virtue of targeting a more tumor-specific surface receptor, was more selective for malignant cells 
and thus less toxic. The interleukin-3 receptor (IL3R), a target with a more tumor-specific expression 
pattern, was chosen for these reasons. Moreover, IL3R is an additionally attractive target because it 
is over-expressed on some progenitor cells of myeloid malignancies  [15, 16].  
 
Interleukin-3 (IL3) is a cytokine, which supports the proliferation and terminal differentiation of certain 
multi-potential and committed myeloid and lymphoid progenitors.  The IL3R is composed of an and 
 subunit, and binding of IL3 to the receptor causes rapid internalization of the ligand-receptor 
complex [17].  IL3R are overexpressed on human myeloid leukemic stem cells and progenitors but 
low-absent on normal human hematopoietic stem cells, and leukemic cells proliferate in response to 
exogenous IL3 [18].  High affinity IL3R are absent from most normal tissues [19].  Low affinity IL3R 
have been reported on human mast cells, endothelium, testes and brain, but it is not known whether 
these non-hematopoietic receptors are able to internalize ligand [20 - 23].  Rhesus monkeys have 
receptors, which can bind and physiologically respond to human IL3 [24].  Two groups prepared DT 
fusion proteins with murine IL3 [25, 26].  In both cases, selective cytotoxicity to murine malignant 
myeloid cells was observed.  A fraction of normal murine stem cells was spared.  Anti-leukemic 
efficacy was observed in a murine leukemia model.  Because of the broad range of expression of 
IL3R among myeloid leukemias, its absence from most normal tissues including normal human 
hematopoietic stem cells, its rapid internalization on cross-linking, the availability of a relevant animal 
model for safety testing, and the encouraging results with a murine receptor targeted DT fusion 
protein, we chose IL3 for construction of the next generation fusion protein. 
 
 
 
1.2 
Preclinical Information on DT388IL3 
 
Constructions. Plasmids encoding four different DT388IL3 molecules were made, and recombinant 
proteins were produced in E. coli [27].  The molecules included DT388-Met-His-human IL3, DT388-
Met-His-(Gly4-Ser)2-human IL3, DT388-Met-His-humanIL3-Leu-Glu-(His)6, and Met-Gly-(Ser)2-(His)6-
(Ser)2-Gly-Leu-Val-Pro-Arg-Gly-Ser-His-Met-Ala-Ser-Met-DT388- Met-His-human IL3.  The DT388-
Met-His-human IL3 or SL-401 gave the best yields, purity, IL3R affinity and potency.   
  
Selective cytotoxicity to cell lines. Inhibition of thymidine incorporation, inhibition of colony formation, 
and apoptosis induction were measured after SL-401 incubation with eight human AML cell lines 
[28].  Four of eight AML cell lines were sensitive with IC50s of 1 to 50pM.  SL-401 sensitivity 
correlated with the number of high affinity IL3R (p = 0.03).      
 
Efficacy for leukemic cell killing. Inhibition of human AML colony-forming cells (AML-CFC) with SL-
401 exposure was measured in three studies [29 - 31].  Greater than one log cell kill was observed 
in 3/9, 3/7 and 9/25 samples, respectively.  In the last study, a correlation between log cell kill and 
blast high affinity IL3R density was found (p = 0.004).   In the second study, inhibition of earlier 


 
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leukemic stem cells (long-term culture-initiating cells, suspension culture-initiating cells, and 
NOD/SCID mice engrafting cells) was also observed in 3/7 samples.  In each of these three 
samples, the surviving treated human cells lacked the leukemic cytogenetic abnormality.   
 
Safety on normal stem cells. Normal marrow progenitors were incubated with SL-401 and assayed 
for colony growth and NOD/SCID mice repopulating frequency [32].  There was a 60-80% reduction 
in colony-forming cells but no inhibition of long-term culture-initiating cells, suspension culture-
initiating cells, or NOD/SCID mice engrafting cells.   
 
Safety and efficacy in rodent models. Six week old C57BL/6 female mice tolerated six every other 
day intraperitoneal infusions of 375 g/kg SL-401 with a DLT of renal tubular necrosis [33].  We 
developed an in vivo model of differentiated human AML by retroviral infection of the cytokine-
dependent human AML cell line TF-1 with the v-Src oncogene [34].  When injected either 
intravenously into 300 cGy irradiated SCID mice, animals formed multiple granulocytic sarcomas 
involving the adrenals, kidneys, lymph nodes and other organs.  Leukemic mice treated with 100 
g/kg with five daily intraperitoneal doses of DT388IL3 had a significant prolongation in disease-free 
survival (>120 days versus 37 days, p < 0.001) and only 5/49 (10%) of treated leukemic mice died 
with leukemia [35].  In a separate study, NOD/SCID mice engrafted with six different human AML 
samples treated with SL-401 had significant reductions in AML engraftment at twelve weeks for four 
of six samples and no evidence of residual leukemia for two of the AML samples [36]. 
 
Safety in monkeys. Eight cynomolgus monkeys received up to six every other day intravenous 
infusions of SL-401 40g/kg (n = 2), 60 g/kg (n = 2), or 100g/kg (n = 4) [37, 38].  After one week, 
all monkeys were necropsied.  One female monkey given 100g/kg drug died with vasculitis.  The 
remaining seven monkeys showed either no symptoms or mild to moderate transient malaise and 
anorexia.  There were no reproducible blood test abnormalities or organ damage by histopathology.  
The drug half-life was 30 minutes, and immune responses were minimal.  The SL-401 MTD was 
fifteen-fold higher than the DT388GMCSF MTD.  No significant myelosuppression or liver injury was 
seen. 
 
Lack of toxicity to macrophages. DT388mGMCSF but not DT388mIL3 produces elevations of serum 
transaminases in rodents [39].  In tissue culture, DT388mGMCSF but not DT388mIL3 damages liver 
macrophages.  Cultured human monocytes released tumor necrosis factor-alpha in response to 
DT388GMCSF but not SL-401 [40].  These observations along with the findings in monkeys suggest 
SL-401 may produce less liver toxicity than DT388GMCSF in patients. 
 
Vascular leak syndrome (VLS) toxicity of fusion proteins.  One to two weeks after systemically 
administered peptide toxins and cytokines, vascular damage may occur with hypoalbuminemia, 
hypotension, edema, dyspnea, weight gain and, rarely, hypoxemia.  Tripeptide disintegrin motifs 
may bind to receptors on endothelial cells triggering vascular permeability or apoptosis [41].  There 
are three disintegrin motifs at amino acid residues 7-9, 29-31 and 208-210 of SL-401 that may 
produce VLS similar to DT388GMCSF and denileukin diftitox [42]. 
 
CGMP lots approved. Recombinant protein was produced in E. coli [33].  Inclusion bodies were 
washed, denatured and refolded, and protein dialyzed and purified by column chromatography.  
Seventy-five 3-L bacterial culture preparations were made and pooled for the AT-1 batch (568 mL) 
and twenty-four 3-L bacterial culture preparations made and pooled for the AT-2 batch (169 mL).  
Final material was filter sterilized, aseptically vialed and labeled in 1 mL aliquots, stored at -75oC or 
below, and characterized by Coomassie Plus protein assay, Coomassie-stained SDS-PAGE, limulus 
amebocyte lysate endotoxin assay, human AML TF/H-ras cell cytotoxicity assay, sterility, tandem 
mass spectroscopy, IL3 receptor binding affinity, ADP ribosylation activity, inhibition of normal CFU-
GM, disulfide bone analysis, immunoblots, peptide mapping, stability, HPLC TSK3000, N-terminal 
sequencing, E. coli DNA contamination, C57BL/6 mouse toxicity, cynomolgus monkey toxicity, and 
immunohistochemistry.  FDA approval (IND #11314) for clinical testing was obtained on 11/3/03. 


 
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Pre-clinical studies in BPDCN.  Recently, SL-401 was incubated in vitro with BPDCN cell lines and 
fresh BPDCN blasts from six patients and femtomolar cytotoxicity observed both by MTT assay and 
annexin V staining [43].   
 
1.3 
Clinical information on SL-401 
 
A Phase I dose escalation study was undertaken in 74 patients with relapsed or refractory adult AML 
(n = 56), de novo poor risk elderly AML (n = 11), or high-risk myelodysplastic syndrome (MDS) 
(n=7). Thirty-three AML patients were ≥2nd salvage. Thirty-six percent of the patient’s had 
unfavorable cytogenetics, 59% had intermediate cytogenetics, and 0% had favorable cytogenetics. 
The cytogenetics for 5% of the patients were not determined. The median patient age was 66 years 
(range, 24-84). Patients received SL-401 via a 15 minute intravenous infusion in one of two dosing 
regimens for one cycle to determine the MTD and to evaluate clinical activity. In the first regimen, 
Regimen A, 45 patients received doses ranging from 4 to 12.5 mcg/kg every other day for up to six 
doses [44]. In the second regimen, Regimen B, 29 patients received doses ranging from 7.1 to 22.1 
mcg/kg daily for up to 5 doses [45]. SL-401 was well-tolerated at clinically active doses. Adverse 
events (AEs) that were observed during the trial included grade 1-2 hypoalbuminemia (62%) that 
was manageable and not dose-limiting. Other less common grade 1-2 AEs included fever and chills, 
which were largely infusion-related. Grade 3 or greater AEs included transaminase elevations (21%), 
which were mostly transient, and which was the DLT at 22.1 mcg/kg daily for five days. The MTD for 
Regimen B was established at 16.6 mcg/kg daily for five doses. An MTD was not defined for the 
Regimen A schedule. Notably, there was no treatment-related delayed recovery of the bone marrow. 
This is consistent with the known over-expression of the drug’s target, IL-3R, on leukemia versus 
normal hematopoietic stem cells. Absolute neutrophil count and hemoglobin remained stable, and 
near or above baseline pre-treatment levels, throughout therapy and up to day 30 post-infusion. 
Mean platelet counts were 58,000/uL pre-treatment, 30,000/uL at Day 15, and back to baseline by 
Day 30. Overall, two complete remissions (CRs), 4 partial responses (PRs), and 14 minor responses 
(MRs) including 4 with ≥50% reduction in blasts were observed during the trial. In addition, anti-
tumor activity, defined as blast reductions or disease stabilization, was seen in 46% of patients with 
relapsed or refractory AML, 55% of poor risk elderly AML, and 43% of high risk MDS patients. 
Durable CRs were induced in two patients with chemorefractory AML. One patient, who sustained a 
CR of greater than 15 months duration, had a previous history of refractory AML, including two stem 
cell transplants, and had relapsed for a third time prior to entry onto this study. The second patient 
had a sustained CR of 8 months duration, after failing standard AML induction chemotherapy. This is 
consistent with the dual mechanism of action of SL-401 targeting both blasts and leukemia stem 
cells. In addition, the median survival of ≥2nd salvage AML patients was 3.2 months (95% CI: 2.0, 
8.4) and the 12 months overall survival was 22% (95% CI: 5.1, 45.7), which is favorable compared 
with historical 12-months survival of 2-8%. Also of note, SL-401 demonstrated a clinical anti-cancer 
stem cell (CSC) effect as evidenced by a decrease in CSC activity in patient bone marrows (n=3), as 
determined by an ex vivo colony formation assay pre- and post-SL-401 treatment. The results from 
these 74 patients have been published [45]. 
 
Recently, three BPDCN patients received 3-5 doses of SL-401 over 5-10 days at 12.5µg/kg over 15 
minute infusions.  Toxicities were limited to transient transaminasemia, fever, chills, hypoalbumin-
emia, dyspnea and weight gain.  Drug half-life was 65 minutes and anti-drug antibodies formed after 
two weeks.  All three patients achieved complete remissions lasting 1, 5, and 7months.   
 
 
 
 
 
  
 


 
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2.0 
Objectives 
 
2.1 
Evaluate response rate 
2.2 
Assess the tolerability of the RP2D—five daily dose of 12.5g/kg as 15 min bolus IV 
infusion with delays permitted up to 10 days in BPDCN patients.  
  
2.3 
Define any DLTs of this SL-401 regimen in these patients. 
 
2.4 
Measure the pharmacokinetics and immune responses associated with this SL-401 
regimen. 
 
2.5 
Correlate response with patient disease burden and IL3 receptor density. 
 
3.0 
Patient Selection Criteria 
 
3.1 
Eligibility 
 
3.1.1 
  All patients must be informed about the study and signed informed consent.  
 
3.1.2 
  All patients must have BPDCN diagnosed by morphologic, histochemical   
                                      and cell surface marker criteria [3].   
  
3.1.3     All patients must have failed or be intolerant of chemotherapy and allogeneic  
 
      stem cell transplantation.  
 
3.1.4   Patients must have a performance status of ≤ 2 on the ECOG scale  
 
3.1.5    Patients must have bilirubin <1.5 mg/dl, transaminases <2.5x upper limit of 
            normal, albumin >3gm/dl, creatinine <1.5mg/dl, and adequate cardiac reserve  
            (EF>50%). 
 
3.1.6    Must give written informed consent. 
 
3.1.7    Must be willing to be treated at the University of Texas Southwestern Hospital 
            and clinics. 
 
3.1.8    Females and males must be willing to use an approved form of birth control 
            while on this study and for 2 weeks after completion. 
 
3.1.9     Age > 18 years. 
 
 
 
 
3.2 
Ineligibility 
 
3.2.1 
Failure to meet any of the criteria set forth in Section 3.1. 
 
3.2.2 
Inability to give informed consent because of psychiatric problems, or 
complicated medical problems. 
 
3.2.3 
Serious concurrent medical problems, uncontrolled infections, DIC or 
pregnancy. 
 


 
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3.2.4 
Active CNS leukemia. 
 
3.2.5 
Patients who have had a myocardial infarction within the past six months. 
 
3.2.6 
Pregnant or nursing women will be excluded from study. 
 
3.2.7 
Patients with allergies to diphtheria toxin will be excluded. 
 
3.2.8 
Patients requiring oxygen will be excluded from the study. 
 
3.2.9 
History of congestive heart failure. 
 
 
 
4.0 
Treatment Plan 
 
4.1       Study Design 
 
Prior to Therapy 
 
4.1.1 
Patient sera will be collected and assayed for anti-SL-401 EIA antibodies as 
described [46].   
 
 
4.1.2 
Prior to commencing treatment on any day patient must have a serum 
creatinine <1.5mg/dL to continue drug.   
 
4.1.3 
Patients are admitted to University of Texas Southwestern Hospital and 
Clinics and given normal saline 1 liter IV every day of treatment.  
 
 
normal saline 1L IV qd 
 
Patients will receive treatment for a maximum of five doses over 10 days at a 
maximum of once daily; if there is no drug-related grade 3 non-hematologic 
toxicity, albumin is >2.7 gm/dL and serum creatinine is <1.5mg/dL.  Patients 
will receive 1h prior to each SL-401 treatment: 
 
 
acetaminophen 325 mg po 
 
diphenhydramine 25 mg IV 
 
solumedrol 40 mg IV 
 
famotidine 20 mg IV 
 
The prophylactic regimen was chosen based on the results of the initial 
phase I studies of SL-401.  
 
 
 
 
Therapy  
 
4.1.4 
Patients will be treated with a maximum of five doses of approximately 15min 
IV infusions of SL-401 over a ten day period at a maximum of once daily. The 
second through fifth doses for each patient will only be given if repeat serum 
creatinine is <1.5 mg/dL,albumin is >2.7 gm/dL and there is no drug-related 


 
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grade >3 non-hematologic toxicity prior to each treatment. If albumin is <2.7 
gm/dL, treatment will be held for the day, albumin will be replaced to >2.7 
gm/dL, and treatment can be resumed the following day. All 5 doses must be 
completed within 10 days. 
 
4.1.5 
If two patients experience drug-related dose limiting toxicity, the MTD has 
been exceeded, enrollment at the 12.5g/kg dose will stop, and patients will 
be treated at the next lower dose 10g/kg. If 2 patients experience DLT at this 
lower dose level, the study will be halted.  
 
4.1.6 
A total of eleven patients will be treated. 
 
4.1.7 
Toxicity will be graded according to the NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0.  Drug-related DLT is defined for this 
protocol as any nonhematologic drug-related toxicity of grade 3 except 
transient (<2 weeks) asymptomatic transaminase or CPK elevations or any 
grade 4 drug-related hematologic toxicity (unrelated to leukemia) lasting > 4 
weeks after the last dose of SL-401.  
 
4.1.8 
All patients entered on this phase I study will be evaluated for response as 
outlined in section 7.0.  All patients will have pharmacologic and immunologic 
studies performed as outlined in section 8.0. 
 
4.1.9 
Patients may receive additional treatments with DTIL3 if they have a low 
antibody titer of less than 16ug/ML and partial or complete response to first 
cycle. Patients have had no toxicities at any anti-DTIL3 level observed pre-
treatment. The range has been 0-60ug/ML. Antibody levels less than 10ug/mL 
do not affect DTIL3 pharmacokinetics and hence patients with less than 
10ug/mL are most likely to respond. 
 
4.2            Treatment Schedule and Duration SL-401 Fusion Protein Therapy 
 
4.2.1 
Patients are admitted to UT Southwestern Medical Center Hospital and 
Clinics and given prophylactic medications to prevent side effects. 
Pretreatment 
medications 
include 
acetaminophen 
325 
mg 
po, 
diphenhydramine 25 mg IV, solumedrol 40 mg IV, and famotidine 20 mg IV 
on treatment days one hour before treatment. Normal saline will be given at 
100 cc per hour while the patient is hospitalized for treatment.  This may be 
modified at the physician’s discretion, but at least one liter of normal saline 
will be given each of the treatment days. Vital signs will be obtained pre-
treatment including temperature, respirations, BP, Pulse, and pulse oximetry. 
 
4.2.2 Starting on first treatment day and repeated on each treatment day after 
premedication and pre-treatment lab draws and vital signs measurements, SL-
401 fusion protein will be administered into a free flowing IV of normal saline 
over a period of approximately 15 minutes.  On treatment days, vital signs will 
be measured post infusion at 30 (+/- 5 minutes), 60 (+/- 10 minutes), and 180 
(+/- 10 minutes) minutes, and then q4h (+/- 10 minutes).  Vital signs include 
BP, pulse, temperature, respirations and pulse oximetry.  Strict input and 
output (I/O) and daily weights will be obtained on treatment days.  Patients are 
required to have a Temperature <100.5o F, Pulse <130 and >40, and Systolic 
BP<160 and >80 mmHg prior to therapy. 
 


 
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4.2.3 
Chills associated with study drug administration may be treated with 
meperidine 12.5-50 mg IV or morphine sulphate 1-2 mg IV. Anaphylaxis and 
hypersensitivity 
reactions 
associated 
with 
rash, 
fever, 
urticaria, 
bronchospasm, and angioedema will be treated with 100 mg IV 
methylprednisolone (may substitute for dexamethasone, or hydrocortisone at 
equipotent doses), 25-50 mg IV diphenhydramine.  More severe symptoms 
will also be treated with 0.3 cc epinephrine (1:1000) IV once.  Patients will be 
transferred to an ICU setting for monitoring with Pulse>140 or <40, SBP >160 
or <80 mmHg, or oxygen saturation <90% or any physical signs or symptoms 
of anaphylaxis and hypersensitivity at the physician’s discretion.  Patients 
with anaphylactoid reactions or hypersensitivity reactions will be treated for 
symptoms receive no further SL-401 and be taken off study. 
 
4.2.4 
Symptomatic hypotension will be treated with a bolus of 500 cc normal saline 
and a hold on further drug infusion until resolution.  If the BP fails to improve 
with two 500 cc bolus saline infusions, further standard measures to correct 
the BP will be undertaken and the drug will be withheld on that day.  If low 
BP, without further drug treatment through the next day, no further drug will 
be given to that patient for that course. 
 
 
 
4.2.5 
Vascular leak syndrome is associated with vascular endothelial injury related 
to fusion protein administration and may occur 3-8 days after initiation of 
treatment. Patients may note symptoms of hypotension, weight gain, edema, 
nausea, and anorexia, shortness of breath and, at times, confusion and 
muscle injury.  Exam findings may include hypoalbuminemia, reductions in 
blood oxygen saturation, and chest X-ray pulmonary edema.  Patients with 
hypotension will receive 500cc normal saline boluses.  Patients will have 
serum albumin measurements daily until completion of the drug 
administration and will receive 25gm albumin IV each day the serum albumin 
is <3 gm/dL. Patients with >10% weight gain and no hypotension will receive 
furosemide as clinically indicated.  Patients with grade 3 respiratory 
compromise or grade 4 vascular leak toxicity, due to the study drug, will no 
longer receive the study drug and will be transferred to an ICU setting for 
monitoring and treatment.  Reversibility of low blood pressure or hypoxemia 
with fluids and diuretic, responding within 24 hours will not constitute grade 3 
vascular leak syndrome. 
 
 
  
 
4.2.6 
Peripheral blood counts will be monitored daily during treatment period and 
then the following day. Bone marrow aspiration and biopsy will be done on 
days 15 (+/- 1 day) and 30 (+/- 1 day). Serum chemistries including 
transaminases, CPK, calcium, creatinine, alkaline phosphatase, bilirubin will 
be done daily on days 1-6. CMP will be repeated on days 15 (+/- 1 day) and 
30 (+/- 1 day). Urinalysis will be done weekly and on days 15 (+/- 1 day), and 
30 (+/- 1 day). Any grade 3 or greater laboratory abnormalities will be 
followed with increased frequency as appropriate until resolution of toxicity. 
Thrombocytopenia and anemia will be treated with blood products as 
clinically indicated.  Cryoprecipitate may be used to replace fibrinogen for 
levels <100 mg/dL as cryoprecipitate does not contain significant anti-
DT388IL3 antibodies.   Elevated prothrombin times (INR >2.0) in the absence 
of other abnormalities consistent with DIC will be treated after the end of 
fusion protein infusions (day 6) with fresh frozen plasma one unit daily for one 
week or until INR <2.0.  If the prothrombin time is prolonged to INR >2.5, the 
patient will be treated with fresh frozen plasma one unit daily and continued 


 
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on study. Vitamin K 5mg IV every day may also be used for elevated 
prothrombin time. 
 
  
4.2.7 
Patients with partial remission (PR) or complete remission (CR) at day 30 (+/- 
1 day) marrow and blood sampling, skin exam, and PET/CT scan will have 
repeat bone marrow exam, skin exam and PET/CTscan at day 60 (+/- 1 day) 
to assess duration of response. 
 
 
 4.2.8   Patients will be withdrawn from the study if they show obvious evidence of 
progressive disease while on therapy prior to day 15 (+/- 1 day) marrow and 
blood analysis. Non-responding patients or patients with progression may be 
further treated with other investigational or standard chemotherapy agents.  
 
 4.2.9 
Patients may be re-treated if there is disease progression more than 30 days 
after their initial treatment.  
 
4.3             CNS Leukemia 
 
Documented CNS leukemia while on study will necessitate removal from study and 
treatment at the discretion of the patient's principal physician. 
 
4.4            Concomitant Treatment 
 
4.4.1  Patients should receive full supportive care including transfusions of blood 
and blood products, antibiotics, antiemetics, etc, when appropriate.  
Antiemetics should not include corticosteroids.  Any hematopoietic growth 
factors (e.g., erythropoietin, interleukin-11, G-CSF and GM-CSF) are not 
allowed.  Patients are not allowed intravenous immunoglobulins while on the 
study. 
 
4.4.2  Treatment with other anti-neoplastic drugs after the start of SL-401 therapy 
will result in the patient's removal from study. 
 
4.4.3  Radiation therapy may not be administered while the patient is on this study. 


 
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5.0 
 
Study Parameters  
5.1 Study Parameter Table (see section 4.2) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
aScreening tests should be performed within 28 days of the start of treatment.  CBC with differential, CMP, DIC screen and CPK should be performed 
within 1 week of the start of treatment 
bSee section 5.4. 
cSee section 5.2. 
dSee section 5.3. 
eUrinalysis is only done once per week and at days 15 and 30, or as clinically indicated. 
fCMP including sodium, potassium, chloride, CO2, BUN, glucose, creatinine, calcium, total protein, albumin, total bilirubin, SGOT, SGPT and alk 
phosphatase.  
gEF repeated at one month. 
 
Screeninga 
Days1-
10l 
Day 
15 
(+/- 1 
day) 
Day 
30 
(+/- 1 
day) 
Response Follow-
upb m 
History and Physicalc 
X 
X 
X 
X 
X 
Bone marrow Aspirate 
& Bxd 
X 
 
 
X 
X 
Toxicity Notation 
X 
X 
X 
X 
X 
CBC with Differential 
X 
X 
X 
X 
X 
DIC Screen and CPK 
X 
X 
 
 
X k 
Urinalysis 
X 
X e 
X 
 
 
CMPf, LDH, uric acid 
X 
X 
X 
X 
X 
Chest x-ray (PA & 
lateral) 
X 
 
 
 
 
EKG,EF 
X 
 
 
Xg 
 
Skin 
exam/photographs/bxj 
X 
 
Xj 
Xj 
Xj 
PET/CTscanj 
X 
 
 
Xj 
Xj 
Pregnancy test 
(HCG)h 
X 
 
 
 
 
PK & Immune Studies i
 
 
 
X 
X 
X 
 
LP j 
 
X 
 
 
 
 


 
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hFemales of reproductive potential 
iSee section 5.5. Note PK draws on first and last treatment day. Immune draws on days 1, 15, and 30. 
jAs clinically indicated. 
kCPK only 
lOnly on treatment days 
**.  Scheduled procedures, labs and treatment may be modified by +/- 1 day due to the presence of weekends, vacations, or clinically necessary 
procedures. 
 
 
 
5.2 Physical Examinations 
 
 
 
5.2.1   Screening 
 
 
A detailed history and physical examination must be performed including weight, 
height and body surface area.  Records of prior therapy with duration, dates and 
performance status must be recorded. A detailed neurologic exam and fundoscopic 
exam will be performed as clinically indicated.  
 
 
5.2.2 
Treatment Period 
 
 
A detailed history and physical examination must be performed including weight. We 
will monitor for altered sensorium, headaches or focal neurological findings and 
complete a detailed neurologic and fundoscopic exam as clinically indicated. Patients 
will be followed by nephrology during treatment days if indicated.* 
 
5.2.3 
Photographs will be taken to document lesion changes and response to 
treatment. * 
 
 
5.3 
Bone marrow aspirate and biopsy during off-treatment follow-up must be every three 
months (+/- 2 weeks) for 1 year, then at least semiannually (+/- 3 weeks) for years 2 
and follow-up for 5 years and study will be completed if there was initial marrow 
involvement and a remission is obtained. Bone marrow aspirate and biopsy must 
have differential and estimate of cellularity.  A bone marrow aspirate for 
immunophenotyping should be done with marker analysis for CD4, CD56, and 
CD123 costained populations. Bone marrow cytogenetics must be performed. 
Cytogenetics, histochemistry, and FAB classification need only be performed on the 
initial pretreatment aspirate and biopsy. Follow-up bone marrows must have 
peripheral blood CBC and Differentials.  
 
5.4 
Off-treatment follow-up for patients obtaining remissions will be monthly (+/- 1 day) 
for the first 3 months, then every 3 months for 1 year, then every 6 months for years 
2 and follow-up for 5 years and study will be completed with CBC, differential and 
platelet counts, and CMP, CPK, LDH, bone marrow aspirate and biopsy every 3 
months (+/- 2 weeks), if marrow positive initially for patients with a remission from 
therapy. Again, bone marrow aspirates should assess CD4+CD56+CD123+ 
populations.  Off treatment follow-up for progressing or non-responding patients will 
be for survival and patients will be contacted by phone. Additional therapy data may 
be collected from their primary care physician.* 
 
*Procedures, Physical Exam, labs, photographs (as clinically indicated), 
bone marrow aspirate, biopsy, and PET/CT scan can be done where the 
patients reside and sent to the Research Coordinator at UT 
Southwestern Medical Center.  
 
5.5 
Correlative Studies 
 


 
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5.5.1 Circulating concentrations of biologically active SL-401 fusion protein in the 
blood sent to Scott & White Cancer Research Institute.   
 
Measurement of the half-life of SL-401 in the blood in patients will permit correlation 
of drug levels and leukemia cell exposure (time x concentration) with clinical toxicities 
and response.  Further, different patient leukemia burdens may influence drug 
pharmacodynamics. 
 
2 ml venous blood samples (red tops) will be drawn at the times shown below.  Blood 
will be allowed to clot 30 minutes at room temperature and then centrifuged 2,000g x 
15 minutes, and serum collected and frozen at -75oC or below until assayed for SL-
401 bioactive concentration.  Label tube with study number, patient’s initials, patient 
ID number, date, and time of draw. Store blood samples at -75oC or below until 
delivered.  Please deliver samples to Jung Hee Woo, PhD, Cancer Research 
Institute, 5701 South Airport Road, Temple, Texas 76502. 
 
Blood samples (red tops) will be obtained pretreatment and at 5, 30, and 90 minutes 
post-infusion on the first treatment day and identically on the last treatment day.   
 
Serum samples collected pretreatment and at 5, 30, and 90 minutes post-infusion on 
the first and last treatment day infusions will be collected and stored at -75oC or 
below until assayed.  Ten microliters of normal human serum will be mixed with L 
of SL-401 and 89 L of RPMI 1640 (BioWhittaker, Walkersville, MD) plus 10% fetal 
bovine serum (FBS, Irvine Scientific, Irvine, CA) to yield a final concentration of 
19g/mL SL-401. Thirty microliters of this mixture will be combined with 60 L of 
RPMI1640/10% FBS, with 10 further dilutions (1:3) prepared sequentially for the 
standard curve. Similarly, for the rest of the samples, 10 L of sample patient serum 
will be mixed with 90 L of RPMI1640/10% FBS, and again one to three dilutions 
were prepared sequentially by adding 30 L of each dilution to 60 L of 
RPMI1640/10% FBS. Fifty microliters of medium containing the patient serum 
samples or standards will be added to 100 L of medium with 5000 TF/H-ras cells in 
flat-bottom sterile 96-well Costar plates and incubated at 37°C/5% CO2 for 48 h [44]. 
Fifty microliters of medium containing 0.5 Ci [3H]thymidine (DuPont NEN, Boston, 
MA) will then be added to each well and incubation continued at 37°C/5% CO2 for an 
additional 16 h. Cells will then be harvested on a cell harvester (Skatron Instruments, 
Sterling, VA) to glass fiber mats, and the [3H]thymidine counted in a Wallac Betaplate 
Reader gated for 3H. The dilution of patient serum sample yielding a 50% reduction 
in thymidine incorporation (IC50) will be compared to the standard curve to estimate 
the SL-401 concentration. All assays will be performed in duplicate.  
 
5.5.2  Circulating anti-fusion protein Ig concentration sent to University of Texas 
Southwestern Medical Center 
 
2 ml venous blood sample (red tops) will be collected and these are different than 
those obtained in 5.5.1 and sera harvested identically to 5.5.1 and stored at -75oC or 
below until assayed. Label tube with study number, patient initials, patient ID 
number, date, and time of draw. Store blood samples at -75oC or below until 
delivered. Please deliver samples to Jung Hee Woo, PhD, Cancer Research 
Institute, 5701 South Airport Road, Temple, Texas 76502.  
 
Blood samples will be obtained pretreatment on day 1 and on days 15 and 30. Thus, 
only three samples collected during the course for the immune measurements. 
 
5.5.3  Patient marrow BPDCN blast CD123 quantitation 


 
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Pretreatment and day 30 bone marrow aspirates will undergo CD123 quantitation on 
BPDCN cell population using clinical laboratory reagents and measurements.   
 
 


 
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6.0 Treatment Modifications 
 
 
6.1      Reasons for Study Discontinuation 
 
6.1.1 
Progressive disease 
 
 
 
6.1.2  Death 
 
 
6.1.3 
Unacceptable study drug toxicity 
 
 
6.1.4  Patient refusal to continue on protocol 
 
 
6.1.5  Physician’s judgment that discontinuation is in the best interest of the patient 
 
 
6.1.6  Sponsor's decision to discontinue protocol for technical reasons 
 
6.2     Treatment Modification--Therapy Courses 
 
 
 
6.2.1  Hematologic—None 
 
6.2.2  Non-hematologic--Occurrence of any DLT (Section 4.1.7) or drug-related 
grade 3 non-hematologic toxicity except for transient (< 2 weeks) asymptomatic 
transaminase or CPK elevations, during the course of therapy will result in immediate 
discontinuation of the infusion and observation for resolution of the toxicity.  
Additionally, if albumin is <2.7 gm/dL, treatment will be held for the day, albumin will 
be replaced to >2.7 gm/dL, and treatment can be resumed the following day. In order 
to receive treatment on any given day, the patient’s creatinine must be <1.5mg/dL. 
Treatment all 5 doses must be completed within 10 days. 
 
6.3 
Response Evaluation Criteria 
 
 The BPDCN response criteria are based on published recommendations [1, 2] as shown 
below:   
 
 
                
 6.3.1 
Complete Response (CR) 
 
 
 
-Normal WBC, Platelets with absent blasts in peripheral bood or 
 
 
 
 Marrow 
 
 
 
-No evidence nodal involvement or liver/spleen involvement by CT 
 
 
 
 Scans or PET/CT scan 
 
 
 
-No skin involvement by exam and biopsy where necessary. 
 
 
6.3.2 
Partial Remission (PR): 
 
 
 
- Decrease of 50% of more in marrow blasts 
 
 
 
- Decrease in nodes/liver/spleen size as per RECIST1.1 criteria. 
 
 
 
- Decrease of 50% or more in skin lesions. 
  
 
  
6.3.3 
Stable Disease: 
 
            -Failure to achieve at least PR, no evidence progression for 2 months 
 
  
 
6.3.4     Failure: 
 
 
   
-Death during treatment or disease progression characterized by: 
 
 
   
-increase in the percentage bone marrow blasts 


 
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-increase in skin or node or liver/spleen size.  
 
 
6.4 
End Point Variables 
 
-DLT (defined in Section 4.1.7) 
 
-Toxicity profile (described in Section 4.1.7 (defined in Section 4.1.5) 
-Clinical response rate (as measured in Section 7.0) 
-Duration of response--defined as time of first response to time of progression. 
-Anti-SL-401 antibodies at day 1, 15, 30 (see Section 8.5) 
-Serum SL-401 levels and half-life (see Section 8.5) 
-Pretreatment marrow blast index and BPDCN blast CD123 density (section 8.5) 
 
 
6.3      Toxicity Criteria 
 
Toxicity will be determined using the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0 for Toxicity and Adverse Event reporting.  A 
copy of the CTCAE version 4.0 can be downloaded from CTEP home page 
(http://ctep.info.nih.gov). 
 
6.4      Toxicity Reporting 
 
 
 
6.4.1  Notify PI, Dr. Arthur Frankel (214) 648-1579 immediately by telephone of 
dose-limiting toxicity as defined by protocol and document in the patient's 
medical records and protocol forms that the chairman was notified. 
 
6.4.2  Any pronounced, unusual or unexpected toxicity should be reported 
immediately to the PI, Dr. Arthur Frankel (214) 648-1579.  The PI must obtain 
a detailed clinical description of the toxicity and report it to the IRB and decide 
whether it should be reported to the FDA . Other study participants will be 
notified.  If the toxicity is reportable, the Study Chairperson will be responsible 
for notifying the FDA as per Federal Register §312.32 IND safety reports. In 
particular, (1) Written reports.  The PI/Study Chairperson/Sponsor shall notify 
FDA in a written IND safety report of any adverse experiences associated 
with use of the drug that is serious and unexpected.  Such notification shall 
be made as soon as possible and no later than 10 working days after the 
Sponsor/Study Chairperson's initial receipt of the information. The written 
notification to the FDA will be transmitted to the FDA Division of the Center 
for Drugs and Biologics. (2) Telephone reports.  The Sponsor shall also notify 
FDA by telephone of any unexpected, fatal or life-threatening experience 
associated with use of the drug in the clinical study conducted under the IND 
no later than 3 working days after receipt of the information and will be 
transmitted to the FDA Division of the Center for Drugs and Biologics, which 
has responsibility for review of the IND. 
 
6.4.3 
Any questions regarding this protocol should be directed to the Study  
Chairperson/PI: 
 
 
 
 
Arthur E. Frankel, MD 
UT Southwestern Medical Center 
Dallas, TX 
(214) 648-1579 


 
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7.0 ADVERSE EVENTS  
 
7.1       Experimental Therapy 
For the most recent safety update, please refer to the current Investigator’s Brochure 
or Study Agent Prescribing Information. 
 
7.2 
Adverse Event Monitoring 
Adverse event data collection and reporting, which are required as part of every 
clinical trial, are done to ensure the safety of subjects enrolled in the studies as well 
as those who will enroll in future studies using similar agents. Adverse events are 
reported in a routine manner at scheduled times during a trial. Additionally, certain 
adverse events must be reported in an expedited manner to allow for optimal 
monitoring of subject safety and care.  
 
All subjects experiencing an adverse event, regardless of its relationship to study 
drug, will be monitored until:  
 the adverse event resolves or the symptoms or signs that constitute the 
adverse event return to baseline;  
 any abnormal laboratory values have returned to baseline;  
 there is a satisfactory explanation other than the study drug for the changes 
observed; or 
 death. 
 
7.2.1 
Definition  
An adverse event is defined as any untoward or unfavorable medical occurrence in a 
human research study participant, including any abnormal sign (for example, 
abnormal physical exam or laboratory finding), symptom, clinical event, or disease, 
that occurs during the subject’s participation in the research, whether or not it is 
considered related to the subject’s participation in the research. 
Adverse events encompass clinical, physical and psychological harms. Adverse 
events occur most commonly in the context of biomedical research, although on 
occasion, they can occur in the context of social and behavioral research. Adverse 
events may be expected or unexpected. 
Severity  
Adverse events will be graded by a numerical score according to the defined NCI 
Common Terminology Criteria for Adverse Events (NCI CTCAE) and version number 
specified in the protocol. Adverse events not specifically defined in the NCI CTCAE 
will be scored on the Adverse Event log according to the general guidelines provided 
by the NCI CTCAE and as outlined below.   
 
Grade 1: Mild  
 
Grade 2: Moderate 
 
Grade 3: Severe or medically significant but not immediately life threatening 
 
Grade 4: Life threatening consequences 
 
Grade 5: Death related to the adverse event 
 
Serious Adverse Events  


 
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ICH Guideline E2A and the UTSW IRB define serious adverse events as those 
events, occurring at any dose, which meets any of the following criteria:  
 
Results in death   
 
Immediately life-threatening  
 
Results in inpatient hospitalization or prolongation of existing hospitalization  
 
Results in persistent or significant disability/incapacity  
 
Results in a congenital anomaly/birth defect  
 
Based upon appropriate medical judgment, may jeopardize the subject’s 
health and may require medical or surgical intervention to prevent one of the other 
outcomes listed in this definition. 
Note: A “Serious adverse event” is by definition an event that meets any of the above 
criteria. Serious adverse events may or may not be related to the research project. A 
serious adverse event determination does not require the event to be related to the 
research. That is, both events completely unrelated to the condition under study and 
events that are expected in the context of the condition under study may be serious 
adverse events, independent of relatedness to the study itself. As examples, a car 
accident requiring overnight hospitalization would be a serious adverse event for any 
research participant; likewise, in a study investigating end-stage cancer care, any 
hospitalization or death would be a serious adverse event, even if the event 
observed is a primary clinical endpoint of the study. 
7.2.2 
Unanticipated Problems: 
The term “unanticipated problem” is found, but not defined in the regulations for the 
Protection of Human Subjects at 45 CFR 46, and the FDA regulations at 21 CFR 56. 
Guidance from the regulatory agencies considers unanticipated problems to include 
any incident, experience, or outcome that meets each of the following criteria: 
 
unexpected; and 
 
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. 
 
Follow-up  
All adverse events will be followed up according to good medical practices.  
  
7.2.3 
Reporting 
Local events requiring expedited reporting, are submitted to the UTSW IRB through 
the UTSW eIRB and to the SCC DSMC Coordinator.  Hardcopies or electronic 
versions of the eIRB report; the NCI ADEERS, FDA Form #3500A forms, or other 
sponsor forms, if applicable; and/or any other supporting documentation available 
should be forwarded to the DSMC Coordinator.  The DSMC Coordinator forwards the 
information onto the DSMC Chairman who determines if immediate action is 
required.  Follow-up eIRB reports, and all subsequent SAE documentation that is 
available are also submitted to the DSMC Chair who determines if further action is 
required.    
  
If the event occurs on a multi-institutional clinical trial coordinated by the Cancer 
Center, the DOT Manager or lead coordinator ensures that all participating sites are 
notified of the event and resulting action, according to FDA guidance for expedited 


 
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reporting. DSMC Chairperson reviews all serious adverse events within upon receipt 
from the DSMC Coordinator.  The DSMC Chairperson determines whether action is 
required and either takes action immediately, convenes a special DSMC session 
(physical or electronic), or defers the action until a regularly scheduled DSMC 
meeting.  
 
 
 
 
 
 
  
Telephone reports to: 
(Investigator: Arthur Frankel, MD, (office) 214-648-1579 
 
UTSW SCC Data Safety Monitoring Committee Coordinator (if fax report is not available) 
within 1 working day to 214-648-7097. 
 
Written reports to: 
(Investigator: Arthur Frankel, MD, (fax) 214-6481578, 5323 Harry Hines Blvd,, Dallas, TX, 
75390-8852 
 
UTSW SCC Data Safety Monitoring Committee Coordinator 
Email: SCCDSMC@utsouthwestern.edu 
Fax: 214-648-7018 or deliver to NB 2.418 
 
UTSW Institutional Review Board (IRB) 
Submit via eIRB with a copy of the final sponsor report as attached supporting 
documentation 
 
1. 
Unexpected Adverse Events 
Non-serious adverse events which are classified as both unexpected (in terms of 
nature, severity and frequency) and possibly related require reporting to the UTSW 
IRB within 10 working days of PI awareness.  
2. 
SAEs 
Local serious adverse events (SAEs) require reporting within 2 working days of PI 
awareness, or as described in the protocol.   
 
3. 
Unanticipated Problems  
Unanticipated problems, including those that occur as non-local events, require 
reporting to the UTSW IRB within 10 working days of PI awareness of the event. 
For further guidance for Investigators regarding safety reporting requirements for 
INDs and BA/BE studies, refer to FDA Draft Guidance document: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Gu
idances/UCM227351.pdf 
7.3 
Steps to Determine If an Adverse Event Requires Expedited Reporting 
Step 1: Identify the type of adverse event using the NCI Common Terminology 
Criteria for Adverse Events (CTCAE v4).  
 
Step 2:Grade the adverse event using the NCI CTCAE v4. 
 


 
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Step 3: Determine whether the adverse event is related to the protocol therapy  
Attribution categories are as follows: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
Note: This includes all events that occur within 30 days of the last dose of protocol 
treatment. Any event that occurs more than 30 days after the last dose of treatment 
and is attributed (possibly, probably, or definitely) to the agent(s) must also be 
reported accordingly. 
 
             Step 4: Determine the prior experience of the adverse event.  
Expected events are those that have been previously identified as resulting from 
administration of the agent. An adverse event is considered unexpected, for 
expedited reporting purposes only, when either the type of event or the severity of 
the event is not listed in: 
 
the current known adverse events listed in the Agent Information  
 
section of this protocol; 
 
the drug package insert; 
 
the current Investigator’s Brochure 
 
8.0 Drug Formulation, Availability and Preparation  
 
8.1 Availability 
SL-401 is an experimental drug produced by Cancer Research Institute of Scott & 
White with approval of the FDA for investigational purposes (IND BB#11314). 
 
8.2 Pharmaceutical Data 
 
 
8.2.1   Formulation 
SL-401 protein is supplied frozen in sterile 2 mL vials containing 1mg drug in 1 
mL of 0.25M NaCl/5mM Tris, pH 8.0.  Lot AT-2 or AT-1 will be used for this 
trial. 
 
 
8.2.2   Reconstitution 
Vials are to be thawed then drawn into a 3 cc syringe and filter sterilized using 
a 0.2 filter.  The drug is aliquoted into sterile screw top CryoTube vials for 
single doses and refrozen at -75oC or below.  The CryoTube vials will be 
labeled with the patient’s identifying markers, the dose, the date on which it 
was prepared, and Caution: New Drug – Limited by Federal (or United States) 
law to investigational use.  CryoTube frozen drug must be used within two 
weeks. On the day of administration, a single aliquot is thawed and diluted in 
saline.  At Scott & White, either commercial saline or the Tris buffered saline 
will be used.  The drug must be administered within one hour of thawing. 
 
 
8.2.3  Storage and Stability 
 Intact vials should be stored at -75oC or below and is stable for over 12 
months.  CryoTube refrozen drug is stable at -75oC or below for over 2 weeks.  
The acceptable temperature variance is at -60oC or lower.  If a freezer 
registers -50oC or higher then the drug will be transferred to an acceptable 
freezer. 
 
 
8.2.4  Administration 


 
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The drug is to be given intravenously via a 3 cc plastic syringe as a 15min 
infusion daily for five days.  DT388IL3 will be administered through a Y-access 
on either a peripheral or central line with normal saline. 
 
 
 
 
8.2.5  Procurement 
Patients are registered with the study coordinator at (214) 648-5107. 
Following patient registration, the protocol administrator will notify Dr. Arthur 
Frankel (214) 648-1579 for dispensing of drug. 
 
 
8.2.6  Drug-related Toxicities 
 
Toxicities believed to be associated with SL-401 from completed and/or 
ongoing clinical trials include: 
 
Frequent (>10%): anorexia, mild proteinuria,.dyspnea/wheezing, edema, 
fever, hypoalbuminemia, hypocalcemia, hypotension, nausea, rigors/chills, 
transaminase elevations, and vascular/capillary leak syndrome. 
 
Less Frequent (>5% and 10%): vomiting and weight gain. 
 
Rare (5%): alkaline phosphatase elevations, low fibrinogen, prolonged 
prothrombin time or partial thromboplastin time, abdominal cramping, 
anaphylaxis, anemia, bilirubin  elevations, brusing, cardiac arrhythmia, 
cardiopulmonary arrest, coagulopathy, CPK changes, creatine kinase 
changes, 
creatinine 
changes, 
diarrhea, 
dizziness, 
fatigue, 
fluid 
overload/retention, 
headache, 
hemorrhage/bleeding, 
hyperglycemia, 
hypertension, hypokalemia, hypomagnesemia, hypoxia, infection (excluding 
sepsis, pneumonia, herpes), INR changes, leukopenia, lymphocytosis, 
lymphopenia, muscle weakness, neutropenia, organ insufficiency, pain, 
petechia, pneumonia, rash, renal failure, respiratory failure, skin lesions, 
thrombocytopenia, tubular necrosis, urine retention, and weakness. 
 
9.0 
Registration and Data Management Procedures 
 
 
9.1 
Registration 
 
Patients may be registered by calling the study coordinator at (214) 648-5107 
between 8:30 AM and 4:30 PM, Monday - Friday.  If the patient meets the eligibility 
criteria, the study coordinator will register the patient with UT Southwestern Medical 
Center Hospital and Clinics.  Patients must be registered before initiation of 
treatment in order to be eligible for the study.  
 
9.2 
Data Management Procedures 
 
9.2.1 
The Case Report Forms (CRF) will be completed by the study coordinator 
and submitted to the Study Chair and Sponsor, Arthur E. Frankel, M.D. and 
made available to the IRB and University of Texas Southwestern DSMC for 
review.  
-Case Report Forms (CRF) to be available to study chair/PI every two weeks 
the patient is on study. 
 
9.2.2 
The signed informed consent form and “Authorization for Use or Disclosure 
of Protected Health Information for Research” will be obtained prior to the 
patient’s entry into the study. 


 
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10.0 
Statistical Considerations 
 
 
10.1  
Design  
This is a phase IB study designed to determine the safe dose of SL-401 (as defined 
in Schema IV) of SL-401 for treatment of patients with BPDCN. From this point on 
assuming no dose limiting toxicity (DLT) occurs, the dose will be administered to 
eleven patients. If two patients enrolled at the 12.5g/kg dosel level experience DLT, 
the MTD has been exceeded and additional patients will be treated at the next lower 
dose level 10sameg/kg.  If two patients experience DLT, the MTD has been 
exceeded, and the study will be halted.   
 
 
10.2  
Feasibility 
 
It is anticipated that approximately eleven patients will be needed for the dosing 
schedule for this phase IB evaluation of BPDCN.  Based on the rarity of the disease 
and accrual to a previous SL-401 Phase I study of 15 patients per year, we expect 
this study to be completed within 2 years.   
 
10.3     Analysis for Response 
 
A total of eleven patients will be treated. Response measurements will be derived 
from the revised criteria of BPDCN response previously reported [1,2]. The lack of 
activity hypothesis (<5% response rate) will be rejected if 2 or more responses are 
seen (80% power for an alternative response rate of 30% at the 10% one-sided 
significance level).  Since we have observed 3/3 CRs to date, we expect this 
hypothesis will be rejected. 
 
Toxicities are dichotomized as none versus any, or none and mild versus moderate 
to severe.  The rates of toxicity, overall response, and complete response, as well as 
their 95% confidence intervals, will be estimated at each dose level.  Tables and 
graphs will be constructed to explore the association between toxicities and 
predictive variables, including pretreatment marrow blast index, pretreatment anti-SL-
401 antibody level, blast IL3R level, and peak serum SL-401 concentration, serum 
SL-401 AUC, patient age, gender, serum creatinine, serum albumin, serum 
transaminase, number of circulating blasts, spleen size, skin disease, node disease, 
and visceral disease.  The Kaplan-Meier methods will be used to estimate the time to 
the development of toxicity.  Similarly, we will explore the association of SL-401 
concentrations, anti-SL-401 concentrations, blast CD123 level, skin/node/organ 
disease, and marrow blast index with patient response.  Results from this pilot phase 
1B study will be used to develop multi-institutional phase II studies using designs that 
minimize the expected sample size under the null hypothesis or designs that allow a 
trade-off between response and toxicity.   
11.0 
STUDY MANAGEMENT 
11.1 
Conflict of Interest 
 
Any investigator who has a conflict of interest with this study (patent ownership, 
royalties, or financial gain greater than the minimum allowable by their institution, 
etc.) must have the conflict reviewed by the Office of Research. All investigators will 
follow the University conflict of interest policy. 
 


 
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11.2 
Institutional Review Board (IRB) Approval and Consent 
 
It is expected that the IRB will have the proper representation and function in 
accordance with federally mandated regulations. The IRB must approve the consent 
form and protocol. 
 
In obtaining and documenting informed consent, the investigator should comply with 
the applicable regulatory requirement(s), and should adhere to Good Clinical 
Practice (GCP) and to ethical principles that have their origin in the Declaration of 
Helsinki. 
 
 
Before recruitment and enrollment onto this study, the subject will be given a full 
explanation of the study and will be given the opportunity to review the consent form. 
Each consent form must include all the relevant elements currently required by the 
FDA Regulations and local or state regulations. Once this essential information has 
been provided to the subject and the investigator is assured that the subject 
understands the implications of participating in the study, the subject will be asked to 
give consent to participate in the study by signing an IRB-approved consent form. 
 
Prior to a patient’s participation in the trial, the written informed consent form should 
be signed and personally dated by the subject and by the person who conducted the 
informed consent discussion. 
11.3 
Registration Procedures 
 All subjects must be registered with the Research Office before enrollment to study.   
Prior to registration, eligibility criteria must be confirmed with the Study Coordinator. 
To register a subject, call 214-648-5107 Monday through Friday, 8:30AM-4:30PM.  
11.4 
Data Management and Monitoring/Auditing 
The SCC DSMC will serve as a primary DSMB. All trial processes from initial 
regulatory approvals to final data submission must be scrutinized to ensure 
compliance with federal, institutional and protocol-specific guidelines, accuracy of data 
capture, and appropriate attention to safety.  Monitoring of adverse events, case 
report forms and overall study conduct is continuously performed at the level of the 
disease oriented team, and, more formally, by scheduled audits performed by the 
Quality Assurance and Education Coordinator (QAC) under the authority of the 
DSMC.    
 
11.5 
Adherence to the Protocol 
Except for an emergency situation in which proper care for the protection, safety, and 
well-being of the study subject requires alternative treatment, the study shall be 
conducted exactly as described in the approved protocol.  
11.5.1 Emergency Modifications 
Investigators may implement a deviation from, or a change of, the protocol to 
eliminate an immediate hazard(s) to trial subjects without prior IRB approval.  
 
For any such emergency modification implemented, a IRB modification form 
must be completed within five (5) business days of making the change. 


 
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11.5.2 Other Protocol Deviations/Violations 
All other planned deviations from the protocol must have prior approval by 
the Principal Investigator and the IRB. According to the IRB, a protocol 
deviation is any unplanned variance from an IRB approved protocol that:  
 
Is generally noted or recognized after it occurs 
 
Has no substantive effect on the risks to research participants 
 
Has no substantive effect on the scientific integrity of the research plan or 
the value of the data collected  
 
Did not result from willful or knowing misconduct on the part of the 
investigator(s).  
 
An unplanned protocol variance is considered a violation if the variance: 
 
Has harmed or increased the risk of harm to one or more research 
participants. 
 
Has damaged the scientific integrity of the data collected for the study. 
 
Results from willful or knowing misconduct on the part of the 
investigator(s). 
 
Demonstrates serious or continuing noncompliance with federal 
regulations, State laws, or University policies. 
 
If a deviation or violation occurs without prior approval from the Principal 
Investigator, please follow the guidelines below: 
 
Protocol Deviations: Personnel will report to any sponsor or data and safety 
monitoring committee in accordance with their policies. Deviations should be 
summarized and reported to the IRB at the time of continuing review. 
 
Protocol Violations: Study personnel should report violations within one (1) 
week of the investigator becoming aware of the event using the same IRB 
online mechanism used to report Unanticipated Problems.  
11.6 
Amendments to the Protocol 
Should amendments to the protocol be required, the amendments will be originated 
and documented by the Principal Investigator.  When an amendment to the protocol 
substantially alters the study design or the potential risk to the patient, a revised 
consent form might be required.  
 
The written amendment, and if required the amended consent form, must be sent to 
the IRB for approval prior to implementation.  
11.7 
Record Retention 
Study documentation includes all Case Report Forms, data correction forms or 
queries, source documents, Sponsor-Investigator correspondence, monitoring 
logs/letters, and regulatory documents (e.g., protocol and amendments, IRB 
correspondence and approval, signed patient consent forms). 
 
Source documents include all recordings of observations or notations of clinical 
activities and all reports and records necessary for the evaluation and reconstruction 
of the clinical research study. 
 
Government agency regulations and directives require that the study investigator 
retain all study documentation pertaining to the conduct of a clinical trial. In the case 


 
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of a study with a drug seeking regulatory approval and marketing, these documents 
shall be retained for at least two years after the last approval of marketing application 
in an International Conference on Harmonization (ICH) region. In all other cases, 
study documents should be kept on file until three years after the completion and 
final study report of this investigational study. 
11.8 
Obligations of Investigators 
The Principal Investigator is responsible for the conduct of the clinical trial at the site 
in accordance with Title 21 of the Code of Federal Regulations and/or the 
Declaration of Helsinki. The Principal Investigator is responsible for personally 
overseeing the treatment of all study patients. The Principal Investigator must assure 
that all study site personnel, including sub-investigators and other study staff 
members, adhere to the study protocol and all FDA/GCP/NCI regulations and 
guidelines regarding clinical trials both during and after study completion. 
 
The Principal Investigator at each institution or site will be responsible for assuring 
that all the required data will be collected and entered onto the Case Report Forms. 
Periodically, monitoring visits may be conducted and the Principal Investigator will 
provide access to his/her original records to permit verification of proper entry of 
data. At the completion of the study, all case report forms will be reviewed by the 
Principal Investigator and will require his/her final signature to verify the accuracy of 
the data. 
 


 
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12.0 
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