Conditions: Aggressive Systemic Mastocytosis Mast Cell Leukemia Systemic Mastocytosis
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 10
Healthy volunteers: no

Brief summary:
This pilot clinical trial studies brentuximab vedotin in treating patients with advanced systemic mastocytosis or mast cell leukemia. Monoclonal antibodies, such as brentuximab vedotin, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them

Detailed description:
Brentuximab vedotin is an antibody with a covalently attached toxin. The antibody portion targets the protein CD30 on the surface of cells, and the toxin acts against those cells.

PRIMARY OBJECTIVES:

I. To evaluate the response rate to SGN-35 (brentuximab vedotin) in patients with tumor necrosis factor receptor superfamily, member 8 (CD30+) advanced systemic mastocytosis (SM) (ASM or mast cell leukemia \[MCL\] with or without an associated hematological clonal non-mast cell lineage disease \[AHNMD\]).

SECONDARY OBJECTIVES:

I. To evaluate the tolerability and safety profile of SGN-35 in patients with SM.

II. To evaluate expression of CD30 on neoplastic mast cells before and during therapy with SGN-35.

III. To evaluate changes in mastocytosis related symptom scores and quality of life (QOL) using a modified Myeloproliferative Neoplasm Symptom Assessment Form (MPNSAF).

IV. To evaluate the duration of response (DoR) and time to response (TTR). V. To evaluate progression-free survival (PFS).

OUTLINE:

Patients receive brentuximab vedotin intravenously (IV) over 30 minutes on day 1. Treatment repeats every 21 days for 8 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 6 weeks for 1 year and then every 12 weeks thereafter.

Arms:
arm 1: Subjects receive a 30-minute IV infusion of brentuximab vedotin once every 21 days for 8 courses, in the absence of disease progression or unacceptable toxicity.

Interventions: intervention 1: Brentuximab vedotin
Intervention descriptions: intervention 1: None

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
A study of brentuximab vedotin (SGN-35) in CD30-positive systemic 
mastocytosis with or without an associated hematological clonal 
non-mast cell lineage disease (AHNMD) 
________________________________________________________ 
Principal Investigator   
Co-Principal Investigator 
Jason Gotlib, MD, MS  
Srdan Verstovsek, MD, PhD 
Associate Professor of Medicine (Hematology)  
Professor, Department of Leukemia  
Stanford Cancer Institute   
Division of Cancer Medicine, 
875 Blake Wilbur Dr, Room 2324  
The Univ. of Texas MD Anderson Cancer Center 
Stanford, CA  94305-5821  
1400 Holcombe Unit:  428 Room:  FC4.2010 
 
Houston, TX  77030  
 
  
EMAIL:  jason.gotlib@stanford.edu  
 
  
EMAIL:  sverstov@mdanderson.org  
  
Study Coordinator 
Study Coordinator    
Cristina Daniels, BS 
Andrea Linder, RN  
Stanford University School of Medicine  
Stanford University School of Medicine    
Division of Hematology  
Division of Hematology   
800 Welch Rd, FC2C46  
800 Welch Rd, FC2C44   
Palo Alto CA 94304  
Palo Alto, CA 94304 
 
 
EMAIL:  crisdan7@stanford.edu  
EMAIL:  alinder@stanford.edu  
 
Biostatistician 
Jason Gotlib, MD, MS  
Associate Professor of Medicine (Hematology) 
Stanford Cancer Institute 
875 Blake Wilbur Dr, Room 2324 
 Stanford, CA  94305-5821 
EMAIL:  Jason.gotlib@stanford.edu  
 
History: 
Original protocol: 
30 October 2012 
Protocol Amendment 1: 10 November 2013 (“version 1.1”) 
Protocol Amendment 2: 3 April 2015  
 
 
 
NCT01807598 
Date:6Dec2018


A study of brentuximab vedotin (SGN-35) in CD30-positive systemic mastocytosis with or without an associated 
hematological clonal non-mast cell lineage disease (AHNMD) 
Page 2 of 55 
Table of Contents 
 
1 
Introduction ....................................................................................................................... 10 
1.1 
Advanced systemic mastocytosis .......................................................................... 10 
1.2 
SGN-35 (brentuximab vedotin) ............................................................................. 11 
1.3       The CD30 antigen in mastocytosis ........................................................................ 13 
1.4       Study Rationale ..................................................................................................... 13 
2 
Study Objectives ................................................................................................................ 13 
2.1       Primary objectives ................................................................................................. 13 
2.2       Secondary objectives ............................................................................................. 12 
2.3      Endpoints ................................................................................................................ 14 
           2.3.1        Primary efficacy endpoint ...................................................................... 14 
           2.3.2        Secondary efficacy endpoints ................................................................. 14 
           2.3.3        Secondary safety endpoints .................................................................... 14 
3 
Investigational Plan ........................................................................................................... 15 
3.1        Overall study design ............................................................................................. 13 
3.2 
Discussion of design .............................................................................................. 15 
3.3 
Study population .................................................................................................... 15 
3.3.1 
Patient population ................................................................................. 15 
3.3.2 
Inclusion and exclusion criteria ............................................................ 15 
4    Treatment……….. .............................................................................................................. 17 
4.1 
Treatment administered (SGN-35) ........................................................................ 17 
4.2.      Investigational study drug SGN-35 ....................................................................... 17 
4.2.1 
Description ............................................................................................ 17 
4.2.2 
Dose and administration ........................................................................ 18 
4.2.3 
Required pre-medication and post-medication ..................................... 19 
4.2.4 
Management of infusion reactions ........................................................ 19 
4.2.5 
Dose modifications................................................................................ 19 
4.3 
Treatment discontinuation ..................................................................................... 22 
4.4.      Concomitant therapy ............................................................................................. 22 
            4.4.1         Cytochrome P450 Metabolism and Drug- Interactions ........................ 23 
4.5       Treatment compliance ........................................................................................... 23 
4.6       Visit schedule and assessments ............................................................................. 23 
4.6.1 
Visit and assessment schedule (see next page) ..................................... 23 
        4.7      Efficacy assessments ............................................................................................. 33 
4.7.1 
Rules for deriving the variable confirmed overall response ................. 33 
4.7.2 
Additional aspects of disease evolution ................................................ 34 
4.8       Safety assessments................................................................................................. 34 


A study of brentuximab vedotin (SGN-35) in CD30-positive systemic mastocytosis with or without an associated 
hematological clonal non-mast cell lineage disease (AHNMD) 
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            4.8.1        Laboratory evaluations .......................................................................... 34 
4.9 
Central histopathology review ............................................................................... 37 
5 
Notable laboratory value criteria, special methods and scales .......................................... 39 
6 
Data handling and record keeping ..................................................................................... 39 
        6.1      Case report forms .................................................................................................. 39    
        6.2      Source documents .................................................................................................. 39    
        6.3      Records retention ................................................................................................... 39    
        6.4      Confidentiality ....................................................................................................... 40 
7      Statistical methods ............................................................................................................ 40  
 
 7.1      Populations ............................................................................................................ 40 
 
 7.2      Background and demographic characteristics ....................................................... 40 
 
 7.3      Study medication ................................................................................................... 40 
 
 7.4      Concomitant therapy ............................................................................................. 40 
 7.5 
Primary objective-  efficacy evaluation ................................................................. 41 
        7.6      Secondary objectives ............................................................................................. 41 
                   7.6.1     Safety evaluation ...................................................................................... 41 
            7.6.2     Expression of CD30 on neoplastic mast cells .......................................... 42 
            7.6.3     Myeloproliferative Neoplasm Symptom Assessment Form 
(MPNSAF) modified for  Mast Cell Symptoms42 
7.6.4      Duration of response (DoR) and time to response (TTR) ....................... 42 
7.6.5      Progression-free survival and overall survival ........................................ 42 
7.7       Interim analyses ..................................................................................................... 43 
7.8       Sample size and power considerations .................................................................. 43 
8      Procedures and Instructions .............................................................................................. 43        
       8.1      Special safety-related procedures ........................................................................... 43 
                   8.1.1         Instructions for rapid notification of serious adverse events ................ 46  
 
            8.1.2         Instructions for rapid notification of pregnancies ................................ 47  
        8.2     Administrative procedures ...................................................................................... 47 
                   8.2.1         Changes to the protocol ........................................................................ 47  
                   8.2.2         Monitoring procedures ......................................................................... 48 
                   8.2.3         Auditing procedures ............................................................................. 48 
                   8.2.4         Handling of study medication  ............................................................. 49 
                   8.2.5         Disclosure and confidentiality .............................................................. 49  
         8.3     Ethics and good clinical practice ........................................................................... 49  
                   8.3.1         Institutional review board/independent ethics committee .................... 49  
                   8.3.2         Informed consent .................................................................................. 50  
9      References ........................................................................................................................ 51  


A study of brentuximab vedotin (SGN-35) in CD30-positive systemic mastocytosis with or without an associated 
hematological clonal non-mast cell lineage disease (AHNMD) 
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List of Tables 
Table 1  Dose reduction algorithms for non-hematologic and hematologic toxicity with 
suspected relationship to SGN-35 ..................................................................................... 21 
Table 2  Visit and assessment schedule .................................................................................... 30 
Table 3  Acceptable combinations for initial and confirmed response .................................... 33 
 
List of Appendices 
Appendix A:  Performance Status Criteria 
Appendix B:  Criteria to Diagnose Systemic Mastocytosis (SM Criteria) 
Appendix C:  Diagnostic Criteria for Aggressive SM and Mast Cell Leukemia  
Appendix D:  Mediator Drugs to Ameliorate Symptoms of Systemic Mastocytosis 
Appendix E:  List of CYP3A Inhibitors and Inducers 
Appendix F:  Myeloproliferative Neoplasms Symptom Assessment Form (MPN-SAF) with 
Mast Cell Disorder Symptoms 
Appendix G:  IWG-MRT-ECNM Response Criteria 


A study of brentuximab vedotin (SGN-35) in CD30-positive systemic mastocytosis with or without an associated 
hematological clonal non-mast cell lineage disease (AHNMD) 
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List of abbreviations 
2-CdA 
2-chlorodeoxyadenosine (cladribine) 
ADME 
Absorption, distribution, metabolism, and excretion 
AE 
adverse event 
AHNMD 
associated hematological clonal non-mast cell lineage disease 
ALT 
alanine aminotransferase/ glutamic pyruvic transaminase/GPT 
AML 
Acute Myeloid Leukemia 
ANC 
Absolute neutrophil count 
ASM 
Aggressive Systemic Mastocytosis 
AST 
aspartate aminotransferase/ glutamic oxaloacetic transaminase/GOT 
ATC 
Anatomical Therapeutic Chemical classification system 
b.i.d. 
bis in diem/ twice a day 
BM 
bone marrow 
CF 
Clinical Finding (C-Finding) 
CEL 
Chronic Eosinophilic Leukemia 
CLL 
Chronic Lymphocytic Leukemia 
CM 
Cutaneous mastocytosis 
CML 
Chronic Myeloid/ Myelogenous Leukemia 
CMML 
Chronic Myelomonocytic Leukemia 
CR 
Complete Remission 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CSR 
Clinical Study Report 
CT 
Computed Tomography 
CTCAE 
Common Toxicity Criteria for Adverse Events 
DAR 
Dosage Administration Record 
DCR 
Disease Control Rate 
DMC 
Data Monitoring Committee 
DoR 
Duration of Response 
DXA 
Dual x-ray energy assessment 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EOS 
End of Study  
EOT 
End of Treatment 
FAS 
Full Analysis Set 
FSH 
Follicular stimulating hormone 
GGT 
Gamma-Glutamyl-Transferase 
GPR 
Good Partial Response 
HES 
Hypereosinophilic Syndrome 
Hgb 
Hemoglobin 
HIV 
Human Immunodeficiency Virus 
HRQoL 
Health-related Quality of Life 
IC 
Inhibitory concentration 


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hematological clonal non-mast cell lineage disease (AHNMD) 
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ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IHC 
Immunohistochemistry 
IIT 
Investigator-initiated trial 
IN 
Investigator notification 
INF-α 
Interferon-α 
INR 
International normalized ratio 
i.v. 
intravenous(ly) 
IR 
Incomplete Remission 
IRB 
Institutional Review Board 
ISM 
Indolent Systemic Mastocytosis 
IUD 
Intrauterine device 
LDH 
Lactate dehydrogenase 
LH 
Luteinizing hormone 
MCL 
Mast Cell Leukemia 
MCS 
Extracutaneous mastocytoma 
MDS 
Myelodysplastic Syndrome 
MedDRA 
Medical Dictionary for Regulatory Activities 
MinR 
Minor Response 
MPD 
Myeloproliferative disorder 
MR 
Major Response 
MRI 
Magnetic Resonance Imaging 
MTD 
Maximum tolerated dose 
NCI 
National Cancer Institute 
NHL 
Non-Hodgkin lymphoma 
NR 
No response 
NYHA 
New York Heart Association 
o.d. 
omnia die / once a day 
ORR 
Overall Response Rate 
OS 
Overall Survival 
PCR 
Pure Clinical Response 
PD 
Progressive Disease 
PEP 
Primary Efficacy Population 
PFS 
Progression-free survival 
PK 
Pharmacokinetics 
p.o. 
per os / by mouth/ orally 
PP 
Per Protocol 
PR 
Partial Response 
PRO 
Patient-reported outcome 
PT 
Prothrombin time 
PTT 
Partial thromboplastin time 
QL 
Quality of Life 
RBC 
Red blood cells 


A study of brentuximab vedotin (SGN-35) in CD30-positive systemic mastocytosis with or without an associated 
hematological clonal non-mast cell lineage disease (AHNMD) 
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REB 
Research Ethics Board 
SAE 
Serious Adverse Event 
SCF 
Stem Cell Factor 
SD 
Stable Disease 
SOP 
Standard Operating Procedure 
SM 
Systemic Mastocytosis 
SOC 
System Organ Class 
SSC 
Study Steering Committee 
SSM 
Smouldering Systemic Mastocytosis 
TD 
Transfusion-dependent 
t.i.d. 
ter in die / three times a day 
TKI 
Tyrosine kinase inhibitor 
TSH 
Thyroid-stimulating hormone 
TTR 
Time to response 
ULN 
Upper limit of normal 
US 
Ultrasound 
VEGF 
Vascular endothelial growth factor 
WBC 
White blood cells 
 


A study of brentuximab vedotin (SGN-35) in CD30-positive systemic mastocytosis with or without an associated 
hematological clonal non-mast cell lineage disease (AHNMD) 
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FLOW CHART 
 


A study of brentuximab vedotin (SGN-35) in CD30-positive systemic mastocytosis with or without an associated 
hematological clonal non-mast cell lineage disease (AHNMD) 
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1 
Introduction 
1.1 
Advanced Systemic Mastocytosis 
Mastocytosis is a heterogeneous disease characterized by abnormal growth and accumulation 
of mast cells in one or more organ systems.  The current World Health Organization 
classification system for mast cell disease defines two major subgroups – cutaneous 
mastocytosis (CM) and systemic mastocytosis (SM) which are further divided into different 
disease variants (Vardiman et al. 2002, Valent et al. 2005, Valent et al. 2007).  
SM is a condition, defined by multifocal histological lesions in the bone marrow and other 
extracutaneous organs, together with cytological and biochemical signs of systemic disease 
(Valent et al. 2005).  SM can show either an indolent or an aggressive clinical course.  
Depending on the stage of the disease, infiltration of organs may occur with or without 
impairment of organ function and patients can shift from one category of mast cell disease 
into another.  In all categories, mediator-related symptoms may occur and may represent a 
serious clinical problem.  Infiltration of organs by mast cells may cause cytopenias, osteolysis, 
pathologic 
fractures, 
hepatosplenomegaly, 
lymphadenopathy, 
and 
malabsorption 
(Vardiman et al. 2002, Valent et al. 2005, Valent et al. 2007).  
ASM and MCL are very rare, comprising only a small proportion of all SM cases.  ASM is 
characterized by a pathologic infiltration of diverse organs by neoplastic mast cells, with 
resulting organ damage (bone marrow, liver, spleen, gastrointestinal tract, skeletal system).  
Respective clinical/laboratory findings are called 'Clinical Findings' (C-Findings).  In this 
context, mast cell infiltration with associated organomegaly only (B-Finding(s), as seen in 
SSM) but no sign of organ damage should not be regarded as C-Finding(s).  In contrast to the 
indolent forms of SM in which the patients can stay for many years or even decades with 
good prognosis, patients with the aggressive form of SM or MCL have a poor prognosis and 
are candidates for cytoreductive or targeted therapy to limit organ infiltration and further 
organ damage (Valent et al. 2005, Valent et al. 2007, Valent et al. 2007, Horny et al. 2007).  
In approximately 30% of SM patients, an AHNMD (myeloid malignancy) is diagnosed.  The 
subvariant categories of AHNMD include SM-AML (acute myeloid leukemia), SM-MDS 
(myelodysplastic syndrome), SM-MDS/MPN (MDS/myeloproliferative neoplasm, eg, chronic 
myelomonocytic leukemia), and SM-HES or SM-CEL (hypereosinophilic syndrome or 
chronic eosinophilic leukemia).  Generally, separate treatment plans for the SM and the 
AHNMD should be established for these patients.  However, the SM and AHNMD may share 
a common pathophysiologic link, and particular treatments may be useful for both the SM and 
myeloid malignancy.  Although the intent of SM-directed therapy is to target neoplastic mast 
cells, it may not always be possible to identify whether organ damage is due to the SM or 
AHNMD component or both.  Patients with CEL-associated with the FIPL1-PDGFRα fusion 
gene may exhibit increased mast cells in the bone marrow but are not classified by the WHO 
as having systemic mastocytosis.  It is recommended that such patients be treated with 
imatinib (Valent et al. 2007) and would not be considered eligible for this protocol. 
The most important growth factor for mast cells seems to be stem cell factor (SCF) also 
termed mast cell growth factor or KIT ligand.  SCF induces the development of mast cells 
from their uncommitted CD34+ progenitors.  The effects of SCF on mast cells and mast cell 


A study of brentuximab vedotin (SGN-35) in CD30-positive systemic mastocytosis with or without an associated 
hematological clonal non-mast cell lineage disease (AHNMD) 
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progenitors are mediated through KIT, a tyrosine kinase receptor (for SCF) encoded by the 
KIT proto-oncogene.  SCF and SCF-dependent activation of KIT are essential to the 
development and differentiation of mast cells.  “Gain-of-function mutations” in the kinase 
domain of KIT are associated with enhanced growth of mast cells and their progenitors.  Such 
mutations (eg, D816V) are frequently detected in patients with SM (Valent et al. 2005).  
Specific gene defects are well recognized as the oncogenic factors in SM.  The KIT D816V 
mutation expressed in neoplastic mast cells is by far the most common and is found in all 
variants of SM.  Highly sensitive methods have detected that >90% of patients with SM carry 
the D816V KIT mutation.  Several other KIT gene defects have been identified in patients 
with mast cell disease, but each are likely to be present in less than 5% of diagnosed patients 
(Sotlar et al. 2003, Garcia-Montero et al. 2006, Valent et al. 2005).  
Treatments for SM can be divided into two broad categories (1) those intended to control mast 
cell mediator-related symptoms (eg, antihistamines, epinephrine, or corticosteroids) and (2) 
those intended to limit the MC burden (eg, cytoreductive or targeted therapies).  Due to the 
heterogeneous nature of the disease an individualized approach to the treatment strategy is 
indicated.  To date, there is no approved standard therapy to treat SM available and there are 
only limited options for the treatment of ASM and MCL with the exception of imatinib being 
approved in the US in KIT D816V negative patients or those in whom KIT mutation status is 
unknown.  
Interferon-α (IFN-α) combined with or without corticosteroids, or cladribine can elicit 
response rates in approximately 40% of patients, but almost all are partial in nature and 
short-lived and limited tolerability led to early discontinuation of treatment in some cases 
(Kluin-Nelemans HC et al. 1992, Worobec et al, 1996, Butterfield JH, et al 1998, Tefferi 
A, et al. 2001, Kluin-Nelemans, et al. 2003, Casassus P, et al. 2002, Hauswirth et al. 2004, 
Akin and Metcalfe, 2004, Valent et al. 2007).  In ongoing clinical trials, the KIT inhibitor 
midostaurin can inhibit the imatinib-resistant D816V KIT mutation in vitro, and has shown 
preliminary encouraging efficacy in patients with ASM/MCL with a 38% major response rate 
per Valent Criteria (Gotlib et al, 2010).  
1.2 
SGN-35 (brentuximab vedotin)  
 
Brentuximab vedotin (SGN-35) is a CD30-directed antibody-drug conjugate (ADC) 
consisting of three components:  1) the antibody cAC10, specific for human CD30, 2) the 
highly potent antimicrotubule agent monomethyl auristatin E (MMAE), and 3) a 
protease-cleavable linker that covalently attaches MMAE to cAC10.  The biological activity 
of brentuximab vedotin results from a multi-step process.  Binding of the ADC to CD30 on 
the cell surface initiates internalization of the ADC-CD30 complex, which then traffics to the 
lysosomal compartment.  Within the cell, a single defined active species, MMAE, is released 
via proteolytic cleavage.  Binding of MMAE to tubulin disrupts the microtubule network 
within the cell, induces cell cycle arrest, and results in apoptotic death of the CD30-expressing 
tumor cell. 
 
 
Two phase 2 studies evaluating the efficacy and safety of brentuximab vedotin as a single 
agent were performed in patients with relapsed or refractory Hodgkin lymphoma (HL) and 
systemic anaplastic large cell lymphoma (ALCL).  In the pivotal phase 2 study of relapsed or 


A study of brentuximab vedotin (SGN-35) in CD30-positive systemic mastocytosis with or without an associated 
hematological clonal non-mast cell lineage disease (AHNMD) 
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refractory HL, 75% of patients had an objective response (complete or partial remission) with 
median duration of approximately 7 months.  One-third of patients achieved a complete 
response (CR).  In the phase 2 study of relapsed or refractory systemic ALCL, the objective 
response rate (ORR) was 86%.  Due to few events of progression or death, the median 
duration of objective response was not estimable; however, the lower limit of the 95% 
confidence interval (CI) was 36 weeks.  Over 50% of patients achieved a CR.  Nearly all 
patients (>90%) in both studies experienced a reduction in tumor volume.  
Treatment-emergent adverse events (AEs) occurring in ≥20% of HL and systemic ALCL 
patients in the phase 2 studies were peripheral sensory neuropathy (44%), fatigue (42%), 
nausea (41%), diarrhea (34%), pyrexia (31%), upper respiratory tract infection (28%), 
neutropenia (21%), and vomiting (20%).  These events were primarily Grade 1 or 2, with the 
exception of neutropenia, for which Grade 3 and Grade 4 events were reported for 13% and 
7% of patients, respectively.  Similar patterns and incidences of AEs were generally observed 
for HL and ALCL patients. 
 
Following the recommended intravenous (IV) dose of 1.8 mg/kg every 3 weeks, maximum 
concentrations were typically observed at the end of infusion.  A multi-exponential decline in 
brentuximab vedotin antibody-drug conjugate (ADC) serum concentrations was observed 
with a terminal half-life of approximately 4 to 6 days.  Exposures were approximately dose 
proportional.  After multiple-dose administration of brentuximab vedotin, steady-state was 
achieved by 21 days, consistent with the terminal half-life estimate.  Minimal to no 
accumulation was observed with multiple doses at the q3wk (every 3 weeks) schedule. 
 
The primary treatment-related effects of repeat-dose brentuximab vedotin administration to 
rats and monkeys, bone marrow hypocellularity and lymphoid depletion, and the associated 
decreases in peripheral blood cells are consistent with pharmacologic disruption of 
microtubules caused by MMAE.  Repeat-dose administration of MMAE caused qualitatively 
similar effects while no adverse effects were associated with the repeat-dose administration of 
cAC10.  The no-observed-adverse-effect level (NOAEL) for repeat-dose administration of 
brentuximab vedotin was 0.5 and 1 mg/kg in rat and monkey, respectively.  The highest 
non-severely toxic dose (HNSTD) for repeat-dose administration of brentuximab vedotin was 
5 and 3 mg/kg in rat and monkey, respectively.  In up to one-month repeat-dose toxicity 
studies of brentuximab vedotin in rats at doses up to 15 mg/kg, the following target organs 
were identified:  bone marrow (hypocellularity), thymus (lymphoid depletion), spleen 
(lymphoid depletion), liver (focal coagulative necrosis), intestine (single cell necrosis), testis 
(seminiferous tubular degeneration), and lung (alveolar histiocytosis) in rat only.  Following a 
4-week recovery period, all target organ toxicity was reversible except for testicular toxicity.  
Testicular toxicity in rat was partially resolved following a 16-week off-treatment recovery 
phase (Seattle Genetics, 2010).  
 
1.3 
The CD30 Antigen in Mastocytosis 
 
CD30, a member of the TNF-receptor (TNF-R) superfamily, is a transmembrane glycoprotein 
receptor and is normally found on the surface of activated T cells but has also been detected 


A study of brentuximab vedotin (SGN-35) in CD30-positive systemic mastocytosis with or without an associated 
hematological clonal non-mast cell lineage disease (AHNMD) 
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on a variety of cell types of hematopoietic origin.  The CD30 antigen has a very low 
expression on normal cells but is found on the Hodgkin Reed-Sternberg (RS) cells of HL and 
on ALCL and other T cell lymphoproliferative disorders.  While the function of CD30 has not 
been clearly defined, CD30 has been implicated both in cell death and proliferation(Wahl 
2002).  The utility of CD30 as a diagnostic marker for malignancies, including HL and ALCL, 
its limited normal tissue expression profile, and its apoptosis-inducing characteristics have led 
to the investigation of this antigen as a target for immunotherapy. 
Investigators Drs. Karl Sotlar, Hans-Peter Horny, and Peter Valent and colleagues recently 
identified expression of CD30 in neoplastic mast cells in the majority of patients with 
advanced SM (11/13, 85%), whereas in most patients with indolent SM, few of the neoplastic 
mast cells expressed CD30 (Sotlar et al. 2011, Valent et al. 2011).  The mast cell leukemia 
cell line HMC-1, derived from a patient with aggressive SM also expressed CD30.  CD30 was 
not expressed in bone marrow biopsy samples from patients with reactive mast cell 
hyperplasia or other myeloid neoplasms.  CD30 expression has been observed in some 
myeloid neoplasms (AML). 
1.4 
Study Rationale 
 
Advanced forms of systemic mastocytosis (eg, aggressive systemic mastocytosis [ASM] and 
mast cell leukemia [MCL] with or without an AHNMD) represent a large unmet need.  In 
order to address the challenge of these mast cell disorders, SGN-35 will be assessed in SM 
patients who express the CD30 antigen on their neoplastic mast cells.  
2 
Study Objectives 
2.1 
Primary Objective 
 
To evaluate the response rate to SGN-35 in patients with CD30+ advanced SM (ASM or 
MCL with or without an AHNMD).  
2.2 
Secondary Objectives 
 
1.  To evaluate the tolerability and safety profile of SGN-35 in patients with SM 
2.  To evaluate expression of CD30 on neoplastic mast cells before and during therapy with 
SGN-35  
3.  To evaluate changes in mastocytosis related symptom scores and QOL using a modified 
Myeloproliferative Neoplasm Symptom Assessment Form (MPNSAF) (Scherber et al, 2011) 
4.  To evaluate the duration of response (DoR) and time to response (TTR) 
5.  To evaluate progression-free survival (PFS) and overall survival 
2.3 
Endpoints 
2.3.1 
Primary Efficacy Endpoint 
 


A study of brentuximab vedotin (SGN-35) in CD30-positive systemic mastocytosis with or without an associated 
hematological clonal non-mast cell lineage disease (AHNMD) 
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The primary efficacy endpoint is the overall response rate per consensus international 
response criteria (rate of complete + partial remissions + clinical improvement) (see Appendix 
G).  Response rate per Valent response criteria may be evaluated as part of an exploratory 
analysis. 
2.3.2 
Secondary Efficacy Endpoints 
 
 Immunohistochemical expression of CD30 on neoplastic mast cells in core biopsy 
samples or by flow before SGN-35 treatment and after 4 and 8 cycles of therapy  
 Total symptom score and QOL score using a modified Myeloproliferative Neoplasm 
Symptom Assessment Form (MPN-SAF) 
 Duration of response (DoR) is defined as the time from first onset of confirmed 
response to the date of first documented and confirmed progression or death due to 
ASM/MCL.  Time to response (TTR) is defined as the time from start of treatment 
until the date of onset of  a confirmed response 
 Progression-free survival (PFS) is defined as the time from start of treatment to the 
date of the first documented and confirmed progression or death or institution of new 
therapy  
2.3.3 
Secondary Safety Endpoints 
 Type, incidence, severity, seriousness, and relatedness of adverse events 
 Laboratory abnormalities 
3. 
Investigational Plan 
3.1 
Overall study design 
 
This is a phase II study designed to evaluate whether there is a signal of efficacy of SGN-35 
in patients with CD30+ advanced SM.  Advanced SM is defined as ASM or MCL with or 
without an AHNMD. 
3.2 
Discussion of design 
 
Patients will receive open label SGN-35 at a starting dose of 1.8 mg/kg administered as a 
single IV infusion as on Day 1 of each 21-day cycle as an outpatient.  Patients will be treated 
for eight 21-day cycles.   The best response per international response criteria will be recorded 
by the end of cycle 8.  Because responses must last at least 12 weeks, any clinical 
improvement (CI), partial response (PR), or CR response that commences by the of end of 
cycle 8, and either persists or evolves into a higher quality response for at least 12 weeks will 
be counted as a response.  Patients who demonstrate a response and subsequently meet criteria 
for loss of response (LOR) will be permitted to undergo re-staging and re-treatment with up to 
an additional 8 cycles of SGN-35.  


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3.3 
Study population 
3.3.1 
Patient population 
Patients must have screening evaluations performed within 28 days prior to the first dose of 
study drug and must meet all inclusion and exclusion criteria.  If some histopathologic studies 
for mast cell disease were performed within 3 months prior to signing the consent, such 
material can be used in place of or to complement histopathologic studies for screening after 
discussion between Drs. Gotlib, Verstovsek, and George to ensure sufficient quality and 
quantity of sample for central histopathologic review and testing.  However, any 
histopathologic studies that were not performed should be undertaken during the screening.  
The Principal Investigator or his/her designee prior to enrollment must review results of all 
evaluations, ensuring that all inclusion and exclusion criteria have been satisfied, including 
central histopathology.  In addition, the patient must be thoroughly informed about the study, 
including the visit schedule and required evaluations.  The written informed consent must be 
obtained prior to enrollment. 
3.3.2 Inclusion and exclusion criteria 
Inclusion criteria 
 Aged ≥ 18 years of age  
 Patient must give written informed consent 
 ECOG performance status of 0-3  (Appendix A) 
 Life expectancy > 12 weeks 
 Meeting the following laboratory values: 
 AST and ALT  2.5 x Upper Limit of Normal (ULN) (Exception:    5 x ULN, 
if elevation is considered related to ASM/MCL) 
 Serum direct bilirubin  1.5 x ULN; if considered related to ASM/MCL  3 x 
ULN 
 Serum creatinine  2.0 mg/dL  
 Creatinine clearance (CrCl) ≥ 30 mL/min  
 
 A diagnosis of SM per 2008 WHO Criteria (see Appendix B) 
 Neoplastic mast cells must express CD30 by immunohistochemistry or flow cytometry 
(histopathologic determination made centrally by Dr. Tracy George) 
 Patients with ASM and MCL (diagnostic criteria in Appendix C) with or without an 
AHNMD are required to have at least one of the eligible organ damage findings as defined 
by the international consensus response criteria  
 Both females of childbearing potential and males who have partners of childbearing 
potential must agree to use an effective contraceptive method during the study and for 30 
days following the last dose of study drug. 
 Females of childbearing potential must have a negative serum or urine B-hCG pregnancy 
test result within 7 days prior to the first dose of SGN-35.  Females of non-childbearing 


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potential are those who are postmenopausal greater than 1 year or who have had a bilateral 
tubal ligation or hysterectomy. 
Exclusion criteria 
 Patients unwilling or unable to comply with the protocol. 
 Any other concurrent severe known disease (except carcinoma in-situ) concurrent 
severe and/or uncontrolled medical condition (eg, uncontrolled diabetes, or active 
uncontrolled infection) which could compromise participation in the study.  
 History of another primary malignancy that has not been in remission for at least 3 
years.  (The following are exempt from the 3-year limit: non-melanoma skin cancer, 
fully excised melanoma in situ [Stage 0], curatively treated localized prostate cancer, 
and cervical carcinoma in situ on biopsy or a squamous intraepithelial lesion on PAP 
smear.) 
 Patients with cardiovascular disease including congestive heart failure Grade 3 or 4 
according to the NYHA classification, left ventricular ejection fraction of < 50%, 
myocardial infarction within previous 6 months and poorly controlled hypertension.  
 Women who are pregnant or lactating. 
 Patients with ≥ Grade 2 neuropathy 
 Patients with a known hypersensitivity to any excipient contained in the drug 
formulation. 
 Confirmed prior diagnosis of HIV infection or active viral hepatitis. 
 Patients presenting with an AHNMD requiring immediate cytoreductive therapy or 
targeted drugs (eg, AML). 
 Patients who have received any investigational agent, chemotherapy, interferon-, or 
2-chlorodeoxyadenosine (2-CdA, cladribine) within 30 days prior to Day 1.  
 Patients who have received hematopoietic growth factor support within 14 days of 
Day 1 of SGN-35 
 Use of prednisone (or equivalent corticosteroid dose) for SM up to 10 mg/day or its 
equivalent is allowed, but it cannot have been started during screening.  Patients who 
are on prednisone up to 10 mg/day for medical problems unrelated to SM are also 
permitted on study. 
 Patients with the FIP1L1-PDGFRα fusion even with resistance to imatinib (such 
patients are no longer defined as systemic mastocytosis by the WHO). 
 Patients who have received any treatment with SGN-35 prior to study entry. 
 Patients who have had any surgical procedure, excluding central venous catheter 
placement or other minor procedures (eg, skin biopsy) within 14 days of Day 1. 
 Prior treatment with bleomycin 
4 
TREATMENT 
4.1 
Treatment Administered (SGN-35) 
 


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Investigational drug will be supplied in an open-label manner.  Details of study treatment 
preparation, administration, and storage are described in the Pharmacy Manual. 
4.2 
Investigational Study Drug SGN-35 
4.2.1 
Description 
Brentuximab vedotin is an ADC composed of a CD30-targeted chimeric monoclonal antibody 
(cAC10) that is covalently linked, via an enzyme-cleavable linker, to the anti-tubulin agent 
MMAE.  cAC10 has a typical structure of the human IgG1 subclass.  Brentuximab vedotin is 
produced by the chemical conjugation of MMAE to cAC10.  Each antibody molecule has, on 
average, two of its interchain disulfides reduced and the resulting cysteine residues alkylated 
with SGD-1006 Intermediate (enzyme-cleavable inker + MMAE), leading to a molar ratio of 
4 drug molecules per antibody. 
Brentuximab vedotin is a heterogeneous mixture of a range of drug-load variants and 
isoforms.  The overall average drug-to-antibody mole ratio (MRD) is approximately 4.  The 
calculated molecular mass for the nominal form of brentuximab vedotin is approximately 
153 kDa. 
Pharmaceutical Properties  
4.2.1.1.  Pharmaceutical properties.  Brentuximab vedotin is a sterile, preservative-free, white 
to off-white lyophilized cake or powder, supplied in single-use vials.  Brentuximab vedotin 
drug product is reconstituted with water for injection (WFI), United States Pharmacopeia 
(USP).  The reconstituted brentuximab vedotin drug product is a clear to slightly opalescent, 
colorless solution with no visible particulate matter.  The reconstituted solution is 
subsequently diluted in sterile 0.9% Sodium Chloride for Injection, USP, 5% Dextrose 
Injection USP, or Lactated Ringer’s Injection USP, for IV administration. 
Brentuximab vedotin is the USAN and the INN assigned to SGN-35.  Drug product vials may 
be labeled as SGN-35 or as brentuximab vedotin;  the 2 names can be used interchangeably. 
4.2.1.2.  Formulation.  Each vial contains brentuximab vedotin, trehalose, sodium citrate, and 
polysorbate 80.  The drug product vial is reconstituted with the appropriate amount of Sterile 
Water for Injection.  The pH of reconstituted product is approximately 6.6. 
4.2.2 Dose and Administration 
Study treatment must not be administered as an IV push or bolus.  Study treatment will 
be administered by outpatient IV infusion given over approximately 30 minutes on Day 1 of 
each 21-day cycle.  In the absence of infusion toxicities, the infusion rate for all patients 
should be calculated in order to achieve a 30-minute infusion period.  Study treatment will be 
administered through a dedicated IV line and cannot be mixed with other medications. 
 
The dose of study treatment is 1.8 mg/kg.  Chemical and physical stability of the reconstituted 
brentuximab vedotin drug product has been demonstrated for 24 hours.  Opened and 
reconstituted vials should be used immediately.  If not used immediately, the in-use storage 
should not be longer than 24 hours.  In case infusion is interrupted, the interruption cannot be 
more than 24 hrs from the time of reconstitution of the drug.  


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Patients with treatment-associated Grade 2 peripheral neuropathy will follow dose 
modification as specified in Table 1 in Section 4.2.5.  Dosing is based on patient weight on 
Cycle 1 Day 1 according to the institutional standard;  however, doses will be adjusted for 
patients who experience a ≥ 10% change in weight from baseline.  Actual weight will be used 
except for patients weighing greater than 100 kg; dose will be calculated based on 100 kg for 
these individuals.  The dose will be rounded to the nearest whole number of milligrams 
(Seattle Genetics, 2010). 
 
Patients will be observed on day 1 for close monitoring of potential side effects of drug 
therapy and/or disease-related symptoms due to mast cell mediator release (eg, hypotension, 
anaphylactic shock) for at least 60 minutes after completion of the infusion.  Intensive care 
equipment (eg, crash cart) and/or facilities must be readily available for these trial patients.  
 
4.2.3 Required Pre-medication and Post-medication 
Routine premedication should not be administered prior to the first dose of study treatment. 
However, patients who experience a Grade 1 or 2 infusion-related reaction may receive 
subsequent study treatment with premedication as described in Section 4.2.4 below. 
 
4.2.4 Management of Infusion Reactions 
Infusion-related reactions may occur during the infusion of study treatment.  The infusion is 
to be administered at a site properly equipped and staffed to manage anaphylaxis should it 
occur.  The patient should be observed for at least 60 minutes following the first infusion of 
study treatment.  During this observation period, the IV line should remain open for at least 1 
hour to allow administration of IV drugs if necessary.  All supportive measures consistent 
with optimal patient care will be given throughout the study according to institutional 
standards.  This includes adjusting the infusion time if necessary.  Medications for 
infusion-related reactions should be readily available.  
 
Patients who experience a Grade 1 or 2 infusion-related reaction may receive premedication 
for the current or future potential infusion reactions consisting of acetaminophen(650 mg 
orally) and diphenhydramine (25 to 50 mg orally or 10 to 25 mg IV) or according to 
institutional standards, administered 30 to 60 minutes prior to each 30-minute infusion.  
 
4.2.5 Dose Modifications 
 
Intra-patient dose reduction to 1.2 mg/kg will be allowed depending on the type and severity 
of toxicity.  Table 1 describes the recommended dose modifications for study 
treatment-associated toxicity (toxicity with suspected relationship to SGN-35). 
 
Peripheral Neuropathy:  Peripheral neuropathy should be managed using a combination of 
dose delay and reduction to 1.2 mg/kg.  For new or worsening Grade 2 or 3 neuropathy, 
dosing should be held until neuropathy improves to Grade 1 or baseline and then restarted at 
1.2 mg/kg.  For Grade 4 peripheral neuropathy, SGN-35 should be discontinued. 
 


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Neutropenia:  Neutropenia should be managed by dose delays and reductions.  The dose of 
SGN-35 should be held for Grade 3 or 4 neutropenia until resolution to baseline or Grade 2 or 
lower.  Growth factor support should be considered for subsequent cycles in patients who 
experience Grade 3 or 4 neutropenia.  In patients with recurrent Grade 4 neutropenia despite 
the use of growth factors, discontinuation or dose reduction of SGN-35 to 1.2 mg/kg may be 
considered. 
 
Acute Pancreatitis:  Acute pancreatitis has been identified as an important potential risk 
associated with brentuximab vedotin dosing.  Dosing should be held until a diagnosis of acute 
pancreatitis has been excluded if clinically suspected. 
 
The start of the next cycle may be delayed for up to 30 days if additional time is required for 
the patient to recover from study treatment-associated toxicity experienced during the current 
cycle (Table 1).  Delays of greater than 30 days are prohibited without approval of the 
Principal Investigator of the entire study, Dr. Jason Gotlib. 
Doses reduced for treatment-related toxicity should not be re-escalated. 
 
If 4 out of the 11 patients experience emergent drug-related Grade 3 or 4 non-hematologic 
toxicity, the study will be placed on hold for safety review, and if restarted upon study 
amendment, the starting dose of therapy for subsequent patients would be no more than 
1.2 mg/kg. 
 


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Table 1.  Dose Reduction Algorithms for Non-Hematologic and Hematologic Toxicity With Suspected Relationship to SGN-35 
Toxicity 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Non-Hematologic 
Continue at 
same dose 
level.  
Continue at same dose level, except in the 
event of Grade 2 neuropathy. 
 
For Grade 2 neuropathy, withhold dose 
until toxicity is ≤ Grade 1 or has returned to 
baseline, then reduce the dose to 1.2 mg/kg 
and resume treatment. 
 
If Grade 2 neuropathy recurs at a dose of 
1.2 mg/kg, the patient should be 
discontinued from study. 
Withhold dose until toxicity is ≤ Grade 1 or has returned to 
baseline, then resume treatment at the same dose level. a 
 
If the toxicity has not returned to ≤ Grade 1 after holding the 
dose for 30 days, then the patient should be discontinued from 
the study. 
 
If the same Grade 3 toxicity recurs, withhold dose until 
toxicity is ≤ Grade 1 or has returned to baseline, then reduce to 
the 1.2 mg/kg/level. a   
 
For patients with recurrence of the same Grade 3 toxicity, the 
patient should be discontinued from the study. 
 
For Grade 3 neuropathy, withhold dose until toxicity is 
≤ Grade 1 or has returned to baseline, then reduce the dose to 
1.2 mg/kg and resume treatment. 
 
If Grade 3 neuropathy recurs at a dose of 1.2 mg/kg, the 
patient should be discontinued from study. 
Withhold dose until toxicity is ≤ Grade 1 or 
has returned to baseline, then reduce dose to 
1.2 mg/kg and resume treatment. a 
 
If the toxicity has not returned to ≤ Grade 1 
after holding the dose for 30 days, then the 
patient should be discontinued from the 
study 
 
For patients with recurrence of the same 
Grade 4 toxicity at a dose of 1.2 mg/kg, the 
patient should be discontinued from the 
study 
 
For Grade 4 neuropathy, SGN-35 should be 
discontinued. 
Hematologic 
Continue at 
same dose 
level. 
Continue at same dose level. 
 
 The dose of SGN-35 should be held for Grade 3 or 4 neutropenia until resolution to baseline or Grade 2 
or lower.  Growth factor support should be considered for subsequent cycles in patients who experience 
Grade 3 or 4 neutropenia.  In patients with recurrent Grade 4 neutropenia despite the use of growth 
factors, discontinuation or dose reduction of SGN-35 to 1.2 mg/kg may be considered. 
 Dose interruption for anemia will not be undertaken.  If patients have Grade 2 to 3 of these events at 
baseline only Grade 4 cytopenias suspected to be related to study drug will be considered as hematologic 
toxicity. b  Obtain weekly labs until lab returns to baseline or Grade 2.   
 G-CSF for treatment of neutropenic fever may be used, but not for treatment of neutropenia alone, nor 
for infection prophylaxis in the setting of neutropenia. 
 
a Patients who develop emergent Grade 3 or 4 electrolyte laboratory abnormalities will have the dose of SGN-35 reduced to 1.2 mg/kg in subsequent cycles.  If the same Grade 3 or 4 
electrolyte abnormalities re-occur, SGN-35 will be discontinued. 
b Patients who develop Grade 3 or 4 lymphopenia may continue study treatment without interruption. 


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4.3 
Treatment Discontinuation 
Any patient discontinuing study medication prematurely must have the reason categorized on 
the CRF as one of the following: 
1. adverse event(s) 
2. abnormal laboratory value(s) 
3. abnormal test procedure result(s) 
4. unsatisfactory therapeutic effect 
5. subject's condition no longer requires study treatment 
6. protocol violation 
7. subject withdrew consent 
8. lost to follow-up 
9. administrative problems 
10. death 
Patients who discontinue the study due to a study drug-related adverse event must be followed 
weekly for four weeks, or until resolution or stabilization of the event, whichever occurs first. 
Patients discontinuing prematurely are to be followed every 6 months for survival until study 
closure or death of the patient. 
4.4 
Concomitant therapy 
In general, the use of any concomitant medication/therapies deemed necessary for patient 
supportive care and safety are permitted provided they are documented in the patient records.  
A list of medications which may be used to treat mediator-related symptoms are listed in 
Appendix D.  All medications taken within 30 days of the first dose of study drug and all 
concomitant medications/therapies must be recorded on the Concomitant/Non-Drug Therapy 
CRF.  
 
Women will avoid breast-feeding, and all women of childbearing potential will be required to 
use barrier contraception for the duration of the study and for 3 months post study. 
 
Other anti-cancer agents including chemotherapy, radiation therapy, or biologic response 
modifiers are not permitted during the study.  No other investigational drug is allowed during 
the study.  Hematopoietic growth factors are not permitted during study (except G-CSF for 
neutropenic fever).  Prophylaxis may be used for the prevention of nausea and vomiting and is 
at the discretion of the investigator.  
 
Other anti-cancer agents including chemotherapy, radiation therapy, or biologic response 
modifiers are not permitted during the study.  The exception is the use of hydroxyurea to 
control a proliferative leukocyte count related to a concurrent myeloid neoplasm (eg, CMML, 
or other MDS/MPN, or MPN associated with advanced SM).  No other investigational drug is 
allowed during the study.  Hematopoietic growth factors are not permitted during the study 


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(except G-CSF for neutropenic fever).  The exception is the use of erythropoiesis stimulating 
agents (with or without IV iron) in patients who are Jehovah’s witnesses and for religious 
reasons are not permitted to undergo treatment with blood products.  Prophylaxis may be used 
for the prevention of nausea and vomiting and is at the discretion of the investigator.  
 
During treatment with SGN-35, glucocorticoids can be used in the event of appropriate need, 
as outlined in Appendix D, “Mediator Drugs to Ameliorate Symptoms Related to Systemic 
Mastocytosis.”   
4.4.1 
Cytochrome P450 Metabolism and Drug- Interactions 
 
Because SGN-35 is primarily metabolized by CYP3A enzymes, any drug known to inhibit or 
induce CYP3A4 will likely interact with SGN-35.  The extent is normally more profound with 
CYP3A4 inhibitors than with inducers.  Where possible, investigators should refrain from 
choosing to administer CYP3A4/5 inducers to patients on study prior to initiation, and during 
treatment with SGN-35.  In particular, investigators should NOT give the combination of two 
such agents in patients receiving SGN-35, such as antifungal azoles plus erythromycin or 
azithromycin.  In addition, prior to initiation of SGN-35, and during treatment, concomitant 
use of the following CYP3A4 substrates is discouraged: alprazolam, astemazole, 
atorvastastin, cervistatin, chlorpheniramine, diazepam, indinavir, lovastatin, midazolam, 
nelfinavir, progesterone, ritonavir, saquinavir, tacrolimus, terfenadine, triazolam, and the 
CYP3A4 inducers modafinil, rifabutin, and rifampin.  A list of inhibitors and inducers is 
provided in Appendix E. 
4.5 
Treatment compliance 
Records of study drug used, doses, and intervals between visits will be kept during the study.  
Where appropriate, patients will receive treatment with study drug as outpatients.  Patients 
will be asked to record any symptoms experienced as well as other medications taken.  Dosing 
information for SGN-35 must be documented.  Any change of dose, missed doses or dose 
interruptions must be recorded.  
4.6 
Visit schedule and assessments 
4.6.1 
Visit and assessment schedule (see next page) 
Evaluations  
Pretreatment (Screening) 
 Complete medical history including transfusion history in prior 12 weeks 
 Prior and current medication list 
 Physical exam with spleen measurement  
 ECOG performance status 
 Vital signs (temperature, heart rate, breathing rate, blood pressure, height, weight) 
 12 lead ECG 


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 Magnetic resonance imaging (MRI) or computed tomography (CT) scan of the 
abdomen/pelvis with and without contrast including 3D spleen and liver volumes 
 Bone marrow aspirate and biopsy with cytogenetics, flow cytometry, KIT mutation 
status 
 Chest x-ray (2 views PA and lateral) 
 MPN-SAF modified for mast cell symptoms 
 Hematology, chemistries/liver function tests, serum tryptase, PT, PTT (Please refer to 
section 4.8.1 for detailed lab evaluations) 
 Pregnancy test (women of child bearing potential) 
Day 1 of Cycles 1 to 8 (+/- 3 days): 
 Evaluate for adverse events  
 Interval medical history including transfusion history 
 Physical exam, including measurement of your spleen, weight, and vital signs 
 Current medications 
 ECOG performance status  
 MPN-SAF modified for mast cell symptoms 
 Hematology, chemistries/liver function tests (with phosphorus on Cycle 1 Day 1 only), 
serum tryptase, PT, PTT (Please refer to section 4.8.1 for detailed lab evaluations) 
 Pregnancy test (women of child bearing potential) 
 Drug infusion 
 Response assessment per IWG-MRT-ECNM criteria (starts Cycle 2 Day 1) 
 
For Cycle 5 Day 1 (End of cycle 4) also need to complete the following: 
 MRI or a CT scan of the abdomen/pelvis with and without contrast including 3D 
spleen and liver volumes 
 Chest X-ray-2 views PA and lateral (only if disease-related finding(s) were found at 
baseline) 
 Bone marrow aspirate and biopsy with cytogenetics, flow cytometry, KIT mutation 
status 
Phosphorus will be additionally done on Cycle 1 Day 1;  Cycle 1 Day 3;  and 
Cycle 1 Day 8 only, for complete evaluation of tumor lysis. 
 


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Day 3 of Cycle 1  
 Serum chemistries/liver function tests and  phosphorus 
 Evaluate for adverse events  
 
Days 8 and 15 of Cycle 1 (+/- 3 days) 
 Evaluate for adverse events  
 Hematology 
 Serum chemistries/liver function tests and  phosphorus 
 
Day 10 of Cycles 2-8 (+/- 3 days) 
 Hematology 
 Evaluate for adverse events  
 
End-of-Treatment (End of Cycle 8) Visit  
 Evaluate for adverse events  
 Interval medical history including transfusion history 
 Current medications 
 Physical exam, including measurement of spleen, weight, and vital signs  
 ECOG performance Status  
 MPN-SAF modified for mast cell symptoms 
 Hematology, chemistries/liver function tests, serum tryptase, PT, PTT (Please refer to 
section 4.8.1 for detailed lab evaluations) 
 Pregnancy test (women of child bearing potential)   
 MRI or CT of abdomen/pelvis with and without contrast including 3D spleen and liver 
volumes 
 Chest x-ray 2 views - PA and lateral (only if disease  related finding(s) were found at 
baseline) 
 Bone marrow aspirate and biopsy with cytogenetics, flow cytometry, KIT mutation 
status 
 Response assessment per IWG-MRT-ECNM criteriaDrug Accountability  
 
End of Study (EOS) Visit - if no response to the study drug after 8 cycles of treatment, 
one follow-up visit about 30 days after the end-of-treatment visit  
 Evaluate for adverse events  


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 Interval medical history including transfusion history 
 Current medications 
 Physical exam, including measurement of spleen, weight, and vital signs  
 ECOG performance status  
 MPN-SAF modified for mast cell symptoms 
 Hematology, chemistries/liver function tests, serum tryptase (Please refer to 
Section 4.8.1 for detailed lab evaluations) 
 Pregnancy Test (women of child bearing potential) 
 Response assessment per IWG-MRT-ECNM criteria 
 
Follow-up visits - if patient did exhibit a response to the study drug after 8 cycles of 
treatment according to protocol response criteria, follow-up visits and labs every 6 weeks 
until 48 weeks from beginning of treatment will occur, then every 12 weeks. 
 Evaluate for adverse events  
 Interval medical history including transfusion history 
 Current medications  
 Physical exam, including measurement of spleen, weight, and vital signs  
 ECOG performance status  
 MPN-SAF modified for mast cell symptoms 
 Hematology, chemistries/liver function tests, serum tryptase (Please refer to 
Section 4.8.1 for detailed lab evaluations) 
 Bone Marrow aspirate and biopsy, cytogenetics, flow cytometry, KIT mutation status 
(at week 48, then every 24 weeks) 
 MRI or CT of abdomen/pelvis with and without contrast including 3D spleen and liver 
volumes (at week 48, then every 24 weeks) 
 Drug accountability 
 Response assessment per IWG-MRT-ECNM criteria 
 
Re-Staging if Loss of Response (LOR) (Day -21 to Day -1) 
 Interval medical history including transfusion history 
 Current medication list 
 Physical exam with spleen measurement  
 ECOG performance Status 
 Vital signs (temperature, heart rate, breathing rate, blood pressure, weight) 


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 Magnetic resonance imaging (MRI) or computed tomography (CT) scan of the 
abdomen/pelvis with and without contrast including 3D spleen and liver volumes 
 Bone marrow aspirate and biopsy with cytogenetics, flow cytometry, KIT mutation 
statusChest x-ray (2 views – PA and lateral) 
 MPN-SAF modified for mast cell symptoms 
 Hematology, chemistries/liver function tests, serum tryptase, (Please refer to section 
4.8.1 for detailed lab evaluations) 
 Pregnancy test (women of child bearing potential) 
 Evaluate for adverse events  
 
Re-Treatment Cycles 9 – 16 for patients who exhibit loss of response 
 Repeat schedule of original cycles 1, and 2-8 except coags 
End-of-Re-treatment (End of Cycle 16) Visit  
 Evaluate for adverse events  
 Interval medical history including transfusion history 
 Current medications 
 Physical exam, including measurement of spleen, weight, and vital signs  
 ECOG performance Status  
 MPN-SAF modified for mast cell symptoms 
 Hematology, chemistries/liver function tests, serum tryptase, PT, PTT (Please refer to 
section 4.8.1 for detailed lab evaluations) 
 Pregnancy test (women of child bearing potential)   
 MRI or CT of abdomen/pelvis with and without contrast including 3D spleen and liver 
volumes 
 Chest x-ray (2 views-PA and lateral) (only if disease  related finding(s) were found at 
re-staging) 
 Bone marrow aspirate and biopsy with cytogenetics, flow cytometry, KIT mutation 
status 
 Response assessment per IWG-MRT-ECNM criteria 
 Drug Accountability  
End of Study (EOS) Visit - if no response to the study drug after 16 cycles of treatment, 
one follow-up visit about 30 days after the end-of-treatment visit should be undertaken.  This 
is identical to the EOS visit for non-responders at the end of C8 
Follow-up visits - if patient did exhibit a response to the study drug after 16 cycles of 
treatment according to protocol response criteria, follow-up visits and labs every 6 weeks 
until 48 weeks from beginning of re-treatment.  Then every 12 weeks. 
 Evaluate for adverse events  


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 Interval medical history including transfusion history 
 Current medications  
 Physical exam, including measurement of spleen, weight, and vital signs  
 ECOG performance Status  
 MPN-SAF modified for mast cell symptoms 
 Hematology, chemistries/liver function tests, serum tryptase (Please refer to section 
4.8.1 for detailed lab evaluations) 
 Bone Marrow aspirate and biopsy, cytogenetics, flow cytometry, KIT mutation status 
(at week 48 from day 1 of re-treatment, then every 24 weeks) 
 MRI or CT of abdomen/pelvis with and without contrast including 3D spleen and liver 
volumes (at week 48 from re-treatment, then every 24 weeks) 
 Response assessment per IWG-MRT-ECNM criteria 
 
There will not be any additional treatments after completion of the drug infusion at start of 
cycle 16.  Patient will come for follow up visits per the schedule above as long as they show 
response.  At the time of loss of response, patient will have an end of study visit (with the 
same assessments as at the end of study (EOS) visit for patients with no response at end of 
cycle 8 or 16) and will be taken off the study. 
 
Long-term survival: 
All patients will be followed every 6 months for survival until study closure or death of the 
patient. 


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Table 2.  Visit and Assessment Schedule 
 
 
Assessments within +/- 3 days 
 
 
Screen 
Cycle 1 
Cycle 2-8 
End of 
Treatment  
(EOT) (@ 
completion 
of 8 cycles 
of therapy)   
Day +30  
after EOT 
for 
non-respo
nders 
(g) 
Maintenance 
labs and 
visits after 8 
cycles for 
ongoing 
responders 
(h) 
Re-Staging 
for pts 
who 
exhibit loss 
of 
response 
(LOR) 
Re-Treatment 
Cycles 9-16 (a) 
for pts who 
exhibit loss of 
response 
(LOR)    
Long 
Term 
Survival 
(j) 
Evaluation 
Day -28 
to 
Day -1 
Day   
1(b) 
Day 3  
(can be 
local) 
Day 8 
(can be 
local) 
Day 15 
(can be 
local) 
Day 1 
Day 10 
(can be 
local) 
(EOT) 
(EOS) 
Labs and visits 
q 6 weeks up 
to week 48; 
then q 12 
weeks 
Day -21 
to Day -1 
Repeat schedule 
of original cycles 
1,  2-8 and EOT 
(except PT, PTT) 
 
Informed consent/eligibility criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Complete medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Interval medical history 
 
X 
 
 
 
X 
 
X 
X 
X 
X 
 
 
Prior and concomitant medications 
X 
X 
 
 
 
X 
 
X 
X 
X 
X 
 
 
Transfusion history in prior 12 weeks 
X 
X 
 
 
 
X 
 
X 
X 
X 
X 
 
 
Vital signs, physical exam, body weight, 
height(i) 
X(i) 
X 
 
 
 
X 
 
X 
X 
X 
X 
 
 
ECOG performance status 
X 
X 
 
 
 
X 
 
X 
X 
X 
X 
 
 
MPN-SAF, QOL questionnaires 
X 
X 
 
 
 
X 
 
X 
X 
X 
X 
 
 
12-lead ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology (c) 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Serum chemistries/liver function tests (c) 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
 
Serum tryptase level 
X 
X 
 
 
 
X 
 
X 
X 
X 
X 
 
 
PT and PTT 
X 
X 
 
 
 
X 
 
X 
 
 
 
 
 
Pregnancy test  
X 
X 
 
 
 
X 
 
X 
X 
 
X 
 
 
Chest x-ray (2 views-PA and Lateral)(d) 
X 
 
 
 
 
X(d) 
 
X(d) 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BM aspiration,  cytogenetics, flow 
cytometry, core biopsy, and KIT mutation 
analysis(e) 
X 
 
 
 
 
X (e) 
 
X(e) 
 
X (e) 
X 
 
 
MRI (or CT) abdomen/pelvis with and 
without contrast including 3-D spleen and 
liver volumes (f) 
X 
 
 
 
 
X(f) 
 
X (f) 
 
X(f) 
X 
 
 
Measurement of spleen by palpation 
X 
X 
 
 
 
X 
 
X 
X 
X 
X 
 
 
Drug accountability assessment 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 


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a  
For patients demonstrating loss of response (LOR) after completion of 8 cycles of therapy, re-treatment for up to an additional 8 cycles (eg, cycles 9-16) may be 
undertaken.  Before re-treatment, patients should undergo all re-staging studies as shown in the initial screening period, except that a 12-lead EKG and 
coagulation studies (PT and PTT) are not required.  The re-staging period should be completed within 21 days (+/- 3 days) between identifying a loss of 
response (LOR) and re-initiating treatment.  Cycles 9-16 study drug administration and labs/procedures will be conducted on a schedule identical to 
cycles 1 and 2-8 with an end of treatment (EOT) visit at the completion of cycle 16 of therapy except PT and PTT which will NOT be performed with cycles 
9-16,  end of treatment (EOT) visit at the completion of cycle 16, or the end of study (EOS) visit. 
b  
Day 1 labs do not need to be repeated if obtained during screening within 72 hours of day 1.  Patient infusion on cycle 1, day 1 as well as additional cycles will occur 
in an outpatient infusion center. 
c   Refer to section 4.8.1 for the labs that should be obtained for hematology and chemistries/liver function tests. 
d  
If disease-related findings are found on chest x-ray (2 views PA and lateral) (eg, pleural effusion), then an x-ray will be performed at the end of cycles 4 and 8 or 
EOT, whichever comes first, and at the time of progressive disease or loss of response (LOR).  Chest X-ray (2 views-PA and lateral) will also be performed at the 
time of re-staging.  If disease-related findings are found on chest x-ray (eg, pleural effusion) at the time of re-staging, then an x-ray will be performed at the end of 
cycles 12 and 16 or EOT, whichever comes first, and at the time of progressive disease or loss of response (LOR).  Interval chest x-rays can be performed at the 
discretion of the investigator. 
e   Besides screening, marrows will be performed at the end of cycles 4 and 8 or EOT, whichever comes first, and at the time of progressive disease or loss of response 
(LOR).  A repeat bone marrow aspirate and biopsy should be performed at the end of week 48 and every 6 months thereafter in ongoing responders.  Please refer to 
section 4.9 Central Histopathology Review for items required with bone marrow biopsy and aspiration. 
f  
MRI (or CT scan) abdomen/pelvis with and without contrast including 3-D spleen and liver volumes  will be obtained at screening, at the end of cycle 4, and at the 
end of cycle 8 or EOT, whichever comes first, and at the time of progressive disease or loss of response (LOR).  Interval MRI or CT scans can be performed at the 
discretion of the investigator.  A repeat MRI or CT should be performed at the end of week 48 and every 6 months thereafter in ongoing responders. 
g  
A visit on day +30 will be conducted after the EOT visit for follow-up for non-responders.  This will be end of study visit (EOS)  
h 
 After 8 cycles of therapy are completed, labs and visits with the trial site every 6 weeks up to week 48; then every 12 weeks.  
i  
Height is to be obtained only at screening. 
j  
Long Term Survival: every 6 months after end of study visit until study closure or death of the patient.  
Administer study drug during visit 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
Record Adverse Events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Response assessment per 
IWG-MRT-ECNM Criteria 
 
 
 
 
 
X 
 
X 
X 
X 
 
 
 


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4.7 
Efficacy Assessments 
Efficacy will be determined by overall response based on international consensus response 
criteria (see Appendix G).  
4.7.1   Rules for deriving the variable confirmed overall response 
The confirmation response is the next valid consecutive response at least 84 days (12 
weeks) from initial response.  The time of response is the actual date of response, not the 
end of cycle which includes the response.  
In patients whose response commences in later cycles before the end of cycle 8 (eg, during 
cycle 6, 7, or 8), the duration of response will be assessed by ongoing laboratory studies 
and ongoing visits, performed every 6 weeks.  Patients who exhibit a response during 
cycles 1-8 (or during cycles 9-16), but subsequently demonstrate loss of response before 
cycle 8 is completed (or before cycle 16 is completed for patients being re-treated), such 
individuals will not be re-treated.  Retreatment after cycles 1-8 is only applicable to 
patients who exhibit an ongoing response at the time of completion of cycle 8. 
 
In case report forms/study e-CRFs, the confirmed response will be denoted by a subscript 
'c', whereas initial responses or unconfirmed responses (eg, responses not yet lasting 12 
weeks) will display the subcript 'uc'.  For example, if a Major response is confirmed at 12 
weeks (Table 3 below, column 3), it will be denoted as 'Major Responsec' or 'MRc'; 
whereas an initial Major Response will be denoted as 'Major Responseuc' or 'MRuc'. 
Table 3 
Acceptable combinations for initial and confirmed response  
Initial Response 
Response at 12 weeks 
Confirmed response level 
Majoruc 
Majoruc 
Majorc 
Majoruc 
Partialuc 
Partialc 
Partialuc 
Partialuc 
Partialc 
Partialuc 
CIuc 
CIuc 
CIuc 
Partialuc 
Majoruc 
Majoruc 
CIuc 
Majoruc 
Partialuc 
CIuc 
CIuc 
Partialc 
CIc 
CIc 
CIc 
CIc 
CIc 
 
CI:  "Clinical Improvement" per international response criteria 
4.7.2   Additional aspects to disease evolution 
The international consensus response criteria define both progressive disease and loss of 
response (see Appendix G). 


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4.8 
Safety assessments 
Safety assessments will consist of evaluating all adverse events and serious adverse events, 
laboratory parameters including hematology and chemistry, vital signs, physical 
examinations, and documentation of all concomitant medications and/or therapies.  
4.8.1 
Laboratory evaluations 
All evaluations must be performed according to the Visit Schedule and Assessment (Table 2).  
When abnormal laboratory values or test results constitute an adverse event (ie, induces 
clinical signs/symptoms or requires therapy) they must be recorded on the Adverse Events 
CRF. 
All laboratory values must be drawn and assessed PRIOR to administration of SGN-35 on the 
day of its administration.  Baseline laboratory values need not be repeated if performed within 
72 hours of the initial dose of SGN-35.  
Vital signs and Physical Examination 
A physical examination and vital signs must be performed at baseline, and the beginning of 
each cycle, and at the end of treatment (EOT), or progressive disease, whichever comes first, 
and at time of loss of response (LOR).  Vital signs and physical exams will also occur on day 
+30 after EOT which will be end of study visit in non-responders; in responders—vital signs 
and physical examination will occur every six weeks after completion of 8 cycles of therapy 
until week 48, then every 12 weeks.  
More frequent exams may be performed as clinically indicated.  Vital signs include heart rate, 
blood pressure, and body temperature.  Height (in cms) and weight (in kgs) will be captured at 
baseline and weight (in kgs) will be captured at the beginning of each cycle.  ECOG status 
will be recorded at these visits. 
Information about the physical examination must be present in the source documentation at 
the study site.  Significant findings present prior to the start of study drug must be included in 
the Relevant Medical History/Current Medical Conditions CRF.  Significant findings made 
after the start of study drug that meets the definition of an adverse event must be recorded on 
the CRF.  
Performance Status 
The ECOG Performance Status Scale will be used in this study (Appendix A).  
Hematology 
Hematology will include total white blood cell count with differential (neutrophil count 
lymphocyte, monocyte, eosinophil, basophil, mast cell, blast count, and immature 
granulocytes), hemoglobin, hematocrit, platelet count and reticulocyte count (% and absolute).  
Hematology labs are required at screening, on day 1 of each cycle during cycles 1 to 8 , day 8 
and 15 of cycle 1, day 10 of cycles 2 to 8, at end of treatment (EOT), or time of progressive 
disease (whichever comes first), and/or at time of loss of response (LOR).  Hematology will 
also be drawn on day +30 after EOT in non-responders; in responders—hematology will be 
drawn every six weeks after completion of 8 cycles of therapy until week 48, then every 12 


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weeks.  For cycles 9-16, end of treatment cycle 16 and end of study, hematology labs should 
be repeated exactly as cycle 1-8. 
Blood chemistry 
Biochemistry includes sodium, potassium, chloride, bicarbonate, BUN, creatinine, glucose, 
calcium, total and direct bilirubin, albumin, alkaline phosphatase, SGOT and SGPT, LDH, 
and uric acid, (phosphorus will be additionally done on cycle 1 day 1, cycle 1 day 3 and cycle 
1 day 8 only, for complete evaluation of tumor lysis), amylase, and lipase.  Blood chemistry 
labs are required at screening, on day 1 of each cycle during cycles 1 to 8, day 3 of cycle 1 
(for complete evaluation of tumor lysis), day 8 of cycle 1, day 15 of cycle 1, at the end of 
treatment - (EOT) or at time of progressive disease (whichever comes first), and/or at time of 
loss of response (LOR).  Blood chemistry will also be drawn on day +30 after EOT in 
non-responders; in responders, blood chemistry will be drawn every six weeks after 
completion of 8 cycles of therapy until week 48, then every 12 weeks.  For cycles 9-16, end of 
treatment cycle 16 and end of study, chemistry labs should be repeated exactly as cycle 1-8.  
Phosphorus is not to be repeated after cycle 1 day 8. 
Coagulation  
 
Coagulation includes PT/INR and PTT.  These labs are required on screening, day 1 of each 
cycle during cycles 1 to 8, and at the end of treatment (EOT) after cycle 8, or progressive 
disease, whichever comes first.  PT/INR and PTT are NOT required for re-staging, at cycles 
9-16, end of treatment cycle 16 and end of study. 
Serum Tryptase Level 
Serum tryptase levels are obtained at screening, day 1 of each cycle, at the end of treatment 
(EOT), or at time of progressive disease (whichever comes first), and/or at time of loss of 
response (LOR).  Serum tryptase will also be drawn on day +30 after EOT in non-responders; 
in responders, serum tryptase level will be drawn every six weeks after completion of 8 cycles 
of therapy until week 48, then every 12 weeks.  If the serum tryptase assay sensitivity does 
not permit recording of specific values above 200 ng/ml, the sample should be diluted to 
obtain a specific serum tryptase value rather than a non-specific value of ">200 ng/ml".  
For cycles 9-16, end of treatment cycle 16 and end of study, serum tryptase should be 
repeated exactly as cycle 1-8. 
Pregnancy Test 
A pregnancy test will be obtained relevant patients during screening, day 1, and on day 1 of 
each treatment cycle for cycles 1- 8 (patients who need re-treatment will undergo pregnancy 
testing during re-staging and during potential re-treatment cycles ie, cycles 9-16).  Pregnancy 
test will be done at the end of cycle 8 (end of treatment) and if re-staged, end of treatment 
cycle 16 and end of study (30 day follow up) visit. 
Chest X-Ray (2 views- PA and Lateral) 
A chest-x-ray (2 views-PA and lateral) will be performed at screening.  If findings considered 
disease-related are found on chest x-ray at screening (eg, pleural effusion), then a chest x-ray( 
2 views-PA and lateral) will be performed at the end of cycles 4 and 8 or EOT, whichever 
comes first, and at the time of progressive disease or loss of response (LOR).  A chest X-ray 
(2 views-PA and lateral) will also be done if patient is assessed for re-staging to get additional 


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8 cycles of treatment.  Interval chest x-rays can be performed at the discretion of the 
investigator. 
Electrocardiogram   
An ECG must be performed within 28 days prior to Day 1.  
MRI (or CT) Abdomen / Pelvis with and without contrast including 3D spleen 
and liver volumes  
An MRI Abdomen/Pelvis with and without contrast including 3-D spleen and liver volumes 
(CT with and without contrast including 3-D spleen and liver volumes may be used instead) 
must be performed within 28 days prior to Day 1 and repeated at the end of cycle 4, and at the 
end of cycle 8 or EOT, whichever comes first, and at the time of progressive disease.  Interval 
CT scans can be performed at the discretion of the investigator.  Repeat MRI (or CT) 
abdomen/pelvis with and without contrast including 3D spleen and liver volumes will be 
performed at time of Loss of Response (LOR) through the re-staging studies and repeated 
during re-treatment cycles 9-16 on a schedule identical to cycles 1 and 2-8. 
If patients are removed from study before the end of cycle 4, an MRI (or CT) abdomen / 
pelvis with and without contrast including 3D spleen and liver volumes should be performed 
at completion/discontinuation if feasible.  
 
After completion of 8 cycles, a repeat MRI or CT abdomen/pelvis with and without contrast 
including 3D spleen and liver volumes should be performed at the end of week 48 and every 6 
months thereafter in ongoing responders. 
 
Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) Modified 
for Mast Cell Symptoms (Appendix F) 
The MPN-SAF modified for mast cell symptoms will be completed by the patient at 
screening, day 1 of the trial, day 1 of each cycle through 8 cycles, end of study, and for 
ongoing responders, every 6 weeks at the time of their maintenance visits through week 48, 
then every 12 weeks thereafter.  The MPN-SAF modified for mast cell symptoms will also be 
filled out at time of progressive disease or loss of response (LOR).  It will also be completed 
during re-treatment cycles (cycles 9-16) according to the schedule outlined in cycle 1 and 2-8. 
Visits, Laboratory Studies and Procedures at Time of Loss of Response (LOR) 
At the time of protocol-defined loss of response (LOR) after completion of 8 cycles of 
therapy, patients will undergo all screening labs (except for PT and PTT and 12-lead EKG) to 
re-stage disease before re-initiation of SGN-35 for up to an additional 8 cycles (eg, cycles 
9-16).  For re-treatment during cycles 9-16, the schedule of laboratory studies, exams, and 
procedures will be identical to cycles 1 and 2-8, with an end of treatment (EOT) visit at the 
completion of cycle 16 of therapy except PT and PTT which will not be performed with 
cycles 9-16, end of treatment (EOT) visit at the completion of cycle 16 or end of study.  
4.9 
Central Histopathology Review 
 


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Central histopathology review will be performed in University of New Mexico.  This will 
include review of peripheral blood smear (results of CBC should also be submitted), bone 
marrow aspirate, bone marrow core biopsy and review of any biopsied tissue with mast cell 
involvement.  The time points for collection of bone marrow aspirate and biopsy material 
includes the following: 
 
1. Pre-trial (screening); see note in protocol (section 3.3.1) regarding the use of material 
within 3 months prior to signing study consent: 
If some histopathologic studies for mast cell disease were performed within 3 
months prior to signing the consent, such material can be used in place of or to 
complement histopathologic studies for screening after discussion between Drs. 
Gotlib, Verstovsek, and George to ensure sufficient quality and quantity of 
sample for central histopathologic review and testing.  However, any 
histopathologic studies that were not performed should be undertaken during the 
screening. 
2. End of cycle 4  
3. End of cycle 8, or at the EOT, whichever comes first 
4. At the time of loss of response (LOR) or progressive disease.  For patients with LOR, 
marrows will be performed during the re-staging period and repeated during 
re-treatment cycles 9-16 on a schedule identical to cycles 1 and 2-8. 
5. After completion of 8 cycles, for ongoing responders, a repeat bone marrow aspirate 
and biopsy should be performed at the end of week 48 and every 6 months thereafter. 
 
 Peripheral blood smears and bone marrow aspirates should be unstained or stained with a 
Wright Giemsa stain.  Biopsy slides will be stained with Hematoxylin-Eosin stain.  Special 
stains (ie, reticulin, etc.) and immunohistochemical stains (ie, CD117, tryptase, and CD25, 
and CD30) will be performed on representative paraffin blocks from biopsies of tissues with 
mast cell disease (or unstained slides if blocks cannot be provided).  Flow cytometry 
immunophenotyping will be performed on bone marrow (ideal) or peripheral blood (if mast 
cell leukemia present) for analysis of mast cell phenotype which includes CD117, CD25, 
CD2, and CD30.  
Each institution will perform a KIT D816V mutation from bone marrow aspirate (if aspirate  
not available, then core biopsy material).  Institutions may obtain KIT mutation status from 
peripheral blood.  
The following are requested by Dr. Tracy George at University of New Mexico for 
central histopathology review which must be completed before formal drug treatment is 
started (eg, day 1 infusion).  This information will also be provided separately in a lab 
manual appendix: 
 
 1- 2      peripheral blood smears (unstained preferred) 
 
 1-3    bone marrow aspirate smears (unstained preferred) 


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8-10    unstained bone marrow biopsy slides 
 
  1      heparinized (green top) tube of bone marrow aspirate (3 ml minimum) for flow 
cytometry  
 
5 
Notable laboratory value criteria, special methods and 
scales 
Performance status scale:  ECOG.  
Adverse event scale:  NCI CTC version 4.03. 
6 
Data Handling and Record Keeping 
6.1 
Case Report Forms 
Investigator is responsible for entering the information required by the protocol into the Case 
Report Forms (paper or electronic, that uses validated software and conforms to FDA 
requirements for electronic data capture).  If using electronic Case Report Forms, during 
system failures data is captured on paper and is later transferred to electronic Case Report 
Forms.  The Investigator must certify that the data are complete and accurate by applying an 
electronic signature to the electronic Case Report Form and later receives a CD-ROM or 
paper copies of the patient data for archiving at the investigational site.  
 
All data requested on the CRF must be recorded.  All missing data must be explained.  
6.2 
Source Documents 
Source data is all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial.  Source 
data are contained in source documents   Examples of these original documents, and data 
records include: hospital records, clinical and office charts, laboratory notes, memoranda, 
subjects’ diaries or evaluation checklists, pharmacy dispensing records, recorded data from 
automated instruments, copies or transcriptions certified after verification as being accurate 
and complete, microfiches, photographic negatives, microfilm or magnetic media, x-rays, 
subject files, and records kept at the pharmacy, at the laboratories, and at medico-technical 
departments involved in the clinical trial. 
6.3 
Records Retention 
It is the investigator’s responsibility to retain study essential documents for at least 2 years 
after the last approval of a marketing application in their country and until there are no 
pending or contemplated marketing applications in their country or at least 2 years have 
elapsed since the formal discontinuation of clinical development of the investigational 
product.  These documents should be retained for a longer period if required by an agreement 


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with Seattle Genetics.  In such an instance, it is the responsibility of the lead investigator (the 
study sponsor) to inform other investigators/institutions as to when these documents no longer 
need to be retained. 
6.4 
Confidentiality 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act (HIPAA).  Those 
regulations require a signed subject authorization informing the subject of the following:  
 What protected health information (PHI) will be collected from subjects in this study 
 Who will have access to that information and why 
 Who will use or disclose that information 
 The rights of a research subject to revoke their authorization for use of their PHI.  
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization.  For subjects that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect at least vital status (ie, that the subject is alive) 
at the end of their scheduled study period. 
7 
Statistical methods 
7.1 
Populations 
Two populations will be considered for the evaluation of this study: 
1.  The primary efficacy population includes all patients who have received at least 1 dose of 
SGN-35.  
2.  The safety population includes all patients in the study who received at least one dose of 
SGN-35.  The safety population will be used for all safety analyses. 
7.2 
Background and demographic characteristics 
Qualitative background variables (sex, race, stage of disease, etc.) will be summarized using 
contingency tables.  Appropriate descriptive statistics will be used to summarize quantitative 
background variables (age, weight, etc.).  All demographic and disease related data will be 
listed in detail. 
7.3 
Study medication 
The dosage of SGN-35 of each patient will be listed.  In addition, descriptive statistics will be 
used to summarize the duration of exposure of the study medication, the number of patients 
by the maximum number of doses received, and the number of patients who experienced dose 
reduction by duration of exposure.  The reasons for dose change of the study medication will 
also be listed.  


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7.4 
Concomitant therapy 
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study medication will be summarized by dose level according to the Anatomical-Therapeutic 
Chemical (ATC) classes. 
7.5 
Primary Objective- Efficacy evaluation 
The efficacy of the regimen will be assessed in this study.  The primary efficacy endpoint is 
response rate.  A responder is an ASM or mast cell leukemia patient (with or without an  
AHNMD) who experiences a complete or partial remission, or clinical improvement per 
international consensus response criteria.  Patients with stable disease (SD) or progressive 
disease (SD) are considered non-responders (NR).  Patients with missing tumor assessment or 
who die or discontinue the study before having their first assessment will be considered 
non-responders.  Best clinical response will be tabulated.  The rate of complete remission, 
partial remission, and clinical improvement (CI) will be estimated and its 95% confidence 
interval will be provided.  
7.6 
Secondary Objectives 
7.6.1 
Safety evaluation 
The assessment of safety will be based on the frequency of adverse events and on the number 
of laboratory values that fall outside of pre-determined ranges.  Other safety data will be 
considered as appropriate. 
Adverse events will be summarized by presenting the number and percentage of patients 
having any adverse event, having an adverse event in each body system and having each 
individual adverse event.  Any other information collected (eg, severity or relatedness to study 
medication) will be listed as appropriate. 
Laboratory data will be summarized by presenting shift tables using extended normal ranges 
(baseline to most extreme post-baseline value), by presenting summary statistics of raw data 
and change from baseline values (means, medians, standard deviations, ranges) and by the 
flagging of notable values in data listings. 
Data from other tests will be listed, notable values will be flagged, and any other information 
collected will be listed as appropriate.  Any statistical tests performed to explore the data will 
be used only to highlight any interesting comparisons that may warrant further consideration. 


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7.6.2   Expression of CD30 on neoplastic mast cells  
 
The burden of CD30+ neoplastic mast cells will be determined by immunophenotyping and/or 
immunohistochemistry and will be compared between pre- and post-SGN-35 treatment 
samples.  Evaluation will be undertaken by central pathology review by Dr. Tracy George at 
University of New Mexico.  Reduction of mast cell burden will also be recorded pre-and post 
SGN-35 therapy primarily by evaluation of peripheral blood (if mast cell leukemia) and bone 
marrow aspirate and core biopsy.  Change of serum tryptase levels from baseline at the 
respective assessments will be evaluated as a surrogate marker for histopathologic response. 
7.6.3   Myeloproliferative Neoplasm Symptom Assessment Form 
(MPNSAF) modified for Mast Cell Symptoms 
 
 Total symptom score and QOL will be assessed by a modified version of the MPNSAF 
(modified for mast cell symptoms) by recording mean and median scores with ranges will be 
recorded pre- and post-treatment with SGN-35 (Appendix F). 
7.6.4 
Duration of Response (DoR) and Time to Response (TTR) 
The duration of (confirmed) overall response (DoR) is defined as the time from the start of the 
first confirmed response until the date of the first documented and confirmed disease 
progression or death due to ASM or MCL.  The Kaplan-Meier product-limit method will be 
used to summarize the response duration.  If a patient did not progress or die due to ASM or 
MCL at the time of the analyses, DoR will be censored at the date of the last adequate 
response assessment. 
Time to response (TTR) is defined as the time from the date of start of treatment to the date of 
first confirmed response.  Time to response will be censored at the date of the last adequate 
response assessment in patients did not progress or die due to any cause and at maximum 
follow-up date (ie, date of first patient first visit (FPFV) to date of last patient last visit 
(LPLV) used for the analysis) in patients who progressed or died due to any cause.  
Kaplan-Meier product-limit estimates will be used to summarize the time to response. 
7.6.5 
Progression-free survival (PFS) and overall survival 
Progression-free survival (PFS) is defined as the time from the date of start of treatment until 
the date of first documented confirmed disease progression or death or institution of new 
therapy.  If a patient did not progress or die due to any cause at the time of the analyses, PFS 
will be censored at the date of the last adequate response assessment.  Kaplan-Meier 
product-limit estimates will be used to summarize PFS.  For overall survival, patients will be 
contacted every 6 months until the study closure or death. 
7.7 
Interim analyses 
An interim analysis will be provided after enrolling 11 evaluable patients, as described in 
Section 7.8. 
7.8 
Sample size and power considerations 
 


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The primary endpoint is response rate per international consensus response criteria (see 
Appendix G).  
 
The trial will be carried out as a Simon two-stage Optimum design with a total potential 
sample size of 26 patients (Simon R, 1989).  The first stage will be this investigator-initiated 
phase II study of 11 patients.  We assume that the probability of accepting the treatment when 
the true response rate is < 10% is less than or equal to 10%, and the probability of rejecting 
the treatment when the true response rate is ≥ 30% is less than or equal to 15%.  
Under these assumptions, the stopping rules are as follows:  Accrue a cohort of 11 patients in 
this first stage phase II study.  If 2 or more patients out of 11 respond, the study will be 
amended to enroll an additional 15 patients in the second stage.  If less than 2 responses are 
seen, the study will be halted.  At the end of the second stage, if 5 or more patients out of 26 
respond, the regimen will be considered for further investigation in the treatment of advanced 
mastocytosis.  With this design, the chance of falsely claiming that regimen is efficacious 
(alpha) is 8.7%, and the power is 85%.  The probability of stopping early is 70% under the 
null hypothesis of a 10% response rate is 10%; it is 11% if the true response rate is 30%. 
8 
Procedures and instructions 
8.1 
Special safety-related procedures 
Adverse Event 
An adverse event (AE) is any symptom, sign, illness or experience that develops or 
worsens in severity during the course of the study.  Intercurrent illnesses or injuries 
should be regarded as adverse events.  Abnormal results of diagnostic procedures are 
considered to be adverse events if the abnormality: 
 results in study withdrawal 
 is associated with a serious adverse event 
 is associated with clinical signs or symptoms 
 leads to additional treatment or to further diagnostic tests 
 is considered by the investigator to be of clinical significance 
Serious Adverse Event 
Adverse events are classified as serious or non-serious.  A serious adverse event is any 
AE that is:  
 fatal 
 life-threatening 
 requires or prolongs hospital stay 
 results in persistent or significant disability or incapacity 
 a congenital anomaly or birth defect 
 an important medical event 
Important medical events are those that may not be immediately life threatening, but are 
clearly of major clinical significance.  They may jeopardize the subject, and may require 
intervention to prevent one of the other serious outcomes noted above.  For example, 
drug overdose or abuse, a seizure that did not result in in-patient hospitalization, or 


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intensive treatment of bronchospasm in an emergency department would typically be 
considered serious.  All adverse events that do not meet any of the criteria for serious 
should be regarded as non-serious adverse events.  
Adverse Event Reporting Period 
The study period during which adverse events must be reported is normally defined as 
the period from the initiation of any study procedures to the end of the study treatment 
follow-up.  For this study, the study treatment follow-up is defined as 30 days following 
the last administration of study treatment.  
Preexisting Condition 
A preexisting condition is one that is present at the start of the study.  A preexisting 
condition should be recorded as an adverse event if the frequency, intensity, or the 
character of the condition worsens during the study period.  
General Physical Examination Findings 
At screening, any clinically significant abnormality should be recorded as a preexisting 
condition.  At the end of the study, any new clinically significant findings/abnormalities 
that meet the definition of an adverse event must also be recorded and documented as an 
adverse event.  
Post-study Adverse Event 
All unresolved adverse events should be followed by the investigator until the events are 
resolved, the subject is lost to follow-up, or the adverse event is otherwise explained.  At 
the last scheduled visit, the investigator should instruct each subject to report any 
subsequent event(s) that the subject, or the subject’s personal physician, believes might 
reasonably be related to participation in this study.  The investigator should notify the 
study sponsor of any death or adverse event occurring at any time after a subject has 
discontinued or terminated study participation that may reasonably be related to this 
study.  The sponsor should also be notified if the investigator should become aware of 
the development of cancer or of a congenital anomaly in a subsequently conceived 
offspring of a subject that has participated in this study.  
Abnormal Laboratory Values 
A clinical laboratory abnormality should be documented as an adverse event if any one 
of the following conditions is met:  
 The laboratory abnormality is not otherwise refuted by a repeat test to confirm 
the abnormality 
 The abnormality suggests a disease and/or organ toxicity 
 The abnormality is of a degree that requires active management; eg, change of 
dose, discontinuation of the drug, more frequent follow-up assessments, further 
diagnostic investigation, etc. 
Hospitalization, Prolonged Hospitalization or Surgery 
Any adverse event that results in hospitalization or prolonged hospitalization should be 
documented and reported as a serious adverse event unless specifically instructed 
otherwise in this protocol.  Any condition responsible for surgery should be documented 
as an adverse event if the condition meets the criteria for and adverse event.  


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Neither the condition, hospitalization, prolonged hospitalization, nor surgery are 
reported as an adverse event in the following circumstances: 
 Hospitalization or prolonged hospitalization for diagnostic or elective surgical 
procedures for a preexisting condition.  Surgery should not be reported as an 
outcome of an adverse event if the purpose of the surgery was elective or 
diagnostic and the outcome was uneventful. 
 Hospitalization or prolonged hospitalization required to allow efficacy 
measurement for the study. 
 Hospitalization or prolonged hospitalization for therapy of the target disease of 
the study, unless it is a worsening or increase in frequency of hospital admissions 
as judged by the clinical investigator. 
Recording of Adverse Events 
At each contact with the subject, the investigator must seek information on adverse events by 
specific questioning and, as appropriate, by examination.  Information on all adverse events 
should be recorded immediately in the source document, and entered on the appropriate case 
report form (CRF).  All clearly related signs, symptoms, and abnormal diagnostic procedures 
results should recorded in the source document, though should be grouped under one 
diagnosis. 
All adverse events occurring during the study period must be recorded.  The clinical course of 
each event should be followed until resolution, stabilization, or until it has been determined 
that the study treatment or participation is not the cause.  Serious adverse events that are still 
ongoing at the end of the study period must be followed up to determine the final outcome.  
Any serious adverse event that occurs after the study period and is considered to be possibly 
related to the study treatment or study participation should be recorded and reported 
immediately. 
8.1.1 
Instructions for rapid notification of Serious Adverse Events 
Reporting responsibility 
For all studies for which Seattle Genetics has provided Product: 
 
• Reporting Timeframe:  The Principal Investigator (Stanford) will report to Seattle 
Genetics Drug Safety by facsimile any Serious Adverse Event (SAE) that occurs in a study 
subject within 24 hours 
of first awareness of the event.  The Co-Principal Investigator from the sub-site will report 
any SAEs to the main site (Stanford) within 24 hours by facsimile or by email to 
hkaur@stanford.edu and these will be submitted to Seattle Genetics Drug Safety by Principal 
Investigator. 
 
• Reporting Forms:  The Principal Investigator and Co-Principal Investigator will report 
such SAEs using the Seattle Genetics SAE Report Form or the approved local regulatory form 
(ie, FDA MedWatch form, CIOMS, etc.) to include an assessment of causality to the Product.  
SAEs should be reported as soon as they are determined to meet the definition, even if 
complete information is not yet available. 


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• Reporting Period:  The reportable events that are subject to this provision are those that 
occur from the start of administration of the first dose of the Product through thirty (30) days 
after discontinuation of the Product.  SAEs occurring more than thirty (30) days after 
discontinuation of the Product that are assessed by the Investigator as related to the Product 
should also be reported. 
 
• Follow-up Information:  The Principal Investigator will assist Seattle Genetics in 
investigating any SAE and will provide any follow-up information reasonably requested by 
Seattle Genetics. 
 
• Regulatory Reporting:  Reporting an SAE to Seattle Genetics does not relieve the 
Principal Investigator conducting the study of the responsibility for reporting it to the FDA, 
local regulatory authority, or IRB/IEC as required. 
 
Sponsor Responsibilities 
As the sponsor of the study, the Principal Investigator and/or Institution must ensure that the 
study is conducted in accordance with the provisions of the ICH GCP Guidelines and all 
applicable local and regulatory requirements.  The Principle Investigator must assume all 
regulatory responsibilities including, but not limited to, IRB/IEC approvals, regulatory 
approvals, monitoring responsibilities and any and all reporting obligations to local regulatory 
Authorities. 
EC/IRB Notification by Investigator 
Reports of all serious adverse events (including follow-up information) must be submitted to 
the EC/IRB in accordance with the institutional policy.  Copies of each report and 
documentation of EC/IRB notification and receipt will be kept in the Study binder. 
8.1.2 
Instructions for rapid notification of pregnancies 
Each pregnancy that started during the study must be reported by the investigator to Seattle 
Genetics within 24 hours of learning of its occurrence.  Pregnancies and pregnancy follow-up 
should be reported on the Clinical Trial Pregnancy Form but any serious adverse event 
experienced during pregnancy must be reported on the FDA Form 3500 and Serious Adverse 
Event Report Form.  Pregnancy follow-up should describe the outcome of the pregnancy, 
including any voluntary or spontaneous termination, details of the birth, the presence or 
absence of any congenital abnormalities, birth defects, maternal or newborn complications 
and their relation to the Seattle Genetics study drug (or therapy).  
8.2 
Administrative procedures 
8.2.1 
Changes to the protocol 
Study Initiation 
As the sponsor of the study, the Principal Investigator and/or Institution must provide the 
following to Seattle Genetics prior to initiation of Seattle Genetics support (provision of 
Product): 
• Final study protocol 


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• Fully executed IST Agreement 
• Regulatory Response Documentation (IND or CTA documentation if applicable) 
• IRB/IEC approval 
Study Maintenance 
Throughout the study, Seattle Genetics requires the following: 
• At least one safety study status update per year, to include information on enrollment and 
study completion dates. 
• Notification of any amendment to the original protocol after the research has begun; and 
immediate notification of any amendments made due to safety reasons. 
 
Study Closure 
Any Investigator and/or Institution conducting an IST is contractually required to provide 
Seattle Genetics with a written report of the final study results and a copy of the IND Annual 
Report (or equivalent in rest of world regions).  Upon study closure, the Investigator and/or 
Institution will be required to certify that all safety reporting obligations were met. 
8.2.2 Monitoring procedures 
The Lead study investigator (Study Sponsor) is responsible for reviewing the protocol and 
case report forms with the investigators and their staff prior to study.  The responsibilities of 
the Sponsor (or designee) include project compliance, data abstraction, data reporting, 
regulatory monitoring, problem resolution and prioritization, and coordination of the activities 
of the protocol study team and study-level medical monitoring.  Accrual rates and extent and 
accuracy of evaluations and follow-up are to be monitored periodically throughout the study 
period.  Potential problems will be brought to the attention of the study team for discussion 
and action.  
Investigators are responsible for the completeness of patient records, the accuracy of entries 
on the case report forms, the adherence to the protocol and to Good Clinical Practice, the 
progress of enrollment, and also to ensure that study medication is being stored, dispensed and 
accounted for according to specifications.  Monitoring standards require full verification for 
the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of serious adverse events and the recording of primary efficacy and safety 
variables.  Additional checks of the consistency of the source data with the case report forms 
are performed according to the institutional and regulatory guidelines. 
It is the responsibility of the Principal Investigator at each of the study centers to oversee the 
safety of the study at his/her site.  This safety monitoring will include careful assessment and 
appropriate reporting of adverse events as noted above.  Medical monitoring will include a 
regular assessment of the number and type of serious adverse events. 
 
The data collected for this study will be entered into a secure database.  Source documentation 
will be available to support the computerized patient record.  Random-sample data quality and 
protocol compliance audits will be conducted by the Sponsor (or designee) remotely (fax) or 
in person to check the completeness of patient records, the accuracy of entries on the case 
report forms, the adherence to the protocol and to Good Clinical Practice.  The investigator 
must give the monitor access to relevant hospital or clinical records, to confirm their 


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consistency with the case report form entries.  No information in these records about the 
identity of the subjects will leave the study center.  
8.2.3 
Auditing procedures 
A regulatory authority may wish to conduct an inspection (during the study or even after its 
completion).  If an inspection is requested by a regulatory authority, the investigator must 
inform Seattle Genetics immediately that this request has been made. 
Seattle Genetics Good Clinical Practice Quality Assurance Unit may request to conduct an 
audit of clinical research activities to evaluate compliance with the principles of Good Clinical 
Practice. 
 
8.2.4 
Handling of study medication 
All study medication will be supplied to the principal investigator by Seattle Genetics.  Drug 
supplies must be kept in an appropriate, secure area (eg, locked cabinet) and stored according 
to the conditions specified on the drug labels.  The investigator must maintain an accurate 
record of the shipment and dispensing of study drug in a drug accountability ledger, a copy of 
which must be given to Seattle Genetics at the end of the study.  An accurate record of the 
date and amount of study drug dispensed to each subject must be available for inspection at 
any time. 
All drug supplies are to be used only for this protocol and not for any other purpose.  The 
investigator must not destroy any drug labels, or any partly-used or unused drug supply.  At 
the conclusion of the study, and, as appropriate during the course of the study, the investigator 
will return all used and unused drug containers, drug labels and a copy of the completed drug 
disposition form to Seattle Genetics.  
 
8.2.5 Disclosure and confidentiality 
By signing the protocol, the investigator agrees to keep all information provided by Seattle 
Genetics in strict confidence and to request similar confidentiality from his/her staff and the 
IRB/IEC/REB.  Study documents provided by Seattle Genetics (eg, investigators' brochures, 
and other material) will be stored appropriately to ensure their confidentiality.  The 
information provided by Seattle Genetics to the investigator may not be disclosed to others 
without direct written authorization from Seattle Genetics, except to the extent necessary to 
obtain informed consent from patients who wish to participate in the trial.  
8.3     Ethics and Good Clinical Practice 
This study must be carried out in compliance with the protocol and the principles of Good 
Clinical Practice, as described in  standard operating procedures and:  
1. 
ICH Harmonized Tripartite Guidelines for Good Clinical Practice 1996. 
Directive 91/507/EEC, The Rules Governing Medicinal Products in the European 
Community. 
2. 
US 21 Code of Federal Regulations dealing with clinical studies (including parts 50 
and 56 concerning informed consent and IRB regulations). 


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3. 
Declaration of Helsinki and amendments, concerning medical research in humans 
(Recommendations Guiding Physicians in Biomedical Research Involving Human Subjects). 
The investigator agrees when signing the protocol to adhere to the instructions and procedures 
described in it and thereby to adhere to the principles of Good Clinical Practice that it 
conforms to. 
8.3.1 Institutional Review Board/Independent Ethics Committee 
Before implementing this study, the protocol, the proposed informed consent form and other 
information to subjects, must be reviewed by a properly constituted Institutional Review 
Board/Independent Ethics Committee/Research Ethics Board (IRB/IEC/REB).  A signed and 
dated statement that the protocol and informed consent have been approved by the 
IRB/IEC/REB must be given to Seattle Genetics before study initiation.  The name and 
occupation of the chairman and the members of the IRB/IEC/REB must be supplied to Seattle 
Genetics.  Any amendments to the protocol, other than administrative ones, must be approved 
by this committee. 
8.3.2 
Informed consent 
Patients will be required to sign a statement of informed consent which meets the 
requirements of the code of Federal Regulations (Federal Register Vol. 46, No. 17, Jan. 27, 
1981, part 50) and the IRB of this center.  The medical record should include a statement that 
written informed consent was obtained (and document in the record the date written consent 
was obtained before) and the patient is enrolled in the study.  
The informed consent form is considered to be part of the protocol, and must be submitted by 
the investigator with it for IRB/IEC/REB approval.  
Consent Process   
The investigator must explain to each subject (or legally authorized representative) the nature 
of the study, its purpose, the procedures involved, the expected duration, the potential risks 
and benefits involved and any discomfort it may entail.  Each subject must be informed that 
participation in the study is voluntary and that he/she may withdraw from the study at any 
time and that withdrawal of consent will not affect his/her subsequent medical treatment or 
relationship with the treating physician.  The discussion will review the alternatives available, 
why the risks are reasonable in relation to the anticipated benefits, incentives, costs that will 
or may be incurred as a result of participation in the study, as will the efforts to maintain the 
confidentiality will also be discussed. 
This informed consent should be given by means of a standard written statement, written in 
non-technical language.  The subject should read and consider the statement before signing 
and dating it, and should be given a copy of the signed document.  If the subject cannot read 
or sign the documents, oral presentation may be made or signature given by the subject’s 
legally appointed representative, if witnessed by a person not involved in the study, 
mentioning that the patient could not read or sign the documents.  No patient can enter the 
study before his/her informed consent has been obtained. 
A copy of the signed original consent form will be given to the patient.  


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in a patient with systemic mastocytosis.  N Engl J Med.  326:619-623. 
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adults with systemic mastocytosis: Outcome analysis and response prediction during  
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Andreasson B, Ferarri ML, Rambaldi A, Samuelsson J, Birgegard G, Tefferi A, Harrison 
CN, Radia D, Mesa RA (2011).  The Myeloproliferative Neoplasm Symptom Assessment 
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HP (2011).  Aberrant expression of CD30 in neoplastic mast cells in high-grade 
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APPENDIX A 
Performance Status Criteria 
 
 
Grade 
Descriptions 
Percent 
Description 
 
      0 
Normal activity.  Fully active, 
able to 
Carry on all pre-disease 
performance without restriction. 
    100 
Normal, no complaints, no evidence of 
disease. 
      90 
Able to carry on normal activity; minor 
signs or symptoms of disease. 
 
      1 
Symptoms, but ambulatory.  
Restricted in physically 
strenuous activity, but 
ambulatory and able to carry out 
work of a light or sedentary 
nature (eg, light housework, 
office work). 
      80 
Normal activity with effort; some signs or 
symptoms of disease. 
      70 
Cares for self, unable to carry on normal 
activity or to do active work. 
 
      2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and 
about more than 50% of waking 
hours. 
      60 
Requires occasional assistance, but is able 
to care for most of his/her needs. 
      50 
Requires considerable 
assistance and frequent 
medical care. 
 
      3 
In bed >50% of the time.  
Capable of only limited 
self-care, confined to bed or 
chair more than 50% of waking 
hours. 
      40 
Disabled, requires special care 
and assistance. 
      30 
Severely disabled, hospitalization 
indicated. 
 
      4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to 
bed or chair. 
      20 
Very sick, hospitalization indicated.  
Death not imminent. 
      10 
Moribund, fatal processes progressing 
rapidly. 
      5 
Dead. 
       0 
Dead. 
 
 
      ECOG Performance Status Scale 
 
         Karnovsky Performance Scale 


A study of brentuximab vedotin (SGN-35) in CD30-positive systemic mastocytosis with or without an associated 
hematological clonal non-mast cell lineage disease (AHNMD) 
 
  
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APPENDIX B 
Criteria to Diagnose Systemic Mastocytosis (SM Criteria) 
_________________________________________________________________________________ 
Major criterion  
 
 
Multifocal dense infiltrates of mast cells (>15 mast cells in 
 
 
 
 
 
aggregates) in bone marrow biopsies and/or in sections 
 
 
 
 
 
of other extracutaneous organ(s) 
 
Minor criteria 
 
 
 
a.  >25% of all mast cells are atypical cells (type I or type II) 
 
 
 
 
 
On bone marrow smears or are spindle-shaped in mast cell 
 
 
 
 
 
Infiltrates detected on sections of visceral organs 
 
b. c-kit point mutation at codon 816 in the bone marrow 
or another extracutaneous organ 
 
c. Mast cells in bone marrow or blood or another 
extracutaneous organ express CD2 or/and CD25 
 
d. Baseline serum tryptase concentration > 20 ng/ml 
(in the case of an unrelated myeloid neoplasm, (d) is not 
valid as an SM criterion) 
_________________________________________________________________________________ 
If at least one major and one minor or three minor criteria are fulfilled, then the diagnosis is systemic 
Mastocytosis=SM. 


A study of brentuximab vedotin (SGN-35) in CD30-positive systemic mastocytosis with or without an associated 
hematological clonal non-mast cell lineage disease (AHNMD) 
 
  
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APPENDIX C 
Diagnostic Criteria for Aggressive Systemic Mastocytosis 
and Mast Cell Leukemia 
 
Aggressive Systemic Mastocytosis 
Meets criteria for SM 
One or more “C” findings 
No associated clonal hematologic malignancy/disorder (AHNMD)* 
No evidence of mast cell leukemia 
 
*Patients with aggressive systemic mastocytosis who also are found to have an AHNMD 
are eligible for this protocol 
 
Mast Cell Leukemia 
Meets criteria for SM 
Biopsy shows a diffuse infiltration, usually interstitial pattern, by atypical, immature mast cells 
Bone marrow aspirate smears show 20% or more mast cells 
Mast cells account for 10% or more of peripheral blood white cells 
 
NOTE:  Patients may also be enrolled if mast cells account for <10% of the peripheral blood white 
blood cells; such patients are considered to be in the pre-phase of mast cell leukemia and are referred 
to as “aleukemic mast cell leukemia.” 


A study of brentuximab vedotin (SGN-35) in CD30-positive systemic mastocytosis with or without an associated 
hematological clonal non-mast cell lineage disease (AHNMD) 
 
  
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APPENDIX D 
Mediator Drugs to Ameliorate Symptoms Related to 
Systemic Mastocytosis* 
_________________________________________________________________________ 
Symptom 
 
 
 
Step 
 
Drug(s) to be considered 
___________________________________________________________________________ 
Pruritis, flushing 
 
 
1 
 
H1 + H2-histamine receptor antagonists 
2 
Ketotifen, topical glucocorticoids 
3 
PUVA 
 
Cardiovascular symptoms 
 
1 
 
H1 + H2-histamine receptor antagonists 
 
Recurrent hypotension  
2 
 
Glucocorticoids** 
 
and tachycardia  
 
3 
 
Aspirin (in selected cases) 
 
 
 
 
 
Recurrent shock 
1 
 
H1 + H2-histamine receptor antagonists 
 
 
 
 
 
 
 
   + epinephrine on demand (self injected) 
2 
                   Oral glucocorticoids** + epinephrine on 
   demand (self injected) 
3 
                   Aspirin (in selected cases) + epinephrine 
   on demand 
GI tract  
 
 
 
Peptic ulcer disease 
 
1 
 
H2-histamine receptor antagonists 
2 
Proton-pump inhibitors + H2 blockers 
Diarrhea, abdominal pain, 
cramping, nausea/vomiting 
1 
 
H1 + H2-histamine receptor antagonists 
2 
Oral cromolyn sodium 
3 
Consider trial with leukotriene antagonists 
4 
Short-term glucocorticoids** 
 
Skeletal system  
 
Bone pain 
 
 
1 
 
Analgesias, aspirin-like drugs (if tolerable) 
 
 
 
 
 
 
 
Also consider radiation for severe pain 
 
Osteopenia, diffuse 
 
  osteoporosis  
 
1 
 
Vitamin D + calcium or estrogen/ 
   
 
 
 
 
 
 
 
    testosterone on demand 
2 
Bisphosphonates 
 
Neurologic symptoms  
 
1 
 
H1 + H2-histamine receptor antagonists 
 
 
 
 
 
2 
 
Oral cromolyn sodium  
 
*From Valent et al.  Br J Haematol. 2003; 122:  695-717.  


A study of brentuximab vedotin (SGN-35) in CD30-positive systemic mastocytosis with or without an associated 
hematological clonal non-mast cell lineage disease (AHNMD) 
 
  
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APPENDIX E 
List of CYP3A Inhibitors and Inducers 
 
CYP3A4/5 Inhibitors 
Amiodarone 
Diethyldithiocarbamate 
Grapefruit juice 
Norfloxacin 
Sertindole 
Anastrozole 
Diltiazem 
Indinavir 
Omeprazole 
Sertraline 
Azithromycin 
Dirithromycin 
Isoniazid 
Oxiconazole 
Troglitazone 
Cannabinoids 
Disulfiram 
Itraconazole 
Paroxetine 
Troleandomyci
Cimetidine 
Entacapone 
Ketoconazole 
Propoxyphene 
Valproic Acid 
Clarithromycin 
Erythromycin 
Metronidazole 
Quinidine 
Verapamil 
Clotrimazole 
Ethinyl estradiol 
Miconazole 
Quinine 
Zafirlukast 
Cyclosporine 
Fluconazole 
Nefazodone 
Quinupristin 
Zileuton 
Danazol 
Fluoxetine 
Nelfinavir 
Ranitidine 
 
Delavirdine 
Fluvoxamine 
Nevirapine 
Ritonavir 
 
Dexamethasone 
Gestodene 
Norfluoxetine 
Saquinavir 
 
 
CYP3A4/5 Inducers 
Carbamazepine 
Nafcillin 
Phenylbutazone 
Rifampin 
Troglitazone 
Dexamethasone 
Nelfinavir 
Phenytoin 
Rofecoxib (mild) 
 
Ethosuximide 
Nevirapine 
Primidone 
St. John’s wort 
 
Glucocorticoids 
Oxcarbazepine 
Progesterone 
Sulfadimidine 
 
Griseofulvin 
Phenobarbital 
Rifabutin 
Sulfinpyrazone 
 
 
 


A study of brentuximab vedotin (SGN-35) in CD30-positive systemic mastocytosis with or without an associated 
hematological clonal non-mast cell lineage disease (AHNMD) 
 
  
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APPENDIX F 


A study of brentuximab vedotin (SGN-35) in CD30-positive systemic mastocytosis with or without an associated 
hematological clonal non-mast cell lineage disease (AHNMD) 
 
  
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A study of brentuximab vedotin (SGN-35) in CD30-positive systemic mastocytosis with or without an associated hematological clonal non-mast cell lineage disease (AHNMD) 
 RESPONSE CRITERIA 
Page 54 of 55 
APPENDIX G: 
APPENDIX G 


A study of brentuximab vedotin (SGN-35) in CD30-positive systemic mastocytosis with or without an associated hematological 
clonal non-mast cell lineage disease (AHNMD) 
 RESPONSE CRITERIA 
Page 55 of 55 
 
APPENDIX G: 
APPENDIX G Contd.: