Clinical trial NCT00090987
Conditions: Sarcoma
Keywords: AIDS-related Kaposi sarcoma recurrent Kaposi sarcoma
Sponsor: AIDS Malignancy Consortium
Start date: 2005-06-01; Completion date: 2009-12-01
Enrollment: 30 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
RATIONALE: Imatinib mesylate may stop the growth of tumor cells by blocking the enzymes necessary for their growth.

PURPOSE: This phase II trial is studying how well imatinib mesylate works in treating patients with HIV-related Kaposi's sarcoma.

Detailed description:
OBJECTIVES:

Primary

* Determine clinical response in patients with HIV-related Kaposi's sarcoma treated with imatinib mesylate.

Secondary

* Determine the inhibition of platelet-derived growth factor receptors, as determined by immunohistochemistry, in patients treated with this drug.
* Determine cytokine profiles before and after treatment with this drug in these patients.
* Determine the pharmacokinetic profile of this drug and antiretrovirals in these patients.
* Determine mechanisms of primary and secondary resistance to this drug in these patients.

OUTLINE: This is an open-label, multicenter study.

Patients receive oral imatinib mesylate once daily. Treatment continues for up to 1 year in the absence of disease progression or unacceptable toxicity.

Patients are followed at 30 days.

PROJECTED ACCRUAL: A total of 30 patients will be accrued for this study within 1 year.

Arms: arm 1: Imatinib mesylate (Gleevec) taken 400 mg orally once a day for up to 6 months
Interventions: intervention 1: imatinib mesylate
Intervention descriptions: intervention 1: 400 mg orally once a day for up to 6 months.

Protocol documents:
Prot_SAP_001.pdf: 
AMC # 042 (Version 7.0) 07/24/2007 
NCI Version Date 07/24/07 
 
i 
AMC 
AIDS ASSOCIATED MALIGNANCY CLINICAL TRIALS 
CONSORTIUM 
 
AMC PROTOCOL #042 
 
 
A Phase II Trial of Imatinib Mesylate (GLEEVEC) in Patients with 
HIV Related Kaposi's Sarcoma 
 
 
A Multi-Center Trial of the AIDS Malignancy Consortium 
 
 
 
Sponsored by: 
 
The National Cancer Institute 
Division of Cancer Treatment and Diagnosis 
 
 
 
 
Pharmaceutical Support Provided by: 
Novartis 
IND# 69,364 
 
 
Protocol Chair: 
Henry B. Koon, M.D. 
 
Protocol Co-Chair: 
Ariela Noy, M.D. 


AMC # 042 (Version 7.0) 07/24/2007 
NCI Version Date 07/24/07 
 
ii 
AMC PROTOCOL SIGNATURE PAGE 
 
 
 
I,                           , Principal Investigator at site            , agree to conduct and follow this 
protocol: AMC Protocol #042 - A Phase II Trial of Imatinib Mesylate (GLEEVEC) in 
Patients with HIV Related Kaposi’s Sarcoma (Version 7.0, 07/24/2007), as written according 
to AMC, NCI and FDA guidelines.  I understand that no deviations from the above protocol may 
be made without written permission from the Protocol Chair (s). 
 
 
_________________________________ 
_____________________ 
 
Signature 
Date (mm/dd/yyyy) 


AMC # 042 (Version 7.0) 07/24/2007 
NCI Version Date 07/24/07 
 
iii 
TABLE OF CONTENTS 
 
1.0 
Background/Rationale................................................................................................ 1 
1.1 
GLEEVEC® ...............................................................................................................................................1 
1.2 
BIOLOGIC/CORRELATIVE STUDIES..........................................................................................................11 
1.3 
STUDY DESIGN .......................................................................................................................................15 
2.0 
STUDY OBJECTIVES............................................................................................. 16 
2.1 
PRIMARY OBJECTIVES.............................................................................................................................16 
2.2 
SECONDARY OBJECTIVES........................................................................................................................16 
3.0 
PATIENT SELECTION .......................................................................................... 16 
3.1 
INCLUSION CRITERIA ..............................................................................................................................16 
3.2 
EXCLUSION CRITERIA.............................................................................................................................17 
3.3 
ENROLLMENT PROCEDURES....................................................................................................................18 
4.0 
CLINICAL AND LABORATORY EVALUATIONS........................................... 19 
4.1 
ELIGIBILITY/SCREENING.........................................................................................................................19 
4.2 
EVALUATIONS DURING TREATMENT ......................................................................................................21 
4.3 
EVALUATIONS AT THE TIME OF TREATMENT DISCONTINUATION..........................................................22 
4.4 
FINAL EVALUATIONS/OFF DRUG, OFF STUDY ........................................................................................23 
5.0 
STUDY TREATMENT ............................................................................................ 24 
5.1 
DRUG REGIMENS, ADMINISTRATION AND DURATION ............................................................................24 
5.2 
DRUG ORDERS, TRANSFERS, RETURNS, AND ACCOUNTABILITY ............................................................24 
5.3 
DOSING...................................................................................................................................................25 
5.4 
DOSE MODIFICATIONS FOR NON-HEMATOLOGICAL TOXICITY...............................................................25 
5.5 
DOSE MODIFICATIONS FOR HEMATOLOGICAL TOXICITY........................................................................27 
5.6 
CONCOMITANT THERAPY........................................................................................................................28 
5.7 
PERMITTED MEDICATIONS......................................................................................................................29 
5.8 
PROHIBITED MEDICATIONS.....................................................................................................................30 
5.9 
PROHIBITED FOODS.................................................................................................................................30 
5.10 
TREATMENT COMPLIANCE......................................................................................................................30 
6.0 
REPORTING OF ADVERSE EVENTS................................................................. 31 
6.1 
CLASSIFICATION OF ADVERSE EVENTS BY SEVERITY & RELATIONSHIP TO STUDY DRUG 
ADMINISTRATION ...................................................................................................................................31 
6.2 
ADVERSE EVENT REPORTING TO NOVARTIS...........................................................................................32 
6.3 
ADVERSE EVENTS WITH COMMERCIAL AGENTS ....................................................................................33 
7.0 
CRITERIA FOR TREATMENT DISCONTINUATION..................................... 35 
8.0 
POST-TREATMENT EVALUATION AND EVALUATION AT EARLY 
DISCONTINUATION OF THERAPY................................................................... 36 
9.0 
EVALUATION OF RESPONSE............................................................................. 37 
9.1 
DEFINITION OF RESPONSE.......................................................................................................................37 
10.0 
RECORDS TO BE KEPT........................................................................................ 40 
11.0 
ROLE OF DATA MANAGEMENT....................................................................... 41 
11.1 
CRF INSTRUCTIONS................................................................................................................................41 
11.2 
DATA QUALITY.......................................................................................................................................41 


AMC # 042 (Version 7.0) 07/24/2007 
NCI Version Date 07/24/07 
 
iv 
12.0 
STATISTICAL CONSIDERATIONS .................................................................... 42 
12.1 
SAMPLE SIZE ESTIMATION......................................................................................................................42 
12.2 
STATISTICAL ANALYSIS PLAN ................................................................................................................42 
12.3 
AMC POLICY FOR MONITORING OF PHASE I AND PHASE II TRIALS........................................................43 
13.0 
ETHICAL AND REGULATORY CONSIDERATIONS ..................................... 44 
13.1 
INFORMED CONSENT...............................................................................................................................44 
13.2 
CHANGES TO THE PROTOCOL.................................................................................................................44 
13.3 
WOMEN AND MINORITIES ......................................................................................................................44 
14.0 
REFERENCES.......................................................................................................... 45 
APPENDIX I:  Schedule of Events............................................................................................ 47 
APPENDIX II: Definition of AIDS Indicator Conditions....................................................... 48 
APPENDIX III:  Criteria for Acceptable AIDS Defining Events .......................................... 49 
Appendix IV: Karnofsky Performance Scale........................................................................... 50 
APPENDIX V: Recommended Staging Classification for Kaposi's Sarcoma ...................... 51 
APPENDIX VI:  Model Informed Consent.............................................................................. 52 
APPENDIX VII: ACSR Informed Consent ............................................................................. 62 
APPENDIX VIII: AIDS And Cancer Specimen Resource (ACSR) - Specimen Preparation 
& Shipping Instructions ........................................................................................... 65 
APPENDIX IX: Punch Biopsy................................................................................................... 69 
APPENDIX X: Punch Biopsy .................................................................................................... 72 
APPENDIX XI:  Cytokine Profiles Analysis............................................................................ 76 
APPENDIX XII: Pharmacokinetic Analysis............................................................................ 79 
APPENDIX XIII: HHV-8 Viral Load And Gene Expression................................................. 82 
APPENDIX XIV: New York Heart Association Criteria ....................................................... 85 
APPENDIX XV: Drugs Metabolized By CYP450 Isoenzymes 2D6 And 3A4....................... 86 
APPENDIX XVI: Data Safety And Monitoring Plan.............................................................. 91 
APPENDIX XVII:  Novartis SAE Coversheet......................................................................... 94 
 


AMC # 042 (Version 7.0) 07/24/2007 
NCI Version Date 07/24/07 
 
v 
 
PROTOCOL ROSTER 
 
AMC # 042 
 
 
Protocol Chair:  
Protocol Statistician: 
Henry Koon, M.D. 
Jeannette Y. Lee, Ph.D. 
Case Western Reserve University 
AMC Statistical Center 
2103 Cornell Road / WRB 2204 
University of Alabama at Birmingham 
Cleveland, OH  44106 
1824 Sixth Avenue South – WTI 153 
Tel: (216) 368-1175 
Fax:   (216) 368-1166 
E-mail: Henry.Koon@case.edu 
Birmingham, Alabama  35294-3300  
Tel: (205) 934-5165 
Fax: (205) 975 -7453 
E-mail: jylee@uab.edu 
 
 
 
   
Protocol Co-Chair: 
Data Management/Operations: 
Ariela Noy, MD 
AMC Operations Center  
Memorial Sloan-Kettering Cancer Center 
The EMMES Corporation  
275 York Avenue 
401 N. Washington St., Suite 700 
New York, NY  10021 
Rockville, MD  20850 
Tel: (212) 639-7423 
Tel: (301) 251-1161 
Fax: (646) 422-2284 
Fax: (240) 238-2842 
E-mail: noya@mskcc.org 
E-mail: amcpm@emmes.com  
 
 
 


AMC # 042 (Version 7.0) 07/24/2007 
NCI Version Date 07/24/07 
 
vi 
SITES PARTICIPATING IN AMC # 042 
 
 
This trial is open to all AMC sites for subject accrual. 
 
 
 
 


AMC # 042 (Version 7.0) 07/24/2007 
NCI Version Date 07/24/07 
 
vii 
SCHEMA 
 
TITLE: 
A Phase II Trial of Imatinib Mesylate (Gleevec®) in Patients 
with HIV Related Kaposi’s Sarcoma. 
 
DESIGN: 
Open-label, Phase II Study. 
 
SAMPLE SIZE:  
A maximum of 30 subjects will be enrolled. 
 
POPULATION: 
HIV infected subjects with biopsy proven Kaposi’s sarcoma 
(KS) involving skin, lymph nodes, oral cavity, GI tract and/or 
lungs. GI and pulmonary involvement must be asymptomatic 
or minimally symptomatic and not require systemic cytotoxic 
therapy. 
 
REGIMEN: 
Patients will be taking Gleevec 400 mg orally once a day. 
 
DURATION: 
Patients will continue on study protocol as long as their KS is 
stable or responding for up to 6 months. If a patient has been 
on study for at least 3 months with stable disease and without 
any toxicity, their dose may be increased to 600 mg/day. 
Patients who are responding or have stable disease at 6 months 
may continue on study for an additional 6 months. Protocol 
treatment will be discontinued if the patient develops tumor 
progression, unacceptable toxicity or develops one of the 
protocol defined reasons for treatment discontinuation. 
 
EXPECTED ACCRUAL: 
A maximum of 30 subjects over 12 months. 
 
PRIMARY ENDPOINTS: 
Evaluation of clinical response. 
 
SECONDARY ENDPOINTS: Evaluation of inhibition of PDGF-R as determined by 
immunohistochemistry. 
 
 
Evaluation of cytokine profiles pre and post imatinib therapy. 
 
 
Evaluation of pharmacokinetic profile of imatinib and 
antiretrovirals in HIV patients. 
 
 
Evaluation of mechanisms of primary and secondary resistance 
to imatinib therapy. 
 
 
Evaluation of viral transcription profile of KSHV. 
 


AMC # 042 (Version 7.0) 07/24/2007 
NCI Version Date 07/24/07 
 
1 
1.0 
BACKGROUND/RATIONALE 
Kaposi’s Sarcoma (KS) is a disease of multi-focal vascular proliferation, which 
predominantly involves the skin, but can also involve the visceral organs. AIDS related 
KS is associated with co-infection with the HIV virus and Kaposi’s Sarcoma herpes virus 
(KSHV) (or Human Herpes virus-8).[1] Histologically, these lesions appear as clusters of 
spindle-shaped cells (KS spindle cells), vessels and a variable inflammatory infiltrate. 
These tumors rely on a number of cytokines for growth including interleukin-1, 
interleukin-6, vascular endothelial growth factor (VEGF), basic-fibroblast growth factor 
(b-FGF), stem cell factor (SCF) and platelet derived growth factor (PDGF), which act by 
autocrine and paracrine mechanisms.[2-8] 
Several studies have suggested a role for PDGF and c-kit receptors in KS. When KS 
spindle cells are cultured they express both α and β  PDGF receptors.[9] Cultured KS 
spindle cells growth arrests when placed in PDGF-depleted media, and this arrest can be 
mitigated by the addition of recombinant PDGF.[10] Some of the unanswered questions 
for these studies are whether the cultured cells reflect the KS spindle cells behavior in 
vivo and what the source of the PDGF in vivo is. Indeed only β PDGF-R appears to be 
expressed 
in 
tumor 
specimens 
as 
assayed 
by 
in 
situ 
hybridization 
and 
immunohistochemistry.[6] PDGF is not expressed by these spindle cells, but rather by a 
distinct subpopulation of cells in the KS lesion.[6] 
Once the role of KHSV was elucidated, model systems that use dermal microvasculature 
endothelial cells (DMVEC) were developed to study the effect of KSHV infection on 
gene expression. KSHV infection of DMVECs results in a 5-fold up regulation of the c-
kit receptor[8] and results in a 4-fold change in levels of β PDGF-R transcripts while α 
PDGF-R levels remain unchanged as assayed by cDNA array (unpublished data, AV 
Moses, pers. comm.). In the prior study it was also demonstrated that KSHV-infected 
endothelial cell cultures proliferate in response to the ligand of c-kit, SCF, which is 
basally expressed by cells in culture.[8] Additionally, PDGF had been shown to induce the 
expression of VEGF by cultured KS spindle cells.[7] It is possible that PDGF-R and c-kit 
are involved in two critical pathways in KS development; induction of growth of KS 
spindle cells and induction of angiogenesis through VEGF. This potential role of PDGF-
R and c-kit in the development of KS makes inhibition of these receptors an attractive 
therapeutic target. 
1.1 
Gleevec® 
1.1.1 
General Information 
Imatinib is a signal transduction inhibitor (STI) approved by the 
United States Food and Drug Administration (FDA) for use in patients 
with newly diagnosed chronic myeloid leukemia (CML) or CML in 
blast crisis, accelerated phase, or in chronic phase after failure of 
interferon-alfa therapy.[11] In preclinical studies, Gleevec was found to 
be a potent inhibitor of BCR-ABL as well as PDGF-R and the c-Kit 
receptor. Since its approval, imatinib has been shown to be beneficial 


AMC # 042 (Version 7.0) 07/24/2007 
NCI Version Date 07/24/07 
 
2 
in gastrointestinal stromal tumor (GIST), which is dependent on c-Kit 
as well as dermatofibrosarcoma protuberns and hypereosinophilic 
syndrome, which are dependent on the PDGF pathway.[12,13] The 
availability of imatinib, which inhibits both the PDGF and c-kit 
receptors, allows us to test clinical utility of inhibiting these receptors 
to treat KS. 
Imatinib is highly bioavailable as an oral formulation. The 
pharmacokinetics (PK) of Gleevec has been evaluated in healthy 
subjects and in population pharmacokinetic studies in over 900 
patients. Imatinib is well absorbed after oral administration with Cmax 
achieved within 2-4 hours post-dose. Mean absolute bioavailability is 
98%. Following oral administration in healthy volunteers, the 
elimination half-lives of imatinib and its major active metabolite, the 
N-desmethyl derivative, were approximately 18 and 40 hours, 
respectively. Mean imatinib AUC increased proportionally with 
increasing dose in the range 25–1000 mg. There were no significant 
changes in the PK of imatinib on repeated dosing, and accumulation is 
1.5-2.5 fold at steady state when Gleevec is dosed once daily. At 
clinically relevant concentrations of imatinib, binding to plasma 
proteins is approximately 95% in vitro, mostly to albumin and α1-acid 
glycoprotein. CYP3A4 is the major enzyme responsible for 
metabolism of imatinib. Other cytochrome P450 enzymes, such as 
CYP1A2, CYP2D6, CYP2C9, and CYP2C19, play a minor role in its 
metabolism. 
1.1.2 
Safety Data 
Chronic Myeloid Leukemia 
The majority of Gleevec-treated patients experienced adverse events 
(AEs) at some time. Most events were of mild to moderate grade, but 
drug was discontinued for AEs in 2% of patients in chronic phase, 3% 
in accelerated phase and 5% in blast crisis. The most frequently 
reported drug-related AEs were nausea, vomiting, diarrhea, edema, 
and muscle cramps (see Table 1 for newly diagnosed CML patients 
and Table 2 for other CML patients). Edema was most frequently 
periorbital or in lower limbs and was managed with diuretics, other 
supportive measures, or by reducing the dose of Gleevec. The 
frequency of severe superficial edema was 0.9-5%. 


AMC # 042 (Version 7.0) 07/24/2007 
NCI Version Date 07/24/07 
 
3 
Table 1 
Adverse Experiences Reported in Newly Diagnosed CML Clinical Trial (>10% of All Patients) 
All Grades 
CTC Grades 3/4 
Preferred term(1) 
Gleevec 
N=551 (%) 
IFN+Ara-C 
N=533 (%) 
Gleevec  
N=551 (%) 
IFN+Ara-C
N=533 (%) 
 
Fluid retention 
54.1 
10.1 
0.9 
0.9 
 
- Superficial edema 
53.2 
8.8 
0.9 
0.4 
 
- Other fluid retention events 
3.4 
1.5 
0 
0.6 
 
Nausea 
42.5 
60.8 
0.4 
5.1 
 
Muscle cramps 
35.4 
9.9 
1.1 
0.2 
 
Musculoskeletal pain 
33.6 
40.5 
2.7 
7.7 
 
Rash 
31.9 
25.0 
2.0 
2.1 
 
Fatigue 
30.7 
64.7 
1.1 
24.0 
 
Diarrhea 
30.3 
40.9 
1.3 
3.2 
 
Headache 
28.5 
41.8 
0.4 
3.2 
 
Joint pain 
26.7 
38.3 
2.2 
6.8 
 
Abdominal pain 
23.4 
22.9 
2.0 
3.6 
 
Myalgia 
20.9 
38.6 
1.5 
8.1 
 
Nasopharyngitis 
19.2 
7.7 
0 
0.2 
 
Hemorrhage 
18.9 
19.9 
0.7 
1.3 
 
Dyspepsia 
15.1 
9.0 
0 
0.8 
 
Vomiting 
14.7 
26.6 
0.9 
3.4 
 
Pharyngolaryngeal pain 
14.2 
11.4 
0.2 
0 
 
Dizziness 
13.2 
23.1 
0.5 
3.4 
 
Cough 
12.5 
21.6 
0.2 
0.6 
 Upper respiratory tract   infection 
12.5 
7.9 
0.2 
0.4 
 
Pyrexia 
11.8 
38.6 
0.5 
2.8 
 
Weight increased 
11.6 
1.5 
0.7 
0.2 
 
Insomnia 
11.4 
18.4 
0 
2.3 
(1) All AEs occurring in ≥ 10% of patients are listed regardless of suspected relationship to treatment. 
 


AMC # 042 (Version 7.0) 07/24/2007 
NCI Version Date 07/24/07 
 
4 
Table 2 
Adverse Experiences in ≥ 10% of Patients During Phase II Leukemia Studies 
Preferred Term 
(% of Patients) 
Myeloid Blast Crisis 
n= 260 
Accelerated Phase 
n=235 
Chronic Phase 
n=532 
 
All Grades 
Grade 3/4 
All Grades 
Grade 3/4 
All Grades 
Grade 3/4 
Nausea  
70 
4 
71 
5 
60 
2 
Fluid retention 
71 
12 
73 
6 
66 
3 
Superficial edemas 
67 
5 
71 
4 
64 
2 
Other fluid retention events 
22 
8 
10 
3 
7 
2 
Muscle cramps 
27 
0.8 
42 
0.4 
55 
1 
Diarrhea  
42 
4 
55 
4 
43 
2 
Vomiting  
54 
4 
56 
3 
32 
1 
Hemorrhage 
52 
19 
44 
9 
22 
2 
CNS hemorrhage 
7 
5 
2 
0.9 
1 
1 
Gastrointestinal hemorrhage 
8 
3 
5 
3 
2 
0.4 
Musculoskeletal pain 
43 
9 
46 
9 
35 
2 
Skin rash 
35 
5 
44 
4 
42 
3 
Headache  
27 
5 
30 
2 
34 
0.2 
Fatigue 
29 
3 
41 
4 
40 
1 
Arthralgia 
25 
4 
31 
6 
36 
1 
Dyspepsia 
11 
0 
21 
0 
24 
0 
Myalgia 
8 
0 
22 
2 
25 
0.2 
Weight increased  
5 
0.8 
14 
3 
30 
5 
Pyrexia 
41 
7 
39 
8 
17 
1 
Abdominal pain 
31 
6 
33 
3 
29 
0.6 
Cough 
14 
0.8 
26 
0.9 
17 
0 
Dyspnea 
14 
4 
20 
7 
9 
0.6 
Anorexia 
14 
2 
17 
2 
6 
0 
Constipation 
15 
2 
15 
0.9 
6 
0.2 
Nasopharingitis  
8 
0 
16 
0 
18 
0.2 
Night sweats  
12 
0.8 
14 
1 
10 
0.2 
Pruritus 
8 
1 
13 
0.9 
12 
0.8 
Epistaxis 
13 
3 
13 
0 
5 
0.2 
Hypokalemia 
13 
4 
8 
2 
5 
0.2 
Petechiae 
10 
2 
5 
0.9 
1 
0 
Pneumonia 
12 
6 
8 
6 
3 
0.8 
Weakness 
12 
3 
9 
3 
7 
0.2 
Upper respiratory tract infection  
3 
0 
9 
0.4 
15 
0 
Dizziness 
11 
0.4 
12 
0 
13 
0.2 
Insomnia 
10 
0 
13 
0 
13 
0.2 
Sore throat 
8 
0 
11 
0 
11 
0 
Ecchymosis 
11 
0.4 
6 
0.9 
2 
0 
Rigors 
10 
0 
11 
0.4 
8 
0 
Asthenia 
5 
2 
11 
2 
6 
0 
Influenza 
0.8 
0.4 
6 
0 
10 
0.2 
With the exception of grade1/2 edema (but not grade 3/4), there were no obvious differences in the incidence of AEs in patients treated at 400 and 
600 mg. However, the interpretation of a dose relationship is confounded by the fact that many patients were dose-escalated over time and in all 
studies AEs were analyzed according to starting dose. Patients aged ≥65 years also experienced a higher incidence of edema. 
Less than 50% of patients required dose reduction at any time. Temporary treatment interruptions were required in 25-40% of patients. Despite 
these dose changes, the overall median dose-intensity (expressed in mg/day) in each study remained close to the initially planned dose. 


AMC # 042 (Version 7.0) 07/24/2007 
NCI Version Date 07/24/07 
 
5 
Cardiotoxicity 
Gleevec has been shown to be cardiotoxic in humans in an 
examination of ten individuals who developed significant left 
ventricular dysfunction, thus, congestive heart failure (CHF), during 
their course of therapy. All ten individuals with CML had normal left 
ventricular function before Gleevec therapy was instituted (ejection 
fraction 56+7%). Following treatment (mean of 7.2+5.4 months [range 
1-14 months]), patients had a significantly lower ejection fraction of 
25+8% (P< 0.001) and presented with a significant volume overload 
and symptoms corresponding to a New York Heart Association 
(NYHA) class 3-4 heart failure.[21] Myocardial biopsies performed on 
two of the patients who had no history of coronary disease showed 
prominent membrane whorls in the myocytes, which has been reported 
to be characteristic of toxin-induced myopathies. 
In patients treated with Gleevec on NCI-sponsored trials, the rate of 
high grade left ventricular systolic function was low (approximately 
0.2%), based on AE data available from 1223 patients. However, when 
edema was reported on the basis of a cardiac cause, the rate of Grade 
3/4 edema considered likely related to Gleevec was 1.3% among the 
1223 patients. Other high grade cardiac AEs considered less likely 
related to Gleevec included cardiac ischemia/infarction (0.08%), 
hypertension (1%), and hypotension (0.7%). 
Nonclinical data support the evidence of Gleevec induced 
cardiotoxicity both in vitro and in vivo. When healthy mice were 
treated to evaluate the cardiotoxicity of Gleevec, transmission electron 
micrographs of samples from the hearts of three drug-treated mice 
showed results similar to those seen in studies of individuals on 
Gleevec, including membrane whorls in the sarcoplasmic reticulum, 
and in or immediately adjacent to mitochodria. Treatment of mice with 
200 mg/kg/day led to a significant deterioration in contractile function 
(P <0.003) and moderate left ventricular dilation after 3-4 weeks of 
treatment. This mimics the effect that Gleevec treatment has shown in 
human subjects.  
1.1.3 
Clinically Important Adverse Events 
Because of their relative frequency and clinical significance, several 
AEs occurring during the Phase II leukemia trials were analyzed in 
greater detail, as summarized below. 
1.1.3.1 Edema and Fluid Retention 
Superficial edema was one of the most frequently reported 
AEs but was rarely severe (2-5% Grade 3/4). The most 
frequently involved sites included the periorbital region, 
face and lower limbs. The edema usually appeared within 


AMC # 042 (Version 7.0) 07/24/2007 
NCI Version Date 07/24/07 
 
6 
the first 2 months of treatment. A minority of patients with 
severe edema required dose reduction.  
A minority (<5%) of patients developed central collections 
of fluid (described collectively using the term ‘fluid 
retention’) including one or more of the following: CHF, 
pleural 
effusion, 
ascites, 
pericardial 
effusion 
and 
pulmonary edema. It is unclear if the mechanisms 
underlying peripheral edema and fluid retention are the 
same. Fluid retention was usually managed with diuretics 
and/or dose reduction, or with temporary treatment 
interruption.  
1.1.3.2 Gastrointestinal and CNS Hemorrhages 
In toxicology studies, imatinib was shown to be a local 
irritant, and for that reason, the pattern of GI tract 
hemorrhages was carefully reviewed. These events were 
rare, and severe (Grade 3/4) cases were reported only in 
advanced CML patients. GI hemorrhages occurred in 3-5% 
of patients with advanced CML, and were considered drug-
related in 0-2% and severe in <1.5%. Contributing factors 
such as severe thrombopenia, the use of concomitant 
NSAIDS and a history of gastric ulcer were present in 
most, but not all cases. Upper GI ulceration (esophageal, 
gastric or duodenal) or gastritis/duodenitis were visualized 
at gastroscopy in approximately 50% of patients with GI 
bleeding. Less than 1% of patients discontinued therapy as 
a result of these events.  
1.1.3.3 Cerebral hemorrhages (including subdural hematomas and 
hygromas) were also reported almost exclusively in 
advanced CML patients (1-7%). The majority occurred in 
the context of rapidly progressive disease, with 
concomitant thrombocytopenia. 
1.1.3.4 Skin rash 
An erythematous, pruritic, maculopapular skin rash, most 
prominent over the forearms and trunk but occasionally 
present also on the face, was reported in up to 44% of 
patients treated with imatinib. Onset was generally within 
the first month of therapy. Eosinophilia was rarely seen and 
skin biopsies showed the typical appearances of a toxic 
drug reaction with a mixed infiltration of cells. Occasional 
patients reported pruritus without accompanying rash. In 
most cases, the rash was mild, easily manageable with 
antihistamines and/or topical steroids, and gradually 
subsided without interrupting therapy. However, a 
troublesome skin rash was the most frequent reason (in 


AMC # 042 (Version 7.0) 07/24/2007 
NCI Version Date 07/24/07 
 
7 
<1% of patients overall) for the permanent discontinuation 
of therapy. Approximately 3% of patients developed severe 
skin rashes, some with an exfoliative component. Re-
challenge was usually but not always positive. 
1.1.3.5 Hypophosphatemia/Vitamin D deficiency 
Hypophosphatemia and low levels vitamin D have been 
reported to develop in patients taking imatinib and other 
tyrosine kinase inhibitors.[22] Imatinib may interfere with 
osteoclast function directly by inhibiting PDGF receptor β 
on osteoclasts or indirectly by inhibiting the activation of 
C-FMS receptor. These abnormalities were treated with 
Vitamin D and phosphate supplementation and did not 
require reducing the dose of imatinib. Additionally, they 
did not persist with the withdrawal of imatinib. 
1.1.3.6 Cardiac Toxicity 
Kerkela et al. recently reported 10 patients who had severe 
CHF.[21] Cardiac biopsies showed mitochondrial changes 
consistent with drug toxicity and both clinical and 
pathologic effects could be replicated in mice. The risk of 
severe cardiac toxicity has been estimated to be 
approximately 1%. 
1.1.3.7 Gastrointestinal Stomal Tumor (GIST) 
Treatment with Gleevec was generally well tolerated, 
although nearly every patient experienced minor AEs. The 
most frequently reported AEs were edema, nausea, 
diarrhea, musculoskeletal pain, fatigue, rash, headache, and 
abdominal pain. Most events were of mild to moderate 
severity. Superficial edema, most frequently periorbital or 
lower limb edema was managed with diuretics, other 
supportive measures, or by reducing the dose of Gleevec. 
Severe (CTC grade 3/4) superficial edema was observed in 
two patients, including face edema in one patient. No major 
differences were seen in the severity of AEs between the 
400 mg or 600 mg treatment groups, although overall 
incidence of AEs was somewhat higher in the 600 mg 
treatment group. AEs with a suspected relationship to 
therapy occurring in greater than 10 % of patients in any 
group are presented in Table 3. 


AMC # 042 (Version 7.0) 07/24/2007 
NCI Version Date 07/24/07 
 
8 
Table 3 
Adverse Events with Suspected Relationship to Therapy in GIST (> 10 % in any Group) 
 
All Grades 
Grade 3/4 
Preferred Terms 
Percentage Of Patients 
400 mg 
n = 73 
600 mg 
n = 74 
All Doses 
N = 147 
400 mg 
n = 73 
600 mg 
n = 74 
All Doses 
N = 147 
Any AE 
97 
99 
98 
21 
22 
21 
Edema/fluid retention 
71 
77 
74 
1 
1 
1 
 
Periorbital edema 
45 
50 
48 
0 
0 
0 
   Edema lower limb 
26 
15 
20 
0 
0 
0 
   Face edema 
8 
12 
10 
1 
0 
1 
 
Edema 
7 
14 
10 
0 
0 
0 
   Eyelid edema 
7 
8 
8 
0 
0 
0 
Nausea 
51 
54 
52 
1 
1 
1 
Diarrhea 
40 
50 
45 
1 
3 
2 
Myalgia/musculoskeletal pain 
37 
42 
40 
0 
0 
0 
Fatigue 
30 
39 
35 
0 
0 
0 
Dermatitis/rash 
25 
37 
31 
3 
3 
3 
Headache 
19 
32 
26 
0 
0 
0 
Abdominal pain 
26 
26 
26 
1 
0 
1 
Flatulence 
19 
24 
22 
0 
0 
0 
Vomiting 
14 
12 
13 
0 
1 
1 
Any hemorrhage 
11 
14 
12 
4 
5 
5 
 
Tumor hemorrhage 
1 
4 
3 
1 
4 
3 
 
Upper GI bleed/perforation 
4 
3 
3 
4 
1 
3 
Dyspepsia 
10 
12 
11 
0 
0 
0 
Lacrimation increased 
7 
12 
10 
0 
0 
0 
Anemia 
6 
12 
9 
1 
3 
2 
Loose stools 
7 
10 
8 
0 
0 
0 
Taste disturbance 
3 
14 
8 
0 
0 
0 
There was no hyperuricemia or evidence of tumor lysis syndrome, even in patients with very rapid decreases in tumor volume. 
The most medically significant AEs were gastrointestinal or intra-abdominal hemorrhage in patients with large bulky tumors, 
which occurred in approximately 5 % of patients. 
1.1.4 
Preclinical Studies 
As part of continuing preclinical studies on imatinib, Novartis 
completed the in-life part and the necropsy of 2–year oral (in feed) 
carcinogenicity study in rats at doses of 15, 30 and 60 mg/kg. An 
increased incidence of palpable masses in the urogenital region led to 
an accelerated histopathological analysis of these organs. Target 
organs for neoplastic changes were kidneys in both sexes, urinary 
bladder and preputial gland in males, and clitoral glands in females.  


AMC # 042 (Version 7.0) 07/24/2007 
NCI Version Date 07/24/07 
 
9 
A statistically significant increase in renal benign and malignant 
tumors and the urinary bladder benign tumors were noted only at 60 
mg/kg/day, representing approximately 1.74x to 4.14x human daily 
exposure (based on AUC) to imatinib at the dose of 400 mg/day. In 
addition, a statistically significant increase in benign and malignant 
tumors of the preputial/clitoral gland was noted at 30 and 60 
mg/kg/day, representing approximately 0.5x to 1.7x human daily 
exposure (based on AUC) to imatinib at the dose of 400 mg/day. 
1.1.5 
Summary of Pilot Trial Data 
Based on the in vitro data supporting the role of c-kit and PDGF-R 
activation in KS, a pilot trial at Beth Israel Deaconess Medical Center 
in Boston, MA was initiated. Ten patients who were on stable doses of 
highly active anti-retroviral therapy (HAART) and who had failed first 
line KS therapy have been enrolled. The primary goal of the trial was 
to confirm the expression of c-Kit and PDGF-R in KS lesions and to 
determine the activation status of the c-Kit and PDGF receptors in KS 
at baseline and after 4 weeks of treatment with imatinib. The 
secondary goal was to collect data on the tolerability and clinical 
efficacy of imatinib in HIV–related KS. Patients were treated with 
imatinib 300 mg orally, twice daily with dose reduction permitted for 
toxicity. At baseline and at 4 weeks, patients had tumor measurements, 
a 4 mm punch biopsy of a representative lesion and a plasma sample. 
Patients with a response at 4 weeks were allowed to continue therapy 
until disease progression. AIDS Clinical Trial Group (ACTG) criteria 
were used for clinical response. Five of 10 patients had at least a 
partial response (PR) by clinical criteria after only 4 weeks of imatinib 
therapy. Three of 10 patients had stable disease. The median duration 
of therapy was 7 weeks (range 4 to 26 weeks). The majority of patients 
required dose reduction from 600 mg daily to 400 mg daily after 4 
weeks of therapy. One patient had Grade 4 neutropenia that recurred 
after dose reduction. Five patients had diarrhea (three exhibited Grade 
3, and one Grade 4) that resolved with drug withdrawal. Two of these 
five patients with diarrhea had diarrhea at baseline. Diarrhea returned 
with drug re-challenge, but was manageable with over-the-counter 
anti-diarrhea medications. No significant change in CD4 counts or 
viral load was noted during therapy. 
 
We hypothesize that the high rate of GI toxicity that was observed may 
be related to a PK interaction between imatinib and HAART. Imatinib 
is a substrate for the cytochrome p450 isoenzymes, cyp3A4 and 
cyp2D6. All of the protease inhibitors (PIs) in clinical use at the time 
of this study, which includes, amprenavir, indinavir, lopinavir, 
nelfinavir, ritonavir, saquinavir are cyp3A4 inhibitors with ritonavir 
inhibiting cyp2D6 to a lesser extent. Diarrhea is a side effect common 
to all of the PIs. The other class of antiretrovirals shown to affect the 


AMC # 042 (Version 7.0) 07/24/2007 
NCI Version Date 07/24/07 
 
10 
p450 system is the non-nucleoside reverse transcriptase inhibitors. 
Delavirdine is a cyp3A inhibitor while nevirapine is a cyp3A inducer, 
and efavirenz is a mixed cyp3A inducer/inhibitor. No relationship 
between any specific antiretroviral regimen and the incidence of 
diarrhea was observed in the pilot study. 
 
Plasma samples were analyzed to determine levels of imatinib and its 
major active metabolite, CGP-74588 in the laboratory of Dr. Merrill 
Egorin. At steady state the average imatinib concentration was 1,342 
ng/mg (range 0 to 2,846 ng/mL) and CGP-74588 was 733 ng/mL 
(range 459 to 1,046 ng/mL) (n=9). These levels are low compared to 
CML patients on the same dose schedule, 2,939 ng/mg (range 2,009-
3,497 ng/ml) and 733 ng/mL (range 459-1,046 ng/mL). Plasma 
concentrations of the antiretrovirals were not measured in the pilot 
study. Although this data suggest there is not inhibition of imatinib 
metabolism, the imatinib concentrations may not be representative of 
the steady state concentration. The samples were a random sample 
from Day 28, and by that time, all four patients with diarrhea had 
developed symptoms. The presence of the diarrhea could have affected 
the absorption of imatinib as well as patient adherence to the therapy. 
Because of the high potential of drug interactions in the HIV 
population the pharmacokinetics of imatinib in these patients still 
needs to be established. 
 
We examined tumor biopsies using immunohistochemistry (IHC) with 
phosphospecific antibodies to determine the activation status of the 
PDGF and c-kit pathways. A majority of protein kinases require 
phosphorylation of a serine/theronine or a tyrosine in the activation 
loop to allow kinase activity. Phosphospecific antibodies have been 
raised to a number of these sites and are useful as surrogate markers of 
activity. We used phosphospecific antibodies to PDGF-R and c-Kit as 
well as their downstream effectors, ERK1/ERK2 and AKT. Antibodies 
were used anti-c-Kit (Dako); anti-PDGF-R, anti-phospho-β−PDGF-R 
(tyrosine 751), anti-phospho-AKT (serine 473) and anti-phospho-ERK 
(threonine 202/tyrosine 204) (Cell Signaling, Beverly, MA). We have 
not yet found an anti-phospho-c-kit antibody that works reliably for 
IHC. Six patients had evaluable baseline IHC. All six patients 
demonstrated constitutive expression of PDGF-R and c-Kit receptors. 
Four patients had biopsies at baseline and 4 weeks that were evaluable 
by IHC. Three of four patients demonstrated activation of PDGF-R 
and ERK, a downstream effector of PDGF-R and c-Kit, at baseline 
with inhibition of both pathways after treatment with imatinib. We 
also examine the activation status of AKT, a component of the PI3K 
pathway and downstream target of PDGF-R and c-kit. Activation of 
AKT was not seen at baseline or after treatment in any patients. 
VEGF, which has been shown to be downstream of PDGF-R 


AMC # 042 (Version 7.0) 07/24/2007 
NCI Version Date 07/24/07 
 
11 
activation in culture KS spindle cells, was measured pre and post 
treatment but no significant changes in VEGF concentrations were 
seen. 
1.1.6 
Dose Selection 
In the pilot trial, events requiring dose reductions were four cases of 
diarrhea and one case of neutropenia. After dose reduction the 
majority of patients with diarrhea had their symptoms controlled with 
over the counter medications. A dose of 400 mg a day has been shown 
to induce a 82% hematologic response rate in CML and a 57% 
response rate in GISTs.[11,12] Once we began to aggressively manage 
the diarrhea with medication and dose reduction to 400 mg per day, it 
no longer was a dose limiting toxicity. Based on our clinical 
experience, the majority of KS patients will tolerate 400 mg a day. 
1.2 
Biologic/Correlative Studies 
1.2.1 
Expression/Activation (phosphorylation) imatinib kinase targets and 
signaling intermediates. 
We will determine by immunohistochemistry the expression and 
phosphorylation status of PDGF-R in biopsies from baseline and 8 
days. In our initial study, we did not anticipate the degree of 
pathologic regression after 4 weeks of therapy. The marked decrease 
in KS spindle cells after 4 weeks of therapy not only resulted in the 
qualitative decrease in the phospho-PDGF-R staining but also resulted 
in a quantitative decrease in the cell population that was 
immunoreactive initially. In order to more accurately quantitate the 
effect of imatinib on the phosphorylation state of our targets we will 
examine biopsies at an earlier time point. We decided to biopsy 
patients at 8 days because the t1/2 of imatinib is ~18 hours and the t1/2 of 
it metabolite, CGP-74588, is ~36 hours and patients should reach 
steady state concentration after seven days. We have validated 
phosphospecific antibodies by immunohistochemistry for all of these 
determinants except c-Kit receptor. 
1.2.2 
Early Markers of Response 
Two to 3 months are often required to determine if a KS patient is 
responding to a therapeutic agent. If early markers of response could 
be established that would allow physicians to determine with a degree 
of confidence which patients were going to respond, then patients who 
were not going to respond would be free to pursue other treatment 
options. 
 


AMC # 042 (Version 7.0) 07/24/2007 
NCI Version Date 07/24/07 
 
12 
Because of the importance of cytokines, angiogenic factors and growth 
factors produced in KS, a number of recent KS therapeutic trials 
examined biologic endpoints to determine if they correlated with 
clinical response. All the studies to date have looked at isolated 
biologic endpoints based on a priori predictions regarding KS biology 
and/or the mechanism of action of the drug being studied. In a trial of 
oral 9-cis retinoic acid in KS, soluble Interleukin-6 receptor (sIL6R) 
was significantly lower at baseline in responders and IL-6 levels 
increased in responders.[14] In a study of COL-3, a matrix 
metalloproteinase inhibitor, VEGF levels were shown to decrease in 
responders while b-FGF remained unchanged.[15] These reports 
suggest concentrations of cytokines/growth factors at baseline or 
changes in the concentrations after being on therapy may be used as 
predictors of response for KS therapies. 
 
Because of the critical role cytokines/chemokines play in KS 
development, we hypothesize that these growth factors would be 
useful biologic endpoints that may be predictive of response. In 
previous studies investigators had chosen two or three biological 
endpoints to examine. We will perform a proteomics-based screen for 
biologic endpoints. The reason for this choice is two-fold: 1) This 
method allows us to simultaneously examine the majority cytokines 
and chemokines that are implicated in KS development and, 2) We 
have limited knowledge of which growth factors may be downstream 
of the PDGF-R and c-kit pathways in KS. 
The PerkinElmer Cytokine Chip is designed to analyze the following 
cytokines from a sample in a multiplexed fashion: 
 
 
Table 4.  Cytokines detected by PerkinElmer Cytokine Chip 
 
IL-1 alpha 
IL-1 beta 
IL-1ra  
IL-1R4 
IL-1s RI 
 IL-1s RII 
 IL-2 
IL-2s Ra 
IL-3 
IL-4 
IL-5 
IL-6 
IL-6s R 
IL-7 
IL-8 
IL-10 
IL-12p40 
IL-12p70 
IL-13 
IL-15 
IL-16 
IL-17 
EGF 
ENA-78 
FGF-basic 
G-CSF 
GM-CSF 
IFN gamma 
MCP-1 
MCP-2 
MCP-3 
MIG 
MIP-1 alpha 
MIP-1 beta 
MIP-3 alpha 
sTNF RI 
sTNF RII 
TARC 
TNF alpha 
TNF beta 
VEGF 
 
Included in the kit is a mixture of all cytokines to be used for 
generating four point standard curves. These are used to estimate the 
concentration of each cytokine from the samples. After running the 
assay, slides were imaged using a ScanArray Confocal Laser 
Scanner (PerkinElmer, Cambridge, MA). After imaging, the resulting 
tif files were quantitated using QuantArray software (PerkinElmer, 
Cambridge, MA). The data was then exported as an Excel 2000 
worksheet and these are collated into a single workbook. An analysis 
macro was run that subtracts the local background signal from the 


AMC # 042 (Version 7.0) 07/24/2007 
NCI Version Date 07/24/07 
 
13 
signal of each spot. This method adjusts for any differences in 
background that may occur across an array. The replicate spots are 
then averaged and tested for outliers using the ESD method (extreme 
studentized deviate; N=4; Critical Z=1.48). The standards were 
analyzed by point-to-point linear regression and concentrations of 
experimental samples were estimated from these standards. 
 
We will examine the cytokine profiles of patients at baseline, 7 days 
and 28 days to see if there is any correlation between baseline 
concentrations and clinical response. As noted the standards on the 
cytokine chip are analyzed by point-to-point linear regression and 
concentrations of experimental samples are estimated from these 
standards four-point curve. Thus, the chip should be considered a 
semi-quantitative assay and all cytokines/chemokines that appear to be 
potential predictors will be confirmed by ELISA. 
1.2.2.1 Receptor Mutation Analysis 
Mutations of c-kit and PDGF-R have been shown to play a 
role in tumorigenesis and imatinib resistance. Activating 
mutations of c-Kit have been reported in mastocytosis, 
acute myleogenous leukemia, GISTs, myeloproliferative 
disorders (MPD) and sinonasal lymphomas.[16] In vitro 
studies suggest activating mutations in the kinase domain 
of c-Kit are resistant to inhibition by imatinib. Additionally, 
activating mutations in the kinase domain of PDGF-R α 
have been reported in GISTs.[17] We will correlate the 
presence or absence of c-Kit and/or PDGF-R mutations 
with clinical response to imatinib. 
As the experience with imatinib therapy for CML 
increased, it became clear that some patients who initially 
responded later relapsed. Studies demonstrated multiple 
mechanisms of resistance including over-expression of 
BCR/ABL transcripts, acquisition of new chromosomal 
abnormalities and mutation of the kinase domain. In one 
study, mutations of the kinase domain appeared to be the 
mechanism of resistance in 23 of 43 cases. At the time of 
discontinuation, we will biopsy a lesion that is clearly 
growing or has not responded and sequence PDGF-R and 
c-Kit.  
If any novel mutations are found in either of these cases, 
we will determine in vitro whether they are activating 
mutations and/or resistant to imatinib. 
1.2.2.2 Mechanisms of Toxicity 
By reducing the dose of imatinib to 400 mg per day, the 
incidence of AEs should be decreased, but not eliminated. 


AMC # 042 (Version 7.0) 07/24/2007 
NCI Version Date 07/24/07 
 
14 
We hypothesize three potential mechanisms for the 
increased toxicity of imatinib: 1) antiretrovirals inhibit the 
metabolism of imatinib resulting in higher concentrations 
of imatinib compared to those seen in CML and GIST 
patients; 
2) 
imatinib 
inhibits 
the 
metabolism 
of 
antiretrovirals resulting in higher concentrations of 
antiretrovirals; 3) the increased incidence of diarrhea is 
related to response of occult GI KS lesions. Our 
investigations into the effect of HAART on imatinib in the 
pilot study were inconclusive. Because of the potential 
inhibition of imatinib by antiretrovirals, we will formally 
study the pharmacokinetics of imatinib and antiretrovirals 
during the first 2 weeks of therapy in the first 12 patients. 
Because this study will have a limited number of patients, 
and these patients are taking a variety of antiretroviral 
combinations, we have chosen not to measure the 
concentrations of antiretrovirals unless we note increased 
toxicity with normal imatinib levels in this study. If we do 
see an increase in the plasma level of imatinib, we will 
attempt to correlate this with specific antiretrovirals or 
antiretroviral classes. If we find plasma imatinib 
concentrations to be elevated, we will be able to determine 
a dose that provides comparable concentrations to those 
seen in other patient populations, such as CML. 
Interestingly, the diarrhea usually occurred 2 to 3 weeks 
after the initiation of therapy, and its appearance coincided 
with the onset of clinical response in some patients. This 
observation led to a third potential explanation of the 
diarrhea. The patients who had diarrhea may have had 
occult GI involvement of their KS and the diarrhea was 
related to regression of the GI lesions. The standard 
screening for GI involvement of KS is to test the stool for 
the presence of occult blood. All of the patients enrolled to 
date have tested negative and were presumed not to have 
GI involvement. Regressing KS lesions could potentially 
have a direct irritant effect on the bowel or could produce 
cytokines locally that lead to diarrhea. To determine if there 
is GI involvement of KS, we will offer a colonoscopy to all 
patients who have diarrhea that is not controlled by OTC 
medication. Some might argue that we should screen all 
patients with a colonoscopy prior to enrollment, but we feel 
this would be unjustified at this point since a colonoscopy 
is not without risk and diarrhea does not occur in all 
patients. From a practical standpoint, the results of the 
colonoscopy would have little effect on the conduct of 
current trial since we would withhold therapy until the 


AMC # 042 (Version 7.0) 07/24/2007 
NCI Version Date 07/24/07 
 
15 
diarrhea abated and then restart at a reduced dose. 
However, if the diarrhea is correlated with regression of GI 
lesion, one could justify starting at the same dose level 
once the diarrhea had abated in future trials. 
1.2.2.3 Transcription profile of KSHV. Changes in gene expression 
are a fundamental hallmark of cancer progression and 
invaluable tool of cancer stages. In the case of KS, 
KSHV/HHV-8 has been identified as the etiological agent 
and this assay is designed to identify KSHV genes that 
might change in response to therapy. We will use reverse-
transcription 
(RT) 
coupled 
to 
amplification 
using 
polymerase chain reaction (PCR) to measure the mRNA 
levels of all KSHV/HHV-8 mRNAs in the tumor. This 
assay is a research test only and should not be used to make 
clinical decisions. The purpose of including this assay as 
part of this trial is to determine its usefulness as a 
prognostic marker of disease. 
1.3 
Study Design 
The proposed study design will provide clinical response data for imatinib in 
AIDS-related KS. Additionally the study will allow for investigation of 
mechanisms of resistance, mechanisms of toxicity as well as potentially 
developing predictors of response. 
Patients will continue on study protocol for 6 months. Treatment will be 
extended 6 months if the patient has met the criteria for a response or has stable 
disease. At the end of the 12-month study period, further treatment will be at the 
discretion of the Investigator. Protocol treatment will be discontinued if the 
subject develops tumor progression, unacceptable toxicity or develops one of 
the protocol-defined reasons for treatment discontinuation. In the event of 
toxicity, patients will have their dose reduced (see Section 5.4-5.6). 
Clinical and laboratory evaluations will be performed prior to the initiation of 
study medications and at Days 1, 8, 15, 29 and every 28 days thereafter. 


AMC # 042 (Version 7.0) 07/24/2007 
NCI Version Date 07/24/07 
 
16 
2.0 
STUDY OBJECTIVES 
2.1 
Primary Objectives 
2.1.1 
Evaluation of clinical response. 
2.2 
Secondary Objectives 
2.2.1 
Evaluation of inhibition of PDGF receptor as determined by 
immunohistochemistry. 
2.2.2 
Evaluation of cytokine profiles pre and post imatinib therapy. 
2.2.3 
Evaluation of pharmacokinetic profile of imatinib and antiretrovirals in 
HIV patients. 
2.2.4 
Evaluation of mechanisms of primary and secondary resistance to 
imatinib therapy. 
3.0 
PATIENT SELECTION  
3.1 
Inclusion Criteria 
3.1.1 
Biopsy proven KS involving the skin, lymph nodes, oral cavity, GI 
tract and/or lungs. GI and pulmonary involvement must be 
asymptomatic or minimally symptomatic and not require systemic 
cytotoxic therapy. At least five measurable, previously non-radiated, 
cutaneous lesions must be present, which can be used as indicator 
lesions. Additionally, patient will need three lesions greater or equal to 
5 x 5 mm that are accessible for 4 mm punch biopsy. 
3.1.2 
Serologic documentation of HIV infection at any time prior to study 
entry, as evidenced by positive ELISA, positive Western Blot, or other 
federally approved licensed HIV test. 
3.1.3 
Karnofsky performance status > 60% (Appendix IV). 
3.1.4 
Female patients of child-bearing potential must have a negative 
pregnancy test within 72 hours before initiation of study drug dosing. 
Post menopausal women must be amenorrheic for at least 12 months 
to be considered of non-childbearing potential. Male and female 
patients of reproductive potential must agree to employ an effective 
barrier method of birth control throughout the study and for up to 3 
months following discontinuation of study drug. 
3.1.5 
The following lab parameters within 21 days prior to study entry: 
 Hemoglobin > 8.0 gm/dL. 


AMC # 042 (Version 7.0) 07/24/2007 
NCI Version Date 07/24/07 
 
17 
 Absolute neutrophil count > 1000 cells/mm3. 
 Platelet count > 75,000/mm3. 
 Serum creatinine < 1.5 mg/dL or a measured creatinine clearance 
of > 60 mL/min. 
 Total bilirubin should be normal. If, however, the elevated 
bilirubin is felt to be secondary to indinavir or atazavinir therapy, 
then subjects will be allowed on protocol if total bilirubin < 3.5 
mg/dL, provided that the direct bilirubin is normal. 
 AST (SGOT) and ALT (SGPT) < 2.5 times the ULN. 
3.1.6 
Life expectancy of 3 months or more. 
3.1.7 
Age of 18 or older. 
3.1.8 
Ability and willingness to give informed consent. 
3.1.9 
Subjects must, in the opinion of the Investigator, be capable of 
complying with this protocol. 
3.1.10 
No previous imatinib therapy. 
3.1.11 
Antiretroviral therapy is required for patients except those who have 
exhausted all available treatment options. 
3.2 
Exclusion Criteria 
3.2.1 
Concurrent active opportunistic infection (OI). 
3.2.2 
Patient is ≤ 5 years free of another primary malignancy except: if the 
other primary malignancy is not currently clinically significant or 
requiring active intervention, or if other primary malignancy is a basal 
cell skin cancer or a cervical carcinoma in situ. Existence of any other 
malignant disease is not allowed. 
3.2.3 
Acute treatment for an infection or other serious medical illness within 
14 days prior to study entry. 
3.2.4 
Patients may not have had anti-neoplastic treatment for KS (including 
chemotherapy, radiation therapy, biological therapy, or investigational 
therapy) within 4 weeks (6 weeks for nitrosourea or mitomycin-C) of 
study entry. 
3.2.5 
Previous local therapy of any KS indicator lesion within 60 days, 
unless the lesion has progressed since treatment. Because of the 
possibility of tattooing, and the difficulty in ascertaining clinically 
what is active KS versus residual pigment post treatment, any prior 


AMC # 042 (Version 7.0) 07/24/2007 
NCI Version Date 07/24/07 
 
18 
local treatment to the indicator lesions regardless of the elapsed time 
should not be allowed unless there is evidence of clear-cut progression 
of said lesion. 
3.2.6 
Patient with Grade III/IV cardiac problems as defined by the New 
York Heart Association Criteria (e.g., CHF, myocardial infarction 
within 6 months of study entry) (See Appendix XIV). 
3.2.7 
Female patients who are pregnant or breast-feeding. 
3.2.8 
Patient has another severe and/or life-threatening medical disease. 
3.2.9 
Patient has an acute or known chronic liver disease (e.g., chronic 
active hepatitis, cirrhosis).Patients with known Hepatitis C infection, 
but with documentation of no or minimal fibrosis on liver biopsy may 
be enrolled. 
3.2.10 
Patient has had a major surgery within 2 weeks prior to study entry. 
3.2.11 
Drug-specific 
exclusion 
criteria: 
Coumadin® 
and 
systemic 
corticosteroid treatment, other than replacement doses. 
3.2.12 
Subjects must not have received granulocyte colony stimulating factor 
within 2 weeks of study entry. 
3.3 
Enrollment Procedures  
This study will be available for enrollment at all AMC sites. Sites must have 
this protocol approved by their Institutional Review Boards (IRB) and be 
registered with the AMC Operations Center before they may enroll patients.  
After it has been determined that the patient is eligible and an informed consent 
has been signed by the patient, the patient must be registered on-line via the 
AMC AdvantageEDCSM Internet Data Entry System. Enrollment and data 
collection will occur via the AMC Internet Data Entry System. 
The participating site will ensure the patient meets all eligibility criteria prior to 
completing the protocol-specific eligibility checklist. Patients will be enrolled 
on-line via the AMC Internet Data Entry System no more than one week prior 
to the initiation of treatment (enrollment one day prior to or on the day of 
treatment is strongly encouraged). Once the eligibility checklist is submitted a 
system generated confirmation email will be sent to the enroller upon successful 
completion of the patient enrollment. If the on-line system is inaccessible, the 
site 
should 
notify 
the 
AMC 
Operations 
Center 
(via 
email 
at 
amcpm@emmes.com, or by phone at 301-251-1161) for further instructions. 
 


AMC # 042 (Version 7.0) 07/24/2007 
NCI Version Date 07/24/07 
 
19 
4.0 
CLINICAL AND LABORATORY EVALUATIONS 
All signs, symptoms, HIV-related and AIDS-defining events (refer to Appendices II and 
III), death and toxicities must be documented. All signs, symptoms and laboratory results 
≥ Grade 2 that are felt to be clinically significant or drug-related, and all HIV-related and 
AIDS-defining events and deaths must be recorded on the case report forms (CRFs). 
All prescription medications taken within 14 days prior to study entry and during the 
intervals between each visit must be recorded on CRFs. The duration of all anti-HIV 
medications and all OI treatment and/or prophylaxis medications at the time of 
enrollment must be recorded in the CRF. All non-prescription medications must be 
recorded in the clinic record. 
4.1 
Eligibility/Screening 
4.1.1 
Biopsy diagnostic of KS at any time prior to study entry. 
4.1.2 
Documentation of HIV infection at any time prior to study entry. 
4.1.3 
Chest X-ray to rule out pulmonary KS (must be done within 4 weeks 
of study entry). Pulmonary involvement must be asymptomatic or 
minimally symptomatic and not require systemic cytotoxic therapy. 
Patients with a positive chest x-ray or minimal symptoms suggestive 
of pulmonary disease will have a chest CT performed at entry. 
4.1.4 
A medical history within 21 days of study entry to include the 
following information: 
 Previous HIV-related and non-HIV related diagnoses. 
 Complete prior anti-HIV therapy, immune based therapy and prior 
anti-tumor therapy, including start dates of current anti-HIV 
therapy. 
 All prescription medications taken within the preceding 2 weeks. 
 A signs and symptoms assessment within 2 weeks prior to study 
entry, including history of weight change. 
 Complete physical exam including the following: vital signs, 
height, weight, tumor assessment, and Karnofsky performance 
(Appendix IV) status. 
4.1.5 
Laboratory studies must be obtained within 21 days (unless noted 
otherwise) prior to study entry, and will include the following: 
 Complete blood count with differential and platelets. 


AMC # 042 (Version 7.0) 07/24/2007 
NCI Version Date 07/24/07 
 
20 
 Serum chemistries: liver enzymes (SGOT, SGPT, alkaline 
phosphatase), BUN, creatinine, electrolytes, amylase, bilirubin 
[direct and indirect]), phosphate, and 25-hydroxyvitamin D. 
 Urine phosphate, creatinine for calculation of fractional excretion 
of phosphate (FEPO4). Calculate the FEPO4 using the formula [UrPO4 
x PCr x 100] ÷ [PPO4 x UrCr]. UrPO4= Urine phosphate; UrCr = Urine 
creatinine, PPO4=Plasma Phosphate PCr = Plasma creatinine. 
4.1.5.1 If FEPO4 > 5% or serum phosphate is low, then  
25-hydroxyvitamin D should be drawn at next visit. 
 
For women of child bearing potential, a serum beta 
HCG pregnancy test within 72 hours of study entry. 
 
CD4 count within 4 weeks prior to study entry. 
 
HIV-1 plasma RNA within 4 weeks prior to study 
entry (to be evaluated at local institution). 
 
Stool tested for occult blood. 
4.1.6 
KS Tumor assessments may be performed on day 1 prior to receiving 
study medication, but may be performed no earlier than within 2 
weeks prior to initiating treatment. Tumor measurements should 
include the following: 
 Identify marker lesions: Select five bi-dimensionally measurable 
marker lesions for assessing changes in lesion dimension.  Select 
the largest lesions with clearly defined margins.  If possible, 
marker lesions will be photographed. Additionally, the patient will 
need three lesions greater or equal to 5 x 5 mm that are accessible 
for 4 mm punch biopsy. 
 For patients with < 50 total skin and oral lesions, all lesions must 
be evaluated for changes in number and characteristics. For 
patients with ≥ 50 total skin and oral lesions, choose three 
representative areas, if possible, for evaluating change in lesion 
numbers and characteristics (preferably an area with ≥ 5 lesions). 
NOTE: A representative area is a single extremity (the back, chest, or 
face) that has lesions similar in characteristics, i.e., nodularity, size, 
color, and number, to those found on other parts of the body. A 
representative area does not need to be the area with the largest 
number of lesions, but should contain lesions that are truly 
representative of those throughout the remainder of the body. 


AMC # 042 (Version 7.0) 07/24/2007 
NCI Version Date 07/24/07 
 
21 
4.1.7 
Staging Criteria: KS staging will be based on the modified ACTG 
Oncology Committee Staging Criteria (see Appendix V). 
4.1.8 
Specimens for the AIDS and Cancer Specimen Resource (ACSR) to be 
collected within 28 days prior to study entry (see Appendix VIII for 
specimen handling), if consent obtained (see Appendix VII). 
4.2 
Evaluations During Treatment 
Evaluations may occur up to 7 days before or after the end of the study visit 
indicated. Each cycle will be 28 days. Evaluations will continue as outlined 
below. Patients on the 6-month extension arm will also follow the outline 
below. 
4.2.1 
Clinical assessment on Days 1, 8, 15, 29 and then every 28 days 
thereafter, to include an assessment of the following, at every visit 
(unless otherwise specified): 
4.2.1.1 KS tumor assessment at baseline (to be performed on Day 1 
prior to receiving study medication, but no earlier than 2 
weeks prior to initiating treatment) Day 29, Day 56 and 
every 2 months thereafter (see Section 4.1.6). 
4.2.1.2 A complete physical exam including: vital signs, weight, 
Karnofsky performance status (Appendix IV) and toxicity 
evaluation (Days 8, 15, 29 and then every 28 days 
thereafter). 
4.2.1.3 Signs and Symptoms Review. 
4.2.1.4 Complete blood count with differential and platelets. 
4.2.1.5 Serum chemistries: liver enzymes (SGOT, SGPT, alkaline 
phosphatase), BUN, creatinine, electrolytes, amylase, 
bilirubin (direct and indirect, if total is elevated) and 
phosphate. 
4.2.1.6 Urine phosphate and urine creatinine for calculation of 
fractional excretion of phosphate (FEPO4). [Fractional 
excretion of phosphate=(spot urinary phosphate/serum 
phosphate)/(spot urinary creatinine/serum creatinine) × 
100]. 
4.2.1.6.1 
If FEPO4 > 5% or serum phosphate is low then 
25-hydroxyvitamin D should be drawn at next 
visit or within 7 days (whichever is sooner). 
4.2.1.7 For women of childbearing potential: serum β-HCG at any 
time pregnancy is suspected. 
4.2.1.8 All HIV-related and AIDS-defining events (Appendix III) 
and concomitant medications. 


AMC # 042 (Version 7.0) 07/24/2007 
NCI Version Date 07/24/07 
 
22 
4.2.2 
CD4 count at baseline, Day 29 and every 3 months thereafter. 
4.2.3 
HIV-1 plasma RNA at baseline, Day 29 and every 3 months thereafter 
(to be evaluated at local institution). 
4.2.4 
HHV-8 Viral Load- Day 1 and Day 15 of cycle 1, and on Day 1 of 
cycles 3, 5, 7, 9, 11 (see Appendix XIII). 
4.2.5 
HHV-8 Viral Gene Expression- Day 1 and Day 15 of cycle 1, and on 
Day 1 of cycles 3, 5, 7, 9, 11 (see Appendix XIII). 
4.2.6 
Biologic Endpoints - Biopsies will be performed at baseline (two), at 
Day 8 and at time of progression. One biopsy will be performed at 
baseline and at time of progression or treatment discontinuation for 
receptor mutation analysis. The DNA from these biopsies will be used 
to assess exons 12 and 18 in PDGDR β, and exons 11 and 17 in c-kit 
for mutations that may activate the target receptors or confer resistance 
to imatinib. If mutations are now found in these exons, we will 
sequence other exons in which activating mutations have been 
described. Additionally, RNA from these biopsies will be stored for 
sequencing cDNAs and accessing expression of downstream targets. 
These biopsies will be fresh biopsies stored in RNAlator storage media 
(see Appendix X). Two more biopsies will be performed at baseline 
and on Day 8 for receptor phosphorylation. These biopsies will assess 
inhibition of PDGF receptor and will be performed on each specimen. 
These biopsies will be fixed in 10% formalin (see Appendix X). Serum 
and plasma specimens for cytokine profiles will be taken at baseline, 
Day 8 and Day 29 (see Appendix XI). DNA and RNA from PBMCs in 
these specimens will be stored. The DNA will be used to determine if 
PDGF-R and c-kit mutations are present in circulating PBMCs, which 
are infected with KSHV or are restricted to the KS lesions. The RNA 
will be used for accessing the effect of PDGF-R and c-kit inhibition on 
the expression of cytokines and other potential downstream targets. 
4.2.7 
Pharmacokinetics - The first 12 patients will have PK sampling 
performed on Days 1 and 15. Samples will be collected on both days 
on the following schedule: 0 (immediately prior to patient taking meds 
for that day), 0.5, 1, 2, 3, 4, 8 and 24 (immediately prior to the next 
day’s dose) hours (see Appendix XII). These data will be compared 
with historical PK data acquired at the same time points in normal 
volunteers. 
4.3 
Evaluations At The Time Of Treatment Discontinuation 
At the time of treatment discontinuation all evaluations should be completed as 
soon as possible (see Appendix I, Schedule of Events).  The following should be 
performed upon discontinuation of study drug: 


AMC # 042 (Version 7.0) 07/24/2007 
NCI Version Date 07/24/07 
 
23 
4.3.1 
Complete blood count with differential and platelets. 
4.3.2 
Serum 
chemistries: 
liver 
enzymes 
(SGOT, 
SGPT, 
alkaline 
phosphatase), BUN, creatinine, electrolytes, bilirubin (direct and 
indirect) and phosphate. 
4.3.2.1 Urine phosphate and creatinine for calculation of fractional 
excretion of phosphate (FEPO4).[Fractional excretion of 
phosphate=(spot urinary phosphate/serum phosphate)/(spot 
urinary creatinine/serum creatinine) × 100]. 
4.3.3 
CD4 count and HIV plasma RNA viral load. 
4.3.4 
HHV-8 Viral Load (see Appendix XIII). 
4.3.5 
A complete physical exam including: vitals signs, weight, tumor 
assessment, Karnofsky performance status (Appendix IV), and toxicity 
evaluation. At the time of discontinuation, a lesion that is clearly 
growing or has not responded will be biopsied for receptor mutations. 
If possible, the lesion should be greater or equal to 5 x 5 mm. Biopsy 
should be performed with a 4 mm punch biopsy. 
4.4 
Final Evaluations/Off Drug, Off Study 
AEs must be reported if the AE began any time within 8 weeks of receiving the 
study treatment. Additionally, if a site learns of any incidence of death, cancer 
or fetal anomaly, WHICH IS DRUG RELATED, at any time after the study is 
closed, the site should notify Novartis. This information may provide additional 
insight into the safety of Gleevec. 


AMC # 042 (Version 7.0) 07/24/2007 
NCI Version Date 07/24/07 
 
24 
5.0 
STUDY TREATMENT 
5.1 
Drug Regimens, Administration And Duration 
Novartis will supply Gleevec as 100 mg tablets packaged in bottles. Medication 
labels will comply with the legal requirements of the U.S. and will be printed in 
English. The storage conditions for Gleevec will be described on the medication 
label. Bottles must be stored in a safe, secure location. 
Gleevec is a local irritant and must be taken in a sitting position with a large 
(250 mL) glass of water. Direction of use on medication label: Take as directed 
with a large glass of water. 
5.2 
Drug Orders, Transfers, Returns, And Accountability 
Gleevec will be provided by Novartis for the 12-month study period. 
Questions about drug orders, transfers, returns, or accountability should be 
addressed to BIDMC IND Pharmacy, Keith Belken at 617-667-4249, Monday 
through Friday between 9:00 am and 4:30 pm Eastern Time. 
5.2.1 
Drug Orders 
Once a patient has been registered with the AMC Operations Center, 
the enrolling site will fax a clinical drug request for that patient to the 
Beth Israel Deaconess Medical Center IND pharmacy. If the order is 
received prior to 1:00 pm Eastern Time, it will be processed by IND 
pharmacy and shipped that day; otherwise, drug orders will be shipped 
the following business day. The shipments will be sent via FedEx for 
next business day delivery. Thus, if a patient is registered on 
Wednesday, the order will be processed on Thursday and shipped on 
Friday for delivery on Monday. The initial request will be for a 4-week 
supply of Gleevec. Sites will be sent enough drug for 30 days to cover 
shipping time if the patient continues on the trial. Sites may reorder 
additional Gleevec by completing an NCI Clinical Drug Request form 
and faxing it to the BIDMC IND pharmacy at 617-667-4248. The NCI 
Clinical Drug Request form is available on the NCI home page 
(http://ctep.info.nih.gov) or by calling the PMB at 301-496-5725. The 
patient ID number (e.g. “042-999-999”) and the patient initials (e.g., 
“LFM”) should be entered in the Patient or Special Code field. All 
drug orders will be shipped to the pharmacy of the institution where 
the patient is enrolled.  
5.2.2 
Drug Transfers 
Drug may not be transferred from one patient to another patient, from 
one center to another center, or from one protocol to another protocol.  


AMC # 042 (Version 7.0) 07/24/2007 
NCI Version Date 07/24/07 
 
25 
5.2.3 
Drug Returns 
All unused drug supplies should be destroyed on site and the amount 
recorded.  
5.2.4 
Drug Accountability 
The Investigator, or a responsible party designated by the Investigator, 
must maintain a careful record of the receipt and disposition of all 
drugs received using the NCI Investigational Agent Accountability 
Record available on the CTEP home page (http://nci.cancer.gov) or by 
calling the PMB at 301-496-5725. 
5.3 
Dosing 
Patients will be instructed to take Gleevec 400 mg/day (a total of 4 tablets). 
Patients who have been on study for at least 3 months without any toxicities 
may have their dose increased to 600 mg/day. 
5.4 
Dose Modifications For Non-Hematological Toxicity 
Further continuation of Gleevec treatment after any interruptions lasting longer 
than 2 weeks is not recommended. 
5.4.1 
Grade 2 
If the patient experiences a new Grade 2 non-hematologic toxicity, 
with the exception of hypophosphatemia, study drug must be withheld 
until the toxicity has resolved to ≤ Grade 1. Gleevec may then be 
resumed at the same daily dose. If the Grade 2 toxicity recurs, Gleevec 
must be withheld until the toxicity has resolved to ≤ Grade 1, and the 
daily dose must be reduced by 100 mg if at 400 mg dose level, or by 
200 mg if at 600 mg dose level. If the Grade 2 toxicity recurs, Gleevec 
treatment will be stopped. 
 
For Grade 2 hypophosphatemia the patient should be started on 
Neutra-Phos 250 mg by mouth four times a day. 
 
Additionally, if a patient has a 25-hydroxy D that is > 30 ng/mL, no 
Vitamin D supplementation is needed. If less than 20 ng/mL, give 
Ergocalciferol D2: 50,000 IU weekly x 8 weeks and then maintain 
with daily OTC Vitamin D3 cholecalciferol 1,000 IU daily. If the level 
is between 20 ng/mL and 30 ng/mL, calculate the additional Vitamin 
D the patient will need to add to their current intake by the formula:  
30 - (current level) x 100 = # IUs of OTC cholecalciferol to boost up 
stores to optimum level of 30ng/mL (to increase by 1 ng/mL add 100 
IU of Vitamin D3). For example if current level = 25 ng/mL, the 
patient will need to add 500 IU to their current intake. With 


AMC # 042 (Version 7.0) 07/24/2007 
NCI Version Date 07/24/07 
 
26 
completely optimum Vitamin D levels, patients may be less 
susceptible to hypophosphatemia. 
 
If the Grade 2 hypophosphatemia recurs in spite of supplementation, 
Gleevec must be withheld until the toxicity has resolved to ≤ Grade 1, 
and the daily dose must be reduced by 100 mg if at 400 mg dose level, 
or by 200 mg if at 600 mg dose level. If the Grade 2 
hypophosphatemia recurs after dose reduction, Gleevec treatment will 
be stopped. 
5.4.2 
Grade 3/4 
If the patient experiences Grade 3/4 toxicity, with the exception of 
hypophosphatemia, Gleevec must be withheld until the toxicity has 
resolved to ≤ Grade 1 or baseline, and the daily dose must be reduced 
by 100 mg if at 400 mg dose level, or by 200 mg if at 600 mg dose 
level. If the Grade 3/4 toxicity recurs, Gleevec treatment will be 
stopped. 
 
For Grade 3/4 hypophosphatemia the patient should be started on 
Neutra-Phos 250mg by mouth four times a day and Gleevec should be 
held until resolved to Grade < 1 and then restarted at previous dose. 
 
Additionally, if a patient has a 25-hydroxy D that is > 30 ng/mL, no 
Vitamin D supplementation is needed. If less than 20 ng/mL, give 
Ergocalciferol D2: 50,000 IU weekly x 8 weeks and then maintain 
with daily OTC Vitamin D3 cholecalciferol 1,000 IU daily. If the level 
is between 20ng/mL and 30ng/mL, calculate the additional Vitamin D 
the patient will need to add to their current intake by the formula: 
 30 - (current level) x 100 = # IUs of OTC cholecalciferol to boost up 
stores to optimum level of 30ng/mL (to increase by 1 ng/mL, add 100 
IU of Vitamin D3). For example if current level = 25ng/mL, the 
patient will need to add 500 IU to their current intake. With 
completely optimum Vitamin D levels, patients may be less 
susceptible to hypophosphatemia. 
 
If Grade 3/4 hypophosphatemia recurs in spite of dose reduction, 
Gleevec must be withheld until the toxicity has resolved to ≤ Grade 1 
or baseline, and the daily dose must be reduced by 100 mg if at 400 
mg dose level, or by 200 mg if at 600 mg dose level. If the Grade 3/4 
hypophosphatemia recurs after dose reduction, Gleevec treatment will 
be stopped. 


AMC # 042 (Version 7.0) 07/24/2007 
NCI Version Date 07/24/07 
 
27 
Summary of Dose Modifications for Non-Hematologic Toxicity Excluding 
Hypophosphatemia 
 
OCCURRENCE 
NEW GRADE 2 
GRADE 3/4 
1st 
Hold until ≤ Grade 1, then resume at 
same dose 
Hold until ≤ Grade 1 or baseline, then reduce to 300 
mg/day if at 400 mg dose level, or to 400 mg/day if at 
600 mg dose level. 
2nd 
Hold until ≤ Grade 1 then reduce to 300 
mg/day if at 400 mg dose level, or to 400 
mg/day if at 600 mg dose level. 
Stop treatment 
3rd 
Stop treatment 
N/A 
 
5.5 
Dose Modifications For Hematological Toxicity 
5.5.1 
Grade 1/2 
No dose interruptions or reductions will be performed for Grade 1/2 
hematological toxicity. 
5.5.2 
Grade 3/4  
If the patient experiences a Grade 3/4 hematological toxicity, defined 
as an ANC < 1 x 109/L, or a platelet count < 50 x 109/L, Gleevec must 
be withheld until the toxicity has resolved to ≤ Grade 2. ANC will take 
precedence over a WBC count in determining the degree of 
neutropenia (e.g., doses should not be interrupted for a patient with a 
WBC < 2.0 x 109 /L, but would be for an ANC < 1 x 109/L). If the 
toxicity resolves to < Grade 2 within 2 weeks, Gleevec treatment may 
be resumed at the same dose. If the Grade 3/4 toxicity recurs, Gleevec 
must be withheld. If the toxicity resolves to < Grade 2 within 2 weeks, 
Gleevec may be recommenced with the daily dose reduced by 100 mg 
if at 400 mg dose level, or by 200 mg if at 600 mg dose level. If the 
Grade 3/4 toxicity persists for longer than 2 weeks, Gleevec will be 
stopped. If the Grade 3/4 toxicity recurs after a dose reduction to 300 
mg/day, Gleevec treatment will be stopped. Patients may receive G-
CSF while Gleevec is held as clinically indicated. 
 
No dose reductions will be performed for Grade 1-4 anemia. If the 
patient develops anemia, he/she may be transfused or receive 
Erythopoietin at the discretion of the Investigator. 


AMC # 042 (Version 7.0) 07/24/2007 
NCI Version Date 07/24/07 
 
28 
Summary of Dose Modifications for Hematologic Toxicity 
 
OCCURRENCE 
GRADE 3/4 
1st 
Hold until ≤ Grade 2 within 2 weeks, then resume at same 
dose. If ≤ Grade 2 not reached within 2 weeks, then stop 
treatment. 
2nd-Dose >300 mg 
Hold until ≤ Grade 2 within 2 weeks, then resume 
treatment at 300 mg/day if at 400 mg dose level, or by 200 
mg if at 600 mg dose level.  If ≤ Grade 2 not reached in 2 
weeks, then stop treatment. 
2nd – Dose = 300 mg 
Dose at 2nd occurrence 
Stop treatment. 
 
5.6 
Concomitant Therapy 
In general, concomitant medications and therapies deemed necessary for the 
supportive care and safety of the patient are allowed, provided their use is 
documented in the patient records and on the appropriate CRF. The 
administration of any other therapies intended to treat the primary condition, 
including chemotherapy and biologic agents, is NOT permitted. Similarly, the 
use of other concurrent investigational drugs is not allowed. 
Because of the inherent risk of either reduced activity or enhanced toxicity of 
the concomitant medication and/or Gleevec, drugs known to interact with the 
same CYP450 isoenzymes (2D6 and 3A4) as Gleevec should be used with 
caution.  Patients using concomitant medications known to be metabolized by 
these cytochrome p450 enzymes will not be excluded from the study. However, 
the patients must be carefully monitored for potentiation of toxicity due to 
individual concomitant medication.  Special care has to be given to the 
concomitant use of acetaminophen (e.g., Tylenol or Percocet, paracetamol 
Panadol, etc.) with Gleevec. Any use of concomitant medication must be 
captured in the concomitant medication CRF. (See Appendix XV for complete 
list). 


AMC # 042 (Version 7.0) 07/24/2007 
NCI Version Date 07/24/07 
 
29 
5.7 
Permitted Medications 
5.7.1 
Prophylactic use of loperamide (e.g., Imodium®, with suggested 
dosing as start: 4mg po x 1, then 2 mg po after each loose stool, max 
16 mg/day) is recommended for patients experiencing Grade 1 or 2 
diarrhea, before dose interruption. 
5.7.2 
Chemoprophylaxis for Pneumocystis carinii pneumonia is highly 
recommended for all subjects with a CD4 count of < 200.  
5.7.3 
Topical and/or oral antifungal agents are permitted except oral 
itraconazole and ketoconazole. (Topical agents should not be applied 
to study lesions). 
5.7.4 
Chemoprophylaxis for Mycobacterium avium complex (MAC) is 
required for patients whose CD4 cell counts < 50 cells/mm3, 
preferably with azithromycin 1.2 g orally once a week. 
5.7.5 
Treatment, maintenance or chemoprophylaxis with approved agents 
for OI as clinically indicated. 
5.7.6 
All antibiotics as clinically indicated except for prohibited 
medications. 
5.7.7 
Antiretroviral therapy is permitted and strongly encouraged for any 
subject with a detectable viral load. Patient should be receiving an 
optimal and stable regimen of HAART for a minimum of 12 weeks 
prior to entry. 
5.7.8 
Erythropoietin is permitted at the discretion of the Investigator. 
5.7.9 
Granulocyte colony stimulating factors are permitted as outlined in 
Sections 3.2.12 and 5.6. 
5.7.10 
Regularly prescribed medications such as antipyretics, analgesics, 
allergy 
medications, 
antidepressants, 
sleep 
medications, 
oral 
contraceptives, 
megestrol 
acetate, 
testosterone 
or 
any 
other 
medications are permitted except for prohibited medications (see 
Section 5.8.1.4 – 5.8.1.7).  
5.7.11 
Prophylactic anti-emetics should be withheld until the patient has 
experienced Grade 1 nausea or vomiting.  
5.7.12 
If patient has weight gain greater than 5 pounds above baseline that is 
felt to be due to fluid retention, patient may be started on diuretics at 
the Investigator’s discretion. 


AMC # 042 (Version 7.0) 07/24/2007 
NCI Version Date 07/24/07 
 
30 
5.7.13 
Alternative therapies such as vitamins, acupuncture and visualization 
techniques will be permitted. Subjects should report the use of these 
therapies and they will be recorded.  
5.8 
Prohibited Medications 
5.8.1 
Investigational drugs, with the exception of antiretroviral agents that 
are being obtained through an expanded access protocol. 
5.8.2 
Systemic cytotoxic chemotherapy or any other treatment specifically 
prescribed to treat KS (e.g., radiation, etc.). 
5.8.3 
Since warfarin is metabolized through the CYP450 system, no 
therapeutic anticoagulation with warfarin (e.g. Coumadin) will be 
permitted in patients participating in this study. As an alternative, 
therapeutic anticoagulation may be accomplished using low-molecular 
weight heparin (e.g., Lovenox®) or heparin. A mini-dose coumadin 
derivative (equivalent to 1 mg QD Coumadin) is permitted for 
prophylaxis of central venous catheter thrombosis, at the discretion of 
the treating physician. In general, the use of Coumadin is discouraged 
on this protocol. 
5.8.4 
The routine use of systemic corticosteroid therapy, other than 
replacement doses, is not permitted. 
5.9 
Prohibited Foods 
5.9.1 
Grapefruit juice. 
5.10 
Treatment Compliance 
Records of study medication used, dosages administered, and intervals between 
visits will be kept during the study. Drug accountability will be noted and at the 
completion of the trial. Patients will be asked to return all unused medication at 
the monthly visits. 
Patients will also be given a diary to carry home and will be instructed to record 
each time study drug is administered. The patient will be asked to bring diary at 
each clinic visit. 
Patients will be asked to weigh themselves twice a week and will be asked to 
report to the study team any increase in weight greater than 5 pounds above 
baseline. If weight gain is felt to be due to fluid retention, patient may be started 
on diuretics at the Investigator’s discretion. 


AMC # 042 (Version 7.0) 07/24/2007 
NCI Version Date 07/24/07 
 
31 
6.0 
REPORTING OF ADVERSE EVENTS 
This study will utilize the CTCAE version 3.0 for Common Terminology Criteria for 
Adverse Event reporting. A copy of the CTCAE version 3.0 can be downloaded from the 
CTEP home page (http://ctep.info.nih.gov). All appropriate treatment areas should have 
access to a copy of the CTCAE version 3.0. The documents “NCI Guidelines: Adverse 
Event Reporting Requirements for NCI Investigational Agents” (sections 2 and 3) clearly 
outline reporting criteria. 
This study will be monitored by the Clinical Data Update System (CDUS). Cumulative 
CDUS data will be submitted quarterly to CTEP by electronic means. Reports are due 
January 31, April 30, July 31, and October 31. 
6.1 
Classification Of Adverse Events By Severity & Relationship To Study 
Drug Administration 
6.1.1 
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). 
6.1.2 
Life-Threatening Adverse Event 
Any adverse event that places the patient or subject, in view of the 
investigator, at immediate risk of death from the reaction. 
6.1.3 
Serious Adverse Event (SAE) 
Any adverse event occurring at any dose that results in any of the 
following outcomes: Death, a life-threatening adverse event, inpatient 
hospitalization or prolongation of existing hospitalization, a persistent 
or significant disability/incapacity, or a congenital anomaly/birth 
defect. 
 
Please note for hospitalization – All hospitalizations (or prolongation 
of existing hospitalization) for medical events equivalent to CTCAE 
Grade 3, 4, 5 must be reported regardless of the requirements for Phase 
of study, expected or unexpected, and attribution. For example, do not 
report an admission for pharmacokinetic sampling, but do report an 
admission for a myocardial infarction. 
6.1.4 
Toxicity 
Toxicity is a term NOT clearly defined by regulatory organizations.  
Toxicity has been described as an adverse event that has an attribution 


AMC # 042 (Version 7.0) 07/24/2007 
NCI Version Date 07/24/07 
 
32 
of possibly, probably or definitely related to investigational treatment. 
To minimize confusion the NCI would recommend that the term 
toxicity NOT be utilized for adverse event reporting purposes. The 
CTCAE continues to use the term ‘toxicity’ because of familiarity. 
6.1.5 
Unexpected Adverse Event 
Any adverse event that is not listed in the NCI Agent Specific 
Expected Adverse Event List. This list is updated electronically in real 
time. 
6.1.6 
Adverse Event Expedited Reporting System (AdEERS) (formerly 
known as Adverse Drug Reaction Reporting). 
An electronic system for expedited submission of adverse event 
reports. 
6.1.7 
Attribution 
The determination of whether an adverse event is related to a medical 
treatment or procedure. Attribution categories: 
Definite – The AE is clearly related to the investigational agent(s). 
Probable – The AE is likely related to the investigational agent(s). 
Possible – The AE may be related to the investigational agent(s). 
Unlikely – The AE is doubtfully related to the investigational 
agent(s). 
Unrelated – The AE is clearly NOT related to the investigational 
agent(s). 
6.2 
Adverse Event Reporting To Novartis 
Novartis will need to be notified within 24 hours of any SAE regardless of the 
presumed relationship to Gleevec. 
Instructions for rapid notification of SAEs. 
6.2.1 
Reporting Responsibility 
Each SAE (but not pregnancies) must be reported by the Investigator 
to Novartis within 24 hours of learning of its occurrence, even if it is 
not felt to be treatment-related. Follow-up information about a 
previously reported SAE must also be reported to Novartis within 24 
hours of receiving it. If the SAE has not been previously documented 
(new occurrence) and it is thought to be related to study drug (or 
therapy), the Medical Safety Expert of the Clinical Safety & 
Epidemiology (CS&E) Department may contact the Investigator to 


AMC # 042 (Version 7.0) 07/24/2007 
NCI Version Date 07/24/07 
 
33 
obtain further information. If warranted, an investigator alert may be 
issued, to inform all investigators involved in any study with the same 
drug (or therapy) that this SAE has been reported. 
6.2.2 
Reporting Procedures 
The Investigator must complete the FDA MedWatch 3500 form and 
Novartis SAE coversheet (see Appendix XVII) in English, assess the 
relationship to study treatment and send the initial completed 
MedWatch form and Novartis SAE coversheet by fax 1.888.299.4565 
within 24 hours to the local Novartis Clinical Safety & Epidemiology 
(CS&E) Department. The Investigator must then ensure that the form 
and coversheet are accurately and fully completed with follow-up 
information and fax those to Novartis CS&E Department within 2 to 3 
calendar days for deaths or life-threatening events and 5 calendar days 
for other SAEs. The original and the duplicate copies of the FDA 
MedWatch form, Novartis SAE coversheet, and the fax confirmation 
sheet must be kept with the CRFs at the study site. 
 
Follow-up information should describe whether the event has resolved 
or continues, if and how it was treated, and whether the patient 
continued or discontinued study participation. The MedWatch form, 
Novartis SAE coversheet, and fax confirmation sheet must be retained. 
Pregnancy follow-up should describe the outcome of the pregnancy, 
including any voluntary or spontaneous termination, details of the 
birth, and the presence or absence of any congenital abnormalities or 
birth defects. 
6.3 
Adverse Events With Commercial Agents 
The AE should be reported on the FDA Form 3500 MedWatch (available from 
the FDA website at www.fda.gov/medwatch). The following AEs should be 
reported: 
• 
All life-threatening events (Grade 4), which may be due to drug 
administration. 
• 
All fatal events (Grade 5) while on study (or within 30 days of treatment) 
• 
First occurrence of any previously unknown clinical event (regardless of 
Grade). 
 
The completed form should be forwarded to: 
 
AMC Operations Center 
The EMMES Corporation 
401 N. Washington St., Suite 700 
Rockville, MD  20850 
Fax: (240) 238-2842 


AMC # 042 (Version 7.0) 07/24/2007 
NCI Version Date 07/24/07 
 
34 
 
All AEs, regardless of severity, and whether or not ascribed to study drug 
administration, will be recorded in the appropriate section of the CRF. Patients 
withdrawn from the study due to AEs will be followed by the Investigator until 
the outcome is determined and, when appropriate, additional written reports and 
documentation will be provided. 


AMC # 042 (Version 7.0) 07/24/2007 
NCI Version Date 07/24/07 
 
35 
7.0 
CRITERIA FOR TREATMENT DISCONTINUATION  
• 
Study medication will be interrupted or permanently discontinued for treatment 
related toxicities as outlined in Sections 5.4-5.6. 
• 
Disease progression. 
• 
Subjects who become pregnant or breast-feed or who require systemic 
chemotherapy for the treatment of a malignancy other than KS. 
• 
Subjects who require treatment with medications disallowed as outlined in Sections 
5.6.1.4–5.6.1.7. 
• 
Subjects who are noncompliant with respect to taking drugs, keeping appointments 
or having tests required for the evaluation of drug safety and efficacy. 
• 
Subjects have the right to withdraw from the study at any time for any reason. 
• 
The Investigator has the right to remove subjects from the study for clinical reasons 
which he/she believes are life-threatening to the subject even if such reasons do not 
fall into the toxicity classifications discussed above. 


AMC # 042 (Version 7.0) 07/24/2007 
NCI Version Date 07/24/07 
 
36 
8.0 
POST-TREATMENT EVALUATION AND EVALUATION AT EARLY 
DISCONTINUATION OF THERAPY 
Thirty days after discontinuation, a follow-up visit will include: a complete physical 
exam including: vitals signs, weight, tumor assessment, Karnofsky performance 
status (Appendix IV), and toxicity evaluation. 
 
At a subject's final study visit, the off-study form will be completed.  Permanent 
discontinuation of drug will be documented. 
 
Subjects who withdraw for toxicity reasons should be followed until the toxicity 
resolves/returns to baseline, or at least 1 month, whichever is later. In addition, 
subjects who go off study for reasons other than toxicity should be followed for at 
least 1 month after discontinuing drug. 


AMC # 042 (Version 7.0) 07/24/2007 
NCI Version Date 07/24/07 
 
37 
9.0 
EVALUATION OF RESPONSE 
9.1 
Definition of Response 
9.1.1 
Complete response (CR) is defined as the absence of any detectable 
residual disease, including tumor-associated edema, persisting for at 
least 4 weeks. In patients whose pigmented (brown or tan) macular 
skin lesions persist after apparent CR, biopsy of at least one 
representative lesion is required in order to document the absence of 
malignant cells. In patients known to have had visceral disease, an 
assessment at restaging with appropriate endoscopic or radiographic 
procedures should be made. 
9.1.2 
Clinical CR is defined as the absence of any detectable residual 
disease, including tumor-associated edema, persisting for at least 4 
weeks; AND  
 For patients with pigmented (brown or tan) macular skin lesions 
persisting after apparent CR, biopsy of a representative lesion 
documenting the absence of KS cells is not required; AND 
 For patients known to have had visceral disease, restaging with 
appropriate 
endoscopic 
or 
radiographic 
procedures 
is 
contraindicated or otherwise not performed. 
9.1.3 
Partial Response (PR) is defined as no new lesions (skin or oral), or no 
new visceral sites of involvement (or the appearance or worsening of 
tumor-associated edema or effusions); AND 
 A 50% or greater decrease in the number of all previously existing 
lesions lasting for at least 4 weeks; OR 
 Complete flattening of at least 50% of all previously raised lesions 
(i.e., 50% of all previously nodular or plaque-like lesion become 
macules); OR 
 A 50% decrease in the sum of the products of the largest 
perpendicular diameters of the marker lesions. 
NOTE – Patients with residual tumor-associated edema or effusion 
who otherwise meet the criteria for CR will be classified as having a 
PR. 
9.1.4 
Stable disease is defined as any response not meeting the criteria for 
CR, PR, or progressive disease. 
9.1.5 
Progressive disease is defined as follows: 
 For patients with <50 cutaneous lesions ≥ 25% increase in the sum 
of perpendicular diameters of the indicator lesions. 


AMC # 042 (Version 7.0) 07/24/2007 
NCI Version Date 07/24/07 
 
38 
 OR ≥ 25% increase in the total lesion count, or a minimum of 5 
new lesions, whichever is greater, 
 OR ≥ 25% increase in the number of raised lesions (minimum of 5 
new raised lesions if there are very few raised lesions, for example 
≤ 8), whichever is greater. 
Note: There are body sites where disease is particularly difficult to 
evaluate, and a few new lesions may be counted in spite of the fact that 
a patient is not actually progressing. For example, lesions of the foot, 
particularly those which are flat, are difficult to evaluate because their 
intensity may be variable based on how much edema is present, how 
much the person walked the day before, how long their feet have been 
in a dependent position prior to the physical exam, etc. 
 
 For patients with >50 cutaneous lesions: 
 ≥ 25% increase in the sum of the perpendicular diameters of the 
indicator lesions. 
 OR ≥ 25% increase in the total number of lesions in the 
prospectively defined anatomic sites containing representative 
numbers of lesions, 
 OR a total of 5 new lesions in anatomic sites which were 
previously documented as having no evidence of cutaneous disease 
on the whole body diagram, 
 OR (25% increase in the number of raised lesions. Photographic 
documentation of “gross” or significant progression, particularly in 
areas that were not being followed, will be of particular value. 
 
In order to classify a response as PR, the patient must have at least a 
PR in the cutaneous or noncutaneous sites of disease, and no evidence 
of progression as defined in the above criteria. In order to classify a 
response as a CR, the patient must have a CR in both the cutaneous (if 
applicable) and noncutaneous (if applicable) sites of disease and no 
evidence of progression as defined by the above criteria. 
Noncutaneous Progression 
Progressive disease includes new visceral sites of involvement or 
progression of visceral disease or the development of new or 
increasing tumor-associated edema or effusion lasting at least 1 week, 
which interferes with the patient’s normal activities. Progressive 
visceral disease, for measurable and evaluable disease, should be 
based on RECIST criteria. 


AMC # 042 (Version 7.0) 07/24/2007 
NCI Version Date 07/24/07 
 
39 
9.1.6 
Recurrent disease is defined as the appearance of tumor following 
documentation of a complete remission. 
9.1.7 
Time to response is defined as time from the first dose of Gleevec until 
documentation of first response. 
9.1.8 
Time to progression is defined as time from initiation of Gleevec to 
documentation of first progression. 
9.1.9 
Response duration is defined as the time from first documentation of 
response to documentation of first progression. 


AMC # 042 (Version 7.0) 07/24/2007 
NCI Version Date 07/24/07 
 
40 
10.0 RECORDS TO BE KEPT 
CRFs will be provided for each subject via the AMC AdvantageEDCSM Internet Data 
Entry System upon enrollment. Subjects must not be identified by name on any study 
documents. Data will be recorded on the CRFs using the unique subject identification 
number assigned at registration. Sample CRFs will be available on the AMC Operations 
Center website. 
 


AMC # 042 (Version 7.0) 07/24/2007 
NCI Version Date 07/24/07 
 
41 
11.0 ROLE OF DATA MANAGEMENT 
11.1 
CRF Instructions 
Instructions concerning the recording of study data on CRFs will be provided by 
the Operations Center. 
11.2 
Data Quality 
It is the responsibility of the AMC Operations Center to assure the quality of 
data for the study. This role extends from protocol development to generation of 
the final study database. 


AMC # 042 (Version 7.0) 07/24/2007 
NCI Version Date 07/24/07 
 
42 
12.0 STATISTICAL CONSIDERATIONS 
12.1 
Sample Size Estimation 
The response rate (CR + PR) to imatinib in the pilot study is 50% to date. It is 
well known that some patients have regression of their KS after beginning 
HAART therapy.[18] In order to minimize the effect of HAART being a potential 
confounding factor in response rates, recent studies have required patients on 
HAART to be on stable regimens for 12 weeks prior to initiation of treatment. 
Recent results from two placebo-controlled studies suggest as many 20% of 
responses in KS clinical trials may be delayed responses to HAART alone.[19, 
Walmsley, 1999 #136] Simon’s two-stage design will be used to test the null hypothesis 
that the response rate (CR + PR) if 20% against the alternative that it is 50% at 
the one-sided 0.05 significance level with power of 0.90. Ten patients will be 
enrolled in the first stage. If no more than two patients respond, then the study 
will be stopped. If at least three patients respond, then the study will enroll up to 
a total of 22 patients. If no more than seven patients respond, the drug will be 
considered ineffective. If at least eight patients respond, the null hypothesis will 
be rejected in favor of the alternative hypothesis. The probability of early 
termination of the study is 0.68.  
In our original estimate, we assumed a drop out rate of 10-15% based on our 
experience in the pilot study and calculated a sample size of 25 patients. 
However, we have had a higher drop out rate. Consequently, based on a drop 
out rate of 20-30%, we plan to roll a total of 30 patients to have 22 patients 
evaluable for response. 
In the pilot study, we found that decreasing the dose of imatinib by 33% (600 
mg/day to 400 mg/day) dramatically decreased the incidence of AEs. This dose 
reduction should reduce the steady state concentration of imatinib and it’s 
metabolite by 1 standard deviation of steady state plasma concentration, 
assuming constant clearance. This observation suggests a change in the plasma 
concentration imatinib and/or its metabolite of 1 standard deviation would be 
significant in our patient population. Based on this assumption, a PK sampling 
of 12 patients will provide a power of 88% to detect a 1 standard deviation 
change in the steady state level of imatinib and its metabolite with a type I error 
of 0.05 using a two-sided paired t-test. 
12.2 
Statistical Analysis Plan 
Summary statistics will be used to describe the study population (such as 
ranges, medians of age, gender, baseline performance characteristics). The 
binomial and its exact 95% confidence interval will be used to estimate clinical 
response rate. A two-sided one-group chi-square test will be performed to detect 
a 50% response rate. Due to a small sample size, exact logistic regression may 
be used to evaluate the effect of baseline characteristics and other covariates 
with the clinical response. To evaluate inhibition of PDGF receptor, we will 


AMC # 042 (Version 7.0) 07/24/2007 
NCI Version Date 07/24/07 
 
43 
correlate the presence or absence of c-kit and or PDGF-R mutations with 
clinical response to imatinib by performing chi-square tests or Fisher’s exact 
tests. The cytokine/chemokine profile at baseline, 1 week and 4 weeks after of 
imatinib therapy will be analyzed using the proteomics approach. The 
concentration of each cytokine from the samples will be estimated. Friedman’s 
test will be used to evaluate changes between time points with respect to 
cytokine levels. If a significant difference is detected, the Wilcoxon rank sum 
test will be used for pairwise comparisons. Exact logistic regression analysis 
will be used to detect any correlation between baseline concentrations and 
clinical responses. PK parameters including AUC, Cmax and elimination half-life 
of imatinib will be estimated in the first 12 patients. PK parameters including 
AUC, Cmax and elimination half-life of selected antiretrovirals may be estimated 
in selected patients. Summary statistics will be used to describe PK results. The 
incidence of specific AEs will be summarized by severity grade. The binomial 
proportion and its 95% confidence interval will be used to estimate the 
proportion of patients who experience an AE of severity Grade 3 or higher. The 
proportions of primary and secondary resistance to imatinib therapy will be 
estimated. Chi-square tests or Fisher’s exact tests will be used to evaluate 
associations between c-kit and PDGF-R mutations with resistance to imatinib 
therapy. 
Cluster analyses are planned for the real-time QPCR data. To evaluate the 
associations between single genes and response, categorical data analysis 
methods are proposed. If feasible, a multivariate model relating gene expression 
to response will be performed. 
12.3 
AMC Policy for Monitoring of Phase I and Phase II Trials 
This protocol will follow the AMC’s policy for data monitoring (see Appendix 
XVI, Data Safety and Monitoring Plan). 


AMC # 042 (Version 7.0) 07/24/2007 
NCI Version Date 07/24/07 
 
44 
13.0 ETHICAL AND REGULATORY CONSIDERATIONS 
(See Appendix IV, Informed Consent) 
13.1 
Informed Consent 
The principles of informed consent described in Food and Drug Administration 
(FDA) regulations (21 CFR part 50) must be followed. IRB approval of the 
protocol and the informed consent form must be given in writing. 
The sponsor must receive a copy of the letter of approval from the IRB, which 
specifically approves the protocol and informed consent, before patient 
enrollment. The IRB must also approve any significant changes to the protocol 
and documentation of this approval must be sent to the sponsor. Records of all 
study review and approval documents must be kept on file by the Investigator 
and are subject to FDA inspection during or after completion of the study. AEs 
must be reported to the IRB. The IRB should receive notification of completion 
of the study and final report within 3 months of study completion and 
termination. The Investigator will maintain an accurate and complete record of 
all submissions made to the IRB, including a list of all reports and documents 
submitted. 
13.2 
Changes To The Protocol 
Any change or addition to this protocol requires a written protocol amendment 
that must be approved by Novartis, CTEP and the Investigator before 
implementation. Amendments significantly affecting the safety of subjects, the 
scope of the investigation or the scientific quality of the study, require 
additional approval by the IRB/IEC/REB. A copy of the written approval of the 
IRB/IEC/REB must be sent to Novartis. Amendments affecting only 
administrative aspects of the study do not require formal protocol amendments 
or IRB/IEC/REB approval but the IRB/IEC/REB of each center must be kept 
informed of such administrative changes. 
13.3 
Women And Minorities 
This is a study being conducted by the NCI-sponsored AIDS Malignancy 
Consortium (AMC). As part of their contractual obligations, each participating 
site within the AMC, and the AMC as a whole, is required to assure that the 
participation of women and minority subjects reflects the percentage 
representation of these populations in their geographic region and, for the AMC, 
the United States as a whole. As such, it is expected that the representation of 
subjects on this trial will reflect the constitution of the respective populations. 
 


AMC # 042 (Version 7.0) 07/24/2007 
NCI Version Date 07/24/07 
 
45 
14.0 REFERENCES 
1. 
Schalling, M., et al., A role for a new herpes virus (KSHV) in different forms of Kaposi's 
sarcoma. Nat Med, 1995. 1(7): p. 707-8. 
 
2. 
Ensoli, B., et al., AIDS-Kaposi's sarcoma-derived cells express cytokines with autocrine 
and paracrine growth effects. Science, 1989. 243(4888): p. 223-6. 
 
3. 
Masood, R., et al., Vascular endothelial growth factor/vascular permeability factor is an 
autocrine growth factor for AIDS-Kaposi sarcoma. Proc Natl Acad Sci U S A, 1997. 
94(3): p. 979-84. 
 
4. 
Miles, S.A., et al., AIDS Kaposi sarcoma-derived cells produce and respond to 
interleukin 6. Proc Natl Acad Sci U S A, 1990. 87(11): p. 4068-72. 
 
5. 
Miles, S.A., Pathogenesis of human immunodeficiency virus-related Kaposi's sarcoma. 
Curr Opin Oncol, 1992. 4(5): p. 875-82. 
 
6. 
Sturzl, M., et al., Expression of platelet-derived growth factor and its receptor in AIDS-
related Kaposi sarcoma in vivo suggests paracrine and autocrine mechanisms of tumor 
maintenance. Proc Natl Acad Sci U S A, 1992. 89(15): p. 7046-50. 
 
7. 
Cornali, E., et al., Vascular endothelial growth factor regulates angiogenesis and 
vascular permeability in Kaposi's sarcoma. Am J Pathol, 1996. 149(6): p. 1851-69. 
 
8. 
Moses, A.V., et al., Kaposi's sarcoma-associated herpesvirus-induced upregulation of 
the c-kit proto-oncogene, as identified by gene expression profiling, is essential for the 
transformation of endothelial cells. J Virol, 2002. 76(16): p. 8383-99. 
 
9. 
Werner, S., et al., Cultured Kaposi's sarcoma-derived cells express functional PDGF A-
type and B-type receptors. Exp Cell Res, 1990. 187(1): p. 98-103. 
 
10. 
Roth, W.K., et al., Depletion of PDGF from serum inhibits growth of AIDS-related and 
sporadic Kaposi's sarcoma cells in culture. Oncogene, 1989. 4(4): p. 483-7. 
 
11. 
Talpaz, M., et al., Imatinib induces durable hematologic and cytogenetic responses in 
patients with accelerated phase chronic myeloid leukemia: results of a phase 2 study. 
Blood, 2002. 99(6): p. 1928-37. 
 
12. 
Demetri, G.D., et al., Efficacy and safety of imatinib mesylate in advanced 
gastrointestinal stromal tumors. N Engl J Med, 2002. 347(7): p. 472-80. 
 
13. 
Rubin, B.P., et al., Molecular targeting of platelet-derived growth factor B by imatinib 
mesylate in a patient with metastatic dermatofibrosarcoma protuberans. J Clin Oncol, 
2002. 20(17): p. 3586-91. 
 


AMC # 042 (Version 7.0) 07/24/2007 
NCI Version Date 07/24/07 
 
46 
14. 
Miles, S.A., et al., Antitumor activity of oral 9-cis-retinoic acid in HIV-associated 
Kaposi's sarcoma. Aids, 2002. 16(3): p. 421-9. 
 
15. 
Cianfrocca, M., et al., Matrix metalloproteinase inhibitor COL-3 in the treatment of 
AIDS-related Kaposi's sarcoma: a phase I AIDS malignancy consortium study. J Clin 
Oncol, 2002. 20(1): p. 153-9. 
 
16. 
Longley, B.J., M.J. Reguera, and Y. Ma, Classes of c-KIT activating mutations: proposed 
mechanisms of action and implications for disease classification and therapy. Leuk Res, 
2001. 25(7): p. 571-6. 
 
17. 
Heinrich, M.C., et al., PDGFRA activating mutations in gastrointestinal stromal tumors. 
Science, 2003. 299(5607): p. 708-10. 
 
18. 
Aboulafia, D.M., Regression of acquired immunodeficiency syndrome-related pulmonary 
Kaposi's sarcoma after highly active antiretroviral therapy. Mayo Clin Proc, 1998. 73(5): 
p. 439-43. 
 
19. 
Noy, A. Angiogenesis Inhibitor IM862 is Ineffective Against AIDS-KS in a Randomized, 
Placebo Controlled Trial. in The Sixth International Conference On Malignancies In 
Aids and Other Immunodeficiencies. 2002. National Institutes of Health, Bethesda, MD. 
 
20. 
Parise, R.A., et al., Liquid chromatographic-mass spectrometric assay for quantitation of 
imatinib and its main metabolite (CGP 74588) in plasma. J Chromatogr B Analyt 
Technol Biomed Life Sci, 2003. 791(1-2): p. 39-44. 
 
21. 
Kerkela R., et al., Cardiotoxicity of the cancer therapeutic agent imatinib mesylate. 
Nature Medicine, 2006. p.1-9.  
 
22. 
Berman, E et al., Altered Bone and Mineral Metabolism in Patients Receiving Imatinib 
Mesylate. N Engl J Med 2006; 354:2006-13. 


AMC # 042 (Version 7.0) 07/24/07 
NCI Version Date 07/24/07 
47 
APPENDIX I:  SCHEDULE OF EVENTS 
 
1. 
Anytime prior to study entry. 
2. 
Done within 4 weeks of study entry, if positive x-ray, a chest CT will be performed 
3. 
Serum Chemistries: Liver enzymes (SGOT, SGPT, alkaline phosphatase), BUN, creatinine, electrolytes, amylase, bilirubin (direct and indirect) and phosphate.  25-Hydroxyvitamin D is 
measured at baseline. 
4. 
To be done within 72 hours of study entry and anytime pregnancy is suspected 
5. 
To be done within 4 weeks of study entry. 
6. 
Collect on the first 12 patients: 0 (immediately prior to the patient taking meds for that day), 0.5, 1, 2, 3, 4, 8, and 24 (immediately prior to the next day’s dose) hours. 
7. 
To be done at baseline, D29, D56 and every 2 months thereafter. 
8. 
Within 2 weeks prior to study entry. 
9. 
To be obtained within 21 days prior to study entry. 
10. To be performed on Day 1 prior to receiving study medication but may not be performed earlier than within 2 weeks of initiating treatment. 
11. To be performed at baseline and time of progression or treatment discontinuation. 
12. Day 29 only. 
13. Day 29 and every 3 months thereafter. 
14. To be collected on Day 1 and Day 15 of cycle 1 and on Day 1 of cycles 3, 5, 7, 9, and 11. 
Assessment 
Eligibility/ 
Screening 
Baseline 
D 1 
D 2 
D 8 
D 15 
D 16 
D 29 (and then every 
28 days thereafter) 
D 56 (and every two 
months thereafter) 
Every 3 months 
thereafter 
Treatment 
Discontinuation 
Clinical Studies 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
KS Documentation 
X1 
 
 
 
 
 
 
 
 
 
 
HIV Documentation 
X1 
 
 
 
 
 
 
 
 
 
 
Medical History 
X9 
 
 
 
 
 
 
 
 
 
 
Physical Exam: Vital signs, height, weight, KPS 
X9 
 
X 
 
X 
X 
 
X 
 
 
X 
Signs and Symptoms Review 
X8 
 
X 
 
X 
X 
 
X 
 
 
 
KS Tumor Assessment 
 
 
X10 
 
 
 
 
X7 
X7 
 
X 
KS Staging 
X9 
 
 
 
 
 
 
 
 
 
 
Concomitant Medication Review 
X9 
 
X 
 
X 
X 
 
X 
 
 
 
Adverse Events 
 
 
 
 
X 
X 
 
X 
 
 
X 
Chest x-ray 
X2 
 
 
 
 
 
 
 
 
 
 
Laboratory Studies 
CBC with differential and platelets 
X9 
 
X 
 
X 
X 
 
X 
 
 
X 
Serum Chemistries3 
X9 
 
X 
 
X 
X 
 
X 
 
 
X 
Urine Phosphate and Creatinine  
X9 
 
X 
 
X 
X 
 
X 
 
 
X 
CD4 count 
 
X5 
 
 
 
 
 
X13 
 
X 
X 
Serum beta HCG pregnancy test 
X4 
 
 
 
 
 
 
 
 
 
 
HIV plasma RNA 
 
X5 
 
 
 
 
 
X13 
 
X 
X 
HHV-8 Viral Load 
 
 
X 
 
 
X14 
 
 
 
 
X 
Stool Guaiac 
X9 
 
 
 
 
 
 
 
 
 
 
Serum/plasma for cytokine profile 
 
X 
 
 
X 
 
 
X12 
 
 
 
Pharmacokinetics6 
 
 
X 
X 
 
X 
X 
 
 
 
 
ACSR Donation 
 
X 
 
 
 
 
 
 
 
 
 
Biopsy for receptor phosphorylation 
 
X 
 
 
X 
 
 
 
 
 
 
Biopsy for mutation receptor  
 
X11 
 
 
 
 
 
 
 
 
X 


AMC # 042 (Version 7.0) 07/24/07 
NCI Version Date 07/24/07 
48 
APPENDIX II: DEFINITION OF AIDS INDICATOR CONDITIONS 
 
• 
Aspergillosis, invasive * 
• 
Bartonella henselae infection, disseminated (bacillary angiomatosis, peliosis hepatis)* 
• 
Candidiasis of bronchi, trachea, or lungs * 
• 
Candidiasis, esophageal * 
• 
Cervical cancer, invasive * 
• 
Coccidioidomycosis, disseminated or extrapulmonary * 
• 
Cryptococcosis, extrapulmonary * 
• 
Cryptosporidiosis, chronic intestinal (> 1 month's duration) * 
• 
Cytomegalovirus disease, invasive * 
• 
Cytomegalovirus retinitis * 
• 
Encephalopathy, HIV-related * 
• 
Herpes simplex:  chronic ulcer(s) (> 1 month's duration), bronchitis, pneumonitis, or esophagitis * 
• 
Histoplasmosis, disseminated or extrapulmonary * 
• 
Isosporiasis, chronic intestinal (> 1 month's duration) * 
• 
Kaposi's sarcoma (progression to visceral disease) 
• 
Lymphoma, Burkitt's (or equivalent term) * 
• 
Lymphoma, immunoblastic (or equivalent term) * 
• 
Lymphoma, primary, of brain * 
• 
Microsporidiosis, diarrhea > 1 month or disseminated * 
• 
Mycobacterium avium complex or M. kansasii, disseminated or extrapulmonary * 
• 
Mycobacterium tuberculosis, any site (pulmonary1 or extrapulmonary) * 
• 
Mycobacterium, other species or unidentified species, disseminated or extrapulmonary * 
• 
Nocardiosis, pulmonary, brain or disseminated * 
• 
Pneumocystis carinii pneumonia (new or recurrent diagnosis) 
• 
Progressive multifocal leukoencephalopathy * 
• 
Salmonella septicemia, recurrent * 
• 
Toxoplasmosis of brain * 
• 
Wasting syndrome due to HIV * 
 
* New Diagnosis 
 


AMC # 042 (Version 7.0) 07/24/07 
NCI Version Date 07/24/07 
49 
APPENDIX III:  CRITERIA FOR ACCEPTABLE AIDS DEFINING 
EVENTS 
 
1. 
Microbiologically- or histologically-confirmed AIDS-related opportunistic 
infection; 
 
OR 
 
2. 
Presumptive diagnosis of CMV retinitis, confirmed by an ophthalmologist, or of 
CNS toxoplasmosis or CNS lymphoma by accepted imaging technique; 
 
OR 
 
3. 
Biopsy-proven AIDS-related malignancy.  For the purposes of the protocol, only 
the development of visceral disease will constitute a KS endpoint; 
 
OR 
 
4. 
Physician-documented HIV-1 Cognitive Motor Complex (dementia) or HIV 
wasting syndrome; 
 
OR 
 
5. 
Presumptive diagnosis of PCP as determined by the following: 
 Compatible symptomatology (e.g., fever, cough, shortness of breath). 
 Compatible chest x-ray. 
 pO2 < 85. 
 Absence of other pathogens on sputum examination. 
 Negative blood cultures. 
 Response to appropriate anti-Pneumocystis therapy. 
 
NOTE:  For the purposes of this protocol, a primary study endpoint will be defined as: 
 A new AIDS defining event, OR 
 Recurrent PCP, OR 
 Death. 


AMC # 042 (Version 7.0) 07/24/07 
NCI Version Date 07/24/07 
50 
APPENDIX IV: KARNOFSKY PERFORMANCE SCALE 
 
Description 
Percent 
Karnofsky Performance Scale 
100 
Normal: no complaints: no evidence of disease
90 
Able to carry on normal activity; minor signs 
or symptoms of disease 
Able to carry on normal activity; no
special care needed 
80 
Normal activity with effort: some signs or 
symptoms of disease 
70 
Cares for self, unable to carry on normal 
activity or to do active work 
60 
Requires occasional assistance but is able to 
care for most of needs 
Unable to work, able to live at home
and care for most personal needs: a
varying amount of assistance is
needed 
50 
Requires considerable assistance and frequent 
medical care 
40 
Disabled: requires special care and assistance 
30 
Severely disabled: hospitalization is indicated 
although death is not imminent 
20 
Very sick: hospitalization necessary; active 
supportive treatment is necessary 
10 
Moribund: fatal processes progressing rapidly 
Unable to care for self; requires
equivalent of institutional or hospital
care: disease may be progressing
rapidly 
0 
Dead 
 


AMC # 042 (Version 7.0) 07/24/07 
NCI Version Date 07/24/07 
51 
APPENDIX V: RECOMMENDED STAGING CLASSIFICATION FOR 
KAPOSI'S SARCOMA 
 
 
GOOD RISK (0) 
(All of the following) 
POOR RISK (1) 
(Any of the following) 
Tumor (T) 
-  Confined to skin and/or 
lymph nodes and/or 
minimal oral disease1 
-  Tumor-associated edema 
or ulceration 
-  Extensive oral KS 
-  Gastrointestinal KS 
-  KS in other nonnodal 
viscera 
 
Immune system (I) 
-  CD4 cells ≥ 200/µL 
-  CD4 cells < 200/µL 
 
Systemic illness (S) 
-  No history of OI or 
thrush 
-  No "B" symptoms2 
-  Performance status  
≥ 70 (Karnofsky) 
-  History of OI and/or 
thrush 
- "B" symptoms present 
- Performance status < 70 
- Other HIV-related illness 
(e.g., neurological 
disease, lymphoma) 
 
T0 = 
tumor confined to skin, lymph nodes and/or minimal oral disease. 
T1 = 
any tumor falling under the "Poor Risk" criteria. 
S0 = 
no history of OI or thrush, no "B" symptoms, and Karnofsky Performance status ≥ 70. 
S1 = 
any "Poor Risk" systemic illness signs and symptoms. 
NOTE:  Staging criteria taken from:  Krown SE, Metroka C, Wernz JC.  Kaposi's sarcoma in the 
acquired immunodeficiency syndrome: A proposal for uniform evaluation, response, and staging 
criteria.  J Clin Oncol 1989;7:1201-1207. This criteria was adopted by the ACTG Oncology 
Committee. 
 
 
1Minimal oral disease is nonnodular KS confined to the palate. 
2"B" symptoms are unexplained fever, night sweats, > 10% involuntary weight loss, or diarrhea persisting 
more than 2 weeks. 
 


AMC # 042 (Version 7.0) 07/24/07 
NCI Version Date 07/24/07 
52 
APPENDIX VI:  MODEL INFORMED CONSENT 
 
Phase II Trial of Imatinib Mesylate (Gleevec) in Patients with HIV-Related Kaposi’s 
Sarcoma 
 
This is a clinical trial (a type of research study). Clinical trials include only patients who choose 
to take part. Please take your time to make your decision. Discuss it with your friends and 
family. 
 
You are being asked to take part in this study because you have Kaposi’s sarcoma (KS), the most 
common cancer seen in patients with the acquired immunodeficiency syndrome (AIDS). 
 
WHY IS THIS STUDY BEING DONE? 
The purpose of this study is to find out what effects (good and bad) Gleevec has on you and your 
Kaposi's sarcoma skin tumors. 
 
This research is being done because treatments for Kaposi's sarcoma do not cure the disease and 
better treatments are needed. Gleevec (also known as imatinib) has been approved by the Food 
and Drug Administration (FDA) for use in the treatment of chronic myelogenous leukemia 
(cancer of the blood). Gleevec is experimental for the treatment of KS, and its effectiveness in 
treating KS is unknown. In laboratory studies, it has been found to stop tumor growth by 
interfering with signals from proteins that are necessary for cancer to grow and spread. 
 
HOW MANY PEOPLE WILL TAKE PART IN THE STUDY? 
Approximately 30 patients will participate in this study at multiple medical centers. 
 
WHAT IS INVOLVED IN THE STUDY? 
If you agree to participate and join in this study, the following will occur: 
 
1. 
Eligibility Phase 
 
You will need to have the following exams, tests, or procedures done to find out if you are 
eligible and can participate in the study. 
 
You will have blood (a maximum of 5 tablespoons) drawn for laboratory testing. 
Some of this blood will be used to measure antibodies to HIV infection. We will also 
check your stool for blood. 
 
If you are a woman of childbearing potential, a pregnancy test will also be done. 
 
A medical history and a physical examination will be completed and will include a 
review of all medications that you are taking and an examination of your KS lesions. 
 
You will have a chest x-ray and may be required to have a chest CT scan, which is a 
computerized series of X-rays. 


AMC # 042 (Version 7.0) 07/24/07 
NCI Version Date 07/24/07 
53 
2. 
Treatment Phase 
 
If you are a good candidate for treatment based upon these evaluations, you will 
begin treatment with Gleevec. Two biopsies (removal of small tissue samples) of 
your KS lesions will be required before you begin treatment. The area of the skin 
where the sample will be removed will be numbed with a local anesthetic. Small 
tissue samples will then be removed by cutting the tumor tissue. 
 
On the day you begin treatment, you will have a physical examination including 
measurement of your weight and vital signs (temperature, pulse, respirations and 
blood pressure). Blood (a maximum of 5 tablespoons) will be drawn for laboratory 
testing to monitor your kidney, liver, and bone marrow function. The study doctor 
will examine your KS lesions and may take up to 12 photographs of the lesions to 
document their appearance. Additional photographs will be taken during the course of 
the study to document any changes in appearance. At no time will your entire face 
appear, and any distinguishing features will be removed from the photo so that you 
cannot be identified. Only your initials and subject number will be used to identify 
the photo. 
 
On the first and fifteenth day of your treatment you may have blood drawn to assess 
the level of Gleevec in your blood. On these days you will have additional blood 
drawn to determine if there is any interaction between your HIV medications and 
Gleevec. A small tube or “IV” may be placed in a vein in your arm so that the blood 
can be drawn for testing without additional “needlesticks”. We will also measure your 
HHV-8 viral load. This test measures the amount of the HHV-8 virus, which is a 
virus associated with Kaposi’s sarcoma. This blood test will also be performed on the 
first and fifteenth day of your treatment, every 2 months, and when you finish 
treatment. 4-5 teaspoons of blood will be needed for each blood test. 
 
You will be given a bottle containing Gleevec tablets and instructed to take 4 tablets 
(a total of 400 mg) of Gleevec once a day by mouth. To minimize throat irritation, 
you should take the tablets with food and a large glass of water (8 ounces) while in a 
sitting position. Drinking grapefruit juice during treatment is discouraged because it 
may interfere with the effectiveness of Gleevec.  
 
Your dose may be increased or decreased by your doctor. You will continue to 
receive the drug as long as you do not develop unacceptable side effects, become 
pregnant, show significant worsening of your KS or require systemic therapy for the 
treatment of a malignancy other than KS. 
 
You will be instructed to bring all empty and/or partially filled study medication 
bottles to each monthly visit.  
 
You will need to return to the study center for a visit after 1 week, 2 weeks, and 1 
month of treatment and then once a month for the next 5 to 12 months. At each study 
visit, you will be asked about signs and/or symptoms and about any other medications 
that you are taking. Taking certain medications, including other experimental drugs, 
are not permitted while participating in this research study. 
 
At your study visits, you will have a physical examination including measurement of 
your vital signs and weight. Blood (a maximum of 5 tablespoons) will also be drawn 


AMC # 042 (Version 7.0) 07/24/07 
NCI Version Date 07/24/07 
54 
for laboratory tests including blood counts (which tell your doctor how well your 
bone marrow is functioning), chemistries (which tell your doctor how well your liver 
and kidneys are functioning) and cytokine levels (which tell your doctor the how 
Gleevec is affecting your KS). After 1 week a biopsy of a KS lesion will be 
necessary. This will allow us to determine the effects of Gleevec on the various 
aspects of your tumor. 
 
Evaluation of your disease will occur at your visit after months 1 and 2 of treatment 
and then after every 2 months of treatment. During these evaluations, your doctor will 
visually inspect your lesions for any change in the number of lesions present as well 
as any change in their appearance. Up to 12 photographs of your lesions will be taken 
to document their appearance. If one of your lesions disappears, your doctor may ask 
you for your permission to biopsy the area of skin where the lesion was previously 
located. 
 
You will be asked to weigh yourself twice a week at home and report to the study 
doctor any rapid body weight increase of more than 5 pounds. If you do not have 
access to a scale, you should discuss options with your physician. 
 
3. 
Discontinuation of Treatment 
 
You will initially be treated with Gleevec for 6 months. If at the end of 6 months your 
condition has remained stable or has improved, you may receive treatment with Gleevec 
for another 6 months. Once you have completed the study treatment, you will be asked to 
return to the study center for a final visit. You will have a physical examination including 
measurement of your vital signs and weight. You will be asked about any signs or 
symptoms you have experienced and any other medications you are taking. A blood (a 
maximum of 5 tablespoons) sample will be drawn for laboratory testing. A biopsy of a KS 
lesion may be necessary at the time of discontinuation. 
 
4. 
Early Withdrawal from the Study 
 
The Investigator may take you off the study if you are not tolerating the study medications 
or if you do not comply with the study guidelines. You may withdraw from the study at any 
time, and this will not affect any future care or treatment for your disease. Your treatment 
may be stopped by the drug supplier, should the protocol be changed or closed, or if they 
believe that continuation in your case may not be beneficial. This may include 
discontinuing your participation in this study without your consent. At the time of 
withdrawal, you will be asked to undergo the same evaluations you would have had during 
the discontinuation of treatment visit, as described above. 
 
5. 
Standard procedures being done because you are in this study include: 
 A chest x-ray if you are a woman who could become pregnant, a pregnancy test will be 
done before treatment. 
6. 
Non standard procedures being done because you are in this study include:  


AMC # 042 (Version 7.0) 07/24/07 
NCI Version Date 07/24/07 
55 
 Punch biopsies of two KS lesions on your skin before you start treatment and after 1 
week and at the end of study treatment. There will be a total of 4 biopsies during the 
course of this study. A punch biopsy involves removal of a small piece of one of your 
tumors. These biopsies will be done to find out whether treatment has any effect on the 
cells in your Kaposi’s sarcoma. 
 A blood test to measure the level of Gleevec in your blood. This blood test will be 
performed on the day you begin treatment, and after 2 weeks of treatment. 4-5 
teaspoons of blood will be needed for eight separate blood draws to measure Gleevec in 
your blood. This will be done on Day 1 and Day 15 (hour 0, 0.5, 1, 2, 3, 4, 8 and 24 
hours).  
If one of your KS tumors goes away, your doctor may ask your permission to biopsy the area of 
skin where the lesion used to be. A pathologist will examine the biopsy to see if there are any 
tumor cells left. 
 
You will be asked to donate tissues and fluids to the AIDS and Cancer Specimen Resource 
(ACSR). If you agree, your permission will be obtained in a separate consent form. If you don't 
agree, it will not prevent you from taking part in this study. 
 
HOW LONG WILL I BE IN THE STUDY? 
We think you will be in the study for up to 1 year. 
The researcher may decide to take you off this study if: 
 Your condition worsens or your doctor believes that further treatment would be of no 
benefit to you or would be dangerous;  
 Your doctors see side effects they consider dangerous; 
 You are unable to consistently take the study medication or frequently miss 
appointments or miss tests required to see if the treatment is safe and effective and to 
see how the treatment works; 
 You need treatment with other drugs that are not allowed in combination with Gleevec; 
 You become pregnant. 
You can stop participating at any time. However, if you decide to stop participating in the study, 
we encourage you to talk to the researcher and your regular doctor first. 
 
WHAT ARE THE RISKS OF THE STUDY? 
While on the study, you are at risk for these side effects. You should discuss these with the 
researcher and/or your regular doctor. There also may be other side effects that we cannot 
predict. Other drugs will be given to make side effects less serious and uncomfortable. Many 
side effects go away shortly after the drug is stopped, but in some cases side effects can be 
serious or long-lasting or permanent. 


AMC # 042 (Version 7.0) 07/24/07 
NCI Version Date 07/24/07 
56 
1. Risks and side effects related to the drug we are studying include: 
Very Likely 
  
 
Headache 
 
Nausea 
 
Vomiting 
 
Diarrhea 
 
Indigestion 
 
Dermatitis 
 
Eczema 
 
Rash 
 
Fever 
 
Muscle spasms and cramps 
 
Pain in the muscles, joints, limbs and bones, 
and joint swelling and edema (fluid 
retention) of the limbs, face and around the 
eyes 
 
edema (fluid retention) of the 
limbs, face and around the eyes 
 
Less Likely but Serious 
 
 
Psychotic reactions 
 
Anorexia (uncontrolled lack of appetite 
and weight loss) 
 
Numbness of the hands or feet 
 
Depression 
 
Wearing down of the eye nerve. 
 
Taste disturbance 
 
Flatulence (gas in the digestive tract) 
 
Inflammation of the abdomen, liver, 
spleen, stomach, intestines, colon, 
voluntary muscles, heart tissue, and 
kidneys 
 
Inflammation and possible fluid 
accumulation in the space around the 
lungs (pleurisy) 
 
Increased tear production 
 
Inflammation of the eyes 
(conjunctivitis) 
 
Dizziness 
 
Night sweats 
 
Abdominal pain or distension 
 
Itching 
 
Dry mouth 
 
Cough 
 
Dry skin 
 
Nasopharyngitis (inflammation of the 
nasal passages) 
 
Petechia (purplish red spots on the skin) 
 
Hearing loss 
 
Unusual hair loss or thinning 
 
Weakness 
 
Fatigue 
 
Increased blood sugar 
 
Increased blood pressure 
 
Insomnia (sleeping difficulties) 


AMC # 042 (Version 7.0) 07/24/07 
NCI Version Date 07/24/07 
57 
 
Bone decay and low blood sugar that 
could lead to coma 
 
Nose bleeds 
 
Reduced vision 
 
Constipation 
 
Shock 
 
Reddening of the skin 
 
Mood swings 
 
Shortness of breath 
 
Increased muscle tension  
 
Pneumonia 
 
Increased weight 
 Decreased renal (kidney) phosphates 
and blood phosphate level 
 
2. Abnormal laboratory test values observed in some patients required temporarily interrupting 
the study drug, or reducing the dose. The laboratory abnormalities included elevated liver or 
renal (kidney) function values, low platelet, white blood cell or red blood cell counts and 
disturbances in electrolyte (chemicals found in the blood, e.g. sodium, potassium, 
magnesium, calcium) balance. Lowering of your white blood cell count could lead to an 
increased risk of infection and slower healing. Lowering of your platelet count could lead to 
an increased risk of bleeding. Lowering of your red blood cells can lead to fatigue. If you 
should develop a fever when your white blood count is low, you may need to be hospitalized 
to receive treatment. Transfusions may be required to counteract the effects of low platelet or 
red blood cell counts. Elevated liver function values can indicate liver damage. Your 
laboratory values will be monitored closely, and the dose of your medication will be adjusted 
if your blood tests are abnormal. Based upon experience from previous clinical trials, it is 
expected that these effects may be reversed by decreasing the dose of the drug, or by 
temporarily stopping the study drug. 
 
3. Gleevec is often associated with edema (fluid retention) and occasionally the fluid retention 
can be serious. Some patients have reported a rapid gain in body weight. Other patients have 
developed pleural effusions (fluid around lungs) and/or ascites (swollen abdomen), or 
pulmonary edema (fluid in the lungs), or pericardial effusions (fluid in the sac that surrounds 
the heart), all of which occasionally may be serious. A minority have developed signs of 
congestive heart failure, a premature heartbeat, and a sac forming in the wall of the artery. 
Therefore, you are asked to closely monitor your body weight twice a week and report to 
your doctor any rapid increase greater than 5 pounds. If this happens, a check-up including 
physical examination, blood tests and X-rays will be performed as required by your 
condition. One patient taking Gleevec who had no known history of liver problems has died 
due to liver failure while in a clinical study. The patient was also taking acetaminophen 
(Tylenol®), also known as paracetamol in European countries. You should not take more than 
650 mg of acetaminophen every 4 hours. If you take more than one dose of acetaminophen, 
you should notify the study doctors. Kidney failure as well as multi-organ failure has been 
noted. Degeneration of the brain, liver, retina, and skeletal muscle cells have been noted as 
well as the bursting of a patient’s spleen and pus found in the folds of the liver. 
 
Because some over the counter and prescription medications can reduce the effectiveness or 
enhance the side effects of Gleevec and/or Gleevec can increase the side effects or lessen the 


AMC # 042 (Version 7.0) 07/24/07 
NCI Version Date 07/24/07 
58 
effectiveness of some medications, it is recommended that you review all over-the-counter, 
health food supplements and prescription medications that you are taking, with your 
physician prior to taking them. In addition, you must not drink grapefruit juice while taking 
Gleevec. 
 
4. Upper gastrointestinal bleeding, brain hemorrhages (bleeding in the brain), bleeding in the 
eye socket (anterior chamber hemorrhage) and inflammation of the capillaries have been 
reported in a minority of patients. One patient with a history of heart problems experienced 
chest pain while taking the study drug. Some patients have experienced blood in their urine, 
which if severe caused death. Another patient experienced abnormal growth of nervous 
system cells (neuroendocrine tumor). It has been reported that one patient developed 
Parkinson’s disease, a slowly progressive disease of the nervous system that causes your 
body to experience uncontrollable spasms. One patient, on another study, developed a fistula 
(an abnormal pathway or channel) in his esophagus near a surgical site. 
 
5. Congestive Heart Failure (CHF) is a rare, but serious adverse event that may develop while 
you are taking the study medication, Gleevec. CHF is characterized by a decrease in left 
ventricular systolic function (thickening of the membranes in your heart so that it is unable to 
adequately pump blood throughout the body). Ten patients with chronic myelogenous 
leukemia developed severe CHF while being treated with Gleevec. Prior to taking Gleevec, 
all patients had normal left ventricular function (no CHF). These effects on the heart have 
also been seen in mice treated with Gleevec. 
 
In NCI-sponsored clinical trials, other cardiac events have occurred that are likely related to 
Gleevec. These include cardiac ischemia/infarction, hypertension, and hypotension. 
 
Some of the symptoms listed above have led to death in a few patients. You will be closely 
monitored for any side effects and should report any changes in the way you feel to your 
doctor. You will be kept fully informed of any events that occur during the course of the trial 
that might affect your safety. 
 
Study medication must be kept in a secure place, out of the reach of children. Accidental 
ingestion of Gleevec may cause harmful effects, and the study doctor must be notified 
immediately if anyone other than you takes Gleevec by mistake. 
 
6. The risk of renal (kidney) phosphate loss and hypophosphatemia (decreased blood phosphate 
levels) and low levels of vitamin D have been reported in patients taking Gleevec. These 
abnormalities were treated with Vitamin D and phosphate supplements. 
 
7. Reproductive Risks 
 
Because Gleevec may affect an unborn baby, you should not become pregnant or father a 
baby while on this study. Women who are pregnant or nursing a child may NOT participate 
in this trial. Women who are either pregnant or breast-feeding will not be allowed to start or 
continue in the study. An effective form of contraception should be used by men who could 
father a child as well as women who could become pregnant. A barrier method of 


AMC # 042 (Version 7.0) 07/24/07 
NCI Version Date 07/24/07 
59 
contraception (a condom or diaphragm) should be used while taking this medication, and for 
3 months afterwards. If you are a woman who could become pregnant, or a man who could 
father a child, ask about counseling and more information about preventing pregnancy. You 
should not breast-feed a baby while on this study. If you think you may have become 
pregnant during the clinical trial, contact your doctor immediately. 
 
8. In non-human animal studies, imatinib has been found to cause cancer of the bladder, 
kidneys and ureters. At this time, it is uncertain whether imatinib can cause cancer in 
humans. 
 
For more information about risks and side effects, ask the researcher. 
 
 
ARE THERE BENEFITS TO TAKING PART IN THE STUDY? 
If you agree to take part in this study, there may or may not be direct medical benefit to you. A 
possible benefit of treatment with Gleevec is that your KS will get smaller or go away. We hope 
what is learned from this study will help other patients with KS in the future. 
 
 
WHAT OTHER OPTIONS ARE THERE? 
Instead of being in this study, you have these options: 
 
Chemotherapy 
 
Interferon Therapy 
 
Radiation Therapy 
 
Local Treatment such as freezing of lesions, topical Panretin gel, or injection of lesions 
with chemotherapy 
 
Other experimental treatments if they are available to you 
 
No therapy at this time, with care to help you feel more comfortable. 
 
Please talk to your regular doctor about these and other options. 
 
WHAT ABOUT CONFIDENTIALITY? 
Efforts will be made to keep your personal information confidential. We cannot guarantee 
absolute confidentiality. Your personal information may be disclosed if required by law. 
Organizations that may inspect and/or copy your research records for quality assurance and data 
analysis include groups such as trained staff at (Institution Name), and trained staff from the 
AIDS Malignancy Clinical Trials Consortium (AMC), the National Cancer Institute (NCI), AMC 
Operations Center (Data Coordinators) the Food and Drug Administration (FDA), and qualified 
representatives of Novartis. 
 


AMC # 042 (Version 7.0) 07/24/07 
NCI Version Date 07/24/07 
60 
WHAT ARE THE COSTS? 
Taking part in this study may lead to added costs to you or your insurance company. Please ask 
about any expected added costs or insurance problems. 
You will not be billed for the cost of research studies. This includes: 
 
Biopsies before and during treatment that will be done to find out how Gleevec might 
be working on the tumor cells in your KS lesions and blood tests to measure the HIV 
viral load. 
 
Novartis Pharmaceuticals will provide you with Gleevec free of charge while you are 
being treated on this study. 
You or your insurance company will be charged for tests considered part of the routine care of 
your disease. This includes: 
 
Any blood tests, x-rays, scans or biopsies needed to confirm whether you can 
participate in this study. 
 
Chest x-rays required by the study. 
 
Any hospitalizations. 
 
The costs of any medicines needed to control side effects from your treatment. 
 
Doctor's fees. 
 
Blood tests done to check for side effects of treatment and the effects of treatment on 
HIV and your immune function. 
 
Other x-rays and scans needed to evaluate your condition during your participation in 
this study. 
In the case of injury or illness resulting from this study, emergency medical treatment is 
available but will be provided at the usual charge. No funds have been set aside to compensate 
you in the event of injury. 
 
You or your insurance company will be charged for continuing medical care and/or 
hospitalization. 
 
You will receive no payment for taking part in this study. 
 
 
WHAT ARE MY RIGHTS AS A PARTICIPANT? 
Taking part in this study is voluntary. You may choose not to take part or may leave the study at 
any time. Leaving the study will not result in any penalty or loss of benefits to which you are 
entitled. 
 
We will tell you about new information that may affect your health, welfare, or willingness to 
stay in this study. 
 


AMC # 042 (Version 7.0) 07/24/07 
NCI Version Date 07/24/07 
61 
WHOM DO I CALL IF I HAVE QUESTIONS OR PROBLEMS? 
For questions about the study or a research-related injury, contact the researcher. 
 
____________________(NAME{S}) at __________________ (TELEPHONE NUMBER). 
 
For questions about your rights as a research participant, contact the _________________ (NAME OF 
CENTER) Institutional Review Board (which is a group of people who review the research to protect 
your rights) at __________________ (TELEPHONE NUMBER). A non-physician whom you may call 
for information about the consent process, research patient's rights, or research-related injury is 
________________ (TELEPHONE NUMBER). 
 
 
WHERE CAN I GET MORE INFORMATION? 
You may call the NCI's Cancer Information Service at 1 800 4 CANCER (1 800 422 6237) or 
TTY: 1 800 332 8615 
 
Visit the NCI's Web sites: 
 CancerTrials: comprehensive clinical trials information 
http://cancertrials.nci.nih.gov. 
 CancerNet: accurate cancer information including PDQ 
http://cancernet.nci.nih.gov. 
 
You will get a copy of this form. You may also request a copy of the protocol (full study plan). 
 
SIGNATURE 
 
I agree to take part in this study. 
 
 
 
Participant ___________________________  Date ____________________ 


AMC # 042 (Version 7.0) 07/24/07 
NCI Version Date 07/24/07 
62 
APPENDIX VII: ACSR INFORMED CONSENT 
 
INFORMED CONSENT FORM 
RESEARCH STUDY 
AIDS AND CANCER SPECIMEN RESOURCE (ACSR) 
 
 
A. 
INTRODUCTION 
 
You are being asked to donate tissue for research.  Before you decide to be a part of this 
research study, you need to understand the risks and benefits so that you can make an 
informed decision.  This is known as informed consent. 
 
This consent form provides information about the research study, which has been 
explained to you.  Once you understand the study and the tests it requires, you will be 
asked to sign this form if you want to take part in the study.  Your decision to take part in 
the study is voluntary.  This means that you are free to choose if you will take part in the 
study. 
 
B. 
PURPOSE 
 
The National Cancer Institute has set up a Bank for tissues and biological fluids from 
HIV-positive and HIV-negative individuals in order to have specimens available for 
scientists studying malignancies associated with HIV disease.  Individuals who have had 
biopsies to determine a malignancy are being asked for permission to take some of the 
tissue for the Bank.  Only tissue in excess of that required for decision making will be 
given to the Bank.  If it turns out that your physician needs more of your tissue for 
additional studies, the Bank will release all of your tissue back to your doctor.  No 
additional tissues will be taken from your body for the Bank. 
 
In addition, you are requested to donate some of your blood to the Bank so that scientists 
will also be able to look for any deviation in these body fluids that may explain the 
malignancy. 
 
C. 
PROCEDURES 
 
You are being asked for consent to place some of the biopsy material in the ACSR.  If 
you agree to allow the ACSR to have some of your tissue, we would also like to: 
 
1. Confidentially obtain some clinical information from your medical records that could 
be useful to research investigators.  The report of the information retrieved from your 
medical record that is given to research investigators will not have your name, or 
include any information, which could personally identify you. 
 


AMC # 042 (Version 7.0) 07/24/07 
NCI Version Date 07/24/07 
63 
2. Obtain some blood for the Bank.  Up to twenty (20) milliliters of blood will be 
obtained at your next visit to your physician. 
If during the course of treatment by your physician, it is necessary to perform any of the 
following procedures for diagnostic reasons, you will be asked, at that time, to consent to 
having a portion of that specimen sent to the Bank.  These requests will not require you to 
make any additional visits to your doctor or have any additional specimens taken just for 
the Bank.  The Bank will only receive part of your specimen, and only what is in excess.  
No additional materials will be removed for the purposes of the Bank alone.  Samples of 
interest would include, (but are not limited to): 
 
Spinal fluid. 
 
Airway washes. 
 
Fluid around lungs and intestines. 
 
Additional biopsy material. 
 
You will not be asked to fill out any forms for any of these specimens. 
 
D. 
POSSIBLE RISKS 
 
There is a possibility of a bruise and slight pain at the time the blood samples are taken.  
There is also the possibility of fainting and infection at the site of the blood draw.   
 
E. 
POSSIBLE BENEFITS 
 
It may be that there will be no direct benefit to you by consenting to allow the Bank to 
have portions of your biopsies and biological fluids.  However, there may be possible 
benefits to medical knowledge and HIV-infected individuals in the future. 
 
F. 
COSTS 
 
There will not be any additional costs to you for consenting to participate in the AIDS 
and Cancer Specimen Bank. 
 
G. 
PAYMENT FOR INJURY OR HARM 
 
As the lists of risks shows, taking part in this research study may result in injury or harm 
to you.  If you require immediate medical care, you should go to an emergency room.  
Otherwise, the doctor in charge of the study will take care of you or help you get the care 
you need.  You will be sent a bill for whatever medical care you receive.  All or part of 
your bill may be paid by the sponsor of the research study (according to its agreement 
with the AIDS Associated Malignancies Clinical Trials Consortium), or by your health 
insurance.  (Institution) will not pay for the care.  Likewise, (Institution) will not pay 
you for pain, worry, lost income, or non-medical care costs that might occur from taking 
part in this research study. 
 


AMC # 042 (Version 7.0) 07/24/07 
NCI Version Date 07/24/07 
64 
H. 
PRIVACY 
 
Your hospital medical records will be confidentially reviewed to obtain clinical 
information that could be useful to research investigators.  However, the report of this 
information will not have your name or social security number anywhere on the report, so 
you will not be easily identified.  The results of this research study will be given to the 
AIDS Associated Malignancies Clinical Trials Consortium (AMC), the National Cancer 
Institute, EMMES Data Coordinators,, and may be asked for by the Department of Health 
and Human Services.  In addition, the Committee on Human Research of (Institution) 
may see your records.  Except for these people, records from this study will be kept 
private unless you authorize their release or release is required by law (i.e. court 
subpoena).  Any publications of this study will not use your name, identify you 
personally, or include any information which could personally identify you. 
 
I. 
QUESTIONS 
 
If you have any questions about this research study, you should contact  
Dr. (_____________) at (Phone Number) (day) or (Phone Number) (night), or the 
person in charge of the study, (_____________), the study coordinator, at (Phone 
Number).  If you have any questions about your rights as a research subject, you should 
call (IRB Representative), in (Institution) Office of Human Research at 
(______________).  (IRB Representative) is your representative and is not employed by 
the individuals conducting the study. 
 
J. 
SIGNATURES 
 
By signing this consent form you are agreeing that the study has been explained to you, 
that you understand the study, and that all your questions have been answered.  You are 
signing that you agree to take part in this study.  You will be given a copy of this consent 
form.  By signing this form, you will not give up any of your legal rights. 
 
_________________________________ 
______________________ 
Patient  
 
 
 
 
 
 
Date 
 
 
 
 
 
 
 
 
   
________________________________ 
  ______________________              
Person obtaining consent 
 
 
 
 
Date 
 
_______________________________            ______________________ 
Witness 
 
 
 
 
 
 
Date 
 


AMC # 042 (Version 7.0) 07/24/07 
NCI Version Date 07/24/07 
65 
APPENDIX VIII: AIDS AND CANCER SPECIMEN RESOURCE (ACSR) - 
SPECIMEN PREPARATION & SHIPPING INSTRUCTIONS 
 
A. 
COLLECTION 
 
Consent patient for ACSR donation. Collect 20 cc of whole blood in ACD tubes.  
 
B. 
SHIPPING 
 
To ship bloods, place the tubes into a canister of a STP-100 SAF-T-PAK shipper 
wrapping each tube in bubble wrap and using the absorbent paper at the bottom of the 
canister.  Mailers for shipping donations will be supplied by the ACSR upon request.  
Please allow a few days for receipt of the mailers.  Each sample tube should be labeled 
using a sharpie pen with the following information: 
 
Protocol #: AMC 042  
 
9 digit Patient #  
 
Date and time of collection  
 
Specimen type, i.e., WB=Whole Blood, P=Plasma, S=Serum 
 
Specimen purpose: Donation 
Place the lid on the canister and place it inside of the ambient SAF-T-PAK shipper. Fold 
and pack ACSR form inside shipping box. Seal the ambient shipper with cellophane 
shipping tape. Label the ambient shipper with the "Infectious substance" diamond shaped 
label. On one side, in black marker write “BIOLOGIC SUBSTANCE, CATEGORY B”, 
your name or name of responsible person, date of collection and phone number of the 
person responsible for the package.  
 
B.1 
Specimen Shipment 
 
Specimens are accepted MONDAY through THURSDAY. Specimens are not 
accepted on Friday.: 
 
All BLOOD (whole blood, plasma, serum) specimens should be shipped by 
overnight express at room temperature to: 
ACSR Blood Receiving Laboratory 
Johns Hopkins University 
1650 Orleans Street, CRB-384 
Baltimore, MD  21231-1000 
TEL: (410) 955-8721 
FAX: (443) 287-3217 
 


AMC # 042 (Version 7.0) 07/24/07 
NCI Version Date 07/24/07 
66 
All TISSUE specimens should be shipped by overnight express to: 
Dr. Sylvia Silver 
George Washington University Medical Center 
2300 I Street, NW, Room 507 
Washington, DC  20037 
Phone: (202) 994-1444 
Fax: (202) 994-5056 
 
Please use the AMC Operations Center FedEx account # to ship: 
 
 
B.2  
Instructions for Specimens Collected on Friday 
 
PREPARATION OF PLASMA AND MONONUCLEAR CELLS 
 
It is preferable that separation occurs as soon as possible. If necessary, whole 
blood in acid citrate dextrose (yellow top tube) can be held at room temperature 
for no more than 24 hours. 
 
Materials:  
Lymphocyte Separation Medium (LSM Solution, Ficoll-Hypaque - sterile) 
15 ml conical centrifuge tubes (sterile) 
PBS (sterile) 
1, 5 ml and 10 ml serologic pipettes (sterile) 
NUNC tubes 
Alcohol-saturated, control rate freezer container 
DMSO freezing media: 
 50% Cryoprotective Medium, Cambrex (catalog no.: 12-132A) 
 50% Heat Inactivated Fetal Bovine Serum 
 
1. 
Preparation of Plasma Samples  
a. The 7 ml tube of whole blood in acid citrate dextrose should be rotated 
gently 2 or 3 times before being centrifuged. Do not transfer before 
centrifugation.  
b. The cells are separated by centrifugation at 500 g for 10 minutes.  
c. 0.5ml aliquots of plasma are removed and put into 1.5 ml screw top 
tubes and transferred to liquid nitrogen storage. 
 
2. 
Peripheral Blood Mononuclear Cell Separation and Freezing  
a. The cells and plasma remaining from the previous step are transferred 
into a 15 ml conical tube, capped and re-suspended by gently tapping the 
bottom of the tube.  
b. Sterile PBS should be added to the suspended cells until the final 
volume is 8 ml; invert to mix.  


AMC # 042 (Version 7.0) 07/24/07 
NCI Version Date 07/24/07 
67 
c. The 8 ml whole blood-PBS mixture should be carefully overlaid onto 4 
ml of room temperature LSM or Ficoll-Hypaque solution in a sterile 15 
ml conical tube. A sharp interface should exist between the LSM and the 
whole blood mixture. (If the layer of LSM gets mixed with the blood-
PBS, the tube should be gently rotated to mix the blood, PBS, and LSM, 
and transfer to a 50 ml sterile conical tube. An equal volume of PBS is 
added, and the cells are separated at 600 g for 15 minutes. After removal 
of LSM-PBS supernatant, return to Step b).  
d. The 15 ml conical tube for 30 minutes at 900 g at room temperature. The 
mononuclear leukocytes (principally lymphocytes and monocytes) will 
band at plasma/LSM interface.  
e. The fluffy white layer just below the plasma layer should be aspirated 
off, along with approximately half of the LSM layer under it, and 
transferred to an appropriately labeled 15 ml sterile conical centrifuge 
tube. Mix by gentle rotation.  
f. Washed twice in sterile PBS - centrifuge at 500 g for 10 minutes.  
g. Cell pellet should be mixed well with a gentle finger-tapping action.  
h. Using a 1 ml pipette, the *DMSO freezing mixture should be added drop 
wise to the cell pellet suspension. Gently finger-tap between drops. If the 
cell pellet is small, only 1 ml of freezing media is added (and only one 
aliquot of cells is frozen). If the cell pellet is large, up to 4 ml of freezing 
media can be added in a drop wise fashion. (Cell densities of 1 - 10 
million PBMC/ml are best for cryopreservation. If a hemocytometer is 
available, the optimal concentration is 5 million PBMC/ml).  
 
*Important-Do not put the DMSO containing media on the cell 
button all at once.  
 
3. Freeze the cell suspension in 0.5 ml aliquots in sterile NUNC vials by 
placing the NUNC tubes in a room temperature, alcohol saturated, control 
rate freezer container and store in the -80°C freezer overnight. Transfer the 
cell suspension into the liquid nitrogen temperature freezer for long-term 
storage the next working day. 
 
***PLEASE DOUBLE CHECK PACKAGING OF SHIPPER AND DO 
NOT DEVIATE FROM REQUESTED LABELING***  
 
Shipping frozen aliquots requires the use of packaging acceptable for dry ice 
and Class 9 label with weight of dry ice written on package 
 
Please Note: The shipper will be mailed back to the AMC site.  
 
The STP-100 SAF-T-PAK shipper is a complete kit w/all trappings, bubble 
wrap, absorbent paper, labels, everything (but to reuse the shipper, you will 
need new labels, wrap, etc).   
 


AMC # 042 (Version 7.0) 07/24/07 
NCI Version Date 07/24/07 
68 
B.3 
Record of Specimens 
 
This study will track specimens via GlobalTraceSM, a component of the AMC 
AdvantageEDCSM system. The GlobalTrace shipment manifest must accompany 
all specimen shipments. 
 


AMC # 042 (Version 7.0) 07/24/07 
NCI Version Date 07/24/07 
69 
APPENDIX IX: PUNCH BIOPSY 
 
EXPRESSION/ACTIVATION (PHOSPHORYLATION) IMATINIB TARGETS AND 
SIGNALING INTERMEDIATES 
 
 
A. 
METHODOLOGY 
 
A.1 
Biopsies will be performed with a 4 mm punch biopsy at baseline and Day 8 of 
treatment. Fixed tissue samples in formalin will be received from trial sites.  They 
will be embedded in paraffin blocks with an orientation that allows for sectioning 
perpendicular to the skin surface. Staining of slides will be batched in order that 
pre and post sections are stained at the same time to control for variability.  Two 
ribbons of four to five tissue sections 5 um thick will be placed one below the 
other on ProbeOn Plus slides (Fischer). The two ribbons will be treated identically 
except the top ribbon will receive the primary antibody and the bottom ribbon, 
which is serving as a negative control, will not.   Slides will be stained using the 
following antibodies: LANA, anti-PDGF-R and anti-phospho-PDGF-R (Tyrosine 
783) (Cell Signaling, Beverly, MA).  H&E stains will also be performed on all pre 
and post specimens. 
 
A.2 
Within 48 hours of sectioning, slides will de-paraffinized in xylene and ethanol.  
Antigen retrieval will be performed by boiling the slides for 10 minutes in pH 6 
citrate buffer followed by 10 minutes in 3% H2O2. The slides for phospho–PDGF-
R require 15 minutes in 1mM EDTA, pH 8.0 prior to H2O2. The slides are then 
incubated overnight with the primary antibody at a 1/100 dilution for anti-PDGF-
R, a 1/100 dilution for anti-LANA, and a 1/50 dilution anti-phospho-PDGFR at 
40C. The slides are then incubated for 30 minutes with 100 µL of biotinylated 
anti-rabbit secondary antibody, then for 30 minutes with ABC avidin/biotin 
(Vector Labs, Burlingame, CA) with washes in after each incubation.  Slides were 
incubated in ethanol and xylene prior to mounting coverslips. 
 
A.3 
All slides will be assigned a random numerical identifier and will be presented in 
a blinded fashion to two pathology reviewers (Drs. Tahan and Dahiya).  Based on 
review of the slides from the pilot study, it was determined nearly all of the KS 
spindle cells stained uniformly positive with minimal heterogeneity, and after 
treatment their immunoreactivity decreased uniformly. Staining intensity of basal 
keratinocytes is reduced after treatment with imatinib, precluding using them as 
an internal standard for assessment of lesional cell staining intensity in post-
treatment samples.  Immunoreactivity of lesional KS cells will thus be scored on a 
scale of 0 to 5+ by two pathologists, with 0 being the negative control staining of 
basal keratinocytes and 5+ being equal to the staining intensity of basal 
keratinocytes in pretreatment samples, and a final score for each sample based on 
the average of 4 sections.   
 


AMC # 042 (Version 7.0) 07/24/07 
NCI Version Date 07/24/07 
70 
A.4 
Analysis: Immunohistochemical methods are amenable to statistical assessment.  
For instance, even using an activation specific antibody, Weber and his colleagues 
have been able to statistically correlate erk1/erk2 activation with tumor grade and 
stage of prostate cancer [52]. In this study we will classify the activation of 
PDGF-R as low (score of 0, 1+ or 2+) or high (score of 3+, 4+ or 5+).  The 
breakpoint for this grouping is based on our observations of degree of inhibition 
in the pilot trial. Biopsy pairs that score as high at baseline and low at seven days 
will be considered PDGF-R inhibited, and those that score as high at baseline and 
high at seven days will be considered PDGF-R not inhibited. Pairs that score low 
at baseline will be omitted from the analysis. For the purposes of Aims 2 and 3, 
clinical response is defined as partial or complete response and non-response will 
be classified as stable disease or disease progression.  Our a priori hypothesis is 
that inhibition of PDGF-R at 7 days correlates with clinical response. A chi 2 test 
will be used to test whether phosphorylation of PDGF-R (low or high) at 7 days 
predicted clinical response.   
 
B. 
SPECIMEN COLLECTION 
 
Biopsies should be obtained by standard punch technique, using a 4 mm punch. The 
biopsy should be, if possible, completely within the margins of the lesions. Selection of 
lesions for biopsy is described in Section 4.1.6. 
 
The specimen should then be placed in 10% neutral buffered formalin and labeled as 
follows: 
 
Protocol #: AMC 042 
 
9 digit Patient # 
 
Patient initials 
 
Study Period: Baseline or Day 8 
 
Date and time of collection 
 
Purpose:  Phosphorylation 
 
C. 
SPECIMEN SHIPPING 
 
Specimens are accepted MONDAY through THURSDAY. (Because overnight shipping 
is required for these samples, the only specimens to come to Dr. Koon’s lab on Mondays 
will be those from Beth Israel itself. For sites other than Beth Israel, visits involving these 
labs should be scheduled for Monday through Wednesday and samples shipped overnight 
for receipt in Dr. Koon’s lab Tuesday through Thursday and if for some reason sites need 
to ship on Thursday or Friday, please contact Dr. Koon). UNLESS OTHER SHIPPING 
ARRANGEMENTS HAVE BEEN MADE IN ADVANCE WITH THE LAB, ALL 
SPECIMENS should be shipped within 24 hours of collection. 
 


AMC # 042 (Version 7.0) 07/24/07 
NCI Version Date 07/24/07 
71 
Samples should be stored at room temperature and shipped within 24 hours of collection 
to:  
 
Henry B. Koon, M.D. 
Case Western Reserve University 
2103 Cornell Road / WRB 2204 
Cleveland, OH 44106 
Tel:  (216) 368-1175 
Fax: (216) 368-1166 
 
Use FED-EX "Dangerous Goods" airway bills for shipping. FED-EX account for the 
shipment: 
. It is only to be used for billing shipment of specimens to the 
lab where the sample is processed and/or stored. Call FED-EX at1-800-463-3339 and 
press 0. Ask for customer service "dangerous goods" department. A FED-EX 
representative will assist in the specific wording required on the airway bills for pick-up 
and delivery of "Dangerous Goods". Place the completed airway bill marked “Priority 
Overnight” and the typed “Shippers Declaration for Dangerous Goods” on top of the 
shipper box inside of a plastic FED-EX pouch. 
 
***PLEASE DOUBLE CHECK PACKAGING OF SHIPPER AND DO NOT 
DEVIATE FROM REQUESTED LABELING. 
 
Please Note: The shipper will be mailed back to the AMC site.  
The STP-100 SAF-T-PAK shipper (VWR Cat # 11217-163) is a complete kit w/ all 
trappings, bubble wrap, absorbent paper, labels, everything (but to reuse the shipper, you 
will need new labels, wrap, etc).  There is a refurbishment kit w/ extra bubble- wrap, 
absorbent material (STP102) (VWR Cat # 11217-166) enough for 15 mailings. 
 
D. 
RECORD OF SPECIMENS 
 
A copy of the specimen log at the end of Appendix X will be provided with the specimen 
collection pack which will be completed and accompany the sample when shipped. 
 
This study will track specimens via GlobalTraceSM, a component of the AMC 
AdvantageEDCSM system. The GlobalTrace shipment manifest must accompany all 
specimen shipments. 
 
 


AMC # 042 (Version 7.0) 07/24/07 
NCI Version Date 07/24/07 
72 
APPENDIX X: PUNCH BIOPSY 
 
RECEPTOR MUTATION ANALYSIS 
 
 
A. 
METHODOLOGY 
 
Each patient will have a 4 mm punch biopsy performed at baseline and at the time of 
progression or treatment discontinuation of a representative lesion. RNA and genomic 
DNA will be isolated from samples. PCR primers for the genomic DNA were designed to 
begin in the flanking introns and cover the entire exon being studied The PCR products 
will be gel purified and will then be subcloned into PCR4blunt-TOPO vector. The ligated 
vectors for each exon will then be used to transform competent E. Coli XL1 blue and the 
bacteria will be plated and grown overnight. Single colonies will be picked and then 
mini-prepped. The DNA from the mini-preps will be sequenced. Because the malignant 
cells of KS will only be a portion of the biopsy, the heterogeneity of the tumor must be 
taken into account before we can declare a negative result. Based on our previous studies 
we estimate that approximately 50% of a 4 mm punch biopsy is composed of KS spindle 
cells which express PDGF-R β and c-kit. If only one allele of the KS spindle cell has a 
mutation and the ratio of normal to mutant cells is one to one, only one out of four exons 
carry the mutation. To calculate the number of sequences to perform on each exon to 
assure a mutation was not missed, we first decided level of 95% confidence level was 
acceptable. The number of assays required is the number of times the negative result 
(normal sequence) must happen to be less that or equal to 5% (100% -95%).  
Mathematically this can solved as a probability problem. 
 
(p {normal sequence})n   <  0.05  where n is number of assays and p(normal sequence) = 
0.75 
 
This transforms to (0.75)n   <  0.05 Æ   n log(0.75) < log (0.05) Æ  n (-0.125) = - 1.301)      
n= 10.41Æ 11 
 
Thus to achieve a 95% confidence of not missing a mutation each exon will be sequenced 
11 times. If a positive mutant clone is discovered, it is possible that the mutation is an 
error introduced by PCR. We are using PFU polymerase, which has a lower mistake rate 
than Taq polymerase to reduce the incidence of mistakes. Because PFU still has a 
mistake rate of 1 in 10,000 nucleotides all mutants will have to be confirmed by two 
more clones from different PCR reactions to be considered a positive result. If mutations 
are present, we will determine if they correlate with non-response. 
 
B. 
SPECIMEN COLLECTION 
 
Biopsies should be obtained by standard punch technique, using a 4 mm punch. The 
biopsy should be, if possible, completely within the margins of the lesions. Selection of 
lesions for biopsy is described in Section 3.1.1. The biopsy will be placed in an RNAlater 


AMC # 042 (Version 7.0) 07/24/07 
NCI Version Date 07/24/07 
73 
tissue protect tube (these tubes can be obtained by contacting Dr. Koon’s lab) and labeled 
as follows: 
 
Protocol #: AMC 042 
 
9 digit Patient # 
 
Patient initials 
 
Study Period: Baseline, progression or discontinuation  
 
Date and time of collection 
 
Purpose:  Mutation receptor 
 
C. 
SPECIMEN SHIPPING 
 
Specimens are accepted MONDAY through THURSDAY.  (Because overnight shipping 
is required for these samples, the only specimens to come to Dr. Koon’s lab on Mondays 
will be those from Beth Israel itself. For sites other than Beth Israel, visits involving these 
labs should be scheduled for Monday through Wednesday and samples shipped overnight 
for receipt in Dr. Koon’s lab Tuesday through Thursday and if for some reason sites need 
to ship on Thursday or Friday, please contact Dr. Koon). UNLESS OTHER SHIPPING 
ARRANGEMENTS HAVE BEEN MADE IN ADVANCE WITH THE LAB, ALL 
SPECIMENS should be shipped within 24 hours of collection. 
 
Samples should be stored at room temperature and shipped within 24 hours of collection 
to:  
 
Henry B. Koon, M.D. 
Case Western Reserve University 
2103 Cornell Road / WRB 2204 
Cleveland, OH 44106 
Tel:  (216) 368-1175 
Fax: (216) 368-1166 
 
Use FED-EX "Dangerous Goods" airway bills for shipping. FED-EX account for the 
shipment: 
. It is only to be used for billing shipment of specimens to the 
lab where the sample is processed and/or stored.  Call FED-EX at1-800-463-3339 and 
press 0.  Ask for customer service "dangerous goods" department. A FED-EX 
representative will assist in the specific wording required on the airway bills for pick-up 
and delivery of "Dangerous Goods". Place the completed airway bill marked “Priority 
Overnight” and the typed “Shippers Declaration for Dangerous Goods” on top of the 
shipper box inside of a plastic FED-EX pouch. 
 
***PLEASE DOUBLE CHECK PACKAGING OF SHIPPER AND DO NOT 
DEVIATE FROM REQUESTED LABELING. 
 


AMC # 042 (Version 7.0) 07/24/07 
NCI Version Date 07/24/07 
74 
Please Note: The shipper will be mailed back to the AMC site. 
The STP-100 SAF-T-PAK shipper (VWR Cat # 11217-163) is a complete kit w/ all 
trappings, bubble wrap, absorbent paper, labels, everything (but to reuse the shipper, you 
will need new labels, wrap, etc). There is a refurbishment kit w/ extra bubble-wrap, 
absorbent material (STP102) (VWR Cat # 11217-166) enough for 15 mailings. 
 
D. 
RECORD OF SPECIMENS 
 
A copy of the specimen log at the end of Appendix X will be provided with the specimen 
collection pack which will be completed and accompany the sample when shipped. 
 
This study will track specimens via GlobalTraceSM, a component of the AMC 
AdvantageEDCSM system. The GlobalTrace shipment manifest must accompany all 
specimen shipments. 


AMC # 042 (Version 7.0) 07/24/07 
NCI Version Date 07/24/07 
75 
AMC PROTOCOL 042 
 
A Phase II Trial of Imatinib Mesylate in Patients with HIV Related Kaposi’s Sarcoma 
 
Biopsy Log - for Baseline, DAY, 8 and Progression 
 
 
PI: _______________________________________ 
 
SITE OR INSTITUTION NAME: ___________________________________ 
 
PATIENT ID: _________________________________ 
 
Contact Name& Tel.: ___________________________ 
 
Cycle: _____________ Day: ___________ 
 
Biopsies 
 
TIMEPOINT 
DATE 
TIME 
Initials 
COMMENTS 
 
 
 
Phosphorylation - formalin 
Baseline 
 
 
 
Mutation Assay – RNAlater 
Day 8 
 
 
 
Phosphorylation - formalin 
Progression 
 
 
 
Mutation Assay – RNAlater 
 
Initials 
Signature 
 
 
 
 
 
 
 
Shipping Address: 
 
Henry B. Koon, M.D. 
Case Western Reserve University 
2103 Cornell Road / WRB 2204 
Cleveland, OH 44106 
Tel:  (216) 368-1175 
Fax: (216) 368-1166 
 
 


AMC # 042 (Version 7.0) 07/24/07 
NCI Version Date 07/24/07 
76 
APPENDIX XI:  CYTOKINE PROFILES ANALYSIS 
 
A. 
METHODOLOGY 
 
In this study we will examine the patient cytokine profiles at baseline, Day 8 and Day 29. 
Plasma samples will be assayed using the PerkinElmer cytokine chip as described in the 
preliminary data. As noted the standards on the cytokine chip are analyzed by point-to-
point linear regression and concentrations of experimental samples are estimated from 
these standard four-point curves. Thus the chip should be considered a semi-quantitative 
assay and all cytokines/chemokines that appear to be potential predictors will be 
confirmed by ELISA. 
 
The concentrations of cytokines that are found to be potential predictors by single variant 
analysis will be determined using commercially available ELISAs. R&D Systems 
(Minneapolis, MN) produces colorimetric sandwich ELISAs that correspond to the 
cytokines and chemokines on the cytokine chip. Depending on the ELISA, the intra-assay 
precision has a CV of 3 to 14 percent and the inter-assay precision has a CV of 7 to 14 
percent. The concentrations determined by ELISA will then be analyzed by single variant 
and multivariate analysis to determine if there is any correlation between concentration at 
baseline or changes in concentrations after treatment and clinical response.  
 
B. 
SPECIMEN COLLECTION  
 
Serum (red top) and plasma (green top) specimens should be collected at baseline, 8 days 
and 29 days (approximately 5ml). Centrifuged at 2,400 xg for 15 minutes. Plasma and 
serum should be aliquoted into 2 nunc tubes which will be provided with labels by the 
Koon lab in the specimen collection packs. Ship one tube of each to the Koon lab and 
keep other at the site in – 70 degrees and cover labels with freezer tape. Please label with 
appropriate red or green top label. The specimens should be labeled as follows: 
 
Protocol #: AMC 042 
 
9 digit Patient # 
 
Patient initials 
 
Study Period:  Baseline, day 8 or day 29 
 
Date and time of collection 
 
Purpose:  Cytokines 
 
C. 
SPECIMEN SHIPPING 
 
Specimens are accepted MONDAY through THURSDAY. (Because overnight shipping 
is required for these samples, the only specimens to come to Dr. Koon’s lab on Mondays 
will be those from Beth Israel itself. For sites other than Beth Israel, visits involving these 
labs should be scheduled for Monday through Wednesday and samples shipped overnight 


AMC # 042 (Version 7.0) 07/24/07 
NCI Version Date 07/24/07 
77 
for receipt in Dr. Koon’s lab Tuesday through Thursday and if for some reason sites need 
to ship on Thursday or Friday, please contact Dr. Koon). UNLESS OTHER SHIPPING 
ARRANGEMENTS HAVE BEEN MADE IN ADVANCE WITH THE LAB, ALL 
SPECIMENS should be shipped within 24 hours of collection. 
 
Samples should be stored in a –70C freezer and shipped on dry ice within 24 hours of 
collection to:  
 
 
Henry B. Koon, M.D. 
Case Western Reserve University 
2103 Cornell Road / WRB 2204 
Cleveland, OH 44106 
Tel:  (216) 368-1175 
Fax: (216) 368-1166 
 
Use FED-EX "Dangerous Goods" airway bills for shipping. FED-EX account for the 
shipment: 
. It is only to be used for billing shipment of specimens to the lab 
where the sample is processed and/or stored. Call FED-EX at1-800-463-3339 and press 
0. Ask for customer service "dangerous goods" department. A FED-EX representative 
will assist in the specific wording required on the airway bills for pick-up and delivery of 
"Dangerous Goods". Place the completed airway bill marked “Priority Overnight” and 
the typed “Shippers Declaration for Dangerous Goods” on top of the shipper box inside 
of a plastic FED-EX pouch. ***PLEASE DOUBLE CHECK PACKAGING OF 
SHIPPER AND DO NOT DEVIATE FROM REQUESTED LABELING. 
 
Please Note: The shipper will be mailed back to the AMC site.  
The STP-100 SAF-T-PAK shipper (VWR Cat # 11217-163) is a complete kit w/ all 
trappings, bubble wrap, absorbent paper, labels, everything (but to reuse the shipper, you 
will need new labels, wrap, etc).  There is a refurbishment kit w/ extra bubble- wrap, 
absorbent material (STP102) (VWR Cat # 11217-166) enough for 15 mailings. 
 
D. 
RECORD OF SPECIMENS 
 
A copy of the specimen log at the end of Appendix XI will be provided with the 
specimen collection pack which will be completed and accompany the sample when 
shipped. 
 
This study will track specimens via GlobalTraceSM, a component of the AMC 
AdvantageEDCSM system. The GlobalTrace shipment manifest must accompany all 
specimen shipments. 


AMC # 042 (Version 7.0) 07/24/07 
NCI Version Date 07/24/07 
78 
AMC PROTOCOL 042 
 
A Phase II Trial of Imatinib Mesylate in Patients with HIV Related Kaposi’s Sarcoma 
 
CYTOKINE PROFILES for Baseline, DAY, 8 and DAY 29 
 
PI: _______________________________________ 
 
SITE OR INSTITUTION NAME: ___________________________________ 
 
PATIENT ID: _________________________________ 
 
Contact Name& Tel.: ___________________________ 
 
Cycle: _____________ Day: ___________ 
 
CYTOKINE PROFILES  
 
TIMEPOINT 
DATE 
TIME 
Initials 
COMMENTS 
Baseline 
 
 
 
 
Day 8 
 
 
 
 
Day 29 
 
 
 
 
 
Samples will be collected in one heparinized tube (green top) and one red top tube. Centrifuged 
at 2,400 xg for 15 minutes. Plasma should be aliquoted into 2 nunc tubes, ship one to Henry 
Koon keep other at site in – 70 degrees and cover labels with freezer tape. Please label with 
appropriate red or green top label. 
 
Initials 
Signature 
 
 
 
 
 
 
 
Shipping Address: 
Henry B. Koon, M.D. 
Case Western Reserve University 
2103 Cornell Road / WRB 2204 
Cleveland, OH  44106 
Tel:  (216) 368-1175 
Fax: (216) 368-1166 


AMC # 042 (Version 7.0) 07/24/07 
NCI Version Date 07/24/07 
79 
APPENDIX XII: PHARMACOKINETIC ANALYSIS 
 
A. 
METHODOLOGY 
 
Blood samples will be collected for pharmacokinetic analysis on Days 1 and 15 as 
detailed in the protocol. Plasma concentrations of imatinib and its major active 
metabolite, CGP-74588, will be determined with a previously described and validated 
liquid chromatographic-mass spectrometric assay.[20] 
 
B. 
SPECIMEN COLLECTION 
 
Samples will be collected in heparinized tubes (green top) and centrifuged at 2,400 xg for 
5 minutes. Plasma will be aliquoted into 2 nunc tubes, which will be provided with labels 
by the Koon lab in specimen collection packs. Ship one tube to the Koon lab and keep 
other at the site in – 70 degrees and cover labels with freezer tape. Please label with 
appropriate label. The specimens should be labeled as follows: 
 
Protocol #: AMC 042 
 
9 digit Patient # 
 
Patient initials 
 
Study Period:  Day 1 or Day 8 
 
Date and time of collection 
 
Purpose:  PK 
 
C. 
SPECIMEN SHIPPING 
 
Specimens are accepted MONDAY through THURSDAY. (Because overnight shipping 
is required for these samples, the only specimens to come to Dr. Koon’s lab on Mondays 
will be those from Beth Israel itself. For sites other than Beth Israel, visits involving these 
labs should be scheduled for Monday through Wednesday and samples shipped overnight 
for receipt in Dr. Koon’s lab Tuesday through Thursday and if for some reason sites need 
to ship on Thursday or Friday, please contact Dr. Koon). UNLESS OTHER SHIPPING 
ARRANGEMENTS HAVE BEEN MADE IN ADVANCE WITH THE LAB, ALL 
SPECIMENS should be shipped within 24 hours of collection. 
 
Samples should be stored in a –70C freezer and shipped on dry ice within 24 hours of 
collection to:  
 
Henry B. Koon, M.D. 
Case Western Reserve University 
2103 Cornell Road / WRB 2204 
Cleveland, OH  44106 
Tel:  (216) 368-1175 
Fax: (216) 368-1166 


AMC # 042 (Version 7.0) 07/24/07 
NCI Version Date 07/24/07 
80 
 
Use FedEx account number 
 to ship all PK samples. 
 
Please Note: The shipper will be mailed back to the AMC site.  
The STP-100 SAF-T-PAK shipper (VWR Cat # 11217-163) is a complete kit w/ all 
trappings, bubble wrap, absorbent paper, labels, everything (but to reuse the shipper, you 
will need new labels, wrap, etc).  There is a refurbishment kit w/ extra bubble-wrap, 
absorbent material (STP102) (VWR Cat # 11217-166) enough for 15 mailings.  
 
D. 
RECORD OF SPECIMENS 
 
A copy of the specimen log at the end of Appendix XII will be provided with the 
specimen collection pack which will be completed and accompany the sample when 
shipped. 
 
This study will track specimens via GlobalTraceSM, a component of the AMC 
AdvantageEDCSM system. The GlobalTrace shipment manifest must accompany all 
specimen shipments. 
 


AMC # 042 (Version 7.0) 07/24/07 
NCI Version Date 07/24/07 
81 
AMC PROTOCOL 042 
 
A Phase II Trial of Imatinib Mesylate in Patients with HIV Related Kaposi’s Sarcoma 
 
PHARMACOKINETIC SAMPLE COLLECTION LOG for Days 1 and 15 
 
PI: _______________________________________ 
 
SITE OR INSTITUTION NAME: ___________________________________ 
 
PATIENT ID: _________________________________ 
 
Contact Name& Tel.: ___________________________ 
 
Cycle: _____________ Day: ___________ 
 
1. 
PHARMACOKINETIC SAMPLE COLLECTION (PLASMA) 
 
Day 1 or Day 15 (Please circle one) 
TIMEPOINT 
DATE 
TIME 
Initials 
COMMENTS 
Pre-dose 0 hrs. 
 
 
 
Dosing – Gleevec 400mg po 
 
 
 
 
30 minutes 
 
 
 
 
I Hour 
 
 
 
 
2 Hours 
 
 
 
 
3 Hours 
 
 
 
 
4 Hours 
 
 
 
 
8 Hours 
 
 
 
 
24 Hours Pre-dose 
 
 
 
 
 
2. 
SPECIMEN COLLECTION INSTRUCTION 
 
Samples will be collected in heparnized tubes (green top)(6cc on ice) and centrifuged at 
2,400 xg for 15 minutes. Plasma should be aliquoted into 2 nunc tubes, ship one to Henry 
Koon keep other at site in – 70 degrees and cover labels with freezer tape. 
 
Shipping Address: 
 
Henry B. Koon, M.D. 
Case Western Reserve University 
2103 Cornell Road / WRB 2204 
Cleveland, OH  44106 
Tel:  (216) 368-1175 
Fax: (216) 368-1166 


AMC # 042 (Version 7.0) 07/24/07 
NCI Version Date 07/24/07 
82 
 
APPENDIX XIII: HHV-8 VIRAL LOAD AND GENE EXPRESSION 
 
A. 
DESCRIPTION OF ASSAY 
 
This assay is used to quantify the burden of HHV-8 (Human Herpesvirus Type 8, or 
Kaposi's sarcoma associated virus, KSHV) present in circulating peripheral blood 
mononuclear cells (PBMC). Cells are separated from whole blood by Ficoll 
centrifugation, DNA extracted from purified PBMC by column extraction, and the 
number of HHV-8 copies determined using a quantitative competitive DNA PCR assay. 
Results are expressed in numbers of copies per million PBMC. The limit of detection for 
this assay depends upon the amount of DNA available, but is generally <50 copies/10
6 
PBMC.  Changes > 1.7-fold are unlikely to be due to assay variation, but HHV-8 burden 
does not appear to be as constant as HIV viral load. While some preliminary data 
indicates that untreated individuals with an average HHV-8 burden of >100 copies/10
6 
cells may be at greater risk of progression, this assay is a research test only, and should 
not be used to make clinical decisions. The purpose of including this assay as part of this 
trial is to determine its usefulness as a prognostic marker. 
 
A.1 
Changes in gene expression are a fundamental hallmark of cancer progression and 
invaluable tool of cancer stages. In the case of KS, KSHV/HHV-8 has been 
identified as the etiological agent and this assay is designed to identify KSHV 
genes that might change in response to therapy. We will use reverse-transcription 
(RT) coupled to amplification using polymerase chain reaction (PCR) to measure 
the mRNA levels of all KSHV/HHV-8 mRNAs in the tumor. This assay is a 
research test only and should not be used to make clinical decisions. The purpose 
of including this assay as part of this trial is to determine its usefulness as a 
prognostic marker.  
 
A.2 
Reverse-transcription (RT) coupled to amplification using polymerase chain 
reaction (PCR) is widely recognized as the most sensitive method to detect the 
presence of specific RNAs. We will use real-time quantitative RT-PCR. This 
assay measures the amount of PCR product based on intercalation of a fluorescent 
dye. Fluorescence is recorded at each cycle. So-called Ct-values indicate the cycle 
at which the fluorescence crosses a particular threshold (5 times standard 
deviation (SD) of the non-template control (NTC)). Hence, Ct-values indicate the 
abundance of a given mRNA on a log scale. A low Ct value represents a highly 
abundant target mRNA (Heid, Genome Res. 6:968-94 (1996). We have 
experience doing these assays at the University of North Carolina Lineberger 
Cancer Center. 
 
A.3 
Cells are separated from whole blood by Ficoll centrifugation. Total RNA will be 
isolated using RNAzol (Tel-Test, Inc., Friendswood, Texas) according to the 
supplier's protocol and reverse-transcribed using Mo-MuLV reverse transcriptase 
and 120 pmol random hexanucleotide primers (Applied Biosystems Inc., Foster 


AMC # 042 (Version 7.0) 07/24/07 
NCI Version Date 07/24/07 
83 
City, CA). After incubation at 42°C for 35 min, the reaction was stopped by 
heating to 95°C for 5 min, the cDNA pool was diluted, and the resulting sample 
analyzed by real-time quantitative PCR using a dedicated MJR Opticon2 machine 
and universal cycle conditions. We will use commercial SYBRgreen-based PCR 
(SYBR® Green, Applied Biosystems Inc., Foster City, CA) as a uniform 
detection method. 
 
B. 
GENERAL 
 
To ship HHV-8 specimens, use a diagnostic shipper approved for a volume of at least  
30 cc. The Ambinder lab recommends the use of the SAF-T-PAK STP 210 diagnostic 
cardboard shipper. These shippers may be ordered at the SAF-T-PAK website 
www.saftpak.com. The following instructions below are for use with the recommended 
STP-210 shipper. If using another federally approved diagnostic shipper, please follow 
instructions provided for that specific shipper. 
 
NOTE:  Specimens MUST BE SHIPPED Mondays through Thursdays as PRIORITY 
OVERNIGHT. Specimens are NOT ACCEPTED ON SATURDAYS in the Ambinder 
Lab. 
 
 
C. 
SPECIMEN PREPARATION 
 
C.1 
Draw three 10 cc (ml) green top (heparin) tubes from study patient.  
With a black, water resistant, sharpie pen, label each specimen with the following 
information: 
 
Protocol #: AMC 042  
 
9 digit Patient #  
 
Patient initials 
 
Study Period-Day 1, Day 15, cycle 3, cycle 5, cycle 7,cycle 9, cycle 11 or 
Treatment Discontinuation 
 
Date and time of collection  
 
Specimen type- "Whole Blood" 
 
Specimen purpose: "HHV-8 PCR" 
C.2 
Seal the tops of the three 10 cc heparin green tops with parafilm. 
 
D. 
PACKAGING AND FED-EX FORMS 
 
a. 
Place the three sealed tubes into bubble wrap (provided in STP-210 kit). 
b. 
Tape around the bubble wrap so that the roll stays together and the tubes cannot fall 
out or break. 
c. 
Place absorbent material sheet around the bubble wrapped tubes and slip into a 
biohazard poly-bag and “self-seal”. 
d. 
Place poly-bag containing tubes into the white TYVEK bag and seal. 


AMC # 042 (Version 7.0) 07/24/07 
NCI Version Date 07/24/07 
84 
e. 
Place the TYVEK bag into the STP-210 diagnostic cardboard shipper. Seal the 
cardboard shipper with clear packing/shipping tape. 
f. 
Affix the FED-EX airbill on blank side of the shipper making sure that it is marked 
“FED-EX PRIORITY OVERNIGHT”. 
g. 
Mark “OTHER” in the airbill under “Packaging”. 
h. 
Under 
airbill 
section 
“special 
Handling” 
indicate 
“YES-SHIPPERS 
DECLARATION NOT REQUIRED”. 
i. 
Enter FED-EX account # 
 
j. 
Place “From/To” information onto areas provided on the shipper. 
 
Shipping Address is: 
Ambinder Lab  
 
 
 
 
Johns Hopkins Oncology 
 
 
 
 
1650 Orleans Street, CRB-384 
 
  
 
 
Baltimore, MD  21231-1000 
 
 
 
 
Tel:  (410) 955-8721 
 
 
 
 
Fax:  (443) 287-3217 
 
k. 
Make certain that shipper is already either pre-labeled with ‘UN#3373’ stamp, or 
make a paper label with ‘UN#3373” and affix it to the shipper. 
l. 
Make certain that the net volume of the specimen being shipped is written in the 
space provided on the shipper or make a separate label with the volume in ml (so 
three 10 cc tubes is 30 ml) and affix to the shipper. 
m. 
Affix airbill to shipper so that the ‘UN’ and ‘VOLUME’ labels are visible. 
n. 
RETAIN THE TOP COPY OF THE AIRWAY BILL FOR YOUR RECORDS. 
o. 
Place the box in the FedEx pickup area at your site or call to request a package 
pickup. 
 
Please Note: The shippers will be mailed back to each AMC site. 
 
E. 
RECORD OF SPECIMENS 
 
This study will track specimens via GlobalTraceSM, a component of the AMC 
AdvantageEDCSM system. The GlobalTrace shipment manifest must accompany all 
specimen shipments. 
 


AMC # 042 (Version 7.0) 07/24/07 
NCI Version Date 07/24/07 
85 
APPENDIX XIV: NEW YORK HEART ASSOCIATION CRITERIA 
 
A. 
CLASS I (MILD) 
 
 
No limitation of physical activity. Ordinary physical activity does not cause undue 
fatigue, palpitation, or dyspnea (shortness of breath). 
 
B. 
CLASS II (MILD) 
 
 
Slight limitation of physical activity. Comfortable at rest, but ordinary physical activity 
results in fatigue, palpitation, or dyspnea. 
 
C. 
CLASS III (MODERATE) 
 
 
Marked limitation of physical activity. Comfortable at rest, but less than ordinary activity 
causes fatigue, palpitation, or dyspnea. 
 
D. 
CLASS IV (SEVERE) 
 
 
Unable to carry out any physical activity without discomfort. Symptoms of cardiac 
insufficiency at rest. If any physical activity is undertaken, discomfort is increased. 


AMC # 042 (Version 7.0) 07/24/07 
NCI Version Date 07/24/07 
86 
APPENDIX XV: DRUGS METABOLIZED BY CYP450 ISOENZYMES 2D6 
AND 3A4 
 
CYP2D6 
Substrates 
Amitriptyline (hydroxylation) 
Amphetamine 
Betaxolol 
Bisoprolol 
Brofaromine 
Buturolol 
Bupropion 
Captopril 
Carvedilol 
Cevimeline 
Chlorpheniramine 
Chlorpromazine 
Cinnarizine 
Clomipramine (hydroxylation) 
Clozapine (minor pathway) 
Codeine (hydroxylation, o-
demelhylation) 
Cyclobenzaprine (hydroxylation) 
Cyclophosphamide 
Debrisoquin 
Delavirdine 
Desipramine 
Dexfenfluramine 
Dextromethorphan (o-demethylation) 
Dihydrocodeine 
Diphenhydramine 
Dolasetron 
Donepezil 
Doxepin 
Encainide 
Fenlluramine 
Flecainide 
Fluosetine (minor pathway) 
Fluphenazine 
Haiofantrine 
Haioperidol (minor pathway) 
Hydrocodone 
Hydrocortisone 
Hydroxyamphetamine 
lmipramine (hydroxylation) 
Methamphetamine 
Metoclopramide 
Metoprolol 
Mexitetine 
Mianserin 
Meperidine 
Methadone Mirtazapine (hydroxylation) 
Molindone 
Morphine 
Nortriptyline (hydroxylation) 
Olanzapine (minor, hydroxymethylation) 
Ondansetron 
Orphenadrine 
Oxycodone 
Papaverine 
Paroxetine (minor pathway) 
Penbutolol 
Pentazocine 
Perhexiline 
Perphenazine 
Phenformin 
Pindolol 
Promethazine 
Propafenone 
Propranolol 
Quetiapine 
Remoxipride 
Risperidone 
Ritonavir (minor) 
Ropivacaine 
Selegiline 
Sertindole 
Sertratine (minor pathway) 
Sparteine 
Tamoxifen 
Thioridazine 
Tiagabine 
Timolol 
Tolterodine 
Tramadol 


AMC # 042 (Version 7.0) 07/24/07 
NCI Version Date 07/24/07 
87 
CYP2D6 
Labetalol 
Loratadine 
Maprotiline 
m-Chlorophenylpiperazine (m-CPP) 
 
Trazodone 
Trimipramine 
Tropisetron 
Venlafaxine (o-desmethylation) 
Yohimbine 
Inhibitors 
Amiodarone 
Celecoxib 
Chloroquine 
Chlorpromazine 
Cimelidine 
Citalopram 
Clomipramine 
Codeine 
Deiavirdine 
Desipramine 
Dextropropoxyphene 
Diltiazem 
Doxorubicin 
Entacapone (high dose) 
Fluoxetine 
Fluphenazine 
Fluvoxamine 
Haloperidol 
Labetalol 
Lobeline 
Lomustine 
 
Methadone 
Mibefradil 
Moclobemide 
Nortluoxeline 
Paroxetine 
Perphenazine 
Propafenone 
Quinacrine 
Quinidine 
Ranitidine 
Risperidone (weak) 
Ritonavir 
Sertindole 
Sertraline (weak) 
Thioridazine 
Vaiprolc acid 
Venlafaxine (weak) 
Vinblastine 
Vincristine 
Vinorelbine 
Yohimbine 
 
 


AMC # 042 (Version 7.0) 07/24/07 
NCI Version Date 07/24/07 
88 
 
CYP3A3/4 
Substrates 
Acetaminophen 
Aifentanil 
Alosetron 
Alprazolam 
Amiodarone 
Amitriptyline (minor) 
Amlodipine 
Anastrozole 
Androsterone 
Antipyrine 
Astemizole 
Atorvastatin 
Benzphetamine 
Bepridil 
Bexarotene 
Bromazepam 
Bromocriptine 
Budesonide 
Bupropion (minor) 
Buspirone 
Busutfan 
Caffeine 
Cannabinoids 
Carbamazepine 
Cevimeline 
Cerivastatin 
Digitoxin 
Diltiazem 
Disopyramide 
Docetaxel 
Dolasetron 
Donepezil 
Doxorubicin 
Doxycycline 
Dronabinol 
Enalapril 
Erylhromycin 
Estradiol 
Ethinyl estradiol 
Ethosuximide 
Etoposide 
Exemestene 
Dofetilide (minor) 
Chlorpromazine 
Cimetidine 
Cisapride 
Citałopram 
Clarithromycin 
Clindamycin 
Clomipramine 
Clonazepam 
Clozapine 
Cocaine 
Codeine (demethylation) 
Cortisol 
Cortisone 
Cyclobenzaprine (demethylation) 
Cyclophosphamide 
Cyclosporine 
Dapsone 
Dehydroepiandrostendione 
Delavirdine 
Desmethyldiazepam 
Dexamethasone 
Dextromethorphan (minor, N-
demethylation)  
Diazepam (minor; hydroxylation, N-
demethylation) 
 
Nefazodone 
Nelfinavir 
Nevirapine 
Nicardipine 
Nifedipine 
Niludipine 
Nimodipine 
Nisoldipine 
Nitrendipine 
Omeprazole (sulfonation) 
Ondansetron 
Oral contraceptives 
Orphenadrine 
Paclitaxel 
Pantoprazole 
Pimozide 
Pioglitazone 


AMC # 042 (Version 7.0) 07/24/07 
NCI Version Date 07/24/07 
89 
CYP3A3/4 
Felodipine 
Fentanyl 
Fexotenadine 
Finaxteride 
Fluoxetine 
Flutamide 
Glyburide 
Granisetron 
Halofantrine 
Hydrocortixone 
Hydroxyarginine 
Lfosfamide 
Lmipramine 
Lndinavir 
Lsradipine 
Ltraconazole 
Ketoconazole 
Lansoprazole (minor) 
Letrozole 
Levobupivicaine 
Lidocaine 
Loratadine 
Losartan 
Lovastatin 
Methadone 
Mibefradil 
Miconazole 
Midazolam 
Mifepristone 
Mirtazapine (N-demethylation) 
Montelukast 
Navelbine 
 
Toremifene 
Trazodone 
Tretinoin 
Triazolam 
Troglitazone 
Troleandomycin 
Venlafaxine (N-demethylation) 
Verapamil 
Vinblastine 
 
Pravastatin 
Prednisone 
Progesterone 
Proguanil 
Propafenone 
Quercetin 
Quetiapine 
Quinidine 
Quinine 
Repaglinide 
Retinoic acid 
Rifampin 
Risperidone 
Ritonavir 
Salmeterol 
Saquinavir 
Sertindole 
Sertraline 
Sibutramine 
Sildenafil citrate 
Simvastatin 
Sirolimus 
Sufentanil 
Tacrolimus 
Tamoxifen 
Temazepam 
Teniposide 
Terfenadine 
Testosterone 
Tetrahydrocannabinol 
Theophylline 
Tiagabine 
Tolterodine 
Vincristine 
Warfarin (R-warfarin) 
Yohimbine 
Zaleplon (minor pathway) 
Zatoestron 
Zileuton 
Ziprasidone 
Zolpidem 
Zonisamide 
 
 


AMC # 042 (Version 7.0) 07/24/07 
NCI Version Date 07/24/07 
90 
 
CYP3A3/4 
Inducers 
Carbamazepine 
Dexamethasone 
Ethosuximide 
Glucocorticoids 
Griseofulvin 
Nafcillin 
Nelfinavir 
Nevirapine 
Oxcarbazepine 
Phenobarbital 
Phenylbutazone 
Phenytoin 
Primidone 
Progesterone 
Rifabutin 
Rifampin 
Rofecoxib (mild) 
St John’s wort 
Sulfadimidine 
Sulfinpyrazone 
Troglitazone 
Inhibitors 
Amiodarone 
Anastrozole 
Azithromycin 
Cannabinoids 
Cimetidine 
Clarithromycin 
Clotrimazole 
Cyclosporine 
Danazol 
Delavirdine 
Dexamethasone 
Diethyldithiocarbamate 
Diltiazem 
Dirithromycin 
Disulfiram 
Entacapone (high dose) 
Erythromycin 
Ethinyl estradiol 
Fluconazole (weak) 
Fluoxetine 
Fluvoxamine 
Gestodene 
Grapefruit juice 
lndinavir 
lsoniazid 
ltraconazole  
 
Ketoconazole 
Metronidazole 
Mibefradil 
Miconazole (moderate) 
Nefazodone 
Nelfinavir 
Nevirapine 
Norfloxacin 
Norfluoxetine 
Omeprazole (weak) 
Oxiconazole 
Paroxetine (weak) 
Propoxyphene 
Quinidine 
Quinine 
Quinupristin and dalfopristin 
Ranitidine 
Ritonavir 
Saquinavir 
Sertindole 
Sertraline 
Troglitazone 
Troleandomycin 
Valproic acid (weak) 
Verapamil 
Zafirlukast 
Zileuton 
 
Adapted from Cytochrome P-450 Enzymes and Drug metabolism. In : Lacy CF, Armstrong LL, 
Goldman MP, Lance LL eds. Drug Information Handbook 8th ed. Hudson, OH; LexiComp Inc. 
2000: 1364-1371 


AMC # 042 (Version 7.0) 07/24/07 
NCI Version Date 07/24/07 
91 
APPENDIX XVI: DATA SAFETY AND MONITORING PLAN 
 
Monitoring The Progress Of Trials And The Safety Of Participants 
 
All AMC protocols follow the Cancer Therapy Evaluation Program (CTEP) guidelines for 
reporting of adverse events. All adverse events that meet the expedited reporting requirements of 
the National Cancer Institute (NCI) are reported to the Investigational Drug Branch (IDB) of the 
NCI via the Adverse Event Expedited Reporting System (AdEERS) web application. All 
expedited adverse event reports are also required to be submitted to the local Institutional 
Review Board (IRB) of the reporting institution. If NCI holds the IND or no IND is required for 
a study, the AMC sites report serious adverse events directly to the AMC Operations and Data 
Management Center via AdEERS. In some instances, the AMC sites may report serious adverse 
events directly to the commercial sponsor holding the IND who will then in turn report to the 
AMC Operations and Data Management Center. However, it is preferred that sites report all 
serious adverse events via AdEERS with the Operations and Data Management Center 
forwarding a copy of the report to the sponsor. 
 
The AMC Operations and Data Management Center provides a listing of serious adverse events 
to the Protocol Chair and Co-chair(s) for review on a regular basis. The AMC Operations and 
Data Management Center compiles these events in a tabular format and posts them on the 
password-protected section of the AMC Web site. The AMC Web site is accessible to all AMC 
investigators, co-investigators, and their staff. Email notification that this information is available 
on the web site will be sent to all site PIs. It is the responsibility of each site to provide this 
information to their respective IRBs, if required by their IRB. For blinded studies, the serious 
adverse events are reviewed and tabulated without treatment assignment.  
 
Accrual summaries for each AMC trial are updated nightly on the password-protected section of 
the AMC Web page. The progress of each AMC trial is reviewed regularly by the Protocol Chair 
and also by the appropriate disease-oriented Working Group during scheduled conference calls. 
For phase I dose escalation trials, dose escalation (or dose de-escalation) is based on the rules in 
the protocol and the Protocol Chair and Group Statistician determine whether these criteria have 
been met.  For phase II trials, stopping the trial for toxicity or efficacy, or suspending enrollment 
pending observation of responses in a multi-stage phase II trial, is based on meeting criteria 
stated in the protocol, and the Protocol Chair and Group Statistician determine whether these 
criteria have been met. 
 
For phase III trials, the AMC has formed an independent Data Safety and Monitoring Committee 
(DSMC). Voting members of the DSMC are physicians, statisticians, and a patient advocate. All 
voting members are from outside the AMC. Non-voting members are the NCI scientific project 
officers and an NCI statistician. The AMC Data Safety and Monitoring Committee reviews 
AMC phase III studies in accordance with the National Cancer Institute’s Policy for Data Safety 
and Monitoring. Confidential reports of all phase III trials are prepared by the AMC Group 
Statistician with support from the AMC Operations and Data Management Center. A written 
report containing the current status of each trial monitored, and when appropriate, any toxicity 
and outcome data, are sent to DSMC members by the AMC Operations and Data Management 


AMC # 042 (Version 7.0) 07/24/07 
NCI Version Date 07/24/07 
92 
Center allowing sufficient time for DSMC members to review the report prior to the meeting. 
This report addresses specific toxicity concerns as well as concerns about the conduct of the trial. 
The report may contain recommendations for consideration by the DSMC concerning whether to 
close the trial, report the results, or continue accrual or follow-up. 
 
The results of each DSMC meeting are summarized in a formal report sent by the DSMC Chair 
to the Group Chair and Operations and Data Management Center within 1 week of the meeting. 
The DSMC report contains recommendations on whether to close each study reviewed, whether 
to report the results, and whether to continue accrual or follow-up. A primary recommendation 
(e.g., continue with no change; recommended or required modification; stop) must be included in 
the document. The Group Chair is then responsible for notifying the Protocol Chair and relevant 
Disease-oriented Working Group Chair before the recommendations of the DSMC are carried 
out. In the unlikely event that the Protocol Chair does not concur with the DSMC, then the NCI 
Division Director or designee must be informed of the reason for the disagreement. The Study 
Chair, relevant Disease-oriented Working Group Chair, Group Chair, DSMC Chair and NCI 
Division Director or designee will be responsible for reaching a mutually acceptable decision 
about the study. CTEP approval of a formal amendment will be required prior to any 
implementation of a change to the study.   
 
Following a DSMC meeting, a summary of the serious adverse events reported to the DSMC is 
posted to the AMC Web page. It is each site’s responsibility for conveying this information to its 
IRB. 
 
Plans for Assuring Compliance with Requirements Regarding the Reporting of Adverse 
Events (AE). 
 
For trials monitored by the NCI’s Clinical Data Update System (CDUS), adverse event 
information is transmitted electronically to NCI on a quarterly basis. For trials monitored by 
NCI’s Clinical Trials Monitoring Service (CTMS), adverse event information is transmitted 
electronically to NCI every two weeks. 
 
Plans For Assuring That Any Action Resulting In A Temporary Or Permanent Suspension 
Of An NCI-Funded Clinical Trial Is Reported To The NCI Grant Program Director 
Responsible For The Grant 
 
In the event that termination of the trial or major modification to the protocol is under 
consideration, the Protocol Chair will convene the AMC Data Coordinator and Disease-oriented 
Working Group Chair by conference call to discuss the options. For phase I and II trials, the 
Protocol Chair also has the option of asking the AMC DSMC to review the study. The AMC 
Operations and Data Management Center will inform the CTEP Protocol Information Office 
(PIO) when studies are temporarily or permanently closed. The Cancer Treatment and 
Evaluation Program (CTEP) of the National Cancer Institute (NCI) must approve all protocol 
amendments prior to distributing to the AMC sites. 


AMC # 042 (Version 7.0) 07/24/07 
NCI Version Date 07/24/07 
93 
Plans for Assuring Data Accuracy and Protocol Compliance 
 
All study data for AMC clinical trials are entered directly by AMC site staff into 
AdvantageEDCSM (a web-based data entry and enrollment system). During data entry, the system 
performs validation checks on many fields and performs consistency checks between select 
fields. Range checks are placed on each field to eliminate entry of out-of-range values. Edit 
check programs are run on the database on a set schedule to identify and resolve inconsistencies 
between forms or data collected at different points in time. AMC Operations and Data 
Management Center staff routinely interacts with site staff to resolve any data problems. 
 
In accordance with NCI guidelines, the AMC Operations and Data Management Center conducts 
monitoring visits at the AMC sites to evaluate compliance with regulatory issues, and to review 
data for specific cases by checking source documents. These reports are sent to the site Principle 
Investigator and to the NCI. In the event that major violations are identified, sites are asked to 
provide a plan to correct deficiencies within 30 days. If needed, a repeat site visit is conducted.  
In the event that a site does not correct deficiencies in a pre-determined time frame, the AMC 
Executive Committee has the option of taking action against the site. Possible actions include, 
but are not limited to, suspending enrollment of new patients to AMC trials until deficiencies are 
corrected; recommending a decrease in funding to the site; and requiring specific training for site 
investigators or staff members. 


AMC # 042 (Version 7.0) 07/24/07 
NCI Version Date 07/24/07 
94 
APPENDIX XVII:  NOVARTIS SAE COVERSHEET 
 
 
 
SAE REPORT – IIRP 
 
Please fax to CS&E within 24 hours 
 
Fax: 1-888-299-4565 
 
(If you encounter problems with the fax transmission please call 1 (800) 882-6577) 
 
CONTACT INFORMATION 
 
From 
Number of pages* (including fax cover sheet) 
 
 
*Please remember to include a copy of the MedWatch form 
Phone Number 
Fax Number 
 
 
 
 
STUDY INFORMATION (please print) 
 
Investigator Name 
Trial Drug 
 
 
 
Study/ Protocol Number 
Patient ID/ Number 
Novartis # 
IRB # 
 
 
CASUALITY 
 
Serious Adverse Event 
Relationship to Study Drug 
 
□ Possibly suspected                       □ Not Suspected 
 
□ Possibly suspected                       □ Not Suspected 
 
□ Possibly suspected                       □ Not Suspected 
 
□ Possibly suspected                       □ Not Suspected 
 
□ Possibly suspected                       □ Not Suspected 
 
WAS THIS REPORT SENT TO THE FDA?   □ NO 
      
□ YES 
 
Date _____/_________/______ 
 
 
 
 
 
 
 
 
        (day)    (month)      (year)    
 
 
 
 
              use letter abv 
 
 
 __________________________________             ______________ 
INVESTIGATOR SIGNATURE 
Date 
 
 
 
SINA ID (internal use)