Table 1:

Phase II and III ECOG-ACRIN Trials of 5FU and/or Capecitabine – Description of studies, Cardiovascular (CV) exclusion criteria, and ascertainment of CV events

Study	Agent(s)	Cancer type	Phase, and Accrual	Year study activated	CV exclusion criteria	Baseline CV Data Collected	CTCAE version, grades and attribution*	CV event definitions/ascertainment on Adverse Event (AE) Case Report Form (CRF)
E1103	Capecitabine 1000mg/m2 twice daily + tipifarnib	Metastatic Breast Cancer	Phase II N=71	2004	Symptomatic cardiovascular disease	None	CTC v2, all grades, treatment related**	AE CRF includes: Cardiac ischemia/infarction Dyspnea
E2200	5-FU 400mg/m2 weekly bolus + irinotecan + leucovorin + bevacizumab	Advanced Colorectal	Phase II N=92	2000	None	None	CT v2, all grades, treatment related**	AE CRF includes: Hypertension Dyspnea Thromboembolism
E2204	Capecitabine 825mg/m2 twice daily Arm A: + cetuximab + gemcitabine Arm B: + bevacizumab + gemcitabine	Completely resected pancreatic CA	Phase II(randomized) N=137	2006	Cardiac arrhythmia TIA/stroke Arterial thromboembolic events UA/MI within 12 months of study entry	None	CTCAE v3, all grades, treatment related**	AE CRF includes: Cardiac ischemia/infarction CNS cerebrovascular ischemia Hypertension Dyspnea Thrombosis/thrombus/embolism Grade 3+ TIA/CVA/MI/angina specifically included in the primary endpoint
E2205	5-FU 180mg/m2 CI over 24 hours D 1–35 + oxaliplatin + cetuximab	Operable esophageal cancer	Phase II N=22	2008	Heart failure Stroke/TIA, UA/MI within 6 months of study entry	None	CTCAE v3,grade 3–5, treatment related**	No cardiac AEs specifically ascertained
E2211	Capecitabine 750mg/m2 twice daily only or with Arm A: + temozolomide Arm B: temozolomide only no 5FU	Advanced pancreatic neuroendocrine tumors	Phase II (randomized) N=144***	2013	Arterial thromboembolic events PVD UA, MI within 12 months of study entry	None	CTCAE v4***	No cardiac AEs specifically ascertained
E3200	5FU 400mg/m2 bolus followed by 600mg/m2 CI over 22 hours in arms A and B A: oxaliplatin + leucovorin + bevacizumab B: oxaliplatin + leucovrin C: bevacizumab alone no 5Fu	Advanced Colorectal	Phase III N=829	2001	Heart failure UA/MI within 3 months	None	CTC v2, grade 4–5 hematologic and grade 3–5 non-hematologic, treatment related**	No cardiac AEs specifically ascertained
E3201	5FU bolus followed by CI 2400 mg/m2 over 46 hours adjuvant Arms A, B, D, and E Arms C and F 5FU bolus only	Stage II or III Rectal	Phase III N=179	2003	None	None	CTCAE v3, grade 3–5, treatment related**	No cardiac AEs specifically ascertained
E3204	Capecitabine 825mg/m2 twice daily + oxaliplatin + bevacizumab + radiation then surgery, then adjuvant 5FU 400mg/m2 followed by 2400mg/m2 CI 46 hours + leucovorin +oxaliplatin + bevacizumab	Locally advanced rectal cancer	Phase II N=57	2006	Heart failure PVD. UA/MI within 12 months of study entry	None	CTCAE v3, all grades, treatment related**	AE CRF includes: Chest/thorax Pain NOS Dyspnea Thrombosis/thrombus/embolism
E3205	5-FU 4000mg/m2 CI over 96 hours + cetuximab + cisplatin Arm 1: two cycles Arm 2: one cycle	Anal carcinoma	Phase II N=63	2007	Heart failure Stroke/TIA UA/MI within 6 months of study entry	None	CTCAE v4, grade 3–5, treatment related**	AE CRF includes: Cardiac-ischemia/infarction
E4203	5-FU 400mg/m2 bolus followed by 2400mg/m2 CI over 46 hours Arm B and C: + leucovorin + oxaliplatin + bevacizumab Arm A: irinotecan + oxaliplatin + bevacizumab no 5FU	Metastatic colorectal	Phase II N=211	2005	NYHA III-IV heart failure UA/MI within 6 months of study entry	None	CTCAE v3, all grades, treatment related**	No cardiac AEs specifically ascertained
E5202	5FU 400 mg/m2 bolus followed by 2.4gm/m2 over 46 hours Arm A Arm B: + bevacizumab Arm C: no chemotherapy	Stage II Colon Cancer	Phase III N=2432***	2005	UA/MI within prior 12 months Symptomatic PVD NYHA III/IV HF Symptomatic arrhythmias TIA/Stroke	Perioperative MI	CTCAE v3***	AE CRF includes: Cardiac-ischemia/infarction Cardiac arrhythmia CNS cerebrovascular ischemia Thrombosis/thrombus/embolism
E5204	5FU 400 mg/m2 bolus followed by 2400mg/m2 CI over 46 hours Arm A and B Arm B: + bevacizumab	Stage II or III Rectal cancer	Phase III N=355	2006	UA/MI within prior 12 months PVD, NYHA III/IV HF Symptomatic arrhythmias TIA/Stroke	History of: Diabetes Hypertension	CTCAE v3 grades 3–5, treatment related**	AE CRF includes: Cardiac-ischemia/infarction Pain-Chest/Thorax NOS CNS cerebrovascular ischemia Hypertension Dyspnea Thrombosis/thrombus/embolism
E1305	5FU 1000mg/m2 CI over 96 hours Regimen 2: + cisplatin or carboplatin Regimen 1: docetaxel + cisplatin or carboplatin no 5FU	Recurrent or Metastatic Head and Neck Cancer	Phase III N=403***	2008	UA/MI or Stroke within prior 6 months PVD NYHA II-IV HF Serious cardiac arrhythmia requiring medication PVD with symptoms or prior intervention Stroke within the last 6 months	History of: Arterial thromboembolic events MI, stable angina, unstable angina, HTN Smoking status	CTCAE v4***	AE CRF includes: Acute coronary syndrome
EA1131	Capecitabine 1000mg/m2 twice daily Arm C only Arm A: observation Arm B: cisplatin vs carboplatin	Triple Negative, Stage II or III Breast Cancer	Phase III Projected N=750^	2015	None	None	CTCAE v4^	No cardiac AEs specifically ascertained
EA2133	5FU 4000mg/m2 CI over 96 hours Arm: A + cisplatin Arm B: carboplatin + paclitaxel no 5FU	Advanced Anal Squamous Cell Carcinoma	Phase II Projected N=80^	2016	MI within last 6 months Symptomatic CAD Clinically significant cardiac failure Uncontrolled cardiac arrhythmia	Hypertension	CTCAE v4^	AE CRF includes: Myocardial ischemia/infarction Arrhythmia LV dysfunction
EA2142	Capecitabine 750mg/m2 twice daily Arm A: + temozolomide Arm B: platinum + etoposide no capecitabine	Advanced non-small cell GI Neuroendocrine carcinoma	Phase II (randomized) Projected N=126^	2015	Symptomatic heart failure Unstable angina Cardiac arrhythmias	None	CTCAE v4^	cardiac AEs not specifically ascertained

^*CTCAE version. grades, attribution as reported in the final Clinical Study Report (CSR).

^**includes the following attributions: possible, probably, definitely related to protocol treatment.

^***trial is closed to accrual and final CSR not available to date.

^{^}accrual to trial ongoing to date.