Clinical trial NCT01763606
Conditions: Cancer Patients First-ever Acute Ischemic Stroke
Keywords: Enoxaparin Aspirin stroke 12-264
Sponsor: Memorial Sloan Kettering Cancer Center
Start date: 2012-12-18; Completion date: 2019-04-03
Enrollment: 20 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Patients with cancer who develop stroke are at high risk for future strokes or other clotting events. These patients are routinely treated with medicines that thin their blood, including enoxaparin or aspirin. However, it is unclear which medicine is best and whether these medicines can be adequately studied in a clinical trial.

The purpose of this Phase I/II study is to determine if a clinical trial of different blood thinners in patients with cancer and stroke is possible. In addition, the study aims to compare the effects, good and/or bad, of enoxaparin with those of aspirin on patients with cancer and recent stroke.

Detailed description:

Arms: arm 1: Patients assigned to enoxaparin. arm 2: Patients assigned to Aspirin.
Interventions: intervention 1: Enoxaparin intervention 2: Aspirin
Intervention descriptions: intervention 1: Patients will be receive 6 months of subcutaneous enoxaparin (1 mg/kg BID with a maximum starting dose of 100 mg BID. Patients who weigh more than 100 kg will start at a dose of 100 mg BID; their subsequent dosing will be guided by hematology and may change. intervention 2: Patients will receive 6 months of oral aspirin (81 mg per day unless a higher dose is preferred by study physicians although the maximum acceptable dose will be 325 mg per day).

Protocol documents:
Prot_SAP_000.pdf: 
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A Pilot Trial of Enoxaparin versus Aspirin in Patients with Cancer and Stroke 
 
MSKCC THERAPEUTIC/DIAGNOSTIC PROTOCOL 
 
Principal 
Investigator/Department: 
Lisa DeAngelis, MD 
Neurology 
Co-Principal 
Investigator(s)/Department: 
Babak Navi, MD 
Neurology 
Investigator(s)/Department: 
Edward Avila, MD 
Elena Pentsova, MD 
Thomas Kaley, MD 
Alan Carver, MD 
Christian Grommes, MD 
Xi Chen, MD 
Craig Nolan, MD 
Antonio Omuro, MD 
Igor Gavrilovic, MD 
Ingo Mellinghoff, MD 
Adrienne Boire, MD PhD 
Mariza Daras, MD 
Eli Diamond, MD 
Jacqueline Stone, MD 
Alison Gilgan, NP 
Marcel Smith, NP 
Malbora Perezic-Mustafa, RN 
Mary Elizabeth Davis, RN 
Katherine Panageas, DrPH 
Bianca Santomasso, MD PhD 
Richard Phillips, MD PhD 
Efstathia Tzatha, MD 
Neurology 
Neurology 
Neurology 
Neurology 
Neurology 
Neurology 
Neurology, 
Neurology 
Neurology, 
Neurology 
Neurology 
Neurology 
Neurology 
Neurology 
Nursing 
Nursing 
Nursing 
Nursing 
Epidemiology and Biostatistics: 
Biostatistics 
Neurology 
Neurology 
Neurology 
Consenting 
Professional(s)/Department: 
Lisa DeAngelis, MD 
Babak Navi, MD 
Edward Avila, MD 
Elena Pentsova, MD 
Thomas Kaley, MD 
Alan Carver, MD 
Milan Chheda, MD 
Christian Grommes, MD 
Xi Chen, MD 
Craig Nolan, MD 
Antonio Omuro, MD 
Igor Gavrilovic, MD 
Ingo Mellinghoff, MD 
Eli Diamond, MD 
Mariza Daras, MD 
Neurology 
Neurology 
Neurology 
Neurology 
Neurology 
Neurology 
Neurology 
Neurology 
Neurology 
Neurology 
Neurology 
Neurology 
Neurology 
Neurology 
Neurology 


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Adrienne Boire, MD PhD 
Bianca Santomasso, MD PhD 
Jacqueline Stone, MD 
Richard Phillips, MD PhD 
Efstathia Tzatha, MD 
Neurology 
Neurology 
Neurology 
Neurology 
Neurology 
 
 
 
 
 
Participating Institution(s) 
PI’s Name 
Site’s Role 
New York-Presbyterian Hospital/Columbia 
University Medical Center 
Randolph  Marshall, 
MD 
Data Collection 
Weill Cornell Medical Center 
Babak Navi, MD 
Data Collection 
 
 
OneMSK Sites 
Manhattan 
West Harrison 
Basking Ridge 
Commack 
 
 
 
 
 
Please Note: A Consenting Professional must have completed the mandatory Human 
Subjects Education and Certification Program. 
 
Memorial Sloan-Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 


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MEMORIAL SLOAN-KETTERING CANCER CENTER 
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Table of Contents 
 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA ..................................................................... 4 
 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS .............................................................................. 4 
 
3.0 
BACKGROUND AND RATIONALE ................................................................................... 4 
 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION............................................................ 5 
 
4.1 
Design............................................................................................................................. 5 
 
4.2 
Intervention ..................................................................................................................... 5 
 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS ........................................................................... 6 
 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY ........................................................................... 6 
 
6.1 
Subject Inclusion Criteria................................................................................................. 6 
 
6.2 
Subject Exclusion Criteria ............................................................................................... 7 
 
7.0 
RECRUITMENT PLAN ....................................................................................................... 7 
 
8.0 
PRETREATMENT EVALUATION ...................................................................................... 9 
 
9.0 
TREATMENT/INTERVENTION PLAN................................................................................ 9 
 
10.0 EVALUATION DURING TREATMENT/INTERVENTION ................................................. 10 
 
11.0 TOXICITIES/SIDE EFFECTS ........................................................................................... 11 
 
12.0 CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT ..................... 13 
 
13.0 CRITERIA FOR REMOVAL FROM STUDY ..................................................................... 14 
 
14.0 BIOSTATISTICS .............................................................................................................. 14 
 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES15 
 
15.1 Research Participant Registration ................................................................................. 15 
 
15.2 Randomization .............................................................................................................. 17 
 
16.0 DATA MANAGEMENT ISSUES ....................................................................................... 17 
 
16.1 Quality Assurance ......................................................................................................... 20 
 
16.2 Data and Safety Monitoring ........................................................................................... 21 
 
17.0 PROTECTION OF HUMAN SUBJECTS .......................................................................... 23 
 
17.1 Privacy .......................................................................................................................... 24 
 
17.2 Serious Adverse Event (SAE) Reporting ....................................................................... 24 
 
17.2.1 ................................................................................................................................... 25 
 
18.0 INFORMED CONSENT PROCEDURES .......................................................................... 26 
 
19.0 REFERENCES ................................................................................................................. 27 
 
20.0 APPENDICES .................................................................................................................. 30 


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1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 
 
This is a phase I/II pilot, randomized trial that will compare enoxaparin to aspirin for the 
prevention of recurrent thromboembolic events in patients with active systemic cancer and 
acute ischemic stroke. The goal of this study is to determine whether a randomized trial 
comparing these different antithrombotic strategies in patients with cancer and ischemic 
stroke is safe and feasible. Patients will be randomized to six months of enoxaparin or aspirin 
and followed closely for thromboembolic and bleeding events. 
 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS 
 
Primary aim: To determine whether a randomized trial comparing enoxaparin to aspirin for 
the prevention of recurrent thromboembolic events in patients with active systemic cancer 
and ischemic stroke is feasible. All potentially eligible patients will be rigorously screened for 
and approached by a study investigator for enrollment. The primary feasibility outcome will 
be defined as an enrollment rate of ≥30% for eligible patients. Secondary feasibility 
outcomes will be defined as a dropout or crossover rate of ≤20% for randomized patients, 
and adherence to study drug in ≥75% of enrolled patients. 
 
Secondary aims: (1) To obtain a preliminary evaluation of the safety of enoxaparin and 
aspirin in patients with systemic cancer and acute ischemic stroke. The safety endpoints will 
consist of intracranial hemorrhage, symptomatic intracranial hemorrhage, major bleeding, 
and death. (2) To obtain preliminary data on the efficacy of enoxaparin and aspirin in patients 
with cancer and ischemic stroke to enable accurate sample size calculations for a future 
multi-center trial. Secondary efficacy endpoints will include recurrent ischemic stroke, other 
thromboembolic events and several functional outcome assessments. 
 
3.0 
BACKGROUND AND RATIONALE 
 
Cerebrovascular disease is second only to metastases as a CNS manifestation of cancer 
(Graus et al 1985). Ischemic strokes, which account for half of these events, frequently arise 
from unusual stroke mechanisms due to acquired hypercoagulability from the cancer or 
complications of its therapy (Graus et al 1985; Seok et al 2010; Navi and Segal 2008). Many 
factors contribute to this prothrombotic state, including secreted procoagulant substances, 
inflammatory cytokines, increased affinity between tumor cells and blood, endothelial 
dysfunction, and abnormal protein metabolism (Caine et al 2002). In the largest autopsy- 
based series to date, the two leading causes of symptomatic ischemic stroke were marantic 
endocarditis and cerebral intravascular coagulation, both manifestations of hypercoagulability 
(Graus et al 1985). Based on these histopathologic correlations and few anecdotal case 
series, some experts and guidelines recommend anticoagulation as the first-line treatment 
for secondary stroke prevention in patients with cancer and ischemic stroke (Salem et al 
2004; Rogers 2010). In addition, many physicians favor heparin over warfarin because of 
data from small case series and extrapolation from a trial on venous thromboembolic disease 
(Graus et al 1985; Lee et al 2003). 
 
Conversely, most modern clinical series of patients with systemic cancer and ischemic stroke 
have not supported a prominent role of hypercoagulability in stroke pathophysiology. In fact, 
one large observational study found coagulopathy and marantic endocarditis to account for 


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dipyridamole, or warfarin) immediately after stroke onset as part of routine medical care will 
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only 12% and 3% of all strokes, respectively (Cestari et al 2004). Another similar study found 
atherosclerosis to be the most common cause of ischemic stroke in patients with malignancy, 
and thus proposed antiplatelet agents to be sufficient therapy for most patients with cancer 
and stroke (Chaturvedi et al 1994). Furthermore, many historic indications for anticoagulation 
in ischemic stroke in the non-cancer population have not been supported by randomized 
trials because any reductions in stroke risk were offset by an increased risk of bleeding 
(Chimowitz et al 2005; Mohr et al 2001). Given the conflicting observational data and the 
increased risk of bleeding from bone marrow suppression and frequent invasive procedures 
in patients with cancer, a clinical trial is necessary to determine the optimal secondary stroke 
prevention regiment (e.g., anticoagulants or antiplatelet agents) for these patients. 
 
Our proposed study would be a significant step in optimizing the management of patients 
with systemic cancer and acute ischemic stroke because it would determine if a clinical trial 
comparing anticoagulant (enoxaparin) and antiplatelet therapy (aspirin) in patients with 
cancer and stroke is feasible, and it would provide a preliminary evaluation of the safety of 
these different strategies. The former question is particularly germane as patients with 
cancer may be hesitant to enroll in a secondary stroke prevention trial because of concerns 
over potential medication interactions and the dynamic nature of oncological care. Once 
completed, the findings from this study would streamline the methodological planning and 
sample size calculations for a larger, multi-center trial that would conclusively determine the 
ideal antithrombotic regiment for these patients. Such a trial would enhance physician 
practice patterns, ultimately leading to decreased morbidity and improved patient outcomes. 
 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
 
4.1 
Design 
 
This will be a pilot, randomized, clinical trial comparing enoxaparin to aspirin for the 
prevention of recurrent ischemic stroke and other thromboembolic events in patients with 
active systemic cancer. 
 
This study will allow us to determine whether a larger, fully-powered, efficacy trial comparing 
these different anti-thrombotic strategies in patients with cancer and ischemic stroke would 
be feasible. 
 
4.2 
Intervention 
 
We will recruit 40 adult patients with active systemic cancer who have presented to Memorial 
Sloan-Kettering Cancer Center (MSKCC), Weill Cornell Medical Center (WCMC) or New 
York-Presbyterian Hospital (NYPH)/Columbia University Medical Center (CUMC) as an 
inpatient or outpatient with an acute ischemic stroke within the prior four weeks.  Patients will 
be randomly assigned to receive 6 months of subcutaneous enoxaparin (1 mg/kg BID with a 
maximum starting dose of 100 mg BID) or 6 months of oral aspirin (81 mg per day unless a 
higher dose is preferred by study physicians because of a concomitant medical condition, 
such as coronary artery disease, although the maximum acceptable dose will be 325 mg per 
day). 
 
Patients who receive anti-thrombotic agents (e.g., enoxaparin, aspirin, clopidogrel, 


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deficit(s) with MRI evidence of acute ischemia in a referable location, and no clinical
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be eligible for enrollment as long as they can be randomized within 4 weeks of stroke onset 
and can receive study drug within 1 week of randomization. 
 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS 
 
Enoxaparin sodium (Lovenox ®)  is a low-molecular weight heparin that is approved by the 
FDA for the prevention of deep vein thrombosis in abdominal surgery, total hip and knee 
replacement, and medical patients with immobility during acute illness; the treatment of acute 
deep vein thrombosis or pulmonary embolism; the prophylaxis of ischemic complications of 
unstable angina or non-Q-wave myocardial infarction; and the treatment of acute ST- 
segment elevation myocardial infarction. It is also frequently used “off-label” for the 
prevention of recurrent stroke and other thromboembolic events in patients with ischemic 
stroke and hypercoagulable states, including active cancer. 
 
Enoxaparin is manufactured by Sanofi-Aventis U.S., Inc. and is derived from the intestinal 
mucosa of pigs. It is available as prefilled syringes (30 mg/0.3 ml, 40 mg/0.4 ml), graduated 
prefilled syringes (60 mg/0.6 ml, 80 mg/0.8 ml, 100 mg/1 ml, 120 mg/0.8 ml, 150 mg/1 ml), or 
multiple dose vials (300 mg/3.0 ml). It is administered subcutaneously once or twice a day 
depending on the indication. Commercially available drug will be used for this study. 
 
Aspirin (originally Bayer ®), also known as acetylsalicylic acid, is an over-the-counter 
salicylate drug manufactured by numerous pharmaceutical companies, that has an 
antiplatelet effect by inhibiting the production of thromboxane. It is approved by the FDA for 
the prevention and treatment of stroke, coronary artery disease, and myocardial infarction, as 
well as the treatment of rheumatological conditions and pain. It is administered orally or per 
rectum, and is available in chewable, enteric-coated, immediate-release, and controlled- 
relase forms; available doses include 60, 81, 120, 162, 200, 300, 325, 500, 650, 800, and 
975 mg. For this study, subjects will be told to preferentially purchase regular immediate- 
release 81 mg tabs for oral use . However, other oral formulations (e.g., chewable, enteric- 
coated, or controlled-release forms) and higher doses up to 325 mg per day will also be 
allowed. Commercially available drug will be used for this study. 
 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY 
 
Any adult patient with active systemic cancer diagnosed with acute ischemic stroke at the 
main MSKCC campus, any of MSKCC’s outpatient centers, WCMC or at NYPH/CUMC,within 
the prior four weeks would be eligible. 
 
 
 
6.1 
Subject Inclusion Criteria 
 
• 
18 to 85 years of age. 
• 
Active cancer, defined as a pathologic diagnosis of or treatment for any cancer, other 
than basal-cell or squamous-cell carcinoma of the skin, within the past six months; or 
patients with known recurrent or metastatic disease within the past six months. 
A pathology report issued at the enrolling site confirming the diagnosis of cancer is 
required for study enrollment. 
• 
Acute ischemic stroke within the prior four weeks, defined as a new neurologic 


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or radiologic indication of a non-cerebrovascular mimic, such as a brain metastasis, 
as the etiology of the deficit(s). 
 
6.2 
Subject Exclusion Criteria 
 
• 
Inability to get brain MRI 
• 
Known malignant primary brain tumor. 
• 
Diagnosis of intracranial hemorrhage within the past 3 months, including intratumoral 
hemorrhage into brain metastases from a systemic cancer 
• 
Active or serious bleeding within two weeks of enrollment. 
• 
Patient condition associated with a high risk of bleeding such as recent surgery or 
peptic ulcer disease. 
• 
Clear indication for anticoagulation (e.g., atrial fibrillation) anticipated during the study 
period. 
• 
Clear indication for antiplatelet agents (e.g., cardiac stents); a patient receiving 
aspirin for primary prevention prior to index stroke may be enrolled as long as study 
investigators believe it would be safe for the patient to stop aspirin if the patient was 
randomized to the enoxaparin arm. 
• 
Active bleeding diathesis. 
• 
Platelet count of ≤ 70,000/mm3, an international normalized ratio (INR) > 1.6, or a 
partial thromboplastin time (PTT) > 40 seconds. 
• 
Known allergy to heparin or aspirin or a history of heparin induced thrombocytopenia. 
• 
Serum creatinine > 2 mg/dl. 
• 
AST or ALT > 200 U/L. 
• 
Hemoglobin < 8 gm/dl 
• 
Symptomatic carotid stenosis. 
• 
Active pregnancy. 
• 
Life expectancy < 1 month or current hospice care 
• 
Unavailability for follow-up. 
 
 
7.0 
RECRUITMENT PLAN 
 
A total of 40 patients will be recruited from the Neurology inpatient and consultation 
censuses at the main MSKCC campus, MSKCC outpatient centers, WCMC and 
NYPH/CUMC through screening conducted by research and clinical staff during normal 
business hours. MSKCC is expected to accrue 6 patients per year, while CUMC and WCMC 
are each expected to accrue 4 patients per year. All patients enrolled into the trial must sign 
written informed consent. There are no gender or racial restrictions. 
 
In order to satisfy all of the study’s feasibility endpoints, MSKCC, WCMC and NYPH/CUMC 
staff will screen all ischemic stroke patients and will systematically record the total number of 
patients with ischemic stroke, the total number with ischemic stroke and active systemic 
cancer, the total number that are eligible for the trial (and if not eligible the reason(s) why), 
the total number approached for enrollment, and the total number enrolled. 
 
Patients who drop out of the study before the 3-month timepoint for reasons other than a 
safety or efficacy event or death will be replaced. 
 
Potential research subjects will be identified by a member of the patient’s treatment team, a 
protocol investigator, or research team. If the investigator is a member of the treatment team, 


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he or she will screen their patient’s medical records for suitable research study participants 
and discuss the study and their potential for enrolling in the research study. Potential 
subjects contacted by their treating physician will be referred to the investigator/research 
staff of the study. 
 
The principal investigators may also screen the medical records of patients with whom they 
do not have a treatment relationship for the limited purpose of identifying patients who would 
be eligible to enroll in the study and to record appropriate contact information in order to 
approach these patients regarding the possibility of enrolling in the study. 
 
During the initial conversation between the investigator/research staff and the patient, the 
patient may be asked to provide certain health information that is necessary to the 
recruitment and enrollment process. The investigator/research staff may also review portions 
of their medical records in order to further assess eligibility. They will use the information 
provided by the patient and/or medical record to confirm that the patient is eligible and to 
contact the patient regarding study enrollment. If the patient turns to to be ineligible for the 
research study, the research staff will destroy all information collected on the patient during 
the initial conversation and medial records review, except for any information that must be 
maintained for screening log purposes. 
 
In most cases, the initial contact with the prospective subject will be conducted either by the 
treatment team, investigator, or the research staff working in consultation with the treatment 
team. The recruitment process outlined presents no more than minimal risk to the privacy of 
the patients who are screened and minimal PHI will be maintained as part of a screening log. 
For these reasons, we seek a (partial) limited waiver of authorization for the purposes of (1) 
reviewing medical records to identify potential research subjects and obtain information 
relevant to the enrollment process; (2) conversing with patients regarding possible 
enrollment; (3) handling of PHI contained within those records and provided by the potential 
subjects; and (4) maintaining information in a screening log of patients approached (if 
applicable). 
 
This limited waiver will apply only to MSKCC. Any participating sites that require a limited 
waiver must obtain it from their own local IRB/Privacy Board (PB) via a separate protocol 
addendum or request. It is the responsibility of the MSKCC staff to confirm the participating 
data collection site(s) have a limited waiver approved by their local IRB(s)/PBs. 
 
8.0 
PRETREATMENT EVALUATION 
 
The following studies are required within four weeks of registration, all of which are routinely 
performed as part of standard practice in patients with active cancer and acute stroke: 
 
• 
Complete history and physical exam including neurological exam. 
• 
Modified Rankin Scale. 
• 
NIH Stroke Scale. 
• 
Karnofsky Performance Status Scale. 
• 
Height and weight. 
• 
CBC including WBC differential and platelet count. 
• 
Coagulation studies, including PT, PTT, and INR. 


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• 
Serum D-Dimer and fibrinogen level. 
• 
Comprehensive chemistry panel (see appendix F). 
• 
Electrocardiogram (EKG). 
• 
Carotid artery imaging with MRA, CTA, or ultrasound. 
• 
MRI scan of the brain (contrast is not required). 
 
The complete history and physical examination, height and weight, CBC, coagulation 
studies, comprehensive chemistry panel (see appendix F), EKG, carotid artery imaging, and 
MRI of the brain must be performed before registration, while the other required studies may 
be performed after registration as long as they are done within two weeks after the date of 
registration. 
 
9.0 
TREATMENT/INTERVENTION PLAN 
 
9.1 Subcutaneous Enoxaparin 
 
Half the study patients (n=20) will be randomized to subcutaneous enoxaparin. This medicine 
will be injected twice daily at a dose of 1 mg/kg with a maximum starting dose of 100 mg BID. 
Patients who weigh more than 100 kg will start at a dose of 100 mg BID; their subsequent 
dosing will be guided by hematology and may change. Treatment is routine, and should 
begin within 7 days of randomization (either inpatient or outpatient) and continue for 6 
months. A registered nurse will teach patients randomized to the enoxaparin arm how to 
perform subcutaneous injections; in cases of significant patient handicap, a surrogate of the 
patient will be taught to perform the injections. 
 
9.2 Oral Aspirin 
 
The other half of study patients (n=20) will be randomized to oral aspirin. The medicine will 
be administered daily at a dose of 81 mg unless a concomitant medical condition, such as 
coronary artery disease, dictates a higher dose of aspirin to be administered instead 
(maximum dose 325 mg daily). Treatment is routine, and should begin within 7 days of 
randomization (either inpatient or outpatient) and continue for 6 months. 
 
9.3 Medications to Avoid 
 
The following medications should be avoided during the course of the study in order to 
reduce the risk of bleeding side effects: clopidogrel (Plavix®), prasugrel (Effient®), ticlopidine 
(Ticlid®), cilostazol (Pletal®), dipyridamole (Persantine®, Aggrenox®), ticagrelor (Brilinta®), 
abciximab (Reopro®), antithrombin (Atryn®), antithrombin III (Thrombate III®), argatroban 
(Argatroban®), dabigatran (Pradaxa®), dalteparin (Fragmin®), danaparoid (Orgaran®), 
Desirudin (Iprivask®), fondaparinux (Arixtra®), lepirudin (Refludan®), tinzaparin (Innohep®), 
warfarin (Coumadin®), rivaroxaban (Xarelto®), apixaban (Eliquis®), urokinase 
(Abbokinase®, Kinlytic®), reteplase (Retavase®), and teneceteplase (TNKase®), 
 
Alteplase (Activase®) should also be avoided in patients randomized to the enoxaparin arm; 
however, patients randomized to the aspirin arm who develop an acute ischemic stroke could 
receive alteplase for thrombolysis if they fulfill all standard eligibility criteria. 


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10.0 EVALUATION DURING TREATMENT/INTERVENTION 
 
Routine blood tests consisting of CBC, comprehensive metabolic panel (see appendix F), 
PT, PTT, INR, D-Dimer, and fibrinogen will be performed at 2 weeks (+/- 4 days) and 1 
month (+/- 4 days) after treatment initiation for safety and efficacy purposes in accordance 
with standard clinical practice. 
 
Patients will be evaluated by a study investigator at 1 month (+/- 1 week), 3 months (+/- 1 
week), and 6 months (+/- 1 week) after treatment initiation by clinical visit, which can occur at 
MSKCC’s main hospital and Basking Ridge, Commack and West Harrison regional network 
sites, WCMC, and NYPH/CUMC. The clinical visit will consist of history taking and physical 
examination, and will assess for adherence to study drug (using the 8-point Morisky 
medication adherence scale) and any symptoms or signs of clinical thromboembolism, 
bleeding episodes, or serious adverse events. The study investigator will also assess 
functional outcomes by performing a modified Rankin Scale (mRS), a National Institute of 
Health Stroke Scale (NIHSS), and a Karnofsky Performance Status Scale (KPSS). 
Investigators administering the mRS and NIHSS will be certified to do so. If patients are 
unavailable for an in-person follow-up or their medical condition prohibits them from 
participating, then the patient or their surrogate will be interviewed instead by phone by one 
of the study investigators for outcome measures. Telephone interviews will consist of the 
same assessments as the clinical visit except that there will be no physical examination or 
NIHSS, as these interventions can only be performed in person. 
 
The 8-point Morisky medication adherence scale (MMAS) is a validated and reliable drug 
adherence scale that is commonly used to monitor adherence over the course of a treatment 
(see appendix A) (Morisky et al 2008). The scale consists of eight questions on medication- 
taking behavior and was originally developed to evaluate patient adherence to blood 
pressure medicines but has been effectively used for numerous chronic disorders. Response 
choices are yes/no for items 1 through 7, while item 8 consists of a 5-point Likert scale. For 
items 1 through 7, each response “no” equals 1 point and each response “yes” equals 0 
points, except for item 5, in which a “yes” response equals 1 point and a “no” response 
equals 0 points. For item 8, if a patient chooses response “0”, they receive 1 point, while 
responses “1”, “2”, “3”, and “4” equate to 0.75, 0.5, 0.25, and 0 points, respectively. The 
MMAS will be completed by patients at all scheduled clinical visits (1, 3, and 6 months) and 
study drug adherence will be defined as a mean total score of ≥6 as previous studies have 
demonstrated this cutpoint to effectively differentiate between low and medium or high 
adherence. 
 
The mRS is a validated and widely used neurological disability scale that measures patients’ 
ability to perform activities of daily living. The score ranges from 0 to 6, with 0 indicating no 
symptoms and 6 representing death (see appendix B). Patients’ scores will be calculated by 
a study investigator shortly after the interview with the assistance of a structured 
questionnaire (for reference only). All study investigators performing the mRS will have 
completed an instructional course and be certified in calculating the score prior to the start of 
the project. The score’s strengths are its simplicity, reliability, and easy applicability. 
 
The NIHSS is a validated and commonly used stroke severity scale, ranging from 0 (normal 
exam) to 42 (coma and quadriplegia) (Brott et al 1989; Goldstein et al 1997). It involves a 


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bedside neurological examination that assesses multiple components of patients’ 
neurological function including level of consciousness, speech and language, eye 
movements, visual fields, motor strength, sensory function, and coordination of limbs (see 
appendix D). The test takes approximately 10 minutes to complete—5 minutes to administer 
and another 5 minutes to record the scores properly. All study investigators performing the 
NIHSS will have completed an instructional course and be certified in calculating the scale 
prior to study initiation. The scale will be used to determine patients’ level of impairment 
before and after treatment with the study drugs. 
 
The KPSS is a reliable and commonly used performance scale that quantifies cancer 
patients’ functional status (Karnofsky and Burchenal 1949; Ma et al 2010). The score is often 
used by oncologists to assess cancer patients’ eligibility for clinical trials, estimate prognosis, 
and predict toxicity and likelihood of response to therapy. The score ranges from 100 to 0, 
where 100 is normal with no signs of disease or patient complaints and 0 is death (see 
appendix E). Patients’ scores will be calculated by a study investigator shortly after the 
neurologic examination that will evaluate patients’ activity level and need for assistance. All 
study investigators performing the score will work primarily in a cancer hospital and will be 
familiar with the score and its calculation. 
 
Patients randomized to the aspirin arm who require deep vein thrombosis prevention during 
the study may concomitantly receive prophylactic doses of heparin or other anticoagulants, if 
necessary. However, if patients develops a new indication for treatment dose anticoagulation 
within 6 months of study drug initiation, they will be removed from study drug, and further 
anti-thrombotic therapy, if any, will be dictated by their treating physicians. These patients 
will, however, continue to be followed by study investigators to one-year for survival and 
safety/efficacy outcomes via electronic medical records. 
 
At 6 months, patients will have completed their randomized study treatment. Any subsequent 
anti-thrombotic therapy will be dictated by their treating physicians and can include 
enoxaparin, aspirin, or another medicine. However, patients will continue to be followed by 
study investigators to one-year for survival and safety/efficacy outcomes via electronic 
medical records. 
 
Additionally, if patients develop a safety or efficacy outcome of interest within 6 months of 
treatment initiation, they will be removed from study drug, and further anti-thrombotic 
therapy, if any, will be dictated by their treating physicians. However, these patients will also 
continue to be followed by study investigators to one-year for survival and other outcomes 
via scheduled visits at 1, 3, and 6 months and electronic medical records from 6 months to 1 
year. 
 
11.0 TOXICITIES/SIDE EFFECTS 
 
The greatest risk to patients is hemorrhage from study drugs, particularly the low molecular 
weight heparin enoxaparin. This medication has never been systematically assessed in 
cancer patients with acute stroke, so rates of major hemorrhage must be estimated from 
studies of patients with cancer or stroke in isolation. 
 
The low molecular weight heparin, dalteparin, was associated with a 6% 6-month rate of 
major bleeding but only one case (0.3% of cohort) of intracranial hemorrhage in a large 


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randomized trial of patients with cancer and deep vein thrombosis (Lee et al 2003). Low 
molecular weight heparin has also been associated with a slightly increased risk of major 
hemorrhage in stroke trials performed in the general population (Bath et al 2001; TOAST 
investigators 1998). However, cancer patients are intrinsically hypercoagulable, so a small 
excess risk of major hemorrhage may be outweighed by reduced rates of thromboembolism. 
Furthermore, despite little supportive data, anticoagulation is routinely used for the treatment 
of ischemic stroke in patients with cancer, highlighting the need for a trial to assess the 
safety and feasibility of this practice. 
 
Aspirin use is also associated with a small increased risk of systemic and intracranial 
hemorrhage (1-2% overall rate of major bleeding, mostly due to gastrointestinal 
hemorrhages); however, its cardiovascular benefits clearly outweigh these risks (CAST 
Collaborative group 1997; IST Collaborative group 1997). 
 
If intracranial hemorrhage or major bleeding occurs (see definitions in section 12.0), the 
patient’s study drug (enoxaparin or aspirin) will be discontinued, and the patient will be 
referred for emergency medical evaluation. Furthermore, dose modifications will not be 
allowed for participants experiencing these major side effects while in this study. Therefore, 
any unacceptable toxicity reported by a participant will be considered reason for removal 
from the study, unless otherwise indicated by the MSKCC principal and/or co-principal 
investigator. 
 
In the event of minor bleeding or other minor adverse events, the study drug can be held 
temporarily at the discretion of the treating physician. In such circumstances, the study drug 
should be restarted at a later time point when deemed appropriate by the treating physician. 
Adverse events will be graded using version 4.0 of the NCI Common Terminology Criteria for 
Adverse Events. 
Other potential risks to patients from study drugs include: 
Enoxaparin 
 
• 
<10%: injection site ecchymosis and hematoma, easy bleeding from minor cuts or 
wounds, elevated liver enzymes. 
• 
<5%: anemia, nausea or vomiting, diarrhea, thrombocytopenia. 
• 
<1%: allergic reaction, heparin-induced thrombocytopenia. 
 
Aspirin 
 
• 
<10%: easy bleeding from minor cuts or wounds. 
• 
<5%: dyspepsia, nausea or vomiting, dizziness. 
• 
<1%: allergic reaction, renal dysfunction, hearing loss or tinnitus. 
 
If a patient is discovered at any time to have a platelet count < 70,000/mm3, hemoglobin < 7 
gm/dl, PTT > 80 seconds, INR > 3, or creatinine > 2.5 mg/dl because of chemotherapy or 
other medical reasons, then the patient’s study drug will be temporarily discontinued and 
weekly, relevant blood tests will be performed. The study drug will only be reinstituted if the 
abnormal laboratory values return to acceptable levels as deemed by the principal and/or co- 
principal investigator. Treating physicians will also be encouraged to contact study 


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investigators whenever there is concern for a heightened bleeding risk, so that more vigilant 
monitoring is performed. 
 
To ensure that the study medications are not excessively increasing the rates of serious 
adverse events, an external data and safety monitoring board as detailed in Section 16.2 will 
periodically review all potential adverse events and will have the authority to stop further 
enrollment into the study if unacceptable rates of hemorrhage or death are discovered. 
 
12.0 CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
 
Primary safety and secondary efficacy outcomes will be assessed for by a study investigator 
at 1 month (+/- 1 week), 3 months (+/- 1 week), and 6 months (+/- 1 week)  after initiation of 
treatment by interviewing the patient and/or surrogate via an in-person visit or phone 
conversation and by reviewing any relevant medical records. The occurrence of an outcome 
will be dichotomized as yes or no, although a single patient may have multiple outcomes. 
The outcomes of interest are defined as follows: 
 
Safety Outcomes 
 
Intracranial Hemorrhage: Acute extravasation of blood into the brain parenchyma, 
subarachnoid space, subdural space, or epidural space as demonstrated by neuroimaging, 
surgical exploration, or autopsy. 
 
Symptomatic Intracranial Hemorrhage: Intracranial bleeding associated with any clinical 
deterioration or associated with death. 
 
Major Bleeding: Bleeding associated with death; any intracranial hemorrhage; or a systemic 
hemorrhage requiring hospitalization, blood transfusion, or surgery. 
 
Efficacy Outcomes 
 
Ischemic Stroke: New neurologic deficit(s) with CT or MRI evidence of acute ischemia in a 
referable location, and no clinical or radiologic indication of a non-cerebrovascular mimic as 
the etiology of the deficit(s). 
 
Transient Ischemic Attack: Transient neurologic deficit lasting less than 24 hours, attributed 
to focal brain ischemia without evidence for another etiology or cerebral infarction on CT or 
MRI. 
 
Myocardial Infarction: Any combination of two of the following three criteria: chest pain, 
elevated cardiac enzymes (as per specific laboratory guidelines), or dynamic ECG changes 
consistent with ischemia. 
 
Deep Vein Thrombosis: Thrombosis of the deep venous circulation diagnosed via Doppler 
examination, magnetic resonance venography, or spiral CT. 
 
Pulmonary Embolus: Thrombosis of the pulmonary circulation diagnosed by spiral CT of the 
chest or V/Q scan. 
 
Systemic Arterial Thrombosis: An acute vascular occlusion of an extremity or organ, 


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documented by means of imaging, surgery, or autopsy. 
 
Though our primary objective is to assess the safety and feasibility of the interventions, we 
will also assess functional outcomes at approximately 1 month, 3 months, and 6 months after 
initiation of treament using the mRS score, NIHSS, and KPSS. 
 
13.0 
CRITERIA FOR REMOVAL FROM STUDY 
 
If at anytime the patient develops unacceptable toxicity such as major bleeding, intracranial 
hemorrhage, or a severe allergic reaction, he or she will be removed from the study. 
 
If at anytime the patient is found to be ineligible for the protocol as designated in the section 
on Criteria for Subject Eligibility (i.e., a change in diagnosis), the patient will be removed from 
the study. 
 
If at anytime the patient withdraws consent for continued participation or dies, he or she will 
be removed from the study. 
 
14.0 
BIOSTATISTICS 
 
Patients will be randomized at registration to receive 6 months of subcutaneous enoxaparin 
or 6 months of oral aspirin. Please see section 15.2 for details about this process. 
 
The enrollment rate will be the proportion of eligible patients who enroll in the study. The 
study will be considered feasible if the lower bound of the 95% confidence interval (CI) of the 
enrollment rate exceeds 30%. Therefore, our feasibility criterion will be met if 40 of the first 
100 (40%; 95% CI, 30.3-50.3%) screened and eligible patients enroll. However, even if our 
feasibility criterion is not met, we will continue to target up to another 50 patients (for a total 
of 150 targeted patients) in an attempt to enroll 40 patients and thus obtain sufficient 
preliminary data on safety outcomes. Assuming at least a 30% recruitment rate in eligible 
patients and a 10% dropout rate among randomized patients, and given that MSKCC, 
WCMC and CUMC care for approximately 280 total patients with cancer and recent stroke 
per year, and roughly 15% of these patients would be eligible for this trial (based on 2015 
data and the current eligibility criteria), we anticipate a total enrollment period of 5 years for 
our pre-planned sample size of 40 patients. Therefore, since the trial started January 2013, 
we anticipate that it will be completed by July 2018. 
 
Because this is a pilot trial, the main aim of the study will be to assess the feasibility of 
enrollment and randomization and the safety of the intervention regimens. However, several 
secondary efficacy outcomes will also be assessed to enable accurate sample size 
calculations for a future, larger, multi-center trial that will be sufficiently powered to detect 
clinically relevant differences in efficacy outcomes. All outcomes will be assessed for 
occurrence approximately at 1 month, 3 months, and 6 months after initiation of the study 
drug, and are defined in detail in the Criteria for Therapeutic Response/Outcome 
Assessment section. 
 
The primary feasibility outcome will be the enrollment rate among eligible patients (i.e., 
screened patients that fulfill all subject inclusion and exclusion criterion regardless of whether 
they are approached for enrollment by a study investigator); our target enrollment rate is 


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≥30%. Patients who enroll into the study but then dropout or crossover will still be considered 
successfully enrolled. 
 
Secondary feasibility outcomes will be the dropout or crossover rate among randomized 
patients and the study drug adherence rate among enrolled patients; the target dropout or 
crossover rate is ≤20% and the target adherence rate is ≥75%. Study drug adherence is 
considered a dichotomous variable for individual patients in this study and will be determined 
by the 8-point MMAS. Patients whose mean total MMAS score is ≥6 will be considered 
adherent. As noted in section 7.0, patients who drop out of the study before the 3-month 
timepoint for reasons other than a safety or efficacy event or death will be replaced. 
 
The primary safety outcomes will consist of intracranial hemorrhage, symptomatic intracranial 
hemorrhage, major bleeding, and death. Because the study’s target sample size is small and 
our secondary aim is to only obtain preliminary data on the safety of study drugs (not to 
perform formal analysis of safety data), there will be no pre-specified stopping rule for this 
study. However, an external MSKCC data and safety monitoring board will periodically review 
all potential adverse events and will have the authority to stop further enrollment based on 
any safety concerns. 
 
Secondary efficacy outcomes will include: recurrent ischemic stroke; all strokes (ischemic or 
hemorrhagic); a thromboembolic event composite consisting of recurrent ischemic stroke, 
transient ischemic attack, myocardial infarction, deep vein thrombosis, pulmonary embolism, 
or systemic arterial thrombosis; the modified Rankin Scale at 1, 3 and 6 months (van Swieten 
et al 1988); the National Institute of Health Stroke Scale at 1, 3 and 6 months (Brott et al 
1989); and the Karnofsky Performance Status Scale at 1, 3 and 6 months. 
 
Descriptive statistics will be used to characterize the rates of eligibility, recruitment, 
randomization, dropout, and adherence. The chi-square test will be used to compare the 
rates of safety and efficacy outcomes between groups for dichotomous variables, and 
analysis of covariance (ANCOVA) will be used to evaluate differences in continuous 
variables over time accounting for pre-treatment values. Our primary analysis will use the 
intention-to-treat principle, but we will also perform a secondary as-treated analysis. 
Therefore, for our primary (intention-to-treat) analysis, outcomes will be analyzed according 
to patients’ randomized study drug, regardless of prior anti-thrombotic use in the period 
between stroke onset and study drug initiation or the duration of study drug. 
 
Since this is a pilot trial primarily intended to assess safety and feasibility, we will be 
underpowered to detect any significant differences between groups for our secondary 
efficacy outcomes. However, this pilot trial will enable us to better estimate event rates in our 
population, and thus more accurately perform sample size calculations in the future for a 
fully-powered trial. 
 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 
 
15.1 
Research Participant Registration 
 
Confirm eligibility as defined in the section 6.0, entitled Criteria for Patient/Subject Eligibility. 
Obtain informed consent, by following procedures defined in section 18.0, entitled Informed 


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Consent Procedures. 
 
During the registration process, registering individuals will be required to complete a protocol 
specific Eligibility Checklist. 
 
All participants must be registered through the Protocol Participant Registration (PPR) Office 
at Memorial Sloan-Kettering Cancer Center. PPR is available Monday through Friday from 
8:30am – 5:30pm at 646-735-8000. Registrations must be submitted via the PPR Electronic 
Registration System (http://ppr/). The completed signature page of the written consent/RA or 
verbal script/RA, a completed Eligibility Checklist and other relevant documents must be 
uploaded via the PPR Electronic Registration System. 
 
15.1.1 For Participating Sites 
 
 
Central registration for this study will take place at MSKCC. 
 
To complete registration and enroll a participant from another institution, the study staff at 
that site must contact the designated research staff at MSKCC to notify him/her of the 
participant registration. The site staff then needs to fax or email the registration/eligibility 
documents to: 
 
Benjamin Weill 
Fax: (646) 227-7243 
Email: weillb@mskcc.org 
 
The following documents must be sent for each enrollment within 24 hours of the informed 
consent form being signed: 
 
• The completed or partially completed MSKCC eligibility checklist 
• The signed informed consent and HIPAA Authorization form 
• Supporting source documentation for eligibility questions (laboratory results, pathology 
report, radiology reports, MD notes, physical exam sheets, medical history, prior 
treatment records, and EKG report). 
 
Upon receipt, the research staff at MSKCC will conduct an interim review of all documents. 
If the eligibility checklist is not complete, the patient will be registered PENDING and the site 
is responsible for sending a completed form within 30 days of the consent. 
 
If the eligibility checklist is complete, the participant meets all criteria, all source 
documentation is received, the participating site IRB has granted approval for the protocol, 
and the site is in good standing with MSKCC, the MSKCC research staff will send the 
completed registration documents to the MSKCC PPR Office to be enrolled as stated in 
section 15.1. The participant will be registered. 
 
Once eligibility has been established and the participant is registered, the participant will be 
assigned an MSKCC Clinical Research Database (CRDB) number (protocol participant 
number). This number is unique to the participant and must be written on all data and 
correspondence for the participant. This protocol participant number will be relayed back to 
study staff at the registering site via e-mail and will serve as the enrollment confirmation. 


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15.2 
Randomization 
 
After eligibility is established and consent is obtained, patients will be registered by MSKCC in 
the PPR system and randomized using the CRDB. The treatment group to which the 
participant was assigned to will be available right after registration, by calling the MSKCC 
PPR registry between the hours of 8:30 AM and 5:30 PM, Monday through Friday, or by login 
in the Clinical Research Database Web Client (CRDBi); randomization of eligible patients will 
only occur during these times. Randomization codes will be generated in the CRDB. 
 
Since patients with adenocarcinomas may be intrinsically more hypercoagulable than 
patients with other tumor types (Seok et al 2010), stratified blocked randomization will be 
undertaken to ensure similar numbers of patients with these carcinomas in each group. 
 
Participating sites will receive a formal notification about the randomization status as soon as 
this becomes available. 
 
16.0 DATA MANAGEMENT ISSUES 
 
A MSKCC Research Study Assistant (RSA) will be assigned to the study. The responsibilities 
of the RSA include project compliance, data collection, data abstraction and entry, data 
reporting, regulatory monitoring, problem resolution and prioritization, and coordination of 
activities amongst the protocol study team. 
 
All collected data will be entered into a secure, password-encrypted database at MSKCC 
(CRDB), which only key study personnel will have access to. Source documentation will be 
available to support the computerized patient record. 
 
16.0.1. Data and Source Documentation for Participating Sites 
 
Data 
The participating site(s) will enter data remotely into MSKCC’s internet-based Clinical 
Research Database, termed CRDBi-Multicenter. Standardized Case Report Forms (eCRFS) 
and data entry guidelines have been generated for this study. The site staff will receive 
CRDB training prior to enrolling its first patient. The participating site PI is responsible for 
ensuring these forms are completed accurately and in a timely manner. A schedule of 
required forms is shown in the table below. Participating sites will be responsible for 
completing eCRFs and submitting them to MSKCC per the designated timelines. 
 
Source Documentation 
Source documentation refers to original records of observations, clinical findings and 
evaluations that are subsequently recorded as data. Source documentation should be 
consistent with data entered into eCRFs. Relevant source documentation to be submitted 
throughout the study includes: 
 
• 
Baseline MRI that confirms evidence of acute ischemic stroke 
• 
A pathology report issued in the enrolling site confirming this diagnosis is required for 
study enrollment. 
• 
Treatment records 
• 
Required protocol assessment documents 
• 
Grade 3-5 toxicities/adverse events 
 
Source documentation should include a minimum of two identifiers to allow for data 


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verification. MSK will maintain the confidentiality of any subject-identifiable information it may 
encounter. 
 
16.0.2 Data and Source Documentation Submission for Participating Sites 
 
Participating sites should enter data directly into CRDBi-Multicenter and study-specific 
eCRFs. Source documentation should be sent to MSKCC at the contact provided below. 
Submissions should include a cover page listing all source documentation enclosed per 
participant. 
 
Department of Neurology Clinical Research Team 
Attn: Benjamin Weill, RSA 
633 3rd Avenue, 12th Floor 
New York, NY 10017 
weillb@mskcc.org 
Phone: 646-227-2610 
Fax: 646-227-2461 
 
Participating sites are required to keep copies of each form that is sent via postal mail. 
 
 
16.0.3 Data and Source Documentation Submission Timelines for Participating Sites 
 
Data and source documentation to support data should be transmitted to MSKCC according 
to the following chart: 


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Data and Source Submission Requirements and Timelines for Therapeutic Studies 
 
Baseline 
Treatment 
start 
Treatment 
day 15 
1 
month 
visit 
3 
month 
visit 
6 month 
visit/Off 
treatment 
 
 
Serious 
Adverse 
Events 
Survival 
Follow 
up/Off 
study 
Submission Schedule 
Source 
documentation 
Within 24 
hours (see 
section 
15.1.1) 
w ithin 14 days of visit 
Within 3 
days of 
event (see 
section 
17.2.1); 
updates to 
be submitted 
as available 
w ithin 14 
days of 
visit 
eCRF 
Within 7 
days of 
registration 
Required Forms 
Minimal Dataset: 
Patient Information 
X 
 
Minimal Dataset: 
Initial Disease Info 
X 
 
Minimal Dataset: 
Disease Status 
X 
 
X 
Minimal Dataset: 
Histology 
X 
 
Minimal Dataset: 
Outcome Info 
X 
X 
X 
 
Minimal Dataset: 
Patient Status 
X 
X 
X 
X 
X 
X 
 
X 
General Forms: 
Comorbidity 
X 
X 
X 
X 
X 
General Forms: 
Concomitant Drug 
X 
X 
X 
X 
 
X 
General Forms: 
Diagnostic Test 
X 
 
General Forms: 
Laboratory 
X 
X 
X 
 
General Forms: 
Pathology 
X 
 
General Forms: 
Physical Exam 
X 
X 
X 
X 
 
X 
General Forms: 
Prior Therapy 
X 
 
General Forms: 
Toxicity 
X 
X 
X 
X 
x X 
X 
General Forms: 
Treatment 
X 
X 
X 
X 
 
X 
General Forms: 
Hospitalization 
X 
X 
X 
General Forms: 
Serious Adverse 
Event 
 
X 


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Off-Study Requirements 
 
When a patient is taken off-study, any outstanding data and required source documentation 
are required to be sent to MSKCC no later than 14 calendar days after the off-study date. 
Failure to submit required forms in the timelines requested may result in suspension of 
accrual privileges at a given site until data is updated, and/or withholding of contract 
payments if applicable. 
 
The MSKCC PI may request from outside sites imaging documenting any PR or CR. 
 
16.0.4 Data Review and Queries for Participating Site Data 
 
Research staff at MSKCC will review data and source documentation as it is submitted. Data 
will be monitored against source documentation and discrepancies will be sent as queries to 
the participating sites. Queries will be sent by MSKCC Research staff twice a month. 
 
Participating sites should respond to data queries within 14 days of receipt. 
 
16.1 
Quality Assurance 
 
Weekly registration reports will be generated to monitor patient accruals and completeness 
of registration data. Routine data quality reports will be created to assess for any missing or 
inconsistent data. In addition, accrual rates and the extent and accuracy of outcome 
assessments and follow-up will be monitored periodically throughout the study period, and 
any potential issues will be immediately brought to the attention of the study team for 
discussion and rectification, if necessary. 
 
The study team will also perform random-sample data quality and protocol compliance audits 
at least two times per year to ensure the integrity of the data. 
 
16.1.1 Quality Assurance for Participating Sites 
 
Each site participating in the accrual of participants to this protocol will be audited by the staff 
of the MSKCC study team for protocol and regulatory compliance, data verification and 
source documentation. Audits may be accomplished in one of two ways: (1) selected 
participant records can be audited on-site at participating sites or (2) source documents for 
selected participants will be sent to MSKCC for audit. Audits will usually be determined by 
participant accrual numbers and rate of accrual, but can also be prompted by reported SAEs 
or request of MSKCC PI. 
 
Audits will be conducted at least once shortly after initiation of participant recruitment at a 
site, annually during the study (or more frequently if indicated), and at the end or closeout of 
the trial. The number of participants audited will be determined by available time and the 
complexity of the protocol. 


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The audit will include a review of source documentation to evaluate compliance for: 
 
• 
Informed consent documents and procedures 
• 
Adherence to eligibility criteria 
• 
Protocol defined treatment 
• 
Required baseline, on study and follow-up protocol testing 
 
 
• 
IRB documents (submitted amendments, annual continuing review reports, SAEs) 
• 
Case Report Form submissions to MSKCC: timeliness and accuracy 
 
A wrap-up session will be conducted at the participating site and preliminary findings will be 
discussed with the participating site PI and research team. The preliminary results will be 
sent to the MSKCC PI. 
 
Each audit will be summarized and a final report will be sent to the PI at the audited 
participating site within 30 days of the audit. The report will include a summary of findings, 
participant by participant case review, specific recommendations on any performance and/or 
shortcomings and request for corrective action, when necessary. When corrective action is 
required, the participating site must reply within 45 days of receipt of audit report with their 
corrective action plan. 
 
A copy of the audit report and corrective action plan (if applicable) submitted by the 
participating site must be sent to the MSKCC IRB/PB, CRQA and maintained in the 
department’s protocol regulatory binder. 
 
16.2 
Data and Safety Monitoring 
 
The Data and Safety Monitoring (DSM) Plans at Memorial Sloan-Kettering Cancer Center 
were approved by the National Cancer Institute in September 2001. The plans address the 
new policies set forth by the NCI in the document entitled “Policy of the National Cancer 
Institute for Data and Safety Monitoring of Clinical Trials” which can be found at: 
http://www.cancer.gov/clinicaltrials/conducting/dsm-guidelines/page1. The DSM Plans at 
MSKCC were established and are monitored by the Office of Clinical Research. The 
MSKCC Data and Safety Monitoring Plans can be found on the MSKCC Intranet at: 
http://inside2/clinresearch/Documents/MSKCC%20Data%20and%20Safety%20Monitoring% 
20Plans.pdf 
 
There are several different mechanisms by which clinical trials are monitored for data, safety, 
and quality, including several institutional and departmental processes. For instance, at the 
institutional level, there is protocol monitoring, compliance and data verification audits, 
therapeutic response, and staff education on clinical research QA. Additionally, there are two 
institutional committees—the Data and Safety Monitoring Committee (DSMC) for Phase I 
and II clinical trials, and the Data and Safety Monitoring Board (DSMB) for Phase III clinical 
trials—that are responsible for monitoring the activities of our clinical trials program and 
report to the Center’s Research Council and Institutional Review Board. 
 
During the protocol development and review process, each protocol will be assessed for its 
level of risk and degree of monitoring required. Every type of protocol (e.g., NIH sponsored, 
industry sponspored, NCI cooperative group, etc…) will be addressed and the monitoring 


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procedures will be established at the time of protocol activation. 
 
16.3 Regulatory Documentation 
 
Prior to implementing this protocol at MSKCC, the protocol, informed consent form, HIPAA 
authorization and any other information pertaining to participants must be approved by the 
MSKCC Institutional Review Board/Privacy Board (IRB/PB). Prior to implementing this 
protocol at the participating sites, approval for the MSKCC IRB/PB approved protocol must 
be obtained from the participating site’s IRB. 
 
The following documents must be provided to MSKCC before the participating site can be 
initiated and begin enrolling participants: 
 
• 
Participating Site IRB approval(s) for the protocol, appendices, informed consent form 
and HIPAA authorization 
• 
Participating Site IRB approved consent form 
• 
Participating Site IRB membership list 
• 
Participating Site IRB’s Federal Wide Assurance number and OHRP Registration number 
• 
Curriculum vitae and medical license for each investigator and consenting professional 
• 
Documentation of Human Subject Research Certification training for investigators and 
key staff members at the Participating Site 
• 
Documentation of Good Clinical Practice (GCP) training for the PI and co-PI at each 
participating site. 
• 
Participating site laboratory certifications and reference ranges 
 
Upon receipt of the required documents, MSKCC will formally contact the site and grant 
permission to proceed with enrollment. 
 
16.3.1 Amendments 
 
Each change to the protocol document must be organized and documented by MSKCC and 
first approved by the MSKCC IRB/PB. Upon receipt of MSKCC IRB/PB approval, MSKCC 
will immediately distribute all non expedited amendments to the participating sites, for 
submission to their local IRBs. 
 
Participating sites must obtain approval for all non expedited amendments from their IRB 
within 90 calendar days of MSKCC IRB/PB approval. If the amendment is the result of a 
safety issue or makes eligibility criteria more restrictive, sites will not be permitted to 
continuing enrolling new participants until the participating site IRB approval has been 
granted. 
 
The following documents must be provided to MSKCC for each amendment within the stated 
timelines: 
 
•  Participating Site IRB approval 
•  Participating Site IRB approved informed consent form and HIPAA  authorization 
 
16.3.2 Additional IRB Correspondence 
 
Continuing Review Approval 
The Continuing Review Approval letter from the participating site’s IRB and the most current 
approved version of the informed consent form should be submitted to MSKCC within 7 days 


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of expiration. Failure to submit the re-approval in the stated timeline will result in suspension 
of study activities. 
 
 
 
Deviations and Violations 
A protocol deviation on this study is defined as a request to treat a research participant who 
does not meet all the eligibility criteria, pretreatment evaluation, or who requires alteration in 
their study plan. If a deviation from this protocol is proposed for a potential or existing 
participant at MSKCC or a participating site, approval from the MSKCC IRB/PB is required 
prior to the action. Participating sites should contact the MSKCC PI who will in turn seek 
approval from the MSKCC IRB/PB. 
 
A protocol violation is anything that occurs with a participant, which deviated from the 
protocol without prior approval from the MSKCC IRB/PB. For protocol violations that are 
identified after they occur, the participating site should report to MSKCC as soon as possible. 
The MSKCC PI will in turn report the violation to the MSKCC IRB/PB. 
 
Participating sites should report deviations and violations to their institution’s IRBs as soon as 
possible per that site’s institutional guidelines. Approvals/acknowledgments from the 
participating site IRB for protocol deviations and violations should be submitted to MSKCC as 
received. 
 
Other correspondence 
Participating sites should submit other correspondence to their institution’s IRB according to 
local guidelines, and submit copies of that correspondence to MSKCC. 
 
16.3.3 Document maintenance 
 
 
The MSKCC PI and the Participating Site PI will maintain adequate and accurate records to 
enable the implementation of the protocol to be fully documented and the data to be 
subsequently verified. 
 
The participating sites will ensure that all participating site IRB correspondence (IRB 
approval letters referencing protocol version date and amendment number, IRB approved 
protocol, appendices, informed consent forms, deviations, violations, and approval of 
continuing reviews) is maintained in the regulatory binder on site and sent to MSKCC. 
 
A regulatory binder for each site will also be maintained at MSKCC; this binder may be paper 
or electronic. 
 
After study closure, the participating site will maintain all source documents, study related 
documents and CRFs for 3 years. 
 
16.4 Noncompliance 
 
If a participating site is noncompliant with the protocol document , accrual privileges may be 
suspended and/or contract payments may be withheld (if applicable), until the outstanding 
issues have been resolved. 
 
17.0 
PROTECTION OF HUMAN SUBJECTS 


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IRB PROTOCOL 
IRB#: 12-264 A(11) 
 
 
This study intends to obtain more in-depth information about the safety and feasibility of two 
commercially available drugs, enoxaparin and aspirin, in cancer patients with acute ischemic 
stroke. The findings of the proposed pilot study will enable the planning and development of 
a larger, fully-powered clinical trial that will assess for efficacy. 
 
The potential risks for participants in this study are easy brusing, skin irritation, pain at the 
injection site, dyspepsia, dizziness, diarrhea, nausea and vomiting, hearing loss, tinnitus, 
impaired liver function, thrombocytopenia, anemia, major bleeding, intracranial hemorrhage, 
and allergic reactions. Participants who experience major adverse events (e.g., major 
bleeding, intracranial hemorrhage, severe allergic reactions) caused by the study treatments 
will be readily removed from the study. 
 
All research specific assessments proposed for this study are also used for the assessment 
of non-protocol patients; the burden caused to patients by them is minimal. 
 
This protocol will not include children because most pediatric cancers are hematologic in 
origin and may not induce as much hypercoagulability as the more common carcinomas of 
adulthood (Rogers 2012). Furthermore, strokes are extremely rare events in children. 
 
17.1 
Privacy 
 
MSKCC’s Privacy Office may allow the use and disclosure of protected health information 
pursuant to a completed and signed Research Authorization form. The use and disclosure of 
protected health information will be limited to the individuals described in the Research 
Authorization form. A Research Authorization form must be completed by the Principal 
Investigator and approved by the IRB and Privacy Board (IRB/PB). 
 
17.2 
Serious Adverse Event (SAE) Reporting 
 
Any SAE must be reported to the IRB/PB as soon as possible but no later than 5 calendar 
days. The IRB/PB requires a Clinical Research Database (CRDB) SAE report be submitted 
electronically to the SAE Office at  sae@mskcc.org. 
 
A serious adverse event is any adverse events that: 
 
• 
Results in death. 
• 
Is life-threatening. 
• 
Requires inpatient hospitalization or prolongation of an existing hospitalization. 
• 
Results in a persistent or significant disability or incapacity. 
• 
Results in a congenital anomaly or birth defect. 
• 
Additionally, important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered SAEs when, based on appropriate medical 
judgment, they may jeopardize the patient and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. 
 
The CRDB SAE report should contain the following information: 
Fields populated from CRDB: 
 
• 
Subject’s name (generate the report with only initials if it will be sent outside of 


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MSKCC) 
• 
Medical record number 
• 
Disease/histology (if applicable) 
• 
Protocol number and title 
 
Data needing to be entered: 
 
• 
The date the adverse event occurred 
• 
The adverse event 
• 
Relationship of the adverse event to the treatment (drug, device, or intervention) 
• 
If the AE was expected 
• 
The severity of the AE 
• 
The intervention 
• 
Detailed text that includes the following 
o An explanation of how the AE was handled 
o A description of the subject’s condition 
o Indication if the subject remains in the study 
o If an amendment will need to be made to the protocol and/or consent form. 
The PI’s signature and the date it was signed are required on the completed report. 
17.2.1 Serious Adverse Event (SAE) Reporting for Participating Sites 
 
Responsibility of Participating Sites 
 
• 
Participating sites are responsible for reporting all SAEs to their local IRB per local 
guidelines. Local IRB SAE approvals/acknowledgements must be sent to MSK upon 
receipt. 
• 
Participating sites are responsible for reporting all SAEs to the MSKCC PI via fax or e-mail 
within 3 calendar days of learning of the event. 
• 
Participating sites should notify the MSKCC PI of any grade 5 event immediately. 
• 
Participating sites should use the SAE Report Form found in MSKCC’s internet-based 
Clinical Research Database, CRDBi-Multicenter, to report SAEs to MSKCC. 
 
 
 
 
 
SAE contact information for the Coordinating Center is listed below: 
 
PI: 
Lisa M. DeAngelis, MD 
1275 York Avenue 
New York, NY 10065 
Tel 212-639-7523 
Fax 212-717-3296 
 
Co-PI: 
Babak Navi, MD 
353 E 68th Street 
New York, NY 10065 


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Tel 212-639-7123 
 
Research Study Assistant I: 
Benjamin Weill 
Department of Neurology 
Memorial Sloan-Kettering Cancer Center 
160 E 53rd Street, 2nd Floor 
New York, NY 10022 
Tel: 212.610.0348 
Fax: 646.227.2461 
Email weillb@mskcc.org 
 
 
Responsibility of MSKCC 
 
• 
The MSKCC Research Staff is responsible for submitting all SAEs to the MSKCC IRB/PB 
as specified in 17.2.1 
• 
The MSKCC PI is responsible for informing all participating sites about all deaths and 
unexpected SAEs that are possibly, probably, or definitely related to the study drug within 
30 days of receiving the stamped SAE from the MSKCC IRB/PB. 
• 
Any report pertaining to a grade 5 event will be distributed to the participating sites as 
soon as possible. 
 
17.3 
Safety Reports 
 
• 
MSKCC will distribute outside safety reports to the participating sites immediately upon 
receipt. 
• 
MSKCC must submit outside safety reports to the MSKCC IRB/PB according to 
institutional guidelines. 
• 
Participating sites must submit safety reports to their institution’s IRBs within 30 days of 
receipt from MSKCC or per participating site guidelines. 
 
18.0 
INFORMED CONSENT PROCEDURES 
 
Before protocol-specified procedures are carried out, consenting professionals will explain full 
details of the protocol and study procedures as well as the risks involved to participants prior 
to their inclusion in the study. Participants will also be informed that they are free to withdraw 
from the study at any time. All participants must sign an IRB/PB-approved consent form 
indicating their consent to participate. This consent form meets the requirements of the Code 
of Federal Regulations and the Institutional Review Board/Privacy Board of this Center. The 
consent form will include the following: 
 
1.  The nature and objectives, potential risks and benefits of the intended study. 
2.  The length of study and the likely follow-up required. 
3.  Alternatives to the proposed study. (This will include available standard and 
investigational therapies. In addition, patients will be offered an option of supportive 
care for therapeutic studies.) 
4.  The name of the investigator(s) responsible for the protocol. 
5.  The right of the participant to accept or refuse study interventions/interactions and to 
withdraw from participation at any time. 


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Before any protocol-specific procedures can be carried out, the consenting professional will 
fully explain the aspects of patient privacy concerning research specific information.  In 
addition to signing the IRB Informed Consent, all patients must agree to the Research 
Authorization component of the informed consent form. 
 
Each participant and consenting professional will sign the consent form. The participant must 
receive a copy of the signed informed consent form. 
 
18.1 For Participating Sites 
 
 
The investigators listed on the protocol cover page and their qualified designees at each 
participating site may obtain informed consent and care for the participants according to 
good clinical practice and protocol guidelines. 
 
Signed copies of the informed consent should be distributed as follows: One copy will be 
given to the participant to be retained for their personal records. One copy will be maintained 
on file at the MSKCC. The third copy will be confidentially maintained by the participating 
institution. 
 
A note will be placed in the medical record documenting that informed consent was obtained 
for this study, and that the participant acknowledges the risk of participation. 
 
19.0 
REFERENCES 
 
Bath PM, Lindenstrom E, Boysen G, et al. Tinzaparin in acute ischaemic stroke (TAIST): a 
randomised aspirin-controlled trial. Lancet. Sep 2001;358(9283):702-710. 
 
Brott T, Adams HP, Jr., Olinger CP, et al. Measurements of acute cerebral infarction: a 
clinical examination scale. Stroke. Jul 1989;20(7):864-870. 
 
Bruno A, Shah N, Lin C, et al. Improving the modified Rankin Scale assessment with a 
simplified questionnaire. Stroke. May 2010;41(5):1048-1050. 
 
Caine GJ, Stonelake PS, Lip GY, Kehoe ST. The hypercoagulable state of malignancy: 
pathogenesis and current debate. Neoplasia. Nov-Dec 2002;4(6):465-473. 
 
CAST: randomised placebo-controlled trial of early aspirin use in 20,000 patients with acute 
ischaemic stroke. CAST (Chinese Acute Stroke Trial) Collaborative Group. Lancet. Jun 
1997;349(9066):1641-1649. 
 
Cestari DM, Weine DM, Panageas KS, Segal AZ, DeAngelis LM. Stroke in patients with 
cancer: incidence and etiology. Neurology. Jun 2004;62(11):2025-2030. 
 
Chaturvedi S, Ansell J, Recht L. Should cerebral ischemic events in cancer patients be 
considered a manifestation of hypercoagulability? Stroke. Jun 1994;25(6):1215-1218. 
 
Chimowitz MI, Lynn MJ, Howlett-Smith H, et al. Comparison of warfarin and aspirin for 
symptomatic intracranial arterial stenosis. N Engl J Med. Mar 2005;352(13):1305-1316. 
 
Goldstein LB, Samsa GP. Reliability of the National Institutes of Health Stroke Scale. 


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Extension to non-neurologists in the context of a clinical trial. Stroke. Feb 1997;28(2):307- 
310. 
 
Graus F, Rogers LR, Posner JB. Cerebrovascular complications in patients with cancer. 
Medicine (Baltimore). Jan 1985;64(1):16-35. 
 
Karnofsky DA, Burchenal JH. The clinical evaluation of chemotherapeutic agents in cancer. 
In: Evaluation of chemotherapeutic agents in cancer. Edited by Macleod CM. New York, NY: 
Columbia University Press; 1949:191-205. 
 
Lee AY, Levine MN, Baker RI, et al. Low-molecular-weight heparin versus a coumarin for the 
prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med. Jul 
2003;349(2):146-153. 
 
Low molecular weight heparinoid, ORG 10172 (danaparoid), and outcome after acute 
ischemic stroke: a randomized controlled trial. The Publications Committee for the Trial of 
ORG 10172 in Acute Stroke Treatment (TOAST) Investigators. JAMA. Apr 
1998;279(16):1265-1272. 
 
Ma C, Bandukwala S, Burman D, et al. Interconversion of three measures of performance 
status: An empirical analysis. Eur J Cancer. Dec 2010;46(18):3175-3183. 
 
Mohr JP, Thompson JL, Lazar RM, et al. A comparison of warfarin and aspirin for the 
prevention of recurrent ischemic stroke. N Engl J Med. Nov 2001;345(20):1444-1451. 
 
Morisky DE, Ang A, Krousel-Wood M, Ward H. Predictive validity of a medication adherence 
measure for hypertension control. J Clin Hypertens. 2008;10:348–54. 
 
Navi BB, Segal AZ. Cancer and Stroke. In: Stroke: A Practical Approach. Edited by Geyer 
JD, Gomez CR. Philadelphia, PA: Lippincott Williams & Wilkins; 2008:48-55. 
 
Rogers LR. Cerebrovascular complications in patients with cancer. Semin Neurol. Jul 
2010;30(3):311-319. 
 
Salem DN, Stein PD, Al-Ahmad A, et al. Antithrombotic therapy in valvular heart disease-- 
native and prosthetic: the Seventh ACCP Conference on Antithrombotic and Thrombolytic 
Therapy. Chest. Sep 2004;126(3 Suppl):457S-482S. 
 
Seok JM, Kim SG, Kim JW, et al. Coagulopathy and embolic signal in cancer patients with 
ischemic stroke. Ann Neurol. Aug 2010;68(2):213-219. 
 
The International Stroke Trial (IST): a randomised trial of aspirin, subcutaneous heparin, 
both, or neither among 19435 patients with acute ischaemic stroke. International Stroke Trial 
Collaborative Group. Lancet. May 1997;349(9065):1569-1581. 
 
van Swieten JC, Koudstaal PJ, Visser MC, Schouten HJ, van Gijn J. Interobserver 
agreement for the assessment of handicap in stroke patients. Stroke. May 1988;19(5):604- 
607. 


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20.0 
APPENDICES 
 
Appendix A: 8-point Morisky questionnaire 
 
Appendix B: Modified Rankin Scale. 
 
Appendix D: National Institute of Health Stroke Scale. 
Appendix E: Karnofsky Performance Status Scale. 
Appendix F: Comprehensive Metabolic Panel