Clinical trial NCT02494206
Conditions: Breast Cancer Upper Extremity Lymphedema
Keywords: QBX258 human monoclonal antibodies VAK694 QAX576 15-085
Sponsor: Memorial Sloan Kettering Cancer Center
Start date: 2015-07-01; Completion date: 2018-05-01
Enrollment: 9 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to assess the efficacy of QBX258, a compound developed by Novartis Corporation composed of two antibodies, in reducing arm volume excess in women with stage I-II breast cancer related lymphedema.

Detailed description:

Arms: arm 1: This will be a single arm, open label design pilot study, aiming to test the efficacy of QBX258, a combination of two fully human monoclonal antibodies that neutralize the biologic activity of interleukin 4 and interleukin 13 (IL4/IL13), for the treatment of stage I or II breast cancer related upper extremity lymphedema (BCRL).
Interventions: intervention 1: QBX258
Intervention descriptions: intervention 1: Once patients are registered for the trial, they will be treated with QBX258 (VAK694 3mg/kg and QAX576 6mg/kg) delivered via peripheral intravenous injection once every 4 weeks (+ 1 week) for 4 treatments.

Protocol documents:
Prot_SAP_000.pdf: 
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Immunotherapy for the treatment of breast cancer related upper extremity 
lymphedema (BCRL) protocol # CQBX258X2203T 
 
PROTOCOL FACE PAGE FOR 
MSKCC THERAPEUTIC/DIAGNOSTIC PROTOCOL 
 
Principal 
Investigator/Department: 
Babak Mehrara, MD 
Surgery/Plastic & Reconstructive Service 
Co-Principal 
Investigator(s)/Department: 
Joseph Dayan, MD 
Kimberly Van Zee, MD 
Jacqueline Bromberg, MD, PhD 
Surgery/Plastic & Reconstructive Service 
Surgery/Breast Service 
Medicine/Breast Medicine Service 
Investigator(s)/Department: 
Andrea Barrio, MD 
Raghu Parsad Kataru, PhD 
Shari Goldfarb, MD Maura 
Dickler, MD Shanu Modi, 
MD Elizabeth Comen, MD 
Neil Iyengar, MD 
Ayca Gucalp, MD 
Tiffany Traina, MD 
Sarat Chandarlapaty, MD 
Mario Leitao, MD 
Sharlynn Tuohy, PT, DPT, MBA 
Ting-Ting Kuo, PT, DPT, MBA, 
WCS, CLT 
Jaennette Zucker, PT, DPT 
Laryssa Buoneto, PT 
Andrea Pusic, MD 
Evan Matros, MD 
Peter Cordeiro, MD 
Joseph Disa, MD 
Colleen McCarthy, MD 
Monica Morrow, MD 
Tari King, MD 
Mary Gemignani, MD 
Virgilio Sacchini, MD 
Alexandra Heerdt, MD 
Lisa Sclafani, MD 
Hiram Cody, MD 
George Plitas, MD 
Debra Capko, MD 
Mahmoud El-Tamer, MD 
Melissa Pilewski, MD 
Elyn Riedel, MA 
Melissa Lee-Teh, RPh 
Svetlana Kleyman, MD 
Andrew Weinstein, MD 
Geoffrey Hespe 
Gabriela Garcia Nores, MD 
Jessie Yu, MD 
Surgery/Breast Service 
Surgery/Plastic & Reconstructive Service 
Medicine/Breast Medicine Service 
Medicine/Breast Medicine Service 
Medicine/Breast Medicine Service 
Medicine/Breast Medicine Service 
Medicine/Breast Medicine Service 
Medicine/Breast Medicine Service 
Medicine/Breast Medicine Service 
Medicine/Breast Medicine Service 
Surgery/GYN Service 
Neurology 
Neurology 
Neurology 
Neurology 
Surgery/Plastic & Reconstructive Service 
Surgery/Plastic & Reconstructive Service 
Surgery/Plastic & Reconstructive Service 
Surgery/Plastic & Reconstructive Service 
Surgery/Plastic & Reconstructive Service 
Surgery/Breast Service 
Surgery/Breast Service 
Surgery/Breast Service 
Surgery/Breast Service 
Surgery/Breast Service 
Surgery/Breast Service 
Surgery/Breast Service 
Surgery/Breast Service 
Surgery/Breast Service 
Surgery/Breast Service 
Surgery/Breast Service 
Epidemiology and Biostatistics 
Pharmacy 
Surgery/Plastic & Reconstructive Service 
Surgery/Plastic & Reconstructive Service 
Sloan Kettering Institute 
Sloan Kettering Institute 
Sloan Kettering Institute 


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Consenting 
Professional(s)/Department: 
Babak Mehrara, MD 
Joseph Dayan, MD 
Kimberly Van Zee, MD 
Jacquiline Bromberg, MD 
Andrea Barrio, MD 
Shari Goldfarb, MD 
Maura Dickler, MD 
Shanu Modi, MD 
Elizabeth Comen, MD 
Neil Iyengar, MD 
Ayca Gucalp, MD 
Tiffany Traina, MD 
Sarat Chandarlapaty, MD 
Surgery/Plastic & Reconstructive Service 
Surgery/Plastic & Reconstructive Service 
Surgery/Breast Service 
Medicine/Breast Medicine Service 
Surgery/Breast Service 
Medicine/Breast Medicine Service 
Medicine/Breast Medicine Service 
Medicine/Breast Medicine Service 
Medicine/Breast Medicine Service 
Medicine/Breast Medicine Service 
Medicine/Breast Medicine Service 
Medicine/Breast Medicine Service 
Medicine/Breast Medicine Service 
Please Note: A Consenting Professional must have completed the mandatory Human 
Subjects Education and Certification Program. 
 
 
 
Memorial Sloan-Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 


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MEMORIAL SLOAN-KETTERING CANCER CENTER 
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Table of Contents 
 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA ..................................................................... 4 
 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS .............................................................................. 6 
 
3.0 
BACKGROUND AND RATIONALE ................................................................................... 7 
 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION.......................................................... 10 
 
4.1 
Design........................................................................................................................... 10 
 
4.2 
Intervention ................................................................................................................... 11 
 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS ......................................................................... 14 
 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY ......................................................................... 15 
 
6.1 
Subject Inclusion Criteria............................................................................................... 15 
 
6.2 
Subject Exclusion Criteria ............................................................................................. 15 
 
7.0 
RECRUITMENT PLAN ..................................................................................................... 15 
 
8.0 
PRETREATMENT EVALUATION .................................................................................... 17 
 
9.0 
TREATMENT/INTERVENTION PLAN.............................................................................. 18 
 
10.0 EVALUATION DURING TREATMENT/INTERVENTION ................................................. 19 
 
11.0 TOXICITIES/SIDE EFFECTS ........................................................................................... 21 
 
12.0 CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT ..................... 25 
 
13.0 CRITERIA FOR REMOVAL FROM STUDY ..................................................................... 26 
 
14.0 BIOSTATISTICS .............................................................................................................. 27 
 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES28 
 
15.1 Research Participant Registration ................................................................................. 28 
 
15.2 Randomization .............................................................................................................. 28 
 
16.0 DATA MANAGEMENT ISSUES ....................................................................................... 28 
 
16.1 Quality Assurance ......................................................................................................... 28 
 
16.2 Data and Safety Monitoring ........................................................................................... 28 
 
17.0 PROTECTION OF HUMAN SUBJECTS .......................................................................... 31 
 
17.1 Privacy .......................................................................................................................... 31 
 
17.2 Serious Adverse Event (SAE) Reporting ....................................................................... 31 
 
18.0 INFORMED CONSENT PROCEDURES .......................................................................... 32 
 
19.0 REFERENCES ................................................................................................................. 33 
 
20.0 APPENDICES .................................................................................................................. 36 


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1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 
 
Study Title: Immunotherapy for the treatment of breast cancer related upper extremity lymphedema 
(BCRL) 
 
Duration: All study participants will be followed for 7 months 
 
Background: 
 
Over the past decade, improved understanding of the pathologic processes that regulate a 
variety of chronic disorders has made it possible to devise targeted treatment options that greatly 
reduce the morbidity and treatment costs of these diseases. The purpose of this proposal is to 
develop a similar strategy for patients who suffer from breast cancer related lymphedema (BCRL) 
using a monoclonal antibody targeting the pathological process of this disease. This proposal is a 
direct bench to bedside translation of NIH funded research completed in our laboratory elucidating 
the pathological mechanisms of lymphedema.1-5 
 
Lymphedema is a common and morbid complication of breast cancer treatment developing 
in 1 in 3 women who undergo axillary lymph node dissection.6,7 Lymphedema also occurs in 
approximately 4-9% of women who undergo sentinel lymph node biopsy8,9 and conservative 
estimates suggest that 5-7 million Americans suffer from this disorder.10   In these patients, damaged 
lymphatic circulation results in lifelong swelling and fibroadipose tissue deposition in the affected 
extremity. These pathological changes lead to impaired quality of life, functional deficits, and 
development of severe infections necessitating hospital admission for intravenous antibiotics.11 
However, despite the fact that lymphedema is common and morbid, treatments for this disorder are 
palliative and rely exclusively on compression to prevent swelling and progression of symptoms. 
Importantly, there have been few advancements in the treatment of this disorder, and to date, there 
are no proven targeted treatment options designed to address the pathologic process using a 
mechanistic approach. The proposed study is designed to address these shortfalls and aims to 
translate our preclinical findings in the laboratory elucidating the cellular and molecular mechanisms 
of lymphedema. 
 
Using a variety of animal models, as well as tissue biopsy specimens obtained from patients 
with BCRL, we have previously shown that CD4+ cells play an important role in the pathology of this 
disease by regulating tissue fibrosis and lymphatic dysfunction.1-5  We have shown that similar to 
other fibroproliferative disorders, differentiation of naive CD4+ cells to the T-Helper 2 (Th2) 
phenotype is necessary for this pathology. More importantly, we have shown that targeted blockade 
of Th2 differentiation using monoclonal antibodies (mAbs) directed against interleukin 4 (IL4) and 
interleukin 13 (IL13) markedly decreases the pathological changes of lymphedema in a mouse 
model resulting in significantly decreased fibrosis, decreased adipose deposition, and improved 
lymphatic function.3   This is important because IL4/IL13 blockade using mABs is currently clinically 
used in phase I and phase II studies as an experimental treatment for a variety of fibroproliferative 
disorders including pulmonary fibrosis, keloids, liver fibrosis, kidney fibrosis, asthma, eosinophilic 
esophagitis, among others. These once a month treatments have been well tolerated in both animal 
and human studies with no major adverse events reported. Thus, the use mABs for the treatment of 
lymphedema would be similar to FDA approved treatment options for other chronic disorders such 
as plaque psoriasis and rheumatoid arthritis. These pharmaceutical treatments are a paradigm shift 
in the treatment of lymphedema providing a non-compressive and targeted therapeutic option for 


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patients who suffer from this disease. If the current trial is successful, our plan would be to proceed 
with multicenter trials for phase II and III clinical trials. 
 
Study Objectives: Our primary objective is to evaluate the efficacy of QBX258 in reducing arm 
volume excess in women with stage I-II BCRL. QBX258 is a compound developed by Novartis 
Corporation and is a combination of 2 antibodies that inhibit the bioactivity of IL4 and IL13. 
 
Our secondary objectives are to analyze tolerability and pharmacokinetics of QBX258, evaluate 
the efficacy of drug therapy in decreasing fluid content and fibrosis of the affected extremity, 
determine how this treatment changes quality of life measures using validated quality of life surveys, 
and to elucidate the histological changes in lymphedematous tissues by analyzing skin biopsies 
obtained before and after treatment. 
 
Patient Population: Women ages 18 to 70 who suffer from unilateral stage I or II BCRL as defined 
by the America Society of Lymphology (spontaneously reversible or irreversible lymphedema in 
which the tissue has a spongy consistency with mild to moderate pitting and mild to moderate 
fibrosis of the skin) with a minimum volume excess of 300 mL as compared with the normal upper 
extremity. 
 
Study Design: This will be a single arm, open label pilot study designed to test the efficacy of 
QBX258, a combination of 2 humanized monoclonal antibodies that inhibit the bioactivity of 
interleukin 4 and interleukin 13, for the treatment of stage I or II BCRL.  Patients who meet the 
inclusion criteria will be recruited to the study and baseline lymphedema measurements will be 
performed by a licensed physical therapist.  Patients will then be treated with QBX258 once every 4 
weeks for 4 treatments followed by repeat measures performed within 21 days of the final treatment 
dose. Washout measurements, based on the known pharmacokinetics of monoclonal antibody 
treatment, will be performed 16-20 weeks after the final dose of QBX258 to analyze changes after 
withdrawal of treatment (treatment half life is 4 weeks, therefore 16-20 weeks after last treatment is 
sufficient for complete clearance). During the course of treatment and washout periods, patients will 
continue their usual routine for lymphedema care including the use of skin care products and 
compression garments according to their pre-treatment directions. However, to avoid potential 
confounding effects, patients will avoid the use of intermittent pneumatic compression devices, 
manual lymphatic massage by a physical therapist, laser treatment, or treatment with high 
compression short stretch bandages during the study period.  It is important to note that although 
these modes of treatment are used commonly for lymphedema, the standard of care for the 
treatment of this disease is skin care and compression garments.  In fact, a recent review of the 
literature has shown that these adjunctive treatments have no statistically significant benefit in the 
treatment of lymphedema in the vast majority of well controlled studies when compared to standard 
therapy.12 


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The plan and schema for the study are summarized below. 
 
 
 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS 
 
Primary objective: 
 
• 
Evaluate the efficacy of QBX258 in reducing arm volume excess in women with 
unilateral stage I or stage II BCRL with a minimum volume difference of 300 mL between 
the normal and lymphedematous limb. 
 
Secondary objectives: 
 
• 
Evaluate the efficacy of QBX258 in decreasing fluid content of the affected extremity 
(bioimpedance measurements) 
• 
Examine changes in skin elasticity/fibrosis in response to treatment (skin tonometry). 
• 
Examine how this treatment changes quality of life measures using validated quality of 
life surveys (ULL-27) 
• 
Examine the histological changes in lymphedematous tissues as compared with normal 
tissues by analyzing skin biopsies obtained before and after treatment. 
• 
Analyze tolerability of QBX258 treatment 
• 
Analyze pharmacokinetics of QBX258 treatment 
 
 
 
3.0 
BACKGROUND AND RATIONALE 
 
Targeted monoclonal antibody treatments have revolutionized the treatment of a variety of 
chronic disorders. Over the past decade, improved understanding of the pathologic processes 
that regulate a variety of disabling chronic disorders has made it possible to devise targeted 
treatment options that greatly reduce the morbidity and treatment costs of these diseases.  For 
example, patients with rheumatoid arthritis, chronic plaque psoriasis, ankylosing spondylitis, 
inflammatory bowel disease, and psoriatic arthritis have achieved significant treatment benefits with 
reduced pain, improvements in disease status, decreased hospitalization, and reduced need for 
chronic steroid use.  The purpose of this proposal is to develop a similar strategy for patients who 
suffer from breast cancer related lymphedema (BCRL) using a monoclonal antibody that is targeted 
to the pathological process of this disease. 


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Lymphedema is a common and morbid complication of cancer treatment.  Lymphedema is a 
dreaded complication of breast cancer treatment occurring in 33-50% of patients who undergo 
lymph node dissection.7 Although the number of axillary lymph node dissections performed has 
decreased with introduction of sentinel biopsy procedures, even these relatively minor injuries to the 
lymphatic system cause lymphedema in 4-9% of patients.8,9   As a result, it is estimated that 5-6 
million Americans suffer from lymphedema and as many as 25-50,000 new cases are diagnosed 
annually.10   The incidence of lymphedema is likely to increase due to increased rates of obesity, use 
of radiation therapy, and an aging population since these variables independently increase the risk 
of this complication.13-15 In addition, improved cancer treatment will also increase the burden of 
lymphedema as the development of this complication and survival are directly correlated. 
 
 
Patients with lymphedema complain of pain, heaviness, and decreased arm function. These 
changes signficantly decrease patient reported quality of life and are a significant source of anxiety 
and depression.16,17   Some patients develop frequent and often severe infections of the affected 
extremity requiring hospitalization and antibiotic therapy.11,18    In fact, many patients consider their 
lymphedema as worse than their cancer diagnosis because the latter was finite and resolved with 
treatment while lymphedema is chronic and progressive. 
 
 
Treatment of lymphedema is palliative.  Despite the fact that lymphedema is common and a 
major source of morbidity, there are no proven preventative or curative options. Surgical and 
medical treatments have been reported, however, the results of these studies have been variable 
and in most cases disappointing. As a result, treatment is palliative in nature with the hope of 
preventing disease progression rather than achieving a cure.  Patients are required to constantly 
wear tight fitting, uncomfortable compression garments designed to prevent fluid accumulation. 
Physical therapy treatments are also performed in some cases and are time intensive (4-6 week 
treatment course for an hour a day and 24/7 wrapping with bandages) and expensive (more than 
$10,000/year by one conservative estimate).17   These facts, together with denial of service by many 
insurance companies for garments or therapy, leads to significant rates of non-compliance and 
disease progression. 
 
 
Etiology of lymphedema remains unknown. Development of effective treatments for lymphedema 
has been hampered by the fact that the etiology of this disorder remains unknown. It is unclear for 
instance, why an identical operation leads to lymphedema in some patients and not others. 
Similarly, it is unknown why even trivial lymphatic injury in the form of sentinel lymph node biopsy 
can result in significant lymphedema. Perhaps the most perplexing aspect of lymphedema is the fact 
that progressive arm swelling in most cases occurs in a delayed fashion, usually 1-5 years after 
surgery.19    Thus, although lymphatic injury is clearly the initiating event, the pathologic events that 
follow and lead to the development of lymphedema in a subset of patients remain unknown. This 
gap in our knowledge serves as a significant barrier to the development of targeted, rational 
treatment methods for this disabling and common disorder. 


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Fibrosis is a key regulator of pathology in lymphedema.  Recent studies in our lab have shown 
that fibrosis is a key pathologic process and may serve as a “second hit” following lymphatic injury 
ultimately leading to the development of lymphedema.1,2,4,20   This hypothesis is supported by the fact 
that fibrosis is a hallmark of lymphedema clinically and progression of disease is characterized by 
deposition of fibroadipose tissues and replacement of collecting lymphatic vessels with proliferative 
smooth muscle cells with luminal obliteration.21 In addition, it is well recognized that fibrosis is a 
common cause of end-organ failure in a number of other organ systems including liver, lung, skin, 
kidney, and heart suggesting that lymphedema may simply represent “end-organ failure” of the 
lymphatic system due to fibrosis.22    Fibrosis also provides a rationale for the delayed development 
of lymphedema since the progressive abnormal collagen deposition necessary to cause organ 
dysfunction takes time to accumulate. This hypothesis is also supported by preclinical studies in our 
lab demonstrating that interventions designed to decrease tissue fibrosis in lymphedema potentially 
increase lymphatic function and decrease the pathological consequences of lymphatic injury in a 
variety of mouse models.1-5,20,23 
 
 
Lymphedema results in chronic CD4+ cell inflammation.  Based on our hypothesis that 
lymphedema is fibrosis related end-organ failure of the lymphatic system, our lab has spent the last 
6 years studying the mechanisms that regulate fibrosis in lymphedema. Using mouse models and 
clinical biopsy specimens obtained from patients who suffer from BCRL, we have shown that 
lymphedema, similar to other fibroproliferative diseases, results in chronic tissue inflammation.3  We 
have shown that the majority of inflammatory cells that are present in lymphedematous tissues are 
CD4+ cells and that the severity of lymphedema positively clinically correlates with the degree of 
CD4+ cell inflammation.3   In addition, we have shown that similar to other fibrotic disorders, CD4+ 
cells present in lymphedematous tissue have a mixed T-helper 1 (Th1), T-helper 2 (Th2) 
phenotype.2,5   This is important because previous studies have shown that Th2 cells produce 
profibrotic cytokines such as interleukin 4 (IL4), interleukin 13 (IL13), and transforming growth factor 
beta 1 (TGF-B1). These molecules activate a diverse array of pathways that increase collagen 
synthesis, decrease matrix turnover and remodeling thus resulting in replacement of functional 
parenchyma with scar.22 
 
 
CD4+ cell inflammation and differentiation to Th2 phenotype plays a key role in the pathology 
of lymphedema. We have shown that depletion of CD4+ cells with neutralizing antibodies or loss of 
CD4+ cells in CD4 knockout mice prevents development of lymphedema in our mouse model.5,23 
More importantly, we have shown that blockade of Th2 differentiation with neutralizing antibodies 
directed against IL4 or IL13 not only prevents development of lymphedema after lymphatic injury but 
also can reverse pathological changes in established lymphedema.3   Animals treated with just 3 
doses of antibodies demonstrated marked reversal of tissue fibrosis, had significantly increased 
lymphatic function, and decreased chronic inflammation.  More recently,  in collaboration with our 
colleagues at MD Anderson Cancer Center, we have compared tissue biopsy samples before and 6 
months after lymphatic bypass surgery (a treatment that decreases lymphatic fluid stasis) and have 
found that subjective and objective improvements with these surgical treatments correlate with 
decreased CD4+ cell inflammation, decreased fibrosis, and decreased hyperkeratosis (a clinical 
hallmark of lymphedema).24 


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Taken together, these preclinical and clinical studies strongly suggest that the pathology of 
lymphedema is related to chronic CD4+ cell inflammation, differentiation to Th2 phenotype, and 
tissue fibrosis. Therefore, the use of antifibrotic treatments represents a novel and  targeted 
treatment of this common and morbid complication of cancer treatment. This paradigm shift in the 
treatment of lymphedema provides numerous applications and novel treatment strategies for a 
disease that has previously been primarily treated with dubious preventative measures and palliative 
treatment options. 
 
 
Th2 responses are involved in other fibroproliferative disorders.  Despite differences in 
parenchyma and function, the mechanisms that regulate fibrosis in a variety of organ systems 
including the lung, liver, kidney, and skin are largely conserved and dependent in large part on Th2 
cytokines. The aggregate of a large number of studies has led to the proposal of the Th2 paradigm 
hypothesis by Wynn and colleagues postulating that Th2 responses, as we have observed in 
lymphedema, are a major pathologic response in fibroproliferative disorders.22,25 
These studies 
have led to a application of Th2 blockade in phase I and II clinical trials for the treatment other 
fibrotic disorders including pulmonary fibrosis, keloids, eosinophilic esophagitis, and asthma among 
others.  These studies have focused on the use of monoclonal antibodies against IL4 or IL13 (or 
both) since the use of targeted immunotherapy has been highly successful in a variety of diseases 
including breast cancer (herceptin), melanoma, psoriasis, rheumatoid arthritis, among others. 
Therefore, based on this rationale in this protocol we propose to use a monoclonal IL4/IL13 
neutralizing antibody for the treatment of lymphedema. 
 
 
Blockade of Th2 responses is oncologically safe. T cell resposes in general, and Th2 
differentiation in particular are known regulators of breast cancer tumorigenesis.26,27   Previous 
studies have shown that breast tumors are infiltrated by Th2 cells that strongly express IL4 and IL13 
and that these cytokines prime tumor development by directly interacting with tumor cells, inhibiting 
dendritic cell responses, and regulating expression of cancer cell differentiation markers.26,28,29 Other 
studies have shown that activation of IL4/IL13 signaling pathways increases breast cancer invasion 
and propensity for lung metastasis.30   In addition, several studies have shown that blockade of IL4 
and IL13 with neutralizing antibodies (similar to the approach proposed in this application) inhibit 
tumor growth and metastasis in a variety of tumor types including breast cancer.26,27   These findings 
have led some authors to propose that blockade of Th2 responses may be a viable strategy as 
either a mainstream or alternative method for the treatment of breast and other cancers.31 This 
conclusion is further supported by other studies demonstrating that blockade of Th2 responses 
increases tumor surveillance by immune cell types in a variety of tumors.32-34    Finally, in addition to 
the wealth of experimental data cited above supporting our hypothesis that blockade of Th2 
responses does not increase the risk of breast cancer development, growth, or metastasis, there 
has been no evidence of carcinogenic potential for QBX258 or its component antibodies in long-term 
repeat dose toxicity or preclinical primate studies (performed up to 6 months in duration).   These 
facts together lead us to conclude that the use of QBX258 and resultant IL4/IL13 blockade in breast 
cancer survivors is oncologically safe. 


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Volume measurements are the gold standard method by which efficacy of treatment for BCRL 
is measured.  Previous studies have shown that arm volume measurements over short periods of 
time (as long as 1 year) remain relatively stable unless the patient experiences an acute 
exacerbation resulting from an infection or cellulitis.  For example, Shaw and colleagues in a study 
on the effect of weight loss on BCRL found very little spontaneous changes in limb volumes in 
patients relegated to the control (i.e. no weight loss) group.35   Previous studies have also shown that 
conservative measures that patients use such as compression garments or self massage also do 
not spontaneously decrease arm volumes; rather, these approaches are designed to prevent 
progression of disease.36   Therefore, spontaneous decreases in arm volumes without a clinically 
signficant intervention is unusual. 
 
Numerous studies have shown that volume measurements have high intrarater/interrater and 
test-retest reliability (intraclass correlation coefficient=0.997) of perometer measurements37,38 able to 
detect even relatively modest changes in arm volume with a high degree of sensitivity and specificity.   
Therefore, we expect that changes in arm volume measurements will be a sensitive primary outcome 
measure to analyze therapeutic interventions for BCRL.  In addition, based on a comprehensive 
review of the literature on previous studies reporting positive outcomes in lymphedema treatment 
using various treatment modalities (e.g. laser, pneumatic pump devices), we have found that 
reductions in arm volumes of 20-30% after treatment are considered to be a 
clinically significant endpoint.35,39-49    Based on this analysis, we conclude that novel treatments such 
as Th2 blockade as proposed in this trial would be clinically relevant if they can decrease arm 
volumes by 20-30%. 
 
 
 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
 
4.1 
Design 
 
This will be a single arm, open label design pilot study, aiming to test the efficacy of QBX258, 
a combination of two fully human monoclonal antibodies that neutralize the biologic activity of 
interleukin 4 and interleukin 13 (IL4/IL13), for the treatment of stage I or II breast cancer related 
upper extremity lymphedema (BCRL). Patients with stage I or II BCRL (n=22) who meet the 
inclusion and exclusion criteria (see below) will be recruited to the study and baseline lymphedema 
measurements will be performed.  Based on these measurements, women with a minimum volume 
excess of 300 mL between the normal and lymphedematous arm and at least 6 months postop from 
axillary lymph node dissection will be eligible for the study. We have elected to limit the study to 
patients with stage I or II lymphedema since previous studies have shown that antifibrotic strategies 
are most effective in early stage disease (i.e. when end organ failure is not complete). We have 
chosen not to include patients with latent (stage 0) lymphedema since these patients typically have 
very little difference in arm volumes between the lymphedematous and normal limbs thus making it 
difficult to analyze the relative effectiveness of our treatment on our primary outcome measure 
(volume reduction).  Similarly, we have chosen not to include patients with end stage (stage III) 
lymphedema since it is unlikely that the pathologic changes that have occurred in these cases 
(usually over the course of many years) will be reversed with the short term treatment as proposed 
in this study. 


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Once enrolled, patients will be treated once every 4 weeks for 4 treatments with QBX258 
followed by analysis of our primary and secondary outcome measures within 21 days of the last 
dose of antibody treatment. We will also evaluate outcome measures after a 16-20 week washout 
period to analyze the effect of treatment withdrawal on recurrence of symptoms. During the course 
of the study, patients will continue the use of standard therapy for lymphedema (compressive 
garments, aerobic exercise, weight lifting) according to their pre-treatment directions. However, to 
avoid potential confounding effects of manual lymphatic massage or intense physical therapy, these 
interventions will not be performed in the active treatment period. 
 
4.2 
Intervention 
 
In preclinical studies we have shown that blockade of Th2 cellular differentiation using IL4 or 
IL13 antibodies markedly decreases the pathological effects of lymphedema and improves lymphatic 
function.3,5   Therefore, the objective of this study is to determine if a similar treatment approach is 
effective for the treatment of BCRL, the most common cause of lymphedema in the United States 
and Western countries. Based on our inclusion and exclusion criteria (see below) women with 
stage I or II BCRL with a minimum volume excess of 300 mL and at least 6 months postop from 
axillary lymph node dissection will be recruited for treatment with QBX258 a monoclonal 
IL4/IL13 neutralizing antibody for once every 4 weeks for 4 treatments.  Objective/subjective 
measures of treatment as well as the pharmacokinetics and tolerability of treatment will be 
evaluated. 
 
Primary objective: 
 
 
 
1) 
Arm volume calculations. These measurements will be performed using a perometer 
(Volumerter; Bosl Medizintechnick, Aschen Germany), a non-invasive infra red scanner that 
reproducibly measures the diameter of the extremity at multiple points and calculates arm volumes 
using the truncated cone formula. The perometer has been shown to have excellent 
intrarater/interrater and test-retest reliability (intraclass correlation coefficient=0.997) with a greater 
than 95% specificity for lymphedema.37,38   Analysis of arm volume is considered the “gold-standard” 
for measurement of fluid and adipose accumulation in patients with lymphedema and is used in most 
lymphedema studies to evaluate response to treatment.  Duplicate measurements will be performed 
at baseline following enrollment (0-2 weeks prior to initiation of treatment).  Measurements will be 
performed between the hours of 8AM and 5PM and will be performed by a licensed physical 
therapist at MSKCC.   Volume excess will be calculated as compared with the normal upper 
extremity.  Duplicate arm volumes will be re-measured within 21 days after last dose of QBX258. 
Finally, washout measurements will be performed 16-20 weeks following the last dose of QBX258. 


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Secondary objectives: 
 
 
1) 
Bioimpedance measurements will be performed using the ImpediMed L-DexTM U400 
device.  This device is FDA approved for measurement of tissue dielectric constant and calculates 
the fluid content of tissues using differential transmission of low voltage electrical current.50 
Bioimpedance has very high sensitivity (100%) and specificity (98%) for lymphedema as compared 
with limb volume measurements.51 This approach is widely used commercially in consumer 
electronics as a means of calculating body fat composition and has no reported side effects. The 
relative fluid content of the affected extremity is calculated by comparing the ratio of the normal and 
lymphedematous limbs using single use gel pads similar to those used for an EKG. Bioimpedance 
measurements have been shown to be highly sensitive for detecting changes in fluid content in 
patients with stage I and II lymphedema.50   Bioimpedance measurements will be performed at the 
same sessions as the volumetric analysis. 
 
2) 
Skin fibrosis/elasticity will be assessed using a non-invasive device (Elastimeter; Delfin 
Technologies).   Skin tonometry measurements are a sensitive means of analyzing response to 
treatment and progression of disease in patients with lymphedema.40,52 The ICC for test-retest and 
interrater reliability of tonometry ranges between 0.69-0.88 and tonometry is considered to have very 
high reliability.53   The Elastimeter is a battery operated device that measures the force required to 
indent the skin at a given location. The indentation that is measured is minor and monitored with 
built in force sensors that measure skin elasticity based on a low level deformation force that 
enables instantaneous measurements. There is no change in skin structure and the force is applied 
for less than 3 seconds. Skin fibrosis/elasticity measurements will be performed at the same 
sessions as the volumetric analysis. 
 
3) 
Quality of life survey (ULL 27) will be administered at the same sessions as volumetric 
analysis.  The ULL27 is validated for patients with lymphedema, is simple to complete, and enables 
us to track patient reported outcomes of lymphedema.54,55 The scale is highly precise, accurate, and 
sensitive to changes in symptoms. The ULL 27 is comprised of 27 items divided into three 
dimensions: ‘physical’ (15 items), ‘psychological’ (seven items) and ‘social’ (five items). The recall 
period is short (previous 4 weeks) enabling us to compare pre and post treatment quality of life 
measures. In addition, the ULL27 has been shown to have a high degree of sensitivity for quantifying 
clinical improvements in lymphedema symptoms. The questionnaire and scoring methods are 
appended to this protocol. 
 
4) 
Histologic outcomes. Histologic analysis of tissue changes after targeted therapy is an 
important part of this proposal as it will enable us to perform mechanistic analysis of response to 
Th2 blockade. We have performed this analysis previously on nearly 200 patients in collaboration 
with our colleagues at Stanford University, MD Anderson, and University of Chicago and have 
shown that the biopsy procedure is safe (no adverse effects including infections or wound healing 
complications in any of the patients), simple to perform in an outpatient setting, and extremely well 
tolerated (i.e. no need for pain medications). We have published this protocol and results from this 
analysis in 5 peer reviewed manuscripts.2,3,24,56,57  This analysis has enabled us to validate our 
preclinical models and, as proposed in the current study, will enable us to analyze fibrotic and 
inflammatory responses to treatment.   Because of the important mechanistic information that will be 
provided by the biopsies, the pre and post treatment biopsy procedures will not be optional. 


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5 mm punch biopsies will be obtained from the affected and normal arms. The exact location of the 
biopsy will be determined based on physical exam and will correspond to the location judged to have 
the most edema, fibrosis, and hyperkeratosis.  The hand will not be used for biopsy sites. The 
same location on the arm will be biopsied in both normal and affected limbs.  Histologic analysis will 
include fibrosis (collagen deposition, scar index), inflammation (CD4+ cells, Th2 populations, 
macrophages), hyperkeratosis, and mast cells.  Skin biopsies will be performed at baseline after 
enrollment (0-2 weeks prior to initiation of treatment) and after conclusion of treatment (within 21 
days after last dose of QBX258)  under sterile conditions by Dr. Mehrara or Dr. Dayan in the plastic 
surgery outpatient office. We will use the protocol that we have previously used in our collaborations 
with Stanford University, MD Anderson, and University of Chicago.2,3,24,56,57  Briefly, patients will be 
treated with a dose of antibiotics (Keflex 500mg or clindamycin 900mg PO if allergic to PCN) 1 hour 
before procedure.  A 5 mm punch biopsy will be performed under local anesthesia from the exact 
location in the normal and lymphedematous upper extremity as previously reported. The resulting 
wound will be closed with a single 5-0 suture and standard wound care instructions will be provided. 
The patient will be seen in followup 3-21 days to assess proper wound healing. 
 
5) 
Tolerability of treatment. In general, treatment with QBX258 as well as its individual 
component parts (VAK694 and QAX576)  in both preclinical and clinical studies have been well 
tolerated (see section 11 Toxicology).  There have been no serious adverse effects directly related 
to either QBX258 or its component monoclonal antibodies.  In addition, minor to moderate adverse 
effects have all resolved spontaneously without long-term sequelae.  An objective of this study will 
be to continue these observations and report SAEs or AEs if they were to develop. 
 
6) 
Pharmakokinetics (PK) of QBX258. A number of clinical and primate animal studies have 
evaluated the PK of QBX258 component parts (VAK694 and QAX576). In addition, the PK of 
QBX258 has been analyzed in one clinical study as well as long term primate animal studies. 
Therefore, a secondary aim of this study is to analyze the PK of QBX258 treatment. 
 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS 
 
• 
QBX258 is the combination of two antibodies (VAK694 and QAX576) developed by Novartis 
Corporation to inhibit bioactivity of IL4 and IL13. VAK694 is a fully human monoclonal IgG1k 
antibody (mAb) with a specificity and high affinity for IL4 (KD= 7pM). QAX576 is a fully 
human IgG1k mAB directed against IL13 (KD = 139pM).   The drug (QBX258) as well as 
drug administration equipment (e.g. pumps, tubing) and pharmacy instructions will all be 
supplied by Novartis. 
• 
QBX258 as a combined injection of QAX576 and VAK694 is administered IV and has been 
tested in rhesus monkeys, marmoset monkeys, and humans. 
• 
The Investigational New Drug Application (IND) has been submitted by Novartis Corporation 
and approved to proceed by the FDA (IND #107,646).  Memorial Sloan Kettering Cancer 
Center will cross reference this IND held by Novartis Corporation. 


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Dose Calculation 
 
The doses of the combination antibody components of QBX258 to be used in the current study are 
based on previous/ongoing clinical trials with VAK694 (3mg/kg) and QAX576 (6mg/kg). 
 
In a clinical study of QBX258, sequential i.v. doses of VAK694 (3 mg/kg) and QAX576 (0, 0.3, 1, 
3 and 6 mg/kg, 1 hour after VAK694) were administered on a single occasion. As expected for 
IgG1 type antibodies, the mean systemic  clearances for VAK694 and QAX576 were low (4.1 
mL/day/kg and 3.0 mL/day/kg, respectively). The systemic clearance for VAK694 was not 
modified  upon QAX576 administration, and that for QAX576 was consistent with values observed 
in studies where QAX576 was administered alone. The mean terminal phase half-life for VAK694 
was 23.1 days and not  significantly affected upon QAX576 administration. The mean half-life for 
QAX576 was also  as expected (22.8 days) and in the range of values previously observed when 
QAX576 was administered alone. Given in combination on one occasion, VAK694 and QAX576 
demonstrated  typical IgG1 type kinetics and very similar profiles as compare to when given alone. 
Because they also demonstrated linear PK behaviour, no pharmacokinetic interactions are 
expected as well when these two entities will be administered together on multiple occasions. 
 
Both VAK694 (3mg/kg) and QAX576 (6mg/kg) in the doses chosen for the current study have been 
generally safe and well tolerated in other clinical trials for treatment periods up to 6 months. 
For both antibodies, adverse events have been mild to moderate and have resolved spontaneously 
without sequelae. There have been no study drug-related SAEs for VAK694. SAEs that have been 
suspected to be related to QAX576 include a possible drug interaction with acetaminophen and 
an occurrence of  Ramsay-Hunt syndrome. There were no adverse event with an expected causal 
relationship  and no fatal adverse events with a suspected causal relationship. No significant 
immunogenicity has been observed. 
 
Preparation and packaging 
 
QAX576:  The drug product is a white, solid lyophilisate in 10 mL colorless glass vials with 
rubber stopper and aluminum flip-off cap  to  be  reconstituted  with  water  for  injection  (WFI). 
The powder for solution for infusion/injection contains QAX576 in a formulation of histidine (pH 6.0 
± 0.5), sucrose, glycine and Polysorbate 80. The formulation does not contain a preservative as 
it is to be used for single-dose administration only. It is a solid lyophilisate powder for solution for 
infusion/injection. It is reconstituted with 1.0 mL or 3.4 mL sterile water for injection to yield a solution 
of 150 mg/mL or 50 mg/mL QAX576, respectively, and is used for single dose administration only. 
 
VAK694: 150 mg is a lyophilisate to be reconstituted with 1.0 mL or 3.4 mL sterile water for 
injection to yield a solution of 150 mg/mL or 50 mg/mL VAK694, respectively. The lyophilisate is 
formulated with histidine (pH 6.0 ± 0.5), sucrose, arginine hydrochloride and polysorbate 20. The 
formulation does not contain a preservative as it is to be used for single-dose administration only. It 
is a lyophilisate to be reconstituted with 1.0 mL or 3.4 mL sterile water for injection to yield a 
solution of 150 mg/mL or 50 mg/mL VAK694, respectively. 
 
QAX576 and VAK694 are dosed together as a single infusion. Note that VAK694 and 
QAX576 Powder for Solution for Infusion are to be reconstituted separately. The resulting 
VAK694 and QAX576 Concentrates for Solution for Infusion have to be diluted into the same infusion 
bag sequentially to yield ready-to-use QBX258 Solution for Infusion. 


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Reconstituted VAK694 and QAX576 Powder for Solution for Infusion should not be mixed with 
each other before injection of the Concentrates for Solution for Infusion into the  infusion bag. 
Investigational Product QAX576 and VAK694, will be supplied by Novartis Drug Supply Management 
as patient specific open label bulk medication. 
 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY 
 
We will use the following inclusion and exclusion criteria to identify potential study 
candidates. 
 
6.1 
Subject Inclusion Criteria 
 
• 
Women 18-70  with unilateral stage I or II BCRL 
• 
Volume difference of at least 300 mL between the normal and lymphedematous limb 
based on perometry evaluation 
• 
BMI of 18-30 
• 
No current evidence of breast cancer 
• 
At least 6 months postop from axillary lymph node dissection 
• 
Women of childbearing potential must be willing to use a highly effective form of 
contraception for the duration of the trial and for 18 weeks (5 half-lives) after the last dose 
of treatment 
 
6.2 
Subject Exclusion Criteria 
 
• 
Bilateral lymphedema or history of bilateral axillary lymph node dissection 
• 
Recent history of cellulitis in the affected extremity (within last 3 months) 
• 
Recurrent breast cancer or other malignancy 
• 
Current (within last month) use of chemotherapy for breast or other malignancy 
• 
Currently receiving adjuvant trastuzumab (Herceptin) 
• 
Current (within last 3 months) use of radiation for breast or other malignancy 
• 
Recent (within last month) or current intensive MLD and/or short stretch bandage use 
• 
Unstable lymphedema (i.e. worsening symptoms/measurements in the past 3 months) 
• 
Pregnant or nursing (lactating) women 
• 
Stage III lymphedema 
• 
Patients that take acetaminophen (paracetamol) chronically, i.e. more than 1 g/day for 
more than 3 out of 7 days, or more than 2 g/ day for more than 1 day out of 7 days 
• 
Use of other investigational drugs at the time of enrollment, or within 30 days or 5 half- 
lives of enrollment, whichever is longer 
• 
History of hypersensitivity to any of the study drugs or to drugs of similar 
chemical classes (e.g. monoclonal antibodies, polyclonal gamma globulin, polysorbates). 


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7.0 
RECRUITMENT PLAN 
 
Potential research subjects will be identified by treating physicians in the Plastic Surgery, 
Breast Surgery, Breast Medicine, and rehabilitation medicine services.  If the treating physician is 
also an investigator on the protocol, then s/he will discuss the study with the patient. Otherwise the 
patient will be referred to a study investigator for evaluation. It is estimated that more that 30% of 
women who undergo axillary lymph node dissection for the treatment of breast cancer go on to 
develop lymphedema.  Because these procedures are performed commonly (approximately 
150/year despite the widespread use of sentinel lymph node biopsy) a large number of patients go 
on to develop lymphedema. In addition, because lymphedema is a lifelong condition and our 
treatments for breast cancer have increased survival, a large number of breast cancer survivors 
suffer from lymphedema thus providing a large pool of patients who are eligible for the trial. 
Therefore, patients will be identified as they present to the individual services. To increase 
awareness of the trial, the clinical trial will also be listed on clinicaltrials.gov.  Because breast cancer 
is most commonly diagnosed in women, we will focus our recruitment efforts to women. 
 
 
During the initial assessment, the patient may be asked to provide certain health information 
that is necessary for the recruitment and enrollment process.  Specifically, the diagnosis, current 
treatments, stability, and symptoms of lymphedema will be queried. In addition, the patient will be 
asked about the current status of their disease, history of lymphedema related infections, history of 
fibroproliferative disorders (e.g. pulmonary fibrosis, cirrhosis, keloids), history of axillary surgery, and 
the current treatment plan for their lymphedema. The investigator/research staff may also review 
portions of her medical records at MSKCC in order to further assess eligibility. They will use the 
information provided by the patient and/or medical record to confirm that the patient is eligible and to 
contact the patient regarding study enrollment. If the patient is ineligible for the research study, the 
research staff will destroy all information collected on the patient during the initial conversation and 
medical records review, except for any information that must be maintained for screening log 
purposes. If the woman agrees to study participation, a consenting individual (listed below in section 
15.1) will obtain informed consent from the patient until a goal of 22 eligible patients are entered into 
the study in order to have 20 evaluable patients. 
 
In the majority of cases, we expect that the initial contact with prospective subjects will be 
conducted by the treatment team or investigators/research staff working in consultation with the 
treatment team. The recruitment process outlined in this application presents no more than minimal 
risk to the privacy of potential subjects and minimal PHI will be maintained as part of a screening 
log.  As a result, we request a (partial) limited waiver of authorization in order to (1) 
review medical records to identify potential research subjects and obtain information relevant to the 
enrollment process; (2) Discuss potential enrollment with patients; (3) handling of PHI contained 
within those records and provided by the potential subjects; and (4) maintaining information in a 
screening log of patients approached (if applicable). 


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Once a suitable candidate is identified and volume difference of at least 300 mL between the 
 
 
normal and lymphedematous limbs is confirmed using perometry, the patient will be offered the 
opportunity to join the study.  The discussion process will include the rationale for the study including 
the pathological processes involved, the goals of the study, the length of the study, measurements 
an analyses to be performed, the expected time commitment and number of clinic visits. 
Investigators will discuss with the patient that the proposed trial is a short-term treatment rather than 
a cure for lymphedema and that we expect that the symptoms of lymphedema will recurr once 
treatment has been terminated. The risks of the treatment including potential adverse reactions, 
transfusion/infusion reactions, and hypersensitivity reactions will be discussed in detail with the 
patient. In addition, we will discuss the time commitment of the protocol and schedule for followup 
visits, measurements, biopsies, and blood draws. 
 
 
 
8.0 
PRETREATMENT EVALUATION 
 
The pretreatment evaluation will aim to quantify the objective and subjective changes of 
lymphedema. This analysis will include: 
 
1)  Physical Examination will be performed to evaluate lymphadenopathy, evidence of cancer 
recurrence, and general physical health.  This will include vital signs as well as height/weight 
measurements. 
 
2)  Urine Pregnancy test will be administered prior to enrollment into the study and prior to each 
monthly drug treatment. Although QBX258 treatment has not exhibited evidence of maternal toxicity 
in multiple preclinical trials with marmoset monkeys, there was a trend towards an increased rate of 
spontaneous abortions in these studies.  However, fetuses that were born to monkeys treated with 
QBX258 had normal fetal developmental parameters and there was no evidence of teratogenicity. 
Therefore, patients capable of childbearing recruited to the study will be required to use highly 
effective birth control measures whilst participating in the QBX258 t r ia l and for at least 18 weeks ( 
5 half-lives) after the last dose of QBX258. 
 
3)  Arm volume measurements will be performed in duplicate at baseline using a perometer (Pero- 
Systems).   Measurements will be performed by a licensed physical therapist at the out patient 
physical therapy office located at 53rd and Madison Avenue between the hours of 8AM and 3PM. 
The perometer is a non-invasive infrared scanner that measures the circumference of the upper 
extremity at multiple points.  Volumes are then calculated using the truncated cone formula. This 
analysis is highly reproducible and accurate avoiding the need for traditional volume measurements 
(fluid displacement) or manual limb circumference measurements.  Volume excess will be calculated 
as compared with the normal (i.e. contralateral) upper extremity. 
 
4)  Bioimpedance measurements will be performed to compare the normal and lymphedematous limbs 
using the ImpediMed L-DexTM U400 device. The ImpediMed device is FDA approved and is used to 
estimate the fluid content of tissues based on resistance to transmission of electrical current. These 
measurements are simple to perform and are highly accurate in analyzing changes in early stage 
lymphedema. Bioimpedance measurements will be performed in duplicate at the same time as 
volume measurements. 


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5)  Skin fibrosis will be assessed at the same session as arm volume measurement using a tonometer 
 
 
(Elastimeter; Delfin Techonolgies).  Duplicate measures of a point located 10 cm above and 10 cm 
below the olecranon process on the dorsal and ventral surfaces of the limb will be recorded.  Skin 
fibrosis resulting from hyperkeratosis and fibrosis is a characteristic feature of lymphedema. 
 
6)  Quality of life survey (ULL27) will be administered upon enrollment to quantify the subjective 
measures of lymphedema. These questionnaires are validated lymphedema specific surveys and 
are simple to perform and have been used in previous lymphedema trials performed at MSKCC. 
The questionnaires will be administered within 6 weeks enrollment and prior to the start of therapy. 
 
 
 
7)  Histologic analysis.  A defining feature of lymphedema is skin fibrosis and inflammation. We have 
previously compared skin biopsy specimens from the normal and lymphedematous limbs of patients 
to analyze inflammatory changes and, more recently, to evaluate tissue changes that occur after 
lymphedema surgery. These biopsies have been performed in over 200 patients under IRB 
approved protocols by our collaborators at Stanford University, MD Anderson Medical Center, and 
The University of Chicago and have been well tolerated with minimum pain, no surgical 
complications, and most importantly no postoperative infections. 
 
The procedure will be performed using strict sterile protocol and a single pre-procedure dose 
of antibiotics.   A 5 mm punch biopsy will be obtained from the volar surface of the affected and 
normal arms. The exact location of the biopsy will be determined based on physical exam and will 
correspond to the location judged to have the most edema, fibrosis, and hyperkeratosis.  The hand 
or wrist will not be used for biopsy sites. The same location on the arm will be biopsied in both 
normal and affected limbs. The biopsy will then be fixed and embedded for histological analysis. 
This pretreatment biopsy specimen will be compared with post-treatment biopsies to analyze 
treatment efficacy for decreasing inflammation and fibrosis using our previously published protocols. 
Skin biopsies (both normal and lymphedematous arms) will be performed before and after treatment. 
 
Histologic analysis of biopsy specimens will be performed using our previoulsy published 
reports to analyze inflammation and tissue fibrosis.1-5,20,57 
Briefly, CD4+ and Th2 cells will be 
identified and quantified using immunohistochemical staining according to our previously published 
protocols.3   In addition, we will analyze the degree of tissue fibrosis using collagen staining and 
analysis of Sirius Red Birifringence (scar index) according to our previously published methods.  It is 
important to note that in our previous studies we have shown that the severity of lymphedema 
clinically is positively correlated with the number of CD4+ cells, the number of Th2 cells, and the 
degree of tissue fibrosis. In addition, in other clinical studies comparing pre and postoperative tissue 
biopsy samples in patients who underwent lymphovenous bypass procedures (a surgical treatment 
that aims to bypasses the obstructed lymphatic system to the venous circulation) we have found that 
the severity of CD4+ cell inflammation and fibrosis decreased signficantly after surgery and that this 
response correlarted with symptomatic improvement.24 
 
 
8)  Routine Blood draw. A pretreatment complete blood count and differential will be performed within 
one month of starting the trial to establish baseline values for complete blood count, basic metabolic 
panel, and liver enzymes. 
 
9)  Research Blood draw. A pretreatment PK analysis measurement blood draw will be performed. 


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10) Urine Analysis will be performed to rule out pre-existing urinary conditions. 
 
 
 
9.0 
TREATMENT/INTERVENTION PLAN 
 
Once patients are registered for the trial, they will be treated with QBX258 (VAK694 3mg/kg 
and QAX576 6mg/kg) delivered via peripheral intravenous injection once every 4 weeks (+ 1 week) 
for 4 treatments.  Intravenous access will be limited to the non-lymphedematous limb and will be 
performed using standard techniques.  Infusions will be performed at the Breast Center (BAIC, 66th 
street) and patients will monitored at the infusion center. The infusions will take approximately 2 
hours and patients will be monitored for 2 hours after the completion of infusion. As a result, we 
expect a total time of approximately 4 hours for each infusion session. Infusions will be ordered by 
medical oncologists listed on the protocol. 
 
10.0 EVALUATION DURING TREATMENT/INTERVENTION 
 
Overview of study: 
 
Study Phase 
Screening 
Baseline 
Treatment/FU 
Outcome 
Washout 
 
Weeks 
- 
-2 to 0 
0 
4 
8 
12 
12-15 
28(+3)-32 (+3) 
Inclusion/Exc. 
x 
x 
Demographics 
x 
x 
Physical Exam 
x 
x 
x 
Pregnancy Test 
x 
x 
x 
x 
x 
Evaluation of 
acute transfusion 
reaction 
x 
x 
x 
x 
Pharmacokinetics 
x 
x 
x 
x 
x 
x 
Height 
x 
Weight 
x 
x 
x 
Temperature 
x 
x 
x 
x 
x 
x 
x 
Vital signs 
x 
x 
x 
x 
x 
x 
x 
ECG 
x 
x 
CBC 
x 
x 
Metabolic panel 
x 
x 
Liver Enzymes 
x 
x 
Urine Analysis 
x 
x 
Arm Volumes 
x 
x 
x 
Bioimpedance 
x 
x 
x 
Tonometry 
x 
x 
x 
QOL 
questionnaire 
x 
x 
x 
Skin Biopsy 
x 
x 
Adverse event 
Check 
x 
x 
x 
x 
x 
x 
x 


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Pharmacokinetics 
In order to calculate the pharmacokinetics of both component antibodies of QBX258, blood 
draws will be performed from study subjects according to the following schedule: 
Initial day of dosing: Blood draw will be performed within 30 minutes after the conclusion of infusion + 
5 minutes 
Day 15 (+3 days) after 1st dose 
Days 29, 43, 57, 71, 85, 99, 113, and 141 (+ 3 days) after 1st dose;  Day 183 after 1st dose (+ 10 
days) 
Blood samples will be taken either by direct venipuncture or an indwelling cannula inserted in 
the normal (i.e. non-lymphedematous) hand or forearm vein.  At the specified time points, 4ml of 
blood will be collected in tubes with EDTA as an anticoagulant to obtain 4 aliquots of at least 0.3ml 
of plasma.  All samples will be given a unique sample number and a collection number (de-identified 
of all patient information). The actual sample collection date and time will be entered on the PK 
blood collection page. Samples will be kept upright at -70 degrees celcius on site and sent in batch 
shipments as necessary to AtlanBio for analysis (Z.I. de Brais - 1 rue Graham Bell, 44600 Saint 
Nazaire; France). The plan for PK blood collection is summarized in the diagram below. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Evaluation of acute infusion reaction and tolerability of Q AX258. 
 
The risk of anaphylaxis or  anaphylactoid reactions is present but is minimized due to fact 
that QAX576 and VAK694 are fully human monoclonal antibodies. Anaphylactic reactions are much 
less common to human mAbs than mouse, chimeric or humanized mAbs.58 


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Although very rare, if these reactions occur, they usually do so after the first or any 
subsequent intravenous administration of the drug. Therefore, vital signs will be assessed after 
initiation of infusion and repeated every hour after infusion for a total of 2 hours. Patients will 
be closely monitored and will be evaluated by staff trained in the  management of infusion reactions 
and anaphylaxis. 
 
As with any drug, there is a small chance that subjects will experience an allergic reaction 
to   the  medicine,  such  as  an  allergic  skin  rash,  or  hives.   There   may   be   unknown   or 
unforeseeable risks. We do not  anticipate that the combination of both antibodies poses a high 
risk of allergic reactions based on data with the individual components.   Nevertheless, patients will 
be contacted by telephone within 96 hours after administration of each dose of QX258 and 
queried regarding allergic reactions or systemic symptoms including rash, hives, fevers, nausea, 
vomiting, malaise, headaches, arthralgias, urticaria, and palpitations.  The telephone contact will be 
performed by the study RSA.  This contact information (person calling and patient reports) will be 
recorded in a log created for each patient at the onset of the study.   The log will be kept on a 
secure server.  Patients will be instructed to call or contact study investigators if symptoms develop 
after this period.  In addition, patients will be queried about these symptoms prior to initiation of 2nd, 
3rd, and 4th  infusions.  The patient specific log will be updated at these time points by the study 
RSA.  This plan is based on the experience with other FDA monoclonal antibody treatments (e.g. 
Remicade®) .  Patients who report symptoms or potential adverse effects will be evaluated in 
person and possible relationship to the study will be assessed. 
 
 
Examination of biopsy sites and wound healing 
 
Biopsy sites in both the lymphedematous and normal limbs will be assessed by a consenting 
physician or licensed practitioner 3-21 days after the procedure to ensure that it is healing 
appropriately and rule out evidence of infection. Any potential infections will be reported and treated 
with antibiotics. 
 
Pregnancy test 
 
Given the potential reproductive toxicity of Th2 blockade (see section below on toxicity), a 
urine pregnancy test will be administered to volunteers of childbearing age upon enrollment and 
before each infusion. 
 
Outcome measures of lymphedema treatment 
 
Outcome measures of lymphedema will be assessed as outlined above and include limb 
volume measurements, bioimpedance, skin fibrosis/elasticity, QOL surveys, and histologic analysis. 
Volumetric analysis, bioimpedance, skin fibrosis/elasticity, and QOL surveys will be assessed within 
21 days of the last dose of QBX258 and after a washout period of 16-20 weeks.  In addition, the 
patients weight will be checked at each time point. 


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11.0 
TOXICITIES/SIDE EFFECTS 
 
Identifying and reporting of toxicity or complications 
 
We will utilize the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 for 
grading of all adverse events.  A copy of the CTACE V4.03 can be downloaded from the CTEP 
home page (http://evs.nci.nih.gov/ftp1/CTCAE/About.html).  All investigators and treatment areas will 
have access to a copy of the CTCAE V4.03 
 
 
Definition of an Adverse event:  Any unfavorable and unintended sign (including an abnormal 
laboratory  finding), symptom, or disease temporally associated with the use of a medical treatment 
or procedure regardless of whether it is considered related to the medical treatment or procedure 
(attribution of unrelated, unlikely, possible, probable, or definite). [CTEP, NCI Guidelines: Adverse 
Event Reporting Requirements. January 2005;http://ctep.cancer.gov/reporting/adeers.html]) 
 
 
Definition of an SAE: Any adverse experience occurring during any part of protocol treatment and 
30 days after that results in any of the following outcomes: 
 
 
• 
Death; 
• 
A life-threatening adverse drug experience; 
• 
Inpatient hospitalization or prolongation of existing hospitalization; 
• 
A persistent or significant disability/incapacity; 
 
 
Important   medical   events   that   may  not   result   in   death,   be   life  threatening,  or   require 
hospitalization may be considered an SAE, when, based upon medical judgment, they may 
jeopardize the patient and may require medical or surgical intervention to prevent one of the 
outcomes  listed  in  the  definition.  Any  pregnancy  occurring  on  study  will  be  reported as a 
medically significant event. 
 
 
All AEs and SAEs will be reported to the IRB and sponsoring institution as outlined in 
section 17.2 below.   In the event of a grade III or IV SAE, the study will be halted until 
causality is determined. 
 
 
Patients who experience AE or SAE will be managed by the Breast medical oncologists and plastic 
surgery attendings listed on the protocol. Any potential wound healing issues or complications will 
be addressed by plastic surgery and consultation with Breast Medicine as necessary.  In the event 
that hospital admission is required for management of an SAE, patients will be admitted to the 
Plastic Surgery Service with close consultation and management with the Breast Medical Oncology 
Service. 


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Potential toxicity related to QBX258 treatment in previously conducted trials: QBX258 
has been shown to be well tolerated in both preclinical studies and human trials. In animal studies 
using Rhesus monkeys treated with escalating doses of QBX258 up to a dose of 100mg/kg, there 
were  no   QBX258  treatment-related  deaths.  There  were  no  QBX258-related  clinical  signs  or 
changes in  bodyweight, food consumption, ophthalmic examinations, ECG, heart rate or blood 
pressure.  There  were  no  effects  on  clinical  pathology,  hematology,  clinical   chemistry   and 
urinalysis investigations. There were no effects either on peripheral blood lymphocyte 
immunophenotyping parameters or on immune function (generation of a primary  and secondary T 
cell-dependent IgM and IgG antibody response to KLH). There were no effects on organ weight 
or in macroscopic or microscopic observations, including no effects  on extended histopathology 
of lymphoid organs. 
Similarly, in the first study of QBX258 in humans, sequential intravenous doses of VAK694 
(3mg/kg) and QAX256 (up to 6mg/kg) on a single occasional were safe and well tolerated. In a 
different study of 40 subjects with bronchial asthma, QBX258 treatment was well tolerated with no 
significant imbalance of adverse events between patients treated with QBX258 and placebo.  A 
single serious adverse effect was reported for a subject who was hospitalized following a snake bite 
and required hospitalization.  A second patient had an increase in CPK, however this was not 
suspected to be associated with the drug.  Most other adverse events (e,g. headache, etc) were mild 
or moderate and resolved spontaneously. 
 
The  potential  on-target  risk  of  QBX258  is  further  mitigated  by  experience  with  other 
biological compounds that targeted the actions of IL-4 and IL-13 in humans. For example, trials 
using antibodies  to IL4Ra59  and IL-1360   have been reported to be well tolerated without significant 
adverse events. 
 
Potential  toxicity  related  to  individual  components  of  QBX258  (VAK694  and 
QAX576). Because QBX258 is a combination of 2 separate monoclonal antibodies (VAK694 and 
QAX576), the known toxicity of these individual components and the combination drug are listed 
below. 
 
VAK694 has been well tolerated when administered to human subjects in doses ranging from a 
single infusion of 0.1mg/kg to healthy individuals to four sequential infusions of 3mg/kg given every 
4 weeks to subjects with seasonal allergic rhinitis.  There have been no study drug related SAEs. 
Adverse effects have been mild to moderate and have resolved spontaneously.  No significant 
immunogenicity has been observed. 
• 
Doses as high as 100mg/kg/dose (more than 30 times the dose administered in humans) 
administered once weekly for 4 weeks in cynommolgus monkeys were well tolerated with 
and no treatment or dose level related effects were observed.  There were no clinical signs 
indicative of neurobehavioral effects or quantitative electrocardiographic changes. There 
were no effects on the injection site, body weight, ophthalmology, electrocardiography, 
hematology, clinical biochemistry, immunochemistry, urinalysis, or organ weights. There 
were no spontaneous tumors. 
• 
As of July 2013, 3 VAK694 studies have been completed with one study in healthy 
volunteers and two studies in patients with seasonal rhinitis.  A total of 61 subjects have 
received VAK694. Single doses up to 1mg/kg in healthy volunteers,  multiple doses up to 
1mg/kg weekly x 3 to asymptomatic patients with allergic rhinitis, and multiple doses of 


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3mg/kg every 4 weeks x 4 in patients with seasonal allergic rhinitis were safe and well 
tolerated. 
• 
There has been a single SAE in patients treated with VAK694 (hospitalization for acute 
appendicitis) which was not considered to be related to the study drug.  Adverse events have 
been mild to moderate and have resolved spontaneously without sequela.  These included 
once case of nasal congestion, once case of pharyngolaryngeal pain, 1 patient with a 
headache, and 1 case of traumatic injury of the knee joint. 
 
 
QAX576 has been generally safe and well tolerated in doses up to 6mg/kg every three 
weeks or 10mg/kg every 4 weeks up to 6 months. SAEs suspected to be related to QAX576 include 
a possible drug interaction with acetaminophen and an occurrence of Ramsay-Hunt Syndrome. 
There were no adverse events with an expected causal relationship and no fatal adverse events with 
a  suspected causal relationship. 
 
 
• 
Doses as high as 100mg/kg/twice weekly for up to 13 weeks to marmoset monkeys (>15 fold 
of doses to humans) intravenously had no significant toxicological or local tolerability effects. 
There was no evidence of immunotoxcity.  There were no drug related changes in body 
weight, food consumptions, ophthalmoscopy, electrocardiography, colorectal pathology, 
clinical chemistry or urinalysis, organ weight, or macroscopic organ changes. There was 
also no maternal toxicity however, the incidence of prenatal loss was increased modestly. 
• 
As of December 2012, 10 clinical trials with QAX576 have been completed or terminated 
after enrolling some patients; 3 in healthy volunteers and 7 in patients. The trials consisted 
of allergic rhinitis, pulmonary fibrosis, keloid, and other Th2 related disorders.  A total of 168 
patients have participated in phase I programs and 227 in phase 2 programs. The programs 
have included both women and men in ages ranging from 18-80. 
• 
In a study of 24 healthy volunteers, There were no clinically significant changes noted on 
safety assessments including vital signs, blood chemistries, hematology, urinalysis, physical 
examinations and electrocardiogram measurements at all dose levels. No SAEs were 
reported in this study. A t o t a l o f 2 a dv er s e e f f e c t s w e r e r epo r t e d : 
one subject 
experienced a mild headache and an upper respiratory infection which was not felt to be 
related to QAX576. In another study, one subject experienced a severe episode of migraine 
that was not suspected to be related to QAX576. One patient developed mild arthralgia 
which resolved spontaneously.  No immunogenicity signal was detected and no positive 
antibodies to QAX576 were reported up to 28 days after the study drug administration. 
• 
In a multiple dose study in patients with pulmonary fibrosis secondary to systemic sclerosis, 
five serious adverse events were reported in 2 patients. One patient experienced 
hypotension with mild tachycardia, and pneumonia post bronchoscopy. Another patient 
suffered an episode of pseudo-bowel obstruction. These SAEs were judged by the principal 
investigator as not to be related to the study drug. 
• 
In a double blind placebo controlled study of asthma, a patient injured his back after the 
second dose of study medicated and was prescribed paracetamol.  Afterwards the patient 
presented with some adverse events which lead to hospitalization for the treatment of 
potential paracetamol overdose. 


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Potential toxicity related to Th2 blockade 
 
Infection. Published studies in mice deficient in either cytokine alone do not demonstrate 
an  increased susceptibility to parasitic diseases, reproductive abnormalities, or alterations in 
humoral response.61 Nevertheless, mice that lack both  IL-4 and IL-13 clear intestinal infection with 
helminthes more slowly than wild-type mice or  mice that lack either cytokine alone.62 
Given that 
patients enrolled in our study are unlikely to suffer from parasitic diseases, we feel that this is a low 
risk potential toxicity. 
 
 
Reproductive toxicity. No reproductive abnormalities have been described in mice lacking 
IL-4 and IL-13.62  While the risk of embryofetal toxicity with VAK694 is presently unknown, preliminary 
data from embryo-fetal development (EFD) and combined  EFD pre-/post-natal development  
(PPND) studies with QAX576 in the marmoset do not  exclude an adverse impact of IL-13 
suppression on the pregnancy outcome.  Furthermore, data in animals and in humans support a role 
for Th2 cytokines, including IL-13  and IL-4, in the maintenance of pregnancy.63 
No 
teratogenic effects of QAX576 have been observed. No overt phenotypic abnormalities have been 
observed in mice in which both IL-4 and IL-13  have been disrupted.62    Nevertheless, a 
teratogenic effect of  therapeutic  neutralization of both IL-4 and IL-13 cannot be excluded. For 
these reasons, we will exclude pregnant and lactating women from pa r t i c i pat i on i n t he t r i al .   I n 
addi t i on, w e w i l l c ar ef ul l y m oni t or v o l unt eer s f or pr e g nanc y bef or e and dur i ng t h e 
t r ia l.   Female subjects of child-bearing potential must use highly effective measures of 
contraception (see below) whilst participating in the QBX258 t r ia l and for at least 18 weeks ( 5 
half-lives) after the last dose QBX258. Women who are considered post-menopausal and not of child 
bearing potential i.e. if they have had 12 months of natural (spontaneous) amenorrhea with an 
appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) will not be required 
to use contraception. 
 
Highly effective contraception methods are defined as: 
 
• 
Total abstinence: when this is in line with the preferred and usual lifestyle of the subject. 
[Periodic abstinence (e.g. calendar, ovulation, symptothermal, post ovulation methods) and 
withdrawal are not acceptable methods of contraception], or 
• 
Documented history of sterilization: surgical bilateral oophorectomy (with or without 
hysterectomy) or tubal ligation at least six weeks before taking study treatment. 
• 
Documented history of male partner sterilization or 
• 
Use of a combination of any two of the following (a+b or a+c, or b+c): 
a. Use of oral, injected or implanted hormonal methods of contraception (in case of use of 
oral contraception women should have been stable on the same pill for a minimum of 3 
months before taking study treatment), 
b. Placement of an intrauterine device (IUD) or intrauterine system (IUS), 
c. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository. 


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Liver toxicity. In a mouse model of acetaminophen-induced liver toxicity, in which liver 
damage is associated with increased circulating IL-13, pre-treatment with a neutralizing  antibody 
to IL-13 exacerbated the extent of liver injury.64    Similar findings  were obtained in IL-13 
knockout mice that received high doses of acetaminophen. These data  suggest a possible 
hepatoprotective role for IL-13, and ingestion of acetaminophen (paracetamol) w i l l  b e 
limited in this clinical study. To date, liver toxicity has not been seen in QAX576 human clinical 
trials, however, patients enrolled in this study will be advised to avoid using acetaminophen until the 
trial has completed. 
 
 
 
Potential complications related to biopsy 
 
Biopsy of lymphedematous and normal arms are an important aspect of this application as 
these procedures will enable us to determine if Th2 blockade is successful in reversing the 
pathologic tissue changes associated with lymphedema. In addition, these studies are critical for 
performing mechanistic studies that may further our studies and understanding of lymphedema. We 
have performed these procedures in over 200 patients in collaboration with our colleagues at 
Stanford University, MD Anderson Cancer Center, and the University of Chicago.  No adverse 
events have been reported in these studies and all wounds have healed uneventfully without 
evidence of infection, delayed healing, pain, or lymph leak.  As a result, we expect that we will have 
similar results in the current proposal. If adverse effects (i.e. delayed healing, infection, lymph leak 
etc) are identified, then these will be reported immediately to the principal investigators and the IRB 
and appropriate treatments including antibiotic treatment (PO or IV depending on severity of 
infection), debridement, and further management will be instituted as necessary. 
 
Potential toxicity or complications related to measurements 
 
Measurements performed in this study (perometry, bioimpedance, tonometry) are all non- 
invasive and we do not expect to experience any AEs.  Similarly, the patient reported outcome 
questionnaires administered in this study have been validated and used in hundreds of patients 
without any significant adverse events. 
 
 
 
 
12.0 CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
 
Patients will be considered evaluable if they provide both a baseline and follow-up arm 
volume measurements.   If biopsy data or time points from PK analysis measurement are not 
available at followup due to patient desire to avoid additional surgery or a missed blood draw 
appointment, then the remainder of the outcomes will be analyzed.  Similarly, if impedance, 
tonometry, or QOL data are not available, then other measures available will be analyzed. 
Therapeutic volume changes in the arm will be calculated using the methods published by Anderson 
et al (2000).65   Briefly, the difference in volume measurments between the normal and 
lymphedematous arms at baseline (i.e volume excess) will be compared to the volume differential 
after drug treatment and following the washout period using the following formula: 


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(VL-VN) B - (VL-VN) F 
 
VL = Volume of the lymphedematous arm 
VN = Volume of the normal arm 
B= Baseline 
F = Follow up 
 
 
 
13.0 
CRITERIA FOR REMOVAL FROM STUDY 
 
Patients will be removed from the study according to the following criteria: 
 
• 
Significant toxicity, persistent AE or SAE related or unrelated to the treatment. 
• 
If at any time the patient is diagnosed or develops recurrent breast cancer or suspicious 
changes on laboratory or radiological testing suggestive of malignancy. 
• 
Subject non-compliance with infusions, measurements/analysis at the appropriate time 
intervals. 
• 
Voluntary wish of the subject to withdraw from the protocol. 
• 
Development of cellulitis or infection of the affected extremity. 
• 
Significant progression of lymphedema volume changes during treatment (greater than 30% 
increase in limb volume as assessed by perometry). 
• 
Unexpected pregnancy or non-compliance with the use of birth control methods 
 
The study will be halted in the event of a grade 3 or 4 SAE until investigation of causality with 
drug treatment is concluded. At this point if the SAE is not thought to be caused by drug treatment, 
then the treatment plan will be reviewed with the company and the IRB to decide if the study should 
be restarted. 
 
14.0 
BIOSTATISTICS 
 
This is a prospective, longitudinal, open label pilot study designed to evaluate the efficacy of 
QBX258, a monoclonal antibody treatment designed to block biologic activity of interleukin 4 (IL4) 
and interleukin 13 (IL13).  Our primary end point is volume changes as measured by perometry. 
Our secondary endpoints include pharmacokinetics, bioimpedance measurements, skin tonometry, 
the ULL27 lymphedema questionnaire, and histologic studies. 
 
Sample size calculation:  Based on a review of the literature, reductions of 20-40% in the extent of 
excess lymphedema volume before and after various interventions such as weight loss or cold laser 
have been reported. 35,39-49   However, these interventions have not gained widespread clinical 
incorporation due to compliance issues (weight loss) and time intensive nature of the therapies. 
However, it is commonly accepted that a 30% reduction to any potential therapy for lymphedema is 
a good clinical response and worthy of additional study. We will therefore consider an average 
decrease of 30% in arm volume excess in the cohort as a therapeutic response.  Previous studies 
have also shown that the minimum measurable change in volume is 60-75 cc.66   Therefore, based 
on these findings we have used a minimum volume excess of 300 cc between the normal and 
lymphedematous arms as an inclusion criterion measurable. Thus, a excess volume reduction in a 
patient who has a volume excess of 300 cc prior to treatment would be equal to a 90cc reduction, 
which is greater than the minimal measurable change of 60-75cc (). 


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Using data from the weight loss study sited in the Background section in which perometer 
measuments were used to calculate limb volumes before and after weight loss, we assume a 
baseline mean excess lymphedema volume of 802ml and a standard deviation of 325 for the 
difference in pre and post treatment excess volume. With a sample size of 20 patients, we can 
detect a 30% reduction in excess volume (236ml difference between pre and post treatment) with 
90% power and 5% type I error.  Assuming a 10% drop out rate, we will therefore plan on accruing 
22 patients to meet our study goal. 
 
 
We expect to accrue approximately two patients per month and will complete accrual within one 
year. 
 
Analysis of primary objective:  Our primary aim is to establish the difference in the extent of 
excess lymphedema volume before and after treatment with QBX258. The extent of excess 
lymphedema volume is defined as the difference between the volume of the lymphedematous arm 
and the normal arm at each time point (i.e. Prior to treatment; after treatment, and after washout). 
Since the volume measurement at each time point is taken in duplicate, the average between the 
duplicate measurements will be used to calculate the excess lymphedema volume; see section 
12.0). The difference in the extent of lymphedema between time points will be assessed with paired 
two-sided t-tests comparing the post-treatment and washout measurements with the pre-treatment 
measurements and the post-treatment measurements with the washout measurements.  In addition, 
we will analyze the effect of potential confounding variables such as pre treatment BMI on volume 
reduction using analysis of covariance (ANCOVA) with the arm volume difference after completion of 
treatment as the outcome variable and baseline volume difference and BMI as covariates. We will 
report a two-tailed p-value and a 95% confidence interval for the difference between groups. Data 
will be presented graphically to facilitate analysis. 
 
Analysis of secondary objectives: 
 
Tolerability will be evaluated using toxicity data and will be tabulated by severity.  ULL-27 
questionnaire responses will be graded and scored according to previously published methods (see 
Appendix A).   Changes in each symptom scale (physical, psychological and social) as well as the 
overall score will be compared pre and postn treatment using paired two-sided t-tests. The 
bioimpedance and tonometry measurements yield continuous variables and will be analyzed using 
paired t-tests.  Similarly, histologic analysis of the biopsy specimens will yield data on the number of 
CD4+ cells, the number of Th2 cells, and the degree of tissue fibrosis, all of which are also 
continuous variables. These variables will be compared pre and post treatment using paired t-tests. 
For phamacokinetic analysis, mean volume of distribution at steady state (Vss),mean total systemic 
clearanceand the mean distribution half-life (t1/2α) will be calculated using published methods. 


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15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 
 
15.1 
Research Participant Registration 
Confirm eligibility as defined in the section entitled Criteria for Patient/Subject Eligibility. 
Obtain informed consent, by following procedures defined in section entitled Informed 
Consent Procedures. 
 
During the registration process registering individuals will be required to complete a protocol 
specific Eligibility Checklist. 
 
All participants must be registered through the Protocol Participant Registration (PPR) Office 
at Memorial Sloan Kettering Cancer Center. PPR is available Monday through Friday from 
8:30am – 5:30pm at 646-735-8000. Registrations must be submitted via the PPR Electronic 
Registration System (http://ppr/). The completed signature page of the written consent/RA or 
verbal script/RA, a completed Eligibility Checklist and other relevant documents must be 
uploaded via the PPR Electronic Registration System. 
 
15.2 
Randomization 
 
This is an open label trial and randomization will not be required. 
 
16.0 
DATA MANAGEMENT ISSUES 
 
A Research Study Assistant (RSA) will be assigned to the study and will be responsible for 
project compliance, data collection, abstraction and entry, data reporting, regulatory monitoring, 
problem resolution and prioritization, and coordination of the activities of the protocol study team. 
The data collected for this study will be entered into a secured database (Clinical Research 
Database, CRDB) at Memorial Sloan-Kettering Cancer Center.  Source documentation will be 
available to support the computerized patient record. 
 
 
We will administer the ULL27 questionnaire via either paper forms in private areas of waiting 
rooms at the MSKCC 60th street Plastic Surgery offices, the 64th Street Breast Cancer Center, or 
the Department of Rehabilitation Medicine located at 53rd and Madison Avenues. The QOL 
survey will be completed prior to initiation of therapy, at the conclusion of therapy, and after a 
washout period as outlined above and will be brought to the patients by the study RSA and 
collected after completion.  The data collected in this manner will be entered into a secured 
database (Clinical Research Database, CRDB) at Memorial Sloan-Kettering Cancer Center. 
Source documentation will be available to support the computerized patient record and will be 
kept in a secure locked cabinet. 


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16.1 
Quality Assurance 
 
Registration reports will be generated to monitor patient accruals and completeness of 
registration data.  Routine data quality reports will be generated to assess missing data and 
inconsistencies.  Accrual rates and extent and accuracy of evaluations and follow-up will be 
monitored periodically throughout the study and potential problems will be brought to the 
attention of the study team for discussion and action. 
 
 
Random-Sample data quality and protocol compliance audits will be conducted by the study 
team, at a minimum of two times per year and more frequently if indicated. 
 
 
16.2 
Data and Safety Monitoring 
 
The Data and Safety Monitoring (DSM) plans at Memorial Sloan-Kettering Cancer 
Center were approved by the National Cancer Institute in September 2001. The plans 
address the new policies set forth by the NCI in the document entitled "Policy of the 
National Cancer Institute for Data and Safety Monitoring of Clinical Trials" which can be 
found at: http://mskweb2.mskcc.org/irb/index.htm. 
 
 
Clinical trials are monitored by a number of different mechanisms to ensue data 
safety and quality.  Institutional processes are in place for quality assurance (e.g. protocol 
monitoring, compliance and data verification audits, therapeutic responses, and staff 
education on clinical research).  In addition, there are departmental procedures for quality 
control as well as two institutional committees that are responsible for monitoring the 
activities of our clinical trials programs. The committees: Data and Safety Monitoring 
Committee (DSMC) for Phase I and II clinical trials, and the Data and Safety Monitoring 
Board (DSMB) for Phase III clinical trials, report to the Center’s Research Council and 
Institutional Review Board. 
 
 
During the protocol development and review process, each protocol will be assessed for 
it’s level of risk and degree of monitoring required. Every type of protocol (e.g., NIH 
sponsored, in-house sponsored, industrial sponsored, NCI cooperative group, etc.) will 
be addressed and the monitoring procedures will be established at the time of protocol 
activation. 
 
 
17.0 
PROTECTION OF HUMAN SUBJECTS 
 
Prior to the enrollment of each patient, the risks, benefits and objectives of the study will be 
reviewed with the participant, including a discussion of the possible toxicities and side effects. 
Financial costs and burdens of the trial will be reviewed in detail including a detailed discussion of 
the tests/measurements that will be performed.  The tests and measurements will be the financial 
responsibility of the study.  The cost of traveling to and from the center for evaluation will be the 
financial responsibility of the patient.  Blood work analysis as well as analysis of EKG and other 
monitoring tests will be provided at no cost to the patient.  Every effort will be made to keep study 
records private. 


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Neither the patient's name nor anything else that could identify the patient will be used in any 
reports or publications that result from this study. Trained staff at Memorial Hospital and the 
Institutional Review Board at Memorial Hospital may review medical records if necessary. The 
patient may terminate participation in the study at any time during the trial.  In the event that a 
toxicity or complication arises as a result of the study, the patient will be evaluated and treated at 
no cost to the patient unless it is determined that the adverse effect is not related to the study 
drug in which case treatment costs will be billed to the patients insurance. 
 
 
17.1 
Privacy 
 
 
 
MSKCC’s Privacy Office may allow the use and disclosure of protected health information 
pursuant to a completed and signed Research Authorization form. The use and disclosure of 
protected health information will be limited to the individuals described in the Research 
Authorization form.  A Research Authorization form must be completed by the Principal 
Investigator and approved by the IRB and Privacy Board (IRB/PB). 
 
 
 
17.2 
Serious Adverse Event (SAE) Reporting 
 
Any SAE will be reported to the IRB/PB as soon as possible but no later than 5 calendar 
days. The IRB/PB requires a Clinical Research Database (CRDB) SAE report be submitted 
electronically to the SAE Office at  sae@mskcc.org. The report will contain the following 
information: 
 
Fields populated from CRDB: 
 
• 
Subject’s name (generate the report with only initials if it will be sent outside of 
MSKCC) 
• 
Medical record number 
• 
Disease/histology (if applicable) 
• 
Protocol number and title 
 
Data needing to be entered: 
 
• 
The date the adverse event occurred 
• 
The adverse event 
• 
Relationship of the adverse event to the treatment (drug, device, or intervention) 
• 
If the AE was expected 
• 
The severity of the AE 
• 
The intervention 
• 
Detailed text that includes the following 
o A explanation of how the AE was handled 
o A description of the subject’s condition 
o Indication if the subject remains on the study 
o If an amendment will need to be made to the protocol and/or consent form. 


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The PI’s signature and the date it was signed are required on the completed report. 
 
17.2.1 
 
SAEs (as defined above) will be reported to the sponsoring company (Novartis Corp) in a 
deidentified manner within 15 business day of the event as outline the companies standard 
operating procedures. This report will include: 
 
• 
Protocol number and title 
• 
The date the adverse event occurred 
• 
The adverse event 
• 
Relationship of the adverse event to the treatment (drug, device, or intervention) 
• 
If the AE was expected 
• 
The severity of the AE 
• 
The intervention 
• 
Detailed text that includes the following 
o A explanation of how the AE was handled 
o A description of the subject’s condition 
o Indication if the subject remains on the study 
o If an amendment will need to be made to the protocol and/or consent form. 
 
The SAE will also be reported to the FDA through the IND Office and that report will include the FDA 
assigned IND number and name. 
 
 
 
 
18.0 
INFORMED CONSENT PROCEDURES 
 
Before protocol-specified procedures are carried out, consenting professionals will explain full 
details of the protocol and study procedures as well as the risks involved to participants prior 
to their inclusion in the study. Participants will also be informed that they are free to withdraw 
from the study at any time. All participants must sign an IRB/PB-approved consent form 
indicating their consent to participate. This consent form meets the requirements of the Code 
of Federal Regulations and the Institutional Review Board/Privacy Board of this Center. The 
consent form will include the following: 
 
1.  The nature and objectives, potential risks and benefits of the intended study. 
2.  The length of study and the likely follow-up required. 
3.  Alternatives to the proposed study. (This will include available standard and 
investigational therapies. In addition, patients will be offered an option of supportive 
care for therapeutic studies.) 
4.  The name of the investigator(s) responsible for the protocol. 
5.  The right of the participant to accept or refuse study interventions/interactions and to 
withdraw from participation at any time. 


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Before any protocol-specific procedures can be carried out, the consenting professional will 
fully explain the aspects of patient privacy concerning research specific information.  In 
addition to signing the IRB Informed Consent, all patients must agree to the Research 
Authorization component of the informed consent form. 
 
Each participant and consenting professional will sign the consent form. The participant must 
receive a copy of the signed informed consent form. 
 
 
19.0 
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20.0 
APPENDICES 
 
• 
Appendix A  - QOL Survey 
• 
Appendix B – QOL scoring 
• 
Appendix C – Laboratory Requisition Forms