11.2.6. management of cardiac abnormalities
16.2. data safety monitoring committee

Interim analysis of toxicity, outcome and ongoing scientific investigations will be performed at least every 3 months by the Fox Chase Cancer Center Data Safety Monitoring Committee 2015 Fox Version Date *10/12/2018* 57
(FCCCDSMC). In this capacity the FCCCDSMC will serve as an advisory committee to the OCR. The FCCCDSMC will review those aspects of this trial that are outlined in the responsibilities section of the Data and Safety Monitoring Plan (DSMP). If the committee decides that changes should be made to this trial, it will make recommendations in writing to the Study Sponsor Investigator, the Associate Director of Clinical Research, and the Protocol Management Executive Committee, which, in turn, have the authority to approve or disapprove these recommendations. These changes will be discussed with the Study Sponsor Investigator before they are implemented. These changes may include early termination of accrual. Other changes might include altering the accrual goals or changing the eligibility criteria for the trial.
11.2.6. management of cardiac abnormalities
17.0administrative

This study will be conducted in accordance will local, state and Federal regulations and according to accepted good clinical practice guidelines.
11.2.6. management of cardiac abnormalities
17.1. data reporting

The FCCC Study Monitor will request case report forms to be completed within 2 weeks of the protocol visit. Participating sites are responsible to respond to queries prior to the next scheduled monitoring visit. The OCR staff are responsible for compiling and submitting data to the Sponsor Investigator and statistician on an ongoing basis for monitoring as described in the data safety monitoring plan and reporting to the FCCC Data and Safety Monitoring Committee. All patient information will be stored in an EDC system accessible only to the study team members for the purpose of entering, reviewing and analyzing data. Any paper records, such as case report files, produced will be stored in a secure location. The IST Regulatory Specialist is responsible for distributing and tracking review of all IND Action Letters, Safety Reports, study specific Serious Adverse Events.
11.2.6. management of cardiac abnormalities
17.2. retention of records

Time points for the retention of records are described in detail in the contract between the grantor and the OCR and passed on to the participating site. Please refer to the study specific terms for specific time points. In all cases the Study Monitor must be notified of any plans to move records to an offsite location prior to doing so.
11.2.6. management of cardiac abnormalities
references

1. Taylor BS, Barretina J, Maki RG, Antonescu CR, Singer S, Ladanyi M. Advances in sarcoma genomics and new therapeutic targets. Nature reviews. Cancer 2011;11:541-57. 2. Italiano A, Mathoulin-Pelissier S, Cesne AL, et al. Trends in survival for patients with metastatic soft-tissue sarcoma. Cancer 2011;117:1049-54. 3. van der Graaf WT, Blay JY, Chawla SP, et al. Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet 2012;379:1879-86. 4. Hernando E, Charytonowicz E, Dudas ME, et al. The AKT-mTOR pathway plays a critical role in the development of leiomyosarcomas. Nature medicine 2007;13:748-53. 5. Gibault L, Perot G, Chibon F, et al. New insights in sarcoma oncogenesis: a comprehensive analysis of a large series of 160 soft tissue sarcomas with complex genomics. J Pathol;223:64-71. 6. Kawaguchi K, Oda Y, Saito T, et al. Genetic and epigenetic alterations of the PTEN gene in soft tissue sarcomas. Human pathology 2005;36:357-63. 7. Italiano A, Chen CL, Thomas R, et al. Alterations of the p53 and PIK3CA/AKT/mTOR pathways in angiosarcomas: a pattern distinct from other sarcomas with complex genomics. Cancer 2012;118:5878-87. 8. Movva S, Wen W, Chen W, et al. Multi-platform profiling of over 2000 sarcomas: Identification of biomarkers and novel therapeutic targets. Oncotarget 2015. 9. Gibault L, Ferreira C, Perot G, et al. From PTEN loss of expression to RICTOR role in smooth muscle differentiation: complex involvement of the mTOR pathway in leiomyosarcomas and pleomorphic sarcomas. Mod Pathol;25:197-211. 10. Okuno S, Bailey H, Mahoney MR, et al. A phase 2 study of temsirolimus (CCI-779) in patients with soft tissue sarcomas: a study of the Mayo phase 2 consortium (P2C). Cancer 2011;117:3468-75. 11. Italiano A, Kind M, Stoeckle E, Jones N, Coindre JM, Bui B. Temsirolimus in advanced leiomyosarcomas: patterns of response and correlation with the activation of the mammalian target of rapamycin pathway. Anticancer Drugs 2011;22:463-7. 12. Verschraegen CF, Movva S, Ji Y, et al. A phase I study of the combination of temsirolimus with irinotecan for metastatic sarcoma. Cancers 2013;5:418-29. 13. Chawla SP, Staddon AP, Baker LH, et al. Phase II study of the mammalian target of 2015 Fox Version Date *10/12/2018* 59 rapamycin inhibitor ridaforolimus in patients with advanced bone and soft tissue sarcomas. J Clin Oncol;30:78-84. 14. Chawla SP BJ, Ray-Coquard IL et al Results of the phase III, placebo-controlled trial (SUCCEED) evaluating the mTOR inhibitor ridaforolimus (R) as maintenance therapy in advanced sarcoma patients (pts) following clinical benefit from prior standard cytotoxic chemotherapy (CT)
American Society of Clinical Oncology; 2011; Chicago.  
15. Richter S PP, Hohenberger P. Multicenter, triple-arm, single-stage, phase II trial to determine the efficacy and safety of everolimus (RAD001) in patients with refractory bone or soft tissue sarcomas including GIST. J Clin Oncol 2010;28:15 (suppl; abstr 10038^). 16. Chiang GG, Abraham RT. Targeting the mTOR signaling network in cancer. Trends in molecular medicine 2007;13:433-42. 17. Sabatini DM. mTOR and cancer: insights into a complex relationship. Nature reviews.  
Cancer 2006;6:729-34.  
18. Gregorian C, Nakashima J, Dry SM, et al. PTEN dosage is essential for neurofibroma development and malignant transformation. Proceedings of the National Academy of Sciences of the United States of America 2009;106:19479-84. 19. Keng VW, Rahrmann EP, Watson AL, et al. PTEN and NF1 inactivation in Schwann cells produces a severe phenotype in the peripheral nervous system that promotes the development and malignant progression of peripheral nerve sheath tumors. Cancer Res 2012;72:3405-13. 20. Barretina J, Taylor BS, Banerji S, et al. Subtype-specific genomic alterations define new targets for soft-tissue sarcoma therapy. Nature genetics 2010;42:715-21. 21. Demicco EG, Torres KE, Ghadimi MP, et al. Involvement of the PI3K/Akt pathway in myxoid/round cell liposarcoma. Mod Pathol 2012;25:212-21. 22. Movva S WW, Chen W, Millis SZ, von Mehren M, Gatalica Z, Van Tine BA Predictive biomarker profiling of > 1,900 sarcomas: Identification of potential novel treatment modalities. Journal of Clinical Oncology 2014;32:5s, 2014 (suppl; abstr 10509). 23. Van Glabbeke M, Verweij J, Judson I, Nielsen OS. Progression-free rate as the principal end-point for phase II trials in soft-tissue sarcomas. Eur J Cancer 2002;38:543-9. 24. The Criteria Committee of New York Heart Association. Nomenclature and Criteria for Diagnosis of Diseases of the Heart and Great Vessels. 9 ed. Boston, MA: Little, Brown & Co; 1994.
11.2.6. management of cardiac abnormalities
18.0 appendices

| Appendix A: New York Heart Association Classification of Cardiac Disease   |                                                                                                                                                                                                                                                            |                                                                 |
|----------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------|
| Class                                                                      | Functional Capacity                                                                                                                                                                                                                                        | Objective Assessment                                            |
| I                                                                          | Patients with cardiac disease but without resulting limitations of physical activity. Ordinary physical activity does not cause undue fatigue, palpitation, dyspnea, or anginal pain.                                                                      | No objective evidence of cardiovascular disease.                |
| II                                                                         | Patients with cardiac disease resulting in slight limitation of physical activity. They are comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnea, or anginal pain.                                                     | Objective evidence of minimal cardiovascular disease.           |
| III                                                                        | Patients with cardiac disease resulting in marked limitation of physical activity. They are comfortable at rest. Less than ordinary activity causes fatigue, palpitation, dyspnea, or anginal pain.                                                        | Objective evidence of moderately severe cardiovascular disease. |
| IV                                                                         | Patients with cardiac disease resulting in inability to carry on any physical activity without discomfort. Symptoms of heart failure or the anginal syndrome may be present even at rest. If any physical activity is undertaken, discomfort is increased. | Objective evidence of severe cardiovascular disease.            |
|                                                                           | Source: The Criteria Committee of New York Heart Association. Nomenclature and                                                                                                                                                                             |                                                                 |  
Source: The Criteria Committee of New York Heart Association. Nomenclature and Criteria for Diagnosis of Diseases of the Heart and Great Vessels. Ninth Ed. Boston, MA: Little, Brown & Co; 1994:253-256.24
appendix b list of relevant
18.0 appendices

cimetidine methoxsalen fluvoxamine ciprofloxacin  
| Moderate CYP1A2 Inhibitors   |
|------------------------------|  
| Strong CYP1A2 Inhibitors   |
|----------------------------|  
Source: fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/
ucm093664.htm.  
Note that these lists are not exhaustive.  
| Clinically Significant Enzyme Inducers   |             |                 |
|------------------------------------------|-------------|-----------------|
| carbamazepine                            | rifabutin   | St. John's Wort |
| phenobarbital                            | rifampin    |                 |
| phenytoin                                | rifapentine |                 |