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10.4 caepr for bevacizumab comprehensive

| Other (ovarian  failure)14                                                                                                                                                   | Vaginal fistula             |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------|
| Vaginal hemorrhage                                                                                                                                                           | Vaginal hemorrhage (Gr 3)   |
| RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS  Allergic rhinitis                                                                                                           | Allergic rhinitis (Gr 3)    |
| Bronchopleural fistula  Bronchopulmonary hemorrhage                                                                                                                          |                             |
| Cough                                                                                                                                                                        | Cough (Gr 3)                |
| Dyspnea                                                                                                                                                                      | Dyspnea (Gr 2)              |
| Epistaxis                                                                                                                                                                    | Epistaxis (Gr 3)            |
| Hoarseness                                                                                                                                                                   | Hoarseness (Gr 3)           |
| Respiratory, thoracic and  mediastinal disorders - Other  (nasal-septal perforation)  Respiratory, thoracic and  mediastinal disorders - Other  (tracheo-esophageal fistula) |                             |
| SKIN AND SUBCUTANEOUS TISSUE DISORDERS  Pruritus                                                                                                                             | Pruritus (Gr 2)             |
| Rash maculo-papular                                                                                                                                                          | Rash maculo-papular (Gr 2)  |
| Urticaria                                                                                                                                                                    | Urticaria (Gr 2)            |
| VASCULAR DISORDERS  Hypertension                                                                                                                                             | Hypertension (Gr 3)         |
| Thromboembolic event                                                                                                                                                         | Thromboembolic event (Gr 3) |
| Vascular disorders - Other  (arterial thromboembolic  event)2,15                                                                                                             |                             |  
1This 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 e-mail.  
2The risks of arterial thrombosis such as cardiac or CNS ischemia are increased in elderly patients and in patients with a history of diabetes.  
3Supraventricular arrhythmias may include supraventricular tachycardia, atrial fibrillation and atrial flutter. 4Gastrointestinal fistula may include: Anal fistula, Colonic fistula, Duodenal fistula, Esophageal fistula, Gastric fistula, Gastrointestinal fistula, Rectal fistula, and other sites under the GASTROINTESTINAL DISORDERS SOC.  
5Gastrointestinal hemorrhage may include: Colonic hemorrhage, Duodenal hemorrhage, Esophageal hemorrhage, Esophageal varices hemorrhage, Gastric hemorrhage, Hemorrhoidal hemorrhage, Intra-abdominal hemorrhage, Oral hemorrhage, Rectal hemorrhage, and other sites under the GASTROINTESTINAL DISORDERS SOC.  
6Gastrointestinal obstruction may include: Colonic obstruction, Duodenal obstruction, Esophageal obstruction, Ileal obstruction, Jejunal obstruction, Rectal obstruction, Small intestinal obstruction, and other sites under the GASTROINTESTINAL DISORDERS SOC.  
7Gastrointestinal perforation may include: Colonic perforation, Duodenal perforation, Esophageal perforation, Gastric perforation, Jejunal perforation, Rectal perforation, Small intestinal perforation, and other sites under the GASTROINTESTINAL DISORDERS SOC.  
8Gastrointestinal ulcer may include: Duodenal ulcer, Esophageal ulcer, Gastric ulcer, and other sites under the GASTROINTESTINAL DISORDERS SOC.  
9Infection may include any of the 75 infection sites under the INFECTIONS AND INFESTATIONS SOC.  
10Anastomotic leak may include Gastric anastomotic leak; Gastrointestinal anastomotic leak; Large intestinal anastomotic leak; Rectal anastomotic leak; Small intestinal anastomotic leak; Urostomy leak; Vaginal anastomotic leak 11Metaphyseal dysplasia was observed in young patients who still have active epiphyseal growth plates.  
12Cases of osteonecrosis of the jaw (ONJ) have been reported in cancer patients in association with bevacizumab treatment, the majority of whom had received prior or concomitant treatment with i.v. bisphosphonates.  
13Increased rate of peripheral sensory neuropathy has been observed in trials combining bevacizumab and chemotherapy compared to chemotherapy alone.  
14Ovarian failure, defined as amenorrhea lasting 3 or more months with follicle-stimulating hormone (FSH)
elevation (≥30 mIU/mL), was increased in patients receiving adjuvant bevacizumab plus mFOLFOX compared to mFOLFOX alone (34% vs. 2%). After discontinuation of bevacizumab, resumption of menses and an FSH level
<30 mIU/mL was demonstrated in 22% (7/32) of these women. Long term effects of bevacizumab exposure on fertility are unknown.  
15Arterial thromboembolic event includes visceral arterial ischemia, peripheral arterial ischemia, heart attack and stroke.  
Also reported on bevacizumab (rhuMAb VEGF) trials but with the relationship to bevacizumab (rhuMAb VEGF) still undetermined:
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system disorders - Other (idiopathic thrombocytopenia purpura); Bone marrow hypocellular; Disseminated intravascular coagulation; Hemolysis CARDIAC DISORDERS - Atrioventricular block complete; Atrioventricular block first degree; Cardiac arrest; Myocarditis; Pericardial effusion; Restrictive cardiomyopathy; Right ventricular dysfunction EAR AND LABYRINTH DISORDERS - Ear and labyrinth disorders - Other (tympanic membrane perforation);
Hearing impaired; Tinnitus; Vertigo ENDOCRINE DISORDERS - Hyperthyroidism; Hypothyroidism EYE DISORDERS - Blurred vision; Cataract; Dry eye; Extraocular muscle paresis; Eye disorders - Other
(blindness); Eye disorders - Other (conjunctival hemorrhage); Eye disorders - Other (corneal epithelial defect); Eye disorders - Other (floaters); Eye disorders - Other (ischemic CRVO); Eye disorders - Other (macular pucker); Eye disorders - Other (transient increased IOP > or =30 mm Hg); Eye disorders - Other (vitreous hemorrhage); Eye pain; Keratitis; Optic nerve disorder; Photophobia; Retinal detachment; Retinal tear; Retinopathy; Watering eyes GASTROINTESTINAL DISORDERS - Ascites; Chelitis; Colonic stenosis; Dry mouth; Dysphagia; Enterocolitis; Esophageal pain; Esophageal stenosis; Flatulence; Gastrointestinal disorders - Other (peritonitis); Oral pain; Pancreatitis; Proctitis; Rectal mucositis; Rectal stenosis;Typhlitis GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Death NOS; Edema face; Edema limbs; Edema trunk; Facial pain; Fever; Flu like symptoms; Gait disturbance; Injection site reaction; Localized edema; Multi-organ failure; Sudden death NOS HEPATOBILIARY DISORDERS - Cholecystitis; Gallbladder necrosis; Gallbladder obstruction; Hepatic failure; Hepatic necrosis INFECTIONS AND INFESTATIONS - Infections and infestations - Other (aseptic meningitis)
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Arterial injury; Bruising; Burn; Dermatitis radiation; Fracture INVESTIGATIONS - Activated partial thromboplastin time prolonged; Blood antidiuretic hormone abnormal; CD4 lymphocytes decreased; CPK increased; Carbon monoxide diffusing capacity decreased; Electrocardiogram QT corrected interval prolonged; Forced expiratory volume decreased; GGT increased; INR increased; Lipase increased; Lymphocyte count decreased; Serum amylase increased; Weight gain METABOLISM AND NUTRITION DISORDERS - Acidosis; Hypercalcemia; Hyperglycemia; Hyperkalemia; Hypermagnesemia; Hypernatremia; Hypertriglyceridemia; Hyperuricemia; Hypoalbuminemia; Hypocalcemia; Hypokalemia; Hypomagnesemia; Hyponatremia; Hypophosphatemia MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthritis; Back pain; Bone pain; Chest wall pain; Fibrosis deep connective tissue; Generalized muscle weakness; Head soft tissue necrosis; Joint effusion; Muscle weakness lower limb; Muscle weakness upper limb; Musculoskeletal and connective tissue disorder - Other (aseptic necrotic bone); Musculoskeletal and connective tissue disorder - Other (myasthenia gravis);
Musculoskeletal and connective tissue disorder - Other (polymyalgia rheumatica); Neck pain; Pain in extremity; Pelvic soft tissue necrosis; Soft tissue necrosis lower limb NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Tumor pain NERVOUS SYSTEM DISORDERS - Arachnoiditis; Ataxia; Central nervous system necrosis; Cerebrospinal fluid leakage; Cognitive disturbance; Depressed level of consciousness; Dysesthesia; Dysgeusia; Dysphasia; Encephalopathy; Extrapyramidal disorder; Facial nerve disorder; Hydrocephalus; Leukoencephalopathy; Memory impairment; Nervous system disorders - Other (increased intracranial pressure); Paresthesia; Peripheral motor neuropathy; Pyramidal tract syndrome; Seizure; Somnolence; Tremor; Vasovagal reaction PSYCHIATRIC DISORDERS - Agitation; Anxiety; Confusion; Depression; Insomnia; Libido decreased; Psychosis RENAL AND URINARY DISORDERS - Bladder spasm; Chronic kidney disease; Cystitis noninfective; Renal and urinary disorders - Other (dysuria); Renal and urinary disorders - Other (ureterolithiasis); Renal hemorrhage; Urinary frequency; Urinary incontinence; Urinary retention; Urinary tract obstruction; Urinary tract pain REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Breast pain; Erectile dysfunction; Irregular menstruation; Pelvic pain; Vaginal discharge RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Adult respiratory distress syndrome; Atelectasis; Hypoxia; Nasal congestion; Pulmonary fibrosis; Pulmonary hypertension; Respiratory failure; Respiratory, thoracic and mediastinal disorders - Other (dry nares); Respiratory, thoracic and mediastinal disorders -
Other (pulmonary infarction) SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Dry skin; Hyperhidrosis; Nail loss; Pain of skin; Palmar-plantar erythrodysesthesia syndrome; Photosensitivity; Purpura; Rash acneiform; Skin and subcutaneous tissue disorders - Other (diabetic foot ulcer); Skin and subcutaneous tissue disorders - Other (skin breakdown/ decubitus ulcer); Skin hyperpigmentation; Skin induration; Skin ulceration; Stevens-Johnson syndrome VASCULAR DISORDERS - Flushing; Hot flashes; Hypotension; Lymphocele; Phlebitis; Vasculitis Note: Bevacizumab (rhuMAb VEGF) 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.
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10.5 caepr for sorafenib comprehensive

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. This subset of AEs (SPEER) is a list of events that are protocol specific exceptions to expedited reporting to NCI via CTEP-AERS (except as noted below). Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf for further clarification. *Frequency is provided based on 2157 patients.* Below is the CAEPR for sorafenib (BAY 43-9006).  
NOTE: Report AEs on the SPEER **ONLY IF** they exceed the grade noted in parentheses next to the AE in the SPEER. If this CAEPR is part of a combination protocol using multiple investigational agents and has an AE listed on different SPEERs, use the lower of the grades to determine if expedited reporting is required.  
| Version 2.4, December 21, 20111  Specific Protocol Exceptions  to Expedited Reporting  (SPEER)   |                                                                                         |                         |
|--------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------|-------------------------|
| Adverse Events with Possible                                                                     |                                                                                         |                         |
| Relationship to Sorafenib (BAY 43-9006)   (CTCAE 4.0 Term)  [n= 2157]                            | (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                                                                                 | Gastrointestinal hemorrhage2                                                            |                         |  
| hemorrhage2                                                                                                | (Gr 3)                                                   |
|------------------------------------------------------------------------------------------------------------|----------------------------------------------------------|
| Gastrointestinal  perforation3                                                                             |                                                          |
| 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                                                                                     |                                                          |
| IMMUNE SYSTEM DISORDERS                                                                                    | Anaphylaxis                                              |
| INFECTIONS AND INFESTATIONS  Infection4  INVESTIGATIONS  Activated partial  thromboplastin time  prolonged | Activated partial  thromboplastin time prolonged  (Gr 2) |
| Alanine aminotransferase                                                                                   | Alanine aminotransferase                                 |
| increased                                                                                                  | increased (Gr 3)                                         |
| Alkaline phosphatase                                                                                       | Alkaline phosphatase increased                           |
| increased                                                                                                  | (Gr 3)                                                   |
| Aspartate aminotransferase                                                                                 | Aspartate aminotransferase                               |
| increased                                                                                                  | 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                                                                                           | Lymphocyte count decreased                               |
| decreased                                                                                                  | (Gr 3)                                                   |
| Neutrophil count                                                                                           | Neutrophil count decreased                               |
| 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)                            |
| 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                                                              |                                                     |  
1This 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 e-mail.  
2Gastrointestinal 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.  
3Gastrointestinal 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.  
4Includes all 75 infection sites under the INFECTIONS AND INFESTATIONS SOC.  
Also reported on sorafenib (BAY 43-9006) trials but with the relationship to sorafenib (BAY 43-9006) 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 43-9006) 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.  
10.6 **Data Reporting**
This study will be monitored by the Clinical Data Update System (CDUS) version 3.0. Cumulative CDUS data will be submitted quarterly to CTEP by electronic means (NCI C3D). Reports are due January 31, April 30, July 31, and October 31. *Instructions for submitting data* using the CDUS can be found on the CTEP web site (http://ctep.cancer.gov/reporting/cdus.html).
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11. cooperative research and development

The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI under a Collaborative Agreement (CRADA, CTA) between the Pharmaceutical Company(ies) (hereinafter referred to as Collaborator(s)) and the NCI Division of Cancer Treatment and Diagnosis. Therefore, the following obligations/guidelines, in addition to the provisions in the Intellectual Property Option to Collaborator contained within the terms of award, apply to the use of the Agent(s) in this study: 1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor can Agent(s) be transferred or licensed to any party not participating in the clinical study. Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) and shall be maintained as such by the investigators. The protocol documents for studies utilizing investigational Agents contain confidential information and should not be shared or distributed without the permission of the NCI. If a copy of this protocol is requested by a patient or patient's family member participating on the study, the individual should sign a confidentiality agreement. A suitable model agreement can be downloaded from: http://ctep.cancer.gov 2. For a clinical protocol where there is an investigational Agent used in combination with
(an)other investigational Agent(s), each the subject of different collaborative agreements , the access to and use of data by each Collaborator shall be as follows (data pertaining to such combination use shall hereinafter be referred to as "Multi-Party Data"):
a. NCI must provide all Collaborators with prior written notice regarding the existence and nature of any agreements governing their collaboration with NIH, the design of the proposed combination protocol, and the existence of any obligations that would tend to restrict NCI's participation in the proposed combination protocol.  
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical trial by any other Collaborator solely to the extent necessary to allow said other Collaborator to develop, obtain regulatory approval or commercialize its own investigational Agent.  
c. Any Collaborator having the right to use the Multi-Party Data from these trials must agree in writing prior to the commencement of the trials that it will use the Multi-Party Data solely for development, regulatory approval, and commercialization of its own investigational Agent.  
3. Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement will be made available exclusively to Collaborator(s), the NCI, and the FDA,
as appropriate and unless additional disclosure is required by law or court order. Additionally, all Clinical Data and Results and Raw Data will be collected, used and disclosed consistent with all applicable federal statutes and regulations for the protection of human subjects, including, if applicable, the Standards for Privacy of Individually Identifiable Health Information set forth in 45 C.F.R. Part 164.  
4. When a Collaborator wishes to initiate a data request, the request should first be sent to the NCI, who will then notify the appropriate investigators (Group Chair for Cooperative Group studies, or PI for other studies) of Collaborator's wish to contact them.  
5. Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is a DMC for this clinical trial.  
6. Any manuscripts reporting the results of this clinical trial must be provided to CTEP for immediate delivery to Collaborator(s) for advisory review and comment prior to submission for publication. Collaborator(s) will have 30 days from the date of receipt for review. Collaborator shall have the right to request that publication be delayed for up to an additional 30 days in order to ensure that Collaborator's confidential and proprietary data, in addition to Collaborator(s)'s intellectual property rights, are protected. Copies of abstracts must be provided to CTEP for forwarding to Collaborator(s) for courtesy review as soon as possible and preferably at least three (3) days prior to submission, but in any case, prior to presentation at the meeting or publication in the proceedings. Press releases and other media presentations must also be forwarded to CTEP prior to release. Copies of any manuscript, abstract and/or press release/ media presentation should be sent to:
Regulatory Affairs Branch, CTEP, DCTD, NCI Executive Plaza North, Suite 7111 Bethesda, Maryland 20892 FAX 301-402-1584 Email: anshers@ctep.nci.nih.gov The Regulatory Affairs Branch will then distribute them to Collaborator(s). No publication, manuscript or other form of public disclosure shall contain any of Collaborators confidential/ proprietary information. NOTE: The trial was completed with CTEP September 4, 2014.
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12. statistical considerations 12.1 study

The primary objective of this study is to determine if the clinical response rate of this combination is sufficiently high to warrant further evaluation in patients with ovarian cancer. The clinical outcome will be defined as complete response (CR) or partial response (PR). Secondary objectives include evaluation of progression free survival at greater than or equal to 6 cycles, toxicity, as well as a variety of biologic markers to determine if treatment impacts these parameters, and to see if the changes may be associated with clinical outcome. These studies will include characterization of effects on survival/proliferation, apoptotic, and angiogenic signaling cascades; identification of genetic mutations in raf to determine if this is a potentially important factor in disease response, apply real-time assessments of tumor vascularity and metabolism to characterization of response; and assessment of angiogenic effects of this combination.  
Eligible patients will be stratified upon enrollment according to whether they have received prior bevacizumab or not. In patients with no prior exposure to Bevacizumab, a Simon two-stage optimal design (1) will be used to determine whether the combination of bevacizumab and sorafenib is able to rule out a 20% response rate (p0=0.20) in favor of a more desirable 40% response rate (p1=0.40). Using alpha=0.10 and beta=0.10, initially 17 evaluable patients will be enrolled and receive treatment. If there are 0-3 clinical responses (CR+PR), then no further patients will be enrolled onto this arm of the trial, and this combination will be considered insufficiently active for further consideration in this disease. After 17 patients have been enrolled in this stratum, we will halt accrual until this analysis of the first stage is completed. If 4 or more clinical responses are identified in the first 17 patients enrolled in this stratum, then accrual will continue until a total of 37 patients are enrolled. If 3 to 10 clinical responses are noted in 37 patients, then the agents will not be considered sufficiently active in this disease for this stratum, while 11 or greater responses in 37 patients in this stratum will warrant further investigation in subsequent trials. Under the null hypothesis of 20% response rate, the probability of early termination in this stratum is 55%. In patients with prior exposure to Bevacizumab, a Simon two-stage optimal design (1) will be used to determine whether the combination of bevacizumab and sorafenib is able to rule out a 5% response rate (p0=0.05) in favor of a more desirable 20% response rate (p1=0.20). Using alpha=0.05 and beta=0.10, initially 21 evaluable patients will be enrolled and receive treatment. If there are 0-1 clinical responses (CR+PR), then no further patients will be enrolled onto this arm of the trial, and this combination will be considered insufficiently active for further consideration in this disease. After 21 patients have been enrolled in this stratum, we will halt accrual until this analysis of the first stage is completed. If 2 or more clinical responses are identified in the first 21 patients enrolled in this stratum, then accrual will continue until a total of 41 patients are enrolled. If 2 to 4 clinical responses are noted in 41 patients, then the agents will not be considered sufficiently active in this disease for this stratum, while 5 or greater responses in 41 patients in this stratum will warrant further investigation in subsequent trials. Under the null hypothesis of 5% response rate, the probability of early termination in this stratum is 72%. Additional patients will be accrued to replace any patient who is entered on trial but does not complete the 2 cycle time period for evaluation of the primary endpoint, response (i.e. uncontrolled intercurrent illness, voluntary self-withdrawal, toxicity precluding continuation). Demonstration of progressive disease within that period will not require replacement as it is an outcome response. Any and all adverse events that occur during the time of drug exposure will be counted. Three replacement patients per stratum will be allowed. A variety of markers will be evaluated at baseline as well as at cycle 2, day 1 of treatment. Changes from baseline will be determined in either absolute or relative terms as appropriate, and evaluated for statistical significance, as well as to determine if the changes or the actual values at a time point are associated with clinical response. Paired comparisons with baseline will be done using a paired t-test or Wilcoxon signed rank test as appropriate, and, if accrual is able to continue onto the second stage, the changes will be compared between responders (CR +PR) and non-responders (SD+PD) using a two sample t-test or Wilcoxon rank sum test as appropriate. As a minimum, for a given stratum, even if 10 markers were evaluated compared to baseline, with 20 patients there would be 88% power to declare a given marker change from baseline to be significant at the 0.05 level after adjusting for multiple comparisons by the Bonferroni procedure, although less stringent adjustments may be made in practice as these would be secondary endpoints. PET and MRI parameters will also be obtained at the same time points, and changes in these parameters will also be compared in a similar fashion, both with respect to the changes themselves and with respect to any association with clinical response. In all such cases, these analyses will be considered exploratory and not formally adjusted for multiple comparisons. However, to ensure proper interpretation in the context of a potentially large number of explorations being performed, only p-values <0.01 will be interpretable as being associated with statistical significance. Kaplan-Meier curves depicting time to progression on sorafenib + bevacizumab will be provided for both strata. Appropriate 95% confidence intervals will be formed. Toxicities will be tabulated and the frequency of grade 3 or greater toxicities will be calculated, and appropriate 95% confidence intervals will be formed. As a final exploratory analysis, results from both strata may be pooled if it is determined that the results from both strata are sufficiently similar, that is, if p>0.10 for a test to determine if any set of results differ by stratum. Since patients with prior bevacizumab exposure are expected to potentially have different outcomes than those who do not, this combination of results will be carefully noted to be a secondary evaluation, not necessarily as meaningful as results from within each stratum, and will only be done cautiously if appropriate to do so at all. For those correlative studies that do not meet criteria for statistical significance, they will be used as exploratory analyses for hypothesis generator (please refer to section **12.4** of the protocol).
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12.2 sample size/accrual rate

It is anticipated that 30 patients per year may be enrolled onto the protocol. In order to enroll 78 evaluable patients, an accrual period of up to 3 years is expected.
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12.4 analysis of secondary endpoints

Proteomic and molecular endpoints will be evaluated on the protocol in all available enrolled patients. These will all be considered exploratory analyses and will not have their statistical results adjusted for multiple comparisons. However, all interesting findings will be carefully interpreted as hypothesis generating.  
12.5 **Reporting and Exclusions**  
12.5.1 **Evaluation of toxicity.** All patients will be evaluable for toxicity from the time of their first treatment
12.5.2 **Evaluation of response.** All patients included in the study must be assessed for response to treatment, even if there are major protocol treatment deviations or if they are ineligible. Each patient will be assigned one of the following categories: 1) complete response, 2) partial response, 3) stable disease, 4) progressive disease, 5) early death from malignant disease, 6) early death from toxicity, 7) early death because of other cause, or 9) unknown (not assessable, insufficient data). [Note: By arbitrary convention, category 9 usually designates the "unknown" status of any type of data in a clinical database.] All of the patients who met the eligibility criteria (with the possible exception of those who received no study medication) should be included in the main analysis of the response rate. Patients in response categories 4-9 should be considered as failing to respond to treatment (disease progression). Thus, an incorrect treatment schedule or drug administration does not result in exclusion from the analysis of the response rate. Precise definitions for categories 4-9 will be protocol specific.
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13. human subjects protections 13.1

This study will be open to all women with recurrent epithelial ovarian, fallopian, and peritoneal cancer regardless of gender, ethnicity, or race provided that the aforementioned inclusion and exclusion criteria are met. For safety reasons, only pregnant women and children are excluded from this study. This study will be recruited through internal referral, our local physician referral base, and through various cancer information hotlines (i.e., Clinical Studies Support Center, 1888-624-1937). All individuals with epithelial ovarian, fallopian, and peritoneal cancer that is refractory to standard care are eligible according to the eligibility criteria within section 3. This is a phase II study to determine the efficacy of this combination for the treatment of these cancers. Patients must have failed therapy of proven efficacy for their disease.  
Female patients all racial /ethnic groups are eligible for this study if they meet the eligibility criteria outlined in section 3. To date, there is no information that suggests that differences in drug metabolism or disease response would be expected in one ethnic group compared to another. Efforts will be made to extend accrual to each representative population, but in this preliminary study, a balance must be struck between patient safety considerations and limitations on the number of individuals exposed to potentially toxic and/or ineffective treatments on the one hand and the need to explore racial/ethnic aspects of clinical research on the other hand. If differences in outcome that correlate to ethnic identity are noted, accrual may be expanded, or a follow-up study may be written to investigate those differences more fully.
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13.2 participation of children

Epithelial cancer of the ovary, fallopian tubes, or peritoneum in children is a exceedingly rare, reportable disease. Patients under the age of 18 will be excluded from study.
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13.3 evaluation of benefits and

The potential benefit to a patient who enters study is a reduction in the bulk of her tumor, which may or may not have a favorable impact on symptoms and/or survival. Potential risks include the possible occurrence of any of a range of side effects that are listed in the pharmaceutical section and the consent document. The procedure for protecting against or minimizing risks will be to medically evaluate patients on a regular basis as described earlier, including initial eligibility screening prior to enrollment on the protocol.
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13.4 risks/benefits analysis 13.4.1 potential

13.4.1.1 Risk of serial biopsies: All care will be taken to minimize risks that may be incurred by tumor sampling. However, there are procedure-related risks (such as bleeding, infection and visceral injury) that will be explained fully during informed consent. If patients suffer any physical injury as a result of the biopsies, immediate medical treatment is available at the NIH's Clinical Center in Bethesda, Maryland. Although no compensation is available, any injury will be fully evaluated and treated in keeping with the benefits or care to which patients are entitled under applicable regulations.  
13.4.1.2 Risk of Treatment: Details of the risk of drug therapy are detailed in section 6. 13.4.1.3 Risks of radiation exposure: This study incorporates serial imaging with radioactive substances related to the PET scans and CT scans for biopsy guidance (where needed) in the study. Patients will receive 3 injections of 15 mCi of F-18 FDG for PET. The total effective dose is less than 5 rem. This study is approved by the NIH Radiation Safety Committee.
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13.5 consent and assent process

An associate or principal investigator on the trial will inform patients of the purpose, alternatives, treatment plan, research objectives and follow-up of this trial. The patient will be provided an IRB-approved consent for review and signature and his/her questions will be answered. After a decision is made to enroll into the study, a signature will be obtained from the patient at a subsequent visit. A copy of the signed informed consent will be placed in the patient's medical record and the original held in the Protocol Office. All patients must have a signed informed consent form and an on-study (confirmation of eligibility) form filled out and signed by a participating investigator before entering on study.
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14. data and safety monitoring

Patients are reviewed weekly in team meetings and response data will be reviewed on a quarterly basis as well. All unexpected or serious adverse drug reactions will be reported to the NCI Institutional Review Board (IRB) within 10 working days of the date of occurrence. Safety information from patients enrolled onto the study will be gathered and reported. Any unusual toxicity will be explored for possible causative mechanisms. The safety of the repetitive biopsy procedure will also be determined and reported. Any unanticipated or unknown treatment- or drug-related toxicity(ies) and life-threatening and lethal toxicity(ies) must follow the guidelines described in section 10. Clinical Associates and/or senior staff should notify the Principal Investigator at 301-402-2726 (Dr. Annunziata's), Bldg.10, Rm 12N226 of the occurrence of such toxicity. A summary of the ongoing study will be submitted to the NCI's Institutional Review Board at 12 month intervals and a final report will be sent within six months of study completion at the request of the Institutional Review Board using the CTEP study summary form. The status reported will be submitted and presented at upcoming NCI meetings as requested.
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15. references

1. Singer, G., et al., Mutations in BRAF and KRAS characterize the development of low-grade ovarian serous carcinoma. J Natl Cancer Inst, 2003. 95(6): p. 484-6.  
2. Campbell, S.L., et al., *Increasing complexity of Ras signaling.* Oncogene, 1998. 17(11 Reviews): p. 1395-413.  
3. Chong, H., H.G. Vikis, and K.L. Guan, *Mechanisms of regulating the Raf kinase family.* Cell Signal, 2003. 15(5): p. 463-9.  
4. Cohen, Y., et al., *BRAF mutation in papillary thyroid carcinoma.* J Natl Cancer Inst, 2003.  
95(8): p. 625-7.  
5. Davies, H., et al., *Mutations of the BRAF gene in human cancer.* Nature, 2002. 417(6892): p.  
949-54.  
6. Mercer, K.E. and C.A. Pritchard, Raf proteins and cancer: B-Raf is identified as a mutational target. Biochim Biophys Acta, 2003. **1653**(1): p. 25-40.  
7. Pollock, P.M. and P.S. Meltzer, A genome-based strategy uncovers frequent BRAF mutations in melanoma. Cancer Cell, 2002. 2(1): p. 5-7.  
8. Sawyers, C.L., *Finding the next Gleevec: FLT3 targeted kinase inhibitor therapy for acute* myeloid leukemia. Cancer Cell, 2002. 1(5): p. 413-5.  
9. Tannapfel, A., et al., *Mutations of the BRAF gene in cholangiocarcinoma but not in* hepatocellular carcinoma. Gut, 2003. 52(5): p. 706-12.  
10. Bergers, G., et al., *Benefits of targeting both pericytes and endothelial cells in the tumor* vasculature with kinase inhibitors. J Clin Invest, 2003. 111(9): p. 1287-95.  
11. Ferrara, N., *VEGF and the quest for tumour angiogenesis factors.* Nat Rev Cancer, 2002.  
2(10): p. 795-803.  
12. Apperley, J.F., et al., Response to imatinib mesylate in patients with chronic myeloproliferative diseases with rearrangements of the platelet-derived growth factor receptor beta. N Engl J Med, 2002. 347(7): p. 481-7.  
13. Heinrich, M.C., et al., Inhibition of KIT tyrosine kinase activity: a novel molecular approach to the treatment of KIT-positive malignancies. J Clin Oncol, 2002. 20(6): p. 1692-703.  
14. Alavi, A., et al., *Role of Raf in vascular protection from distinct apoptotic stimuli.* Science, 2003. 301(5629): p. 94-6.  
15. Christian, B., *26-Week intravenous toxicity study with rhuMAb VEGF in cynomolgus* monkeys with a 12 week recovery. 1999, Genetech Report: South San Francisco. p. 97-194.  
16. Ryan, A.M., et al., Preclinical safety evaluation of rhuMAbVEGF, an antiangiogenic humanized monoclonal antibody. Toxicol Pathol, 1999. 27(1): p. 78-86.  
17. Ferrara, N., et al., *Vascular endothelial growth factor is essential for corpus luteum* angiogenesis. Nat Med, 1998. 4(3): p. 336-40.  
18. Gordon, M.S., et al., Phase I safety and pharmacokinetic study of recombinant human antivascular endothelial growth factor in patients with advanced cancer. J Clin Oncol, 2001. 19(3): p. 843-50.  
19. Margolin, K., et al., Phase Ib trial of intravenous recombinant humanized monoclonal antibody to vascular endothelial growth factor in combination with chemotherapy in patients with advanced cancer: pharmacologic and long-term safety data. J Clin Oncol, 2001. 19(3): p. 851-6.  
20. Yang, J.C., et al., A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med, 2003. 349(5): p. 427-34.  
21. Levine, M.N., Prevention of thrombotic disorders in cancer patients undergoing chemotherapy. Thromb Haemost, 1997. 78(1): p. 133-6.  
22. Yang, R., et al., Effects of vascular endothelial growth factor on hemodynamics and cardiac performance. J Cardiovasc Pharmacol, 1996. 27(6): p. 838-44.  
23. Shen, B.Q., D.Y. Lee, and T.F. Zioncheck, *Vascular endothelial growth factor governs* endothelial nitric-oxide synthase expression via a KDR/Flk-1 receptor and a protein kinase C signaling pathway. J Biol Chem, 1999. 274(46): p. 33057-63.  
24. Ostendorf, T., et al., *VEGF(165) mediates glomerular endothelial repair.* J Clin Invest, 1999.  
104(7): p. 913-23.  
25. Ferrara, N., H.P. Gerber, and J. LeCouter, *The biology of VEGF and its receptors.* Nat Med, 2003. 9(6): p. 669-76.  
26. Hurwitz, H., et al. *Bevacizumab (a monoclonal antibody to vascular endothelial growth* factor) prolongs survival in first-line colorectal cancer (CRC): Results of a phase III trial of
bevacizumab in combination with bolus IFL (irinotecan, 5-fluorouracil, leucovorin) as firstline therapy in subjects with metastatic CRC. (Abstactr \#3646). in *American Society of* Clinical Oncology Annual Meeting. 2003. Chicago, IL.  
27. Simon, R., *Optimal two-stage designs for phase II clinical trials.* Control Clin Trials, 1989.  
10(1): p. 1-10.  
28. Weidner, N., et al., Tumor angiogenesis and metastasis--correlation in invasive breast
carcinoma. N Engl J Med, 1991. 324(1): p. 1-8.  
29. Pollock, P.M., et al., *High frequency of BRAF mutations in nevi.* Nat Genet, 2003. 33(1): p.  
19-20.  
30. Therasse, P., et al., *New guidelines to evaluate the response to treatment in solid tumors.*
European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst, 2000. 92(3): p. 205-16.  
31. McPhillips, F., et al. *Association of c-Raf expression with survival and its targeting with* antisense oligonucleotides in ovarian cancer. Br J Cancer. 2001 Nov 30;85(11):1753-8.  
32. Chen, H., et al. VEGF, VEGFRs expressions and activated STATs in ovarian epithelial carcinoma. Gynecol Oncol. 2004 Sep;94(3):630-5.  
33. Mercer, K., et al. *Raf proteins and cancer: B-Raf is identified as a mutational target.*
Biochim Biophys Acta. 2003 Jun 5;1653(1):25-40.  
34. Russell, S., et al. A multistep model for ovarian tumorigenesis: the value of mutation analysis
in the KRAS and BRAF genes. J Pathol. 2004 Jun;203(2):617-9.  
35. Strumberg, D., et al. *Phase I clinical and pharmacokinetic study of the Novel Raf kinase and* vascular endothelial growth factor receptor inhibitor BAY 43-9006 in patients with advanced refractory solid tumors. J Clin Oncol. 2005 Feb 10;23(5):965-72. Epub 2004 Dec 21.  
36. Alvarez Secord, A., et al. The relationship between serum vascular endothelial growth factor, persistent disease, and survival at second-look laparotomy in ovarian cancer. Gynecol Oncol. 2004 Jul;94(1):74-9  
37. Ratain M. et al. *Final findings from a Phase II, placebo-controlled, randomized* discontinuation trial (RDT) of sorafenib (BAY 43-9006) in patients with advanced renal cell carcinoma (RCC). ASCO Annual Meeting 2005 Abstracts.  
38. Escudier B. et al. *Randomized Phase III trial of the Raf kinase and VEGFR inhibitor* sorafenib (BAY 43-9006) in patients with advanced renal cell carcinoma (RCC). ASCO Annual Meeting 2005.  
39. Burger R. et al. *Phase II trial of bevacizumab in persistent or recurrent epithelial ovarian* cancer (EOC) or primary peritoneal cancer (PPC): a Gynecologic Oncology Group (GOG) study. ASCO Annual Meeting 2005.  
40. Garcia A. et al *Interim report of a phase II clinical trial of bevacizumab (Bev) and low dose* metronomic oral cyclophosphamide (mCTX) in recurrent ovarian (OC) and primary peritoneal carcinoma: A California Cancer Consortium Trial. ASCO Annual Meeting 2005.  
41. Veronese, M.L. et al. *Mechanisms of Hypertension Associated With BAY 43-9006* J Clin Oncol. 30 Jan 2006 Epub.  
42. Bookman, M.A. et al. *Optimal therapy of advanced ovarian cancer: carboplatin and* paclitaxel vs. cisplatin and paclitaxel (GOG 158) and an update on GOG0 182-ICON5 Int J Gynecol Cancer. 2003 Nov-Dec;13(6):735-40.  
43. Parmar, M.K. et al. Paclitaxel plus platinum-based chemotherapy versus conventional platinum-based chemotherapy in women with relapsed ovarian cancer: the ICON4/AGO- OVAR-2.2 trial. Lancet. 2003 Jun 21;361(9375):2099-106 44. Azad, N. S. et al. *Combination targeted therapy with sorafenib and bevacizumab results in* enhanced toxicity and antitumor activity. J Clin Oncol. 2008 Aug:26(22):3709-14.
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16. appendix a performance status

| ECOG Performance Status Scale   |                                                                                                                                                               |
|---------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Grade                           | Descriptions                                                                                                                                                  |
| 0                               | Normal activity. Fully active, able to carry on all predisease performance without restriction.  Symptoms, but ambulatory. Restricted in physically  strenuous activity, but ambulatory and able to carry out  work of a light or sedentary nature (e.g., light  housework, office work).                                                                                                                                                               |
| 1                               | In bed <50% of the time. Ambulatory and capable of  all self-care, but unable to carry out any work  activities. Up and about more than 50% of waking  hours. |
| 2                               | In bed >50% of the time. Capable of only limited selfcare, confined to bed or chair more than 50% of                                                                                                                                                               |
| 3                               | waking hours.                                                                                                                                                 |
| 4                               | 100% bedridden. Completely disabled. Cannot carry  on any self-care. Totally confined to bed or chair.                                                        |
| 5                               | Dead.                                                                                                                                                         |
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17. appendix b nci/fda proteomics

Core needle biopsies are used to sample tissue from a specific, defined location. These biopsies may consist of normal, pre-malignant and malignant tissue due to the multi-level tissue sample that is obtained. This type of sample is ideal for studying the micro-tumor environment. Rapid freezing of the sample is required to prevent degradation of the proteins or RNA. Optimal Cutting Temperature (OCT) compound is an alcohol polymer that is liquid at room temperature and a solid at –20oC. This polymer is used to cryo-protect the tissue and provide a medium for cryo-sectioning.
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materials

Cryomolds (Sakura Finetek Ca.t \# 4728) OCT (Sakura Finetek Cat. \# 4583) Dry ice Ultra cold freezer (-700 to -800C)
Needle: 16 or 18 gauge Permanent marker Sterile forceps Sterile Glass slides Aluminum foil or 50ml Falcon tubes
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procedure

1. Prepare all supplies prior to the biopsy procedure to avoid delay once the specimen has been obtained.  
2. Label the handle and the front surface of the cryomold with the sample or patient's
identifying information.  
3. Receive core needle biopsy. 4. Pick the core from the biopsy needle onto a sterile glass slide. 5. Fill cryomold about 1/3 full with OCT. Place the cryomold in dry ice to partially freeze the OCT. The OCT should be jelly-like, not completely frozen.  
6. Carefully lift the core biopsy by both ends with sterile forceps. **Do not stretch the biopsy**
or it will break.  
7. Lay the biopsy as straight as possible in the OCT. Once the sample touches the OCT,
you cannot reposition it or the sample will break apart.  
8. Quickly add OCT on top of the biopsy, completely covering the sample. 9. Ensure the sample is level and freeze immediately in dry ice.  
10. Store wrapped in aluminum foil or in a 50ml Falcon tube at –70oC then offload to liquid
nitrogen.
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note

Do not lay the biopsy on frozen OCT and cover it with liquid OCT. The OCT will not fuse and will split into two sections when cutting the frozen tissue sections.
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frozen section slides

1. Frozen sections for proteomic analysis should be cut at 5-8um on plain, uncoated glass microscope slides.  
2. The tissue section should be placed as close as possible to the center of the slide. Do not
place the frozen section at the end of the slide.  
3. Two tissue sections from the same biopsy may be placed on the same glass slide if space
permits.  
4. Do not allow the tissue section to air on the slide. Freeze immediately on dry ice or at –
80oC.
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18. appendix c study diary

| Patient Name:  Day Please note the  times and dose  of sorafenib  (BAY 43-9006)  that was taken by  mouth.                                                                    | Record Blood  Pressure Daily at  home and have  BP checked  WEEKLY at Dr's  Office during Cycles  1 and 2. (Use  separate form for  Doctor's BP  checks).   | Please note any side  effects you  experienced on this  day   | Do not list your daily  medications, but note any  other medications you took on  this day (both prescription and  nonprescription and the  reason why taken)   |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Monday  Tuesday  Wednesday  Thursday  Friday  Saturday  Sunday  **Record entries daily. Do not record batch entries. If an error is made, draw a line through it and initial. |                                                                                                                                                             |                                                               |                                                                                                                                                                 |
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19. appendix d cytochrome p450

| Substrates            |                        |                     |                      |
|-----------------------|------------------------|---------------------|----------------------|
| Acetaminophen         | Dapsone                | Levobupivicaine     | Risperidone          |
| Alfentanil            | Dehydroepiandrostendio | Lidocaine           | Ritonavir**          |
| ne                    |                        |                     |                      |
| Alosetron             | Delavirdine            | Loratadine          | Salmeterol           |
| Alprazolam            | Desmethyldiazepam      | Losartan            | Saquinavir           |
| Amiodarone            | Dexamethasone          | Lovastatin          | Sertindole           |
| Amitriptyline (minor) | Dextromethorphan       | Methadone           | Sertraline           |
| (minor)               |                        |                     |                      |
| Amlodipine            | Diazepam (minor)       | Mibefradil          | Sibutramine          |
| Anastrozole           | Digitoxin              | Miconazole          | Sildenafil citrate   |
| Androsterone          | Diltiazem              | Midazolam           | Simvastatin          |
| Antipyrine            | Disopyramide           | Mifepristone        | Sirolimus            |
| Astemizole            | Docetaxel              | Mirtazapine         | Sufentanil           |
| Atorvastatin          | Dofetilide (minor)     | Montelukast         | Tacrolimus           |
| Benzphetamine         | Dolasteron             | Navelbine           | Tamoxifen            |
| Bepridil              | Donepezil              | Nefazodone          | Temazepam            |
| Bexarotene            | Doxorubicin            | Nelfinavir          | Teniposide           |
| Bromazepam            | Doxycycline            | Nevirapine          | Terfenadine          |
| Bromocriptine         | Dronabinol             | Nicardipine         | Testosterone         |
| Budesonide            | Enalapril              | Nifedipine          | Tetrahydrocannabinol |
| Bupropion (weak)      | Erythromycin           | Niludipine          | Theophylline         |
| Buspirone             | Estradiol              | Nimodipine          | Tiagabine            |
| Busulfan              | Ethenyl estradiol      | Nisoldipine         | Tolterodine          |
| Caffeine              | Ethosuximide           | Nitrendipine        | Toremifene           |
| Cannabinoids          | Etoposide              | Omeprazole          | Trazodone            |
| (sulfonation)         |                        |                     |                      |
| Carbamazepine         | Exemestane             | Ondasetron          | Tertinoin            |
| Cerivastatin          | Felodipine             | Oral contraceptives | Triazolam            |
| Cevimeline            | Fentanyl               | Orphenadrine        | Troglitazone         |
| Chlorpromazine        | Fexofenadine           | Paclitaxel          | Troleandomycin       |
| Cimetidine            | Finasteride            | Pantoprazole        | Venlafaxine          |
| Cisapride             | Fluoxetine             | Pimozide            | Verapamil            |
| Citalopram            | Flutamide              | Pioglitazone        | Vinblastine          |
| Clarithromycin        | Glyburide              | Pravastatin         | Vincristine          |
| Clindamycin           | Granisetron            | Prednisone          | Warfarin             |
| Clomipramine          | Halofantrine           | Progesterone        | Yohimbine            |
| Clonazepam            | Hydrocortisone         | Proguanil           | Zaleplon (minor)     |
| Clozapine             | Hydroxyarginine        | Propafenone         | Zatoestron           |
| Cocaine               | Ifosfamide             | Quercetin           | Zileuton             |
| Codeine               | Imipramine             | Quetiapine          | Ziprasidone          |  
| Cortisol                                                         | Indinavir            | Quinidine                      | Zolpidem\             |
|------------------------------------------------------------------|----------------------|--------------------------------|-----------------------|
| Cortisone                                                        | Isradipine           | Quinine                        | Zonisamide            |
| Cyclobenzaprine                                                  | Itraconazole         | Repaglinide                    |                       |
| Cyclophosphamide                                                 | Ketoconazole         | Retinoic acid                  |                       |
| Cyclosporine                                                     | Lansoprazole (minor) | Rifampin                       |                       |
| Inducers                                                         |                      |                                |                       |
| Carbamazepine                                                    | Nelfinavir           | Primidone                      | Sulfadimidine         |
| Dexamethasone                                                    | Nevirapine           | Progesterone                   | Sulfinpyrazone        |
| Ethosuximide                                                     | Oxcarbazepine        | Rifabutin                      | Troglitazone          |
| Glucocorticoids                                                  | Phenobarbital        | Rifampin                       |                       |
| Griseofulvin                                                     | Phenylbutazone       | Rofecoxib (minor)              |                       |
| Nafcillin                                                        | Phenytoin            | St. John's Wort                |                       |
| Inhibitors                                                       |                      |                                |                       |
| Amiodarone                                                       | Disulfiram           | Mibefradil                     | Ranitidine            |
| Anastrozole                                                      | Entacapone           | Miconazole (moderate)          | Ritonavir**           |
| Azithromycin                                                     | Erythromycin         | Nefazodone                     | Saquinavir            |
| Cannabinoids                                                     | Ethenyl estradiol    | Nelfinavir                     | Sertindole            |
| Cimetidine                                                       | Fluconazole          | Nevirapine                     | Sertraline            |
| (weak)                                                           |                      |                                |                       |
| Clarithromycin                                                   | Fluoxetine           | Norfloxacin                    | Troglitazone          |
| Clotrimazole                                                     | Fluvoxamine          | Norfluoxetine                  | Troleandomycin        |
| Cyclosporine                                                     | Gestodene            | Omeprazole (weak)              | Valproic acid  (weak) |
| Danazole                                                         | Grapefruit Juice     | Oxiconazole                    | Verapamil             |
| Delavirdine                                                      | Indinavir            | Paroxetine (weak)              | Zarfirlukast          |
| Dexamethasone                                                    | Isoniazid            | Propoxyphene                   | Zileuton              |
| Dimethyldithiocarbamate                                          | Itraconazole**       | Quinidine                      |                       |
| Diltiazem                                                        | Ketoconazole**       | Quinine                        |                       |
| Dirithromycin                                                    | Metronidazole        | Quinupristin and  dalfopristin |                       |
| ** Contraindications  From Drug Information Handbook 8th Edition |                      |                                |                       |
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20. appendix e fact-o quality

Below is a list of statements that other people with your illness have said are important. By circling one (1) number per line, please indicate how true each statement has been for you during the past 7 days.  
  
  
Not at all  
  
0 0 0 Not at all 0 0 0  
  
| 3   |
|-----|
| 3   |
| 3   |
| 3   |  
| I am satisfied with family communication about my           |    |
|-------------------------------------------------------------|----|
| illness                                                     | 0  |
| I feel close to my partner (or the person who is my         |    |
| main support)                                               | 0  |
| Regardless of your current level of sexual activity, please |    |
| answer the following question. If you prefer not to answer  |    |
| it, please check this box and go to the next section.       |    |
| I am satisfied with my sex life                             | 0  |  
0  
| 2   |
|-----|
| 2   |
| 2   |  
3  
| 2   |
|-----|  
| 4   |
|-----|
| 4   |
| 4   |
| 4   |
| 4   |  
4  
| 1   | 1   | 1   |
|-----|-----|-----|  
By circling one (1) number per line, please indicate how true each statement has been for you during the past 7 days.  
  
an an  
  
0  
 0 0 0 Not at all 0 0 0 0
EMOTIONAL WELL-BEING  
| Not    | A little   |
|--------|------------|
| at all | bit        |
| 0      | 1          |  
l 1 1 1 i A little bit 1  
  
  
| My work (include work at home) is fulfilling .....   |
|------------------------------------------------------|
| I am able to enjoy life                              |
| I have accepted my illness .                         |
| I am sleeping well .                                 |
| I am enjoying the things I usually do for fun………………… |
| I am content with the quality of my life right now . |  
| 1   |
|-----|
| 1   |
| l   |
| l   |
| 1   |
| 1   |  
0 0  
| 2   |
|-----|
| 2   |
| 2   |
| 2   |
| 2   |
| 2   |  
0  
| 4   |
|-----|
| 4   |
| 4   |
| 4   |
| 4   |
| 4   |
| 4   |  
| 3   |
|-----|
| د   |
| 3   |
| 3   |
| 3   |
| 3   |
| 3   |  
By circling one (1) number per line, please indicate how true each statement has been for you
untitled h1
during the past 7 days.

| ADDITIONAL CONCERNS                                           | Not   | A little Some-   | Quite   | Very   |    |
|---------------------------------------------------------------|-------|------------------|---------|--------|----|
| at all                                                        | bit   | what             | a bit   | much   |    |
| I have swelling in my stomach area                            | 0     | l                | 2       | 3      | 4  |
| I am losing weight .                                          | 0     | l                | 2       | د      | 4  |
| I have control of my bowels                                   | 0     | 1                | 2       | 3      | 4  |
| 2                                                             |       |                  |         |        |    |
| I have been vomiting .                                        | 0     | 1                | 3       | 4      |    |
| I am bothered by hair loss                                    | 0     | 1                | 2       | 3      | 4  |
| ..                                                            |       |                  |         |        |    |
| I have a good appetite ..........                             | 0     | 2                | 3       |        |    |
| i                                                             | 4     |                  |         |        |    |
| I like the appearance of my body.                             | 0     | l                | 2       | 3      | 4  |
| I am able to get around by myself                             | 0     | 1                | 2       | 3      | 4  |
| I am able to feel like a woman..                              | l     | 2                | 3       |        |    |
| 0                                                             | 4     |                  |         |        |    |
| I have cramps in my stomach area.                             | 0     | i                | 2       | د      | 4  |
| I am interested in sex .                                      | 0     | 1                | 2       | د      | 4  |
| I have concerns about my ability to have children ........... | 0     | 1                | 2       | 3      | 4  |
untitled h1
21. appendix f blood pressure

Week 1:
Name of Health Care Facility:  
  
Date ________________ B/P______________________  
 Done by ___________________________________________ Week 2:  
  
Name of Health Care Facility___________________________  
  
  
  
  
  
Date ________________ B/P______________________  
 Done by ___________________________________________ Week 3:  
  
Name of Health Care Facility___________________________  
  
  
  
  
  
  
  
Date ________________ B/P______________________  
 Done by ___________________________________________ Week 4:
Name of Health Care Facility___________________________  
  
  
  
  
Date ________________ B/P______________________  
 Done by ___________________________________________  
  
  
  
  
Week 1:
Name of Health Care Facility:  
  
Date ________________ B/P______________________  
 Done by ___________________________________________ Week 2:
Name of Health Care Facility___________________________  
  
  
  
  
Date ________________ B/P______________________  
 Done by ___________________________________________ Week 3:
Name of Health Care Facility___________________________  
  
  
  
Date ________________ B/P______________________ Done by ___________________________________________
Week 4:
Name of Health Care Facility___________________________  
  
  
  
  
  
Date ________________ B/P______________________  
 Done by ___________________________________________