Eastern Cooperative Oncology Group

Transcription

1 Group Chair: Robert L. Comis, M.D. Group Statistician: Robert Gray, Ph.D. Eastern Cooperative Coordinating Center Frontier Science 900 Commonwealth Avenue Boston, MA (617) Fax: (617) Randomization: (617) Jean MacDonald, Director of Research Operations Mary Steele, Director of Group Administration TO: FROM: ECOG Clinical Research Associates and Investigators with Patients for ECOG Coordinating Center DATE: June 20, 2012 SUBJECT:, Addendum #13 This addendum has been reviewed and approved by the Central IRB. Enclosed is Addendum #13 for, A Double-blind, Randomized, Placebo-Controlled Phase III Trial of Carboplatin, Paclitaxel and Sorafenib versus Carboplatin, Paclitaxel and Placebo in Patients with Unresectable Locally Advanced or Stage IV Melanoma. A revised cover sheet, indicating the date of the revisions, and replacement pages, incorporating the changes to the protocol have been provided. Please remove the outdated pages and replace them with the enclosed cover and current pages. We recommend that each institution maintain a file containing the original protocol and all subsequent revisions. This addendum is in response to the request for amendment for Sorafenib from John Wright, MD, PhD, Associate Branch Chief, IDB, CTEP, DCTD, NCI, dated December 22, Because this protocol is permanently closed to accrual, this addendum may be handled in one of the following two ways, depending on the status of subjects under the protection of your local IRB. Documentation of this review or adherence to local IRB written SOPs will be requested at subsequent ECOG audits. 1. If all subjects under the protection of the local IRB have discontinued active treatment with Sorafenib, your local IRB will determine whether or not you must submit this addendum for IRB review. 2. If one or more subjects under the protection of the local IRB continue on active treatment with Sorafenib, you must submit this addendum for IRB review. Expedited IRB review of this addendum may be utilized even if there are subjects on active treatment with Sorafenib. However, please consult your local IRB policy since its requirements may differ and require full board review. It is the decision of the local IRB whether or not subjects are to be re-consented. This addendum must be submitted and reviewed by your IRB within 90 days of receipt of this notice, unless your local IRB has different written SOPs, which must be available at future ECOG audits. Addendum #13 includes the following changes: 1. Cover page and Appendix I, page 1: Updated version date. 2. Section 5.8.2, page 17, step 4: Replaced with updated Step 4 instructions reflecting use of the SPEER.

2 3. Section 5.8.3, page 18: Retitled Section to Reporting Procedures and replaced entire section with updated AdEERS reporting procedures. 4. Sections and 5.8.9, pages 21-21a: Removed both section and replaced with one section titled Reporting Second Primary Cancers. Section deleted and not replaced. As a result of these changes, page 21a created. 5. Section 5.9, page 22, first paragraph: Third and fourth sentences removed completely. Corresponding NOTE below replaced with two new NOTES regarding the use of a SPEER. 6. Section 5.9, pages 22-25: Updated CAEPR for Sorafenib with updated version 2.4. ASAEL column has been replaced by a SPEER. 7. Appendix I, pages 8-10: Risk list for Sorafenib replaced with updated version. Enclosure C: CALGB SWOG

3 Eastern Cooperative A Double-blind, Randomized, Placebo-Controlled Phase III Trial of Carboplatin, Paclitaxel and Sorafenib versus Carboplatin, Paclitaxel and Placebo in Patients with Unresectable Locally Advanced or Stage IV Melanoma STUDY CHAIR: Keith T. Flaherty, M.D. STUDY CO-CHAIR: Lynn M. Schuchter, M.D. STUDY STATISTICIAN: Sandra Lee, ScD. MELANOMA COMMITTEE CHAIR: John M. Kirkwood, M.D. MELANOMA COMMITTEE CO-CHAIR: Craig Slingluff, M.D. COMMUNITY CO-CHAIR: Gary Cohen, M.D. SWOG STUDY COORDINATOR: Lawrence E. Flaherty, M.D. Rev. 9/05 CALGB CO-CHAIR: Frank G. Haluska, M.D., Ph.D. Rev. 5/06 LABORATORY CO-CHAIR: Harriet M. Kluger, M.D. Version Date: March 28, 2012 NCI Update Date: June 1, 2011 Sorafenib (NSC# , IND# 69,896) Rev. 9/05 Rev.3/07 STUDY PARTICIPANTS ECOG Entire Group SWOG CALGB This study is supported by the NCI Cancer Trials Support Unit (CTSU). Institutions not aligned with ECOG will participate through the CTSU mechanism (please see the index page and Appendix VII for details). ACTIVATION DATE June 23, 2005 Addendum #1 Incorporated prior to activation Addendum #2 Incorporated prior to activation Addendum #3 Incorporated prior to activation Update #1 Incorporated prior to activation Addendum #4 9/05 Addendum #5 9/05 Addendum #6 5/06 Addendum #7 9/06 Addendum #8 3/07 Update #2 3/07 Update #3 5/07 Addendum #9 11/07 Update #4 11/07 Addendum #10 7/08 ENTIRE PROTOCOL Update #5 7/08 Addendum #11 2/09 Addendum #12 7/10 Update #6 6/11 Addendum #13 6/12

4 Revised 6/11, Update #6 Revised 6/12, Addendum #13 Rev. 6/11 Rev. 6/12 When a study arm includes both investigational and commercial agents, the following rules apply. Sequential administration: When a study includes an investigational agent(s) and a commercial agent(s) on the same study arm, but the commercial agent(s) is given for a period of time prior to starting the investigational agent(s), expedited reporting of adverse events which occur prior to starting the investigational agent(s) would follow the guidelines for commercial agents. Once therapy with the investigational agent(s) is initiated, all expedited reporting of adverse events should follow the investigational guidelines. Steps to determine if an adverse event is to be reported in an expedited manner: Step 1: Identify the type of event: The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 will be utilized until June 30, 2011 for AE reporting. CTCAE version 4.0 will be utilized beginning July 1, All appropriate treatment areas should have access to a copy of the CTCAE version 4.0. A copy of the CTCAE version 4.0 can be downloaded from the CTEP web site ( Step 2: Grade the event using the NCI CTCAE version 4.0. Step 3: Determine whether the adverse event is related to the protocol therapy (investigational or commercial). Attribution categories are as follows: Unrelated, Unlikely, Possible, Probable, and Definite. Step 4: Determine the prior experience of the adverse event. Expected events are those that have been previously identified as resulting from administration of the agent. An adverse event is considered unexpected, for expedited reporting purposes only, when either the type of event or the severity of the event is NOT listed in: NOTE: The NCI SPEER for Sorafenib is included in Section 5.9 of the protocol. FOR THIS PROTOCOL, events listed in the SPEER for Sorafenib should be considered EXPECTED if the grade being reported is the same or lower than the grade noted in the parentheses next to the AE in the SPEER. Events listed in the SPEER column should be considered UNEXPECTED if the grade being reported exceeds the grade noted in parentheses next to the AE in the SPEER. If the event being reported is listed in EITHER the SPEER for Sorafenib or the packageinsert/protocol for the commercial agents, then it is considered expected for AdEERS adverse event reporting purposes, regardless of the grade. The SPEER is presented in the last column of the CAEPR and identified with bold and italicized text. Step 5: Review the Additional instructions, requirements, and exceptions for protocol table in section and footnote b in Section for protocol and/or ECOG specific requirements for expedited reporting of specific adverse events that require special monitoring. Step 6: Determine if the protocol treatment given prior to the adverse event included investigational agent(s), a commercial agent(s), or a combination of investigational and commercial agents. NOTE: If the patient received at least one dose of investigational agent, follow the guidelines in Section If no investigational agent was administered, follow the guidelines in Section NOTE: For general questions regarding expedited reporting requirements, please contact the NCI Medical Help Desk:

5 Revised 6/12, Addendum #13 Rev. 6/12 Rev. 9/06 Rev. 9/06 Rev. 9/ Reporting Procedure This study requires that expedited adverse event reporting use the NCI s Adverse Event Expedited Reporting System (AdEERS). The NCI s guidelines for AdEERS can be found at An AdEERS report must be submitted electronically to ECOG and the appropriate regulatory agencies via the AdEERS Web-based application located at In the rare event when Internet connectivity is disrupted a 24-hour notification is to be made by telephone to the AE Team at ECOG ( ) and the NCI ( ) An electronic report MUST be submitted immediately upon re-establishment of internet connection. Supporting and follow up data: Any supporting or follow up documentation must be faxed to ECOG ( ), Attention: AE within hours. In addition, supporting or follow up documentation must be faxed to the NCI ( ).) in the same timeframe. NCI Technical Help Desk: For any technical questions or system problems regarding the use of the AdEERS application, please contact the NCI Technical Help Desk at ncictephelp@ctep.nci.nih.gov or by phone at or When to report an event in an expedited manner Some adverse events require 24-hour notification (refer to Section 5.8.6). Please complete a 24-Hour Notification Report via the NCl AdEERS website ( within 24 hours of learning of the event. The full AdEERS report must be completed and submitted via AdEERS within 5 calendar days. If the AdEERS system is down, a 24-hour notification call must be made to ECOG ( ) and to NCI ( ). Once the system is restored, a 24-hour Notification Report must be entered into the AdEERS system by the original submitter of the report at the site. When an adverse event requires expedited reporting, submit a full AdEERS report within the timeframes outlined in Sections and NOTE: Adverse events that meet the reporting requirements in Sections or and occur within 30 days of the last dose of protocol treatment must be reported on an expedited adverse event report form (using AdEERS). For any adverse events that occur more than 30 days after the last dose of treatment, only those that have an attribution of possibly, probably, or definitely AND meet the reporting requirements in Section or must be reported on an expedited adverse event report form (using AdEERS) Other recipients of adverse event reports DCTD, NCI will notify ECOG/pharmaceutical collaborator(s) of all AEs reported to FDA. Any additional written AE information requested by ECOG MUST be submitted to the NCI and ECOG. 18

6 Rev. 9/06, 11/ Expedited reporting for commercial agents Commercial reporting requirements are provided below. The commercial agents used in arm X of this study are Carboplatin and Paclitaxel. Expedited reporting requirements for adverse events experienced by patients on arm(s) who have NOT received a Ieast one dose of sorafenib/placebo in this study. Once sorafenib/placebo treatment has been initiated, all expedited reporting of adverse events must follow the investigational guidelines in section Attribution Grade 4 Grade 5 a ECOG and Protocol-Specific Requirements Unrelated or Unlikely Possible, Probable, Definite Unexpected Expected Unexpected Expected See footnote 7 calendar days 7 calendar days (b) for special requirements. 7 calendar days 7 calendar days 7 calendar days 7 Calendar Days: Indicates a full AdEERS report is to be submitted within 7 calendar days of learning of the event. a b This includes all deaths within 30 days of the last dose of treatment regardless of attribution. NOTE: Any death that occurs > 30 days after the last dose of treatment and is attributed possibly, probably, or definitely to the treatment must be reported within 7 calendar days of learning of the event. Protocol-specific expedited reporting requirements: The adverse events listed below also require expedited reporting for this trial: Serious Events: Any event following treatment that results in persistent or significant disabilities/incapacities, congenital anomalies, or birth defects must be reported via AdEERS within 7 calendar days of learning of the event. For instructions on how to specifically report these events via AdEERS, please contact the NCI Medical Help Desk at Rev. 6/ Reporting Second Primary Cancers All cases of second primary cancers, including acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), that occur following treatment on NCI-sponsored trials must be reported to ECOG: A second malignancy is a cancer that is UNRELATED to any prior anticancer treatment (including the treatment on this protocol). Second malignancies require ONLY routine reporting as follows: 1. Submit a completed ECOG Second Primary Form within 30 days to ECOG at ECOG Coordinating Center FSTRF 900 Commonwealth Avenue Boston, MA Submit a copy of the pathology report to ECOG confirming the diagnosis. 3. If the patient has been diagnosed with AML/MDS, submit a copy of the cytogenetics report (if available) to ECOG A secondary malignancy is a cancer CAUSED BY any prior anti-cancer treatment (including the treatment on this protocol). Secondary malignancies require both routine and expedited reporting as follows: 1. Submit a completed ECOG Second Primary Form within 30 days to ECOG at ECOG Coordinating Center FSTRF 900 Commonwealth Avenue Boston, MA

7 2. Report the diagnosis via AdEERS at Report under a.) leukemia secondary to oncology chemotherapy, b.) myelodysplastic syndrome, or c.) treatment related secondary malignancy 3. Submit a copy of the pathology report to ECOG and NCI/CTEP confirming the diagnosis. 4. If the patient has been diagnosed with AML/MDS, submit a copy of the cytogenetics report (if available) to ECOG and NCI/CTEP. NOTE: The ECOG Second Primary Form and the AdEERS report should not be used to report recurrence or development of metastatic disease. NOTE: If a patient has been enrolled in more than one NCI-sponsored study, the ECOG Second Primary Form must be submitted for the most recent trial. ECOG must be provided with a copy of the form and the associated pathology report and cytogenetics report (if available) even if ECOG was not the patient's most recent trial. NOTE: Once data regarding survival and remission status are no longer required by the protocol, no follow-up data should be submitted via AdEERS or by the ECOG Second Primary Form. 21a

8 Rev. 9/05, 9/06, 2/09, 7/10, 6/12 Eastern Cooperative Revised 2/09, Addendum # 11 Revised 7/10, Addendum # Comprehensive Adverse Events and Potential Risks list (CAEPR) For Sorafenib (BAY , NSC ) The Comprehensive Adverse Event and Potential Risks list (CAEPR) provides a single list of reported and/or potential adverse events (AE) associated with an agent using a uniform presentation of events by body system. In addition to the comprehensive list, a subset, the Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate column and is identified with bold and italicized text. Frequency is provided based on 2157 patients. Below is the CAEPR for sorafenib (BAY ). NOTE: FOR THIS PROTOCOL, events listed in the SPEER column should be considered EXPECTED if the grade being reported is the same or lower than the grade noted in the parentheses next to the AE in the SPEER. Events listed in the SPEER column should be considered UNEXPECTED if the grade being reported exceeds the grade noted in parentheses next to the AE in the SPEER. NOTE: If the event being reported is listed in EITHER the SPEER for Sorafenib or the packageinsert/protocol for the commercial agents, then it is considered expected for AdEERS adverse event reporting purposes, regardless of the grade. Adverse Events with Possible Relationship to Sorafenib (BAY ) (CTCAE 4.0 Term) [n= 2157] Version 2.4, December 21, Specific Protocol Exceptions to Expedited Reporting (SPEER) (formerly known as ASAEL) Likely (>20%) Less Likely (<=20%) Rare but Serious (<3%) BLOOD AND LYMPHATIC SYSTEM DISORDERS Anemia Anemia (Gr 3) Febrile neutropenia CARDIAC DISORDERS Acute coronary syndrome Left ventricular systolic dysfunction Myocardial infarction GASTROINTESTINAL DISORDERS Abdominal pain Abdominal pain (Gr 3) Anal mucositis Ascites Constipation Constipation (Gr 2) Diarrhea Diarrhea (Gr 3) Gastrointestinal hemorrhage 2 Gastrointestinal hemorrhage 2 (Gr 3) Gastrointestinal perforation 3 Mucositis oral Nausea Nausea (Gr 3) Rectal mucositis Small intestinal mucositis Vomiting Vomiting (Gr 3) GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS Edema limbs Fatigue Fatigue (Gr 3) Fever Fever (Gr 2) Non-cardiac chest pain 22

9 Revised 2/09, Addendum # 11 Revised 7/10, Addendum #12 IMMUNE SYSTEM DISORDERS INFECTIONS AND INFESTATIONS Infection 4 INVESTIGATIONS Activated partial thromboplastin time prolonged Alanine aminotransferase increased Alkaline phosphatase increased Aspartate aminotransferase increased Anaphylaxis Activated partial thromboplastin time prolonged (Gr 2) Alanine aminotransferase increased (Gr 3) Alkaline phosphatase increased (Gr 3) Aspartate aminotransferase increased (Gr 3) Blood bilirubin increased Blood bilirubin increased (Gr 3) Cholesterol high Creatinine increased Creatinine increased (Gr 3) GGT increased INR increased INR increased (Gr 2) Investigations - Other (bicarbonate, serum-low) Lipase increased Lipase increased (Gr 3) Lymphocyte count decreased Lymphocyte count decreased (Gr 3) Neutrophil count decreased Neutrophil count decreased (Gr 4) Platelet count decreased Platelet count decreased (Gr 4) Serum amylase increased Serum amylase increased (Gr 3) Weight loss Weight loss (Gr 2) White blood cell decreased White blood cell decreased (Gr 4) METABOLISM AND NUTRITION DISORDERS Anorexia Anorexia (Gr 3) Hypercalcemia Hyperglycemia Hyperglycemia (Gr 3) Hyperkalemia Hyperkalemia (Gr 3) Hypernatremia Hyperuricemia Hypoalbuminemia Hypoalbuminemia (Gr 3) Hypocalcemia Hypocalcemia (Gr 3) Hypoglycemia Hypoglycemia (Gr2) Hypokalemia Hypokalemia (Gr 3) Hyponatremia Hyponatremia (Gr 3) Hypophosphatemia Hypophosphatemia (Gr 3) MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS Arthralgia Arthralgia (Gr 3) Back pain Back pain (Gr 3) Bone pain Musculoskeletal and connective tissue disorder - Other (muscle spasms) Myalgia Pain in extremity Pain in extremity (Gr 3) 23

10 Revised 2/09, Addendum # 11 Revised 7/10, Addendum #12 NERVOUS SYSTEM DISORDERS Dizziness Headache Headache (Gr 3) Intracranial hemorrhage Peripheral sensory neuropathy Reversible posterior leukoencephalopathy syndrome PSYCHIATRIC DISORDERS Insomnia RENAL AND URINARY DISORDERS Acute kidney injury Hematuria Renal hemorrhage REPRODUCTIVE SYSTEM AND BREAST DISORDERS Hematosalpinx Ovarian hemorrhage Prostatic hemorrhage Spermatic cord hemorrhage Testicular hemorrhage Uterine hemorrhage Vaginal hemorrhage RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS Bronchopulmonary hemorrhage Cough Cough (Gr 2) Dyspnea Dyspnea (Gr 3) Epistaxis Laryngeal mucositis Pharyngeal mucositis Tracheal mucositis Voice alteration SKIN AND SUBCUTANEOUS TISSUE DISORDERS Alopecia Alopecia (Gr 2) Dry skin Dry skin (Gr 2) Erythema multiforme Palmar-plantar erythrodysesthesia syndrome Palmar-plantar erythrodysesthesia syndrome (Gr 3) Pruritus Pruritus (Gr 3) Rash maculo-papular Rash maculo-papular (Gr 3) Stevens-Johnson syndrome VASCULAR DISORDERS Hypertension Hypertension (Gr 3) Thromboembolic event 24

11 Revised 2/09, Addendum # 11 Revised 7/10, Addendum #12 1 This table will be updated as the toxicity profile of the agent is revised. Updates will be distributed to all Principal Investigators at the time of revision. The current version can be obtained by contacting PIO@CTEP.NCI.NIH.GOV. Your name, the name of the investigator, the protocol and the agent should be included in the . 2 Gastrointestinal hemorrhage includes Anal hemorrhage, Cecal hemorrhage, Colonic hemorrhage, Duodenal hemorrhage, Esophageal hemorrhage, Esophageal varices hemorrhage, Gastric hemorrhage, Hemorrhoidal hemorrhage, Ileal hemorrhage, Intra-abdominal hemorrhage, Jejunal hemorrhage, Lower gastrointestinal hemorrhage, Oral hemorrhage, Pancreatic hemorrhage, Rectal hemorrhage, Retroperitoneal hemorrhage, and Upper gastrointestinal hemorrhage under the GASTROINTESTINAL DISORDERS SOC. 3 Gastrointestinal perforation includes Colonic perforation, Duodenal perforation, Esophageal perforation, Gastric perforation, Ileal perforation, Jejunal perforation, Rectal perforation, and Small intestinal perforation under the GASTROINTESTINAL DISORDERS SOC. 4 Includes all 75 infection sites under the INFECTIONS AND INFESTATIONS SOC. Also reported on sorafenib (BAY ) trials but with the relationship to sorafenib (BAY ) still undetermined: CARDIAC DISORDERS - Atrial fibrillation; Atrial flutter; Chest pain - cardiac; Sinus bradycardia; Sinus tachycardia; Supraventricular tachycardia EAR AND LABYRINTH DISORDERS - Tinnitus ENDOCRINE DISORDERS - Hyperthyroidism; Hypothyroidism EYE DISORDERS - Blurred vision; Cataract; Extraocular muscle paresis GASTROINTESTINAL DISORDERS - Abdominal distension; Dyspepsia; Dysphagia; Flatulence; Ileus; Pancreatitis; Rectal fistula; Small intestinal obstruction GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Edema face; Flu like symptoms; Pain IMMUNE SYSTEM DISORDERS - Allergic reaction INVESTIGATIONS - Fibrinogen decreased METABOLISM AND NUTRITION DISORDERS - Dehydration; Hypermagnesemia; Hypertriglyceridemia; Hypomagnesemia MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthritis; Generalized muscle weakness NERVOUS SYSTEM DISORDERS - Dysgeusia; Encephalopathy; Ischemia cerebrovascular; Memory impairment; Syncope PSYCHIATRIC DISORDERS - Confusion; Depression RENAL AND URINARY DISORDERS - Proteinuria REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Erectile dysfunction RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Hypoxia; Pleural effusion; Pneumonitis; Pneumothorax SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Hyperhidrosis; Purpura; Rash acneiform; Skin and subcutaneous tissue disorders - Other (non-life threatening squamous cell carcinoma of skin: keratoacanthoma type); Skin hypopigmentation VASCULAR DISORDERS - Flushing; Hypotension; Vasculitis Note: Sorafenib (BAY ) in combination with other agents could cause an exacerbation of any adverse event currently known to be caused by the other agent, or the combination may result in events never previously associated with either agent. 25

12 A Double-blind, Randomized, Placebo-Controlled Phase III Trial of Carboplatin, Paclitaxel and Sorafenib versus Carboplatin, Paclitaxel and placebo in Patients with Unresectable Locally Advanced or Stage IV Melanoma Version Date: March 28, 2012 Appendix I Informed Consent Template for Cancer Treatment Trials (English Language) This is a clinical trial, a type of research study. Your study doctor will explain the clinical trial to you. Clinical trials include only people who choose to take part. Please take your time to make your decision about taking part. You may discuss your decision with your friends and family. You can also discuss it with your health care team. If you have any questions, you can ask your study doctor for more explanation. You are being asked to take part in this study because you have melanoma that has spread or cannot be treated with surgery. WHY IS THIS STUDY BEING DONE? The purpose of this study is to compare the effects, good and/or bad, of carboplatin and paclitaxel when given with BAY or placebo on you and your melanoma cancer to find out which is better. Placebo does not contain active medication and should not influence the effect of carboplatin and paclitaxel. BAY may influence the effect, good and/or bad, of carboplatin and paclitaxel. Determining what effect BAY might have is the purpose of this study. You will get either BAY with carboplatin and paclitaxel or placebo with carboplatin and paclitaxel. You will not get both. BAY is investigational and has not been approved by the FDA for use in this type of cancer. Carboplatin and paclitaxel are FDA approved for use in other types of cancer. They are investigational for use in this cancer. HOW MANY PEOPLE WILL TAKE PART IN THE STUDY? About 800 people will take part in this study. Appendix I Page 1 of 19

13 Revised 2/09, Addendum #11 Revised 7/10, Addendum #12 Kidney damage Liver damage and/or failure Seizures Fainting Irregular heartbeat Heart attack Hearing loss Rare but Serious Acute leukemia Death Rev. 9/06, 2/09, 7/10, 6/12 Risks and side effects related to the BAY include those which are: Likely: Belly pain Diarrhea Nausea or the urge to vomit Fatigue or tiredness Increased blood level of a liver enzyme (ALT/SGPT) Increased blood level of a liver or bone enzyme (alkaline phosphatase) Increased blood level of a liver enzyme (AST/SGOT) Increased blood level of a liver pigment (bilirubin) often a sign of liver problems Increased blood level of creatinine (a substance normally eliminated by the kidneys into the urine) Increased INR (measure of the ability of the blood to clot properly) which increases the risk of bleeding Increased blood level of fat-digesting enzyme (lipase) Decreased number of a type of white blood cell (lymphocyte) Decreased number of a type of blood cell that helps to clot blood (platelet) Increased blood level of a digestive enzyme (amylase) Weight loss Decrease in the total number of white blood cells (leukocytes) Loss of appetite Increased blood sugar level Decreased levels of a blood protein called albumin Decreased blood level of calcium Decreased blood level of sodium Decreased blood level of phosphate Hair loss Swelling and redness of the skin on the palms of the hands and soles of the feet Skin rash with the presence of macules (flat discolored area) and papules (raised bump) Appendix I Page 8 of 19

14 Revised 2/09, Addendum #11 Revised 7/10, Addendum #12 Less Likely: Lack of enough red blood cells (anemia) Fever associated with dangerously low levels of a type of white blood cell (neutrophils) Irritation or sores in the lining of the anus Fluid collection in the abdomen Constipation Bleeding in some organ(s) of the digestive tract Irritation or sores in the lining of the mouth Irritation or sores in the lining of the rectum Irritation or sores in the lining of the small bowel Vomiting Swelling of the arms and/or legs Fever Chest pain not heart-related Infection Test that shows a problem in blood clotting Increased blood level of cholesterol Increased blood level of a liver enzyme (GGT) Decreased blood level of carbon dioxide Decreased number of a type of white blood cell (neutrophil/granulocyte) Increased blood level of calcium Increased blood level of potassium Increased blood level of sodium Increased blood level of uric acid, a waste material from food digestion Decreased blood sugar level Decreased blood level of potassium Joint pain Back pain Bone pain Muscle spasms Muscle pain Leg and/or arm pain Dizziness (or sensation of lightheadedness, unsteadiness, or giddiness) Headache or head pain Inflammation (swelling and redness) or degeneration of the peripheral nerves (those nerves outside of brain and spinal cord) causing numbness, tingling, burning Difficulty sleeping or falling asleep Sudden decrease of kidney function Blood in the urine Bleeding in the kidney Presence of blood in a fallopian tube (tube between ovary to uterus [womb]) Bleeding in the ovary Bleeding in the prostate Appendix I Page 9 of 19

15 Revised 2/09, Addendum #11 Revised 7/10, Addendum #12 Bleeding in the spermatic cord (a structure resembling a cord that suspends the testis within the scrotum and contains the vas deferens [the tube that carries sperm] and other vessels and nerves) Bleeding in the testis Bleeding in the uterus (womb) Bleeding in the vagina Bleeding from the lungs Cough Shortness of breath Nose bleed Irritation or sores in the lining of the voice box Irritation or sores in the lining of the throat Irritation or sores in the lining of the windpipe Voice change Dry skin Itching High blood pressure Formation of a blood clot that plugs the blood vessel; blood clots may break loose and travel to another place, such as the lung Rare but Serious: Collection of signs and symptoms that indicate sudden heart disease in which the heart does not get enough oxygen. Sudden symptoms such as chest pain, shortness of breath, or fainting could indicate heart disease and should be reported right away. Signs such as abnormal EKG and blood tests can confirm damage to the heart. Decrease in heart's ability to pump blood during the "active" phase of the heartbeat (systole) Heart attack caused by a blockage or decreased blood supply to the heart Gastrointestinal perforation : A tear or hole in the stomach or gut that can lead to serious complications and may require surgery to repair Serious, life-threatening allergic reaction requiring immediate medical treatment by your doctor. The reaction may include extremely low blood pressure, swelling of the throat, difficulty breathing, and loss of consciousness. Bleeding in the brain Abnormal changes in the brain that can cause a collection of symptoms including headache, confusion, seizures, and vision loss associated with MRI imaging findings (RPLS) Severe reaction of the skin and gut lining that may include rash and shedding or death of tissue Potentially life-threatening condition affecting less than 10% of the skin in which cell death causes the epidermis (outer layer) to separate from the dermis (middle layer) Appendix I Page 10 of 19