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| 5Xy X>A;qlt      | (NL8NK                                |    |
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| Version Date: 09/14/2021                                                                                                                                |                                                                                                                                                   |
|---------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------|
| 6.2                                                                                                                                                     | DATA SHARING Plans ..................................................................................................................49           |
| 6.3                                                                                                                                                     | Response Criteria ..................................................................................................................49            |
| 6.4                                                                                                                                                     | TOXICITY Criteria                                                                                                                                 |
| 7                                                                                                                                                       | NIH REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING PLAN.....51                                                                                 |
| 7.1                                                                                                                                                     | DEFINITIONS                                                                                                                                       |
| 7.2                                                                                                                                                     | OHSRP Office of Compliance and Training/ IRB Reporting ..........................................51                                               |
| 7.3                                                                                                                                                     | NCI Clinical Director Reporting ......................................................................................................52          |
| 7.4                                                                                                                                                     | NIH Required Data and Safety Monitoring Plan ...................................................................52                                |
| 8                                                                                                                                                       | SPONSOR SAFETY REPORTING                                                                                                                          |
| 8.1                                                                                                                                                     | Definitions                                                                                                                                       |
| Assessment of Safety Events                                                                                                                             |                                                                                                                                                   |
| 8.2                                                                                                                                                     | Reporting  of Serious Adverse Events ..........................................................................................54                 |
| 8.3                                                                                                                                                     | Waiver of expedited reporting to CCR......................................................................................54                      |
| 8.4                                                                                                                                                     |                                                                                                                                                   |
| 8.5                                                                                                                                                     | Safety/Other Reporting Criteria to the Pharmaceutical Manufacturer (CTEP) ..........54                                                            |
| 8.6                                                                                                                                                     | Reporting Pregnancy                                                                                                                               |
| 8.7                                                                                                                                                     | Regulatory Reporting for Studies Conducted Under CCR-Sponsored IND ...............55                                                              |
| CLINICAL MONITORING                                                                                                                                     |                                                                                                                                                   |
| 9                                                                                                                                                       | STATISTICAL CONSIDERATIONS ..........................................................................................................56           |
| 10                                                                                                                                                      | Statistical Hypothesis .                                                                                                                          |
| 10.1                                                                                                                                                    |                                                                                                                                                   |
| 10.2                                                                                                                                                    | Sample Size Determination                                                                                                                         |
| 10.3                                                                                                                                                    | Populations for Analyses ......................................................................................................................57 |
| Statistical Analyses                                                                                                                                    |                                                                                                                                                   |
| 10.4                                                                                                                                                    |                                                                                                                                                   |
| l l                                                                                                                                                     | COLLABORATIVE AGREEMENTS .                                                                                                                        |
| 1.1                                                                                                                                                     | Agreement Type .                                                                                                                                  |
| 12                                                                                                                                                      | HUMAN SUBJECTS PROTECTIONS .......................................................................................................58              |
| 12.1                                                                                                                                                    | Rationale For Subject Selection ..........................................................................................................58      |
| Participation of Children ...........................................................................................................................59 |                                                                                                                                                   |
| 12.2                                                                                                                                                    |                                                                                                                                                   |
| 12.3                                                                                                                                                    | Participation of Subjects Unable to Give Consent .....................................................................59                          |
| 12.4                                                                                                                                                    | Evaluation of Benefits and Risks/Discomforts ......................................................................59                             |
| 12.5                                                                                                                                                    | Risks/Benefits Analysis                                                                                                                           |
| Consent Process and Documentation .......................................................................................61                             |                                                                                                                                                   |
| 12.6                                                                                                                                                    |                                                                                                                                                   |
| 13                                                                                                                                                      | REGULATORY AND OPERATIONAL CONSIDERATIONS ................................................62                                                      |
| 13.1                                                                                                                                                    | Study Discontinuation and Closure .........................................................................................62                     |
| 13.2                                                                                                                                                    | Quality Assurance and Quality Control ....................................................................................62                      |
| 13.3                                                                                                                                                    | Conflict of Interest Policy .........................................................................................................63           |
untitled h1
abbreviated title il-15+obinutuzumab in cll

| Confidentiality and Privacy..................................................................................................63   |                                                                                                                                      |
|-----------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------|
| 13.4                                                                                                                              |                                                                                                                                      |
| 14   PHARMACEUTICAL INFORMATION .......................................................................................64         |                                                                                                                                      |
| 14.1                                                                                                                              | rhIL-15 (NSC# 745101) ............................................................................................................64 |
| 14.2                                                                                                                              | Obinutuzumab (NSC# 793436)                                                                                                           |
| 15                                                                                                                                | REFERENCES .                                                                                                                         |
| 16 APPENDICES                                                                                                                     |                                                                                                                                      |
| 16.1                                                                                                                              | APPENDIX A:  Performance Status Criteria...........................................................................77                |
| 16.2                                                                                                                              | APPENDIX B:  Assay For Antibodies To rhIL-15..............................................................78                         |
| APPENDIX C:  IL-15 Dilution Instructions .............................................................................79          |                                                                                                                                      |
| 16.3                                                                                                                              |                                                                                                                                      |
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| @1A 35 2+,12-,42  0A0;, *12/,429 +,B7/+/4C  D+,-,./012/34                                                                                            | *+,-,./012/34                                              | E.-/4/92+12/34 |
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