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| .7879:   | 34456          |             |     |    |    |    |    |    |
|----------|----------------|-------------|-----|----|----|----|----|----|
| ;<=>49   | 98?@ABC D764   | E94F:=4;:   | B   | G  | H  | I  | C  | J  |
| KLMNOPQ  |                |             |     |    |    |    |    |    |
| RSLSKT P | UVQWXYZ[YZ\S]^ | _`^WTabaW_c | ddd |    |    |    |    |    |
| KLMNOPQ  |                |             |     |    |    |    |    |    |
| RSLSKT e | P WXYZ[YZ\S]^  | _`^WTabaW_c | ddd |    |    |    |    |    |
| KLMNOPQ  |                |             |     |    |    |    |    |    |
| RSLSKT , | e WXYZ[YZ\S]^  | _`^WTabaW_c | ddd |    |    |    |    |    |  
| TABLE OF CONTENTS                                                                                                                                   |                                                                                                                                                      |                                                                                                                                                   |
|-----------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------|
| PRÉCIS .                                                                                                                                            |                                                                                                                                                      |                                                                                                                                                   |
| SCHEMA                                                                                                                                              |                                                                                                                                                      |                                                                                                                                                   |
| TABLE OF CONTENTS ................................................................................................................................4 |                                                                                                                                                      |                                                                                                                                                   |
| STATEMENT OF COMPLIANCE                                                                                                                             |                                                                                                                                                      |                                                                                                                                                   |
| INTRODUCTION .                                                                                                                                      |                                                                                                                                                      |                                                                                                                                                   |
| l                                                                                                                                                   | Study Objectives .                                                                                                                                   |                                                                                                                                                   |
| 1.1                                                                                                                                                 |                                                                                                                                                      |                                                                                                                                                   |
| 1.2                                                                                                                                                 | Background and Rationale ......................................................................................................................7     |                                                                                                                                                   |
| 2                                                                                                                                                   | ELIGIBILITY ASSESSMENT AND ENROLLMENT ...................................................................24                                          |                                                                                                                                                   |
| 2.1                                                                                                                                                 | Eligibility Criteria .                                                                                                                               |                                                                                                                                                   |
| 2.2                                                                                                                                                 | Screening Evaluation .............................................................................................................................26 |                                                                                                                                                   |
| 2.3                                                                                                                                                 | Participant Registration and Status Update Procedures ...........................................................27                                  |                                                                                                                                                   |
| Baseline Evaluation                                                                                                                                 |                                                                                                                                                      |                                                                                                                                                   |
| 2.4                                                                                                                                                 |                                                                                                                                                      |                                                                                                                                                   |
| 3                                                                                                                                                   | STUDY IMPLEMENTATION .                                                                                                                               |                                                                                                                                                   |
| 3.1                                                                                                                                                 | Study Design .                                                                                                                                       |                                                                                                                                                   |
| 3.2                                                                                                                                                 | Drug Administration ............................................................................................................................31   |                                                                                                                                                   |
| 3.3                                                                                                                                                 | Dose Modifications ...........................................................................................................................32     |                                                                                                                                                   |
| 3.4                                                                                                                                                 | Clinical Monitoring                                                                                                                                  |                                                                                                                                                   |
| 3.5                                                                                                                                                 | Study Calendar ............................................................................................................................36        |                                                                                                                                                   |
| 3.6                                                                                                                                                 | Criteria for Removal from Protocol Therapy and Off Study Criteria................................41                                                  |                                                                                                                                                   |
| CONCOMITANT MEDICATIONS/MEASURES.......................................................................42                                           |                                                                                                                                                      |                                                                                                                                                   |
| 4                                                                                                                                                   | 4.1                                                                                                                                                  | Premedication for alemtuzumab infusions ...................................................................................42                     |
| 4.2                                                                                                                                                 | Premedication for IL- 15                                                                                                                             |                                                                                                                                                   |
| Prophylaxis for Virus and/or Pneumocystis                                                                                                           |                                                                                                                                                      |                                                                                                                                                   |
| 4.3                                                                                                                                                 |                                                                                                                                                      |                                                                                                                                                   |
| 4.4                                                                                                                                                 | Venous thromboembolism (VTE) prophylaxis                                                                                                             |                                                                                                                                                   |
| 4.5                                                                                                                                                 | Platelets and RBC support ........................................................................................................42                 |                                                                                                                                                   |
| Prohibited Medications ................................................................................................................43           |                                                                                                                                                      |                                                                                                                                                   |
| 4.6                                                                                                                                                 |                                                                                                                                                      |                                                                                                                                                   |
| s                                                                                                                                                   | BIOSPECIMEN COLLECTION............................................................................................................43                 |                                                                                                                                                   |
| 5.1                                                                                                                                                 | Correlative Studies for Research and Special Studies ..........................................................43                                    |                                                                                                                                                   |
| 5.2                                                                                                                                                 | Sample Storage, Tracking and Disposition............................................................................46                               |                                                                                                                                                   |
| DATA COLLECTION AND EVALUATION ...........................................................................47                                        |                                                                                                                                                      |                                                                                                                                                   |
| 6                                                                                                                                                   | 6.1                                                                                                                                                  | DATA COLLECTION ...............................................................................................................................47 |
| 6.2                                                                                                                                                 | DATA SHARING Plans                                                                                                                                   |                                                                                                                                                   |  
| Version Date: 09/24/2021                                                                                                                   |                                                                                                                                               |                                                                                                                                                   |
|--------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------|
| 6.3                                                                                                                                        | Response Criteria ....................................................................................................................49      |                                                                                                                                                   |
| Toxicity Criteria                                                                                                                          |                                                                                                                                               |                                                                                                                                                   |
| 6.4                                                                                                                                        |                                                                                                                                               |                                                                                                                                                   |
| NIH REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING PLAN…..55                                                                            |                                                                                                                                               |                                                                                                                                                   |
| 7.1                                                                                                                                        | Definitions                                                                                                                                   |                                                                                                                                                   |
| 7.2                                                                                                                                        | OHSRP Office of Compliance and Training/ IRB Reporting..................................................55                                    |                                                                                                                                                   |
| NCI Clinical Director Reporting                                                                                                            |                                                                                                                                               |                                                                                                                                                   |
| 7.3                                                                                                                                        |                                                                                                                                               |                                                                                                                                                   |
| 7.4                                                                                                                                        | NIH Required Data and Safety Monitoring Plan .....................................................................................55          |                                                                                                                                                   |
| SPONSOR SAFETY REPORTING                                                                                                                   |                                                                                                                                               |                                                                                                                                                   |
| 8                                                                                                                                          | Assessment Of Safety Events ...............................................................................................................57 |                                                                                                                                                   |
| 8.2                                                                                                                                        |                                                                                                                                               |                                                                                                                                                   |
| 8.3                                                                                                                                        | Reporting of Serious Adverse Events .............................................................................................57           |                                                                                                                                                   |
| 8.4                                                                                                                                        | Safety/Other Reporting Criteria To The Pharmaceutical Manufacturer (CTEP) ..........58                                                        |                                                                                                                                                   |
| Reporting pregnancy                                                                                                                        |                                                                                                                                               |                                                                                                                                                   |
| 8.5                                                                                                                                        |                                                                                                                                               |                                                                                                                                                   |
| 8.6                                                                                                                                        | Regulatory Reporting For Studies Conducted Under CCR Sponsored IND ..................59                                                       |                                                                                                                                                   |
| Clinical Monitoring                                                                                                                        |                                                                                                                                               |                                                                                                                                                   |
| 9                                                                                                                                          | STATISTICAL CONSIDERATIONS ..............................................................................................60                   |                                                                                                                                                   |
| 10                                                                                                                                         | COLLABORATIVE AGREEMENTS .....................................................................................................61              |                                                                                                                                                   |
| 11                                                                                                                                         | 1.1                                                                                                                                           | Agreement Type ................................................................................................................................61 |
| 12    HUMAN SUBJECTS PROTECTIONS ....................................................................................................61    |                                                                                                                                               |                                                                                                                                                   |
| 12.1                                                                                                                                       | Rationale For Subject Selection ...............................................................................................61             |                                                                                                                                                   |
| Participation of Children ..............................................................................................................61 |                                                                                                                                               |                                                                                                                                                   |
| 12.2                                                                                                                                       |                                                                                                                                               |                                                                                                                                                   |
| 12.3                                                                                                                                       | Participation of Subjects Unable to Give Consent .............................................................61                              |                                                                                                                                                   |
| 12.4                                                                                                                                       | Evaluation of Benefits and Risks/Discomforts ................................................................62                               |                                                                                                                                                   |
| Risks/Benefits Analysis                                                                                                                    |                                                                                                                                               |                                                                                                                                                   |
| 12.5                                                                                                                                       |                                                                                                                                               |                                                                                                                                                   |
| 12.6                                                                                                                                       | Consent Process and Documentation ..................................................................................63                        |                                                                                                                                                   |
| 13                                                                                                                                         | REGULATORY AND OPERATIONAL CONSIDERATIONS ................................................63                                                  |                                                                                                                                                   |
| 13.1                                                                                                                                       | Study Discontinuation and Closure ..........................................................................................63                |                                                                                                                                                   |
| Quality Assurance and Quality Control ................................................................................64                   |                                                                                                                                               |                                                                                                                                                   |
| 13.2                                                                                                                                       |                                                                                                                                               |                                                                                                                                                   |
| 13.3                                                                                                                                       | Conflict of Interest Policy ........................................................................................................64        |                                                                                                                                                   |
| 13.4                                                                                                                                       | Confidentiality and Privacy .....................................................................................................64           |                                                                                                                                                   |
| 14   PHARMACEUTICAL INFORMATION .........................................................................................65                |                                                                                                                                               |                                                                                                                                                   |
| Recombinant Human Interleukin-15 (rhIL-15) (NSC# 745101) ...................................65                                             |                                                                                                                                               |                                                                                                                                                   |
| 14.1                                                                                                                                       |                                                                                                                                               |                                                                                                                                                   |
| 14.2                                                                                                                                       | Alemtuzumab (Campath-1H) .......................................................................................................70            |                                                                                                                                                   |
| 15                                                                                                                                         | REFERENCES .                                                                                                                                  |                                                                                                                                                   |  
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the lowest expression and generally being more resistant to alemtuzumab mediated depletion( 19 ,
20 ), leaving many mononuclear cells with the capacity for ADCC (Figure 1).  
A key supposition for this trial is that CAMPATH-1 will not unduly deplete Fc-gamma receptor expressing IL-15 dependent immune subsets that also co-express the surface marker CD52.  In support of this assumption, as just noted, NK cells show the lowest expression of CD52 and monocytes appear resistant to alemtuzumab refractory to CAMPATH-1 mediated complement lysis( 20 ) (Figure 2).  Previously we demonstrated that CAMPATH-1 provided effective therapy for a murine model of adult T-cell leukemia in wild-type mice but that all efficacy was lost in FcR gamma -/~ mice supporting the view that ADCC is the dominant mechanism of efficacy in mice( 14 ).  The fact that alemtuzumab showed efficacy in the therapy of patients with acute ATL
(12 of 17 patients manifesting a PR or CR) and chronic ATL (2 of 3 patients manifesting a response) supports our view that alemtuzumab will not unduly deplete Fc gamma receptor expressing immune subsets required for ADCC.  
  
  
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|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
| ./01N10345467/8 H<510O P<BQ1H /R S4671860 T76:  .=U 46 4 V7>18 ./01 =1>15            | 20345467/8 .13707/8 W<51                                                                                                                                                                                                                                                                                                                                                                                   |
|--------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| ? /<6 /R ,                                                                           | 2861H <M 6/ , M4671860 46 6:1 81I6 ;/01 51>15 ./01 10345467/8 T755 Q1 06/MM1;@ U:70 ;/01 51>15 T755 Q1 ;1354H1;  6:1 B4I7B455Y 4;B787061H1; ;/01 J:7C:106 ;/01 4;B787061H1;L@ ZM  6/ 6:H11 J,L 4;;767/845 M4671860 T755 Q1 1861H1; 46 6:1 81I6 5/T106  ;/01 51>15 7R /85Y , M4671860 T1H1 6H1461; MH1>7/<05Y 46 6:46 ;/01@                                                                                 |
| X F                                                                                  | 2861H <M 6/ , B/H1 M4671860 46 6:70 ;/01 51>15@ [ \R ? /R 6:101 , M4671860 1IM1H71831 .=UK MH/311; 6/ 6:1 81I6  ;/01 51>15@ R - /H B/H1 /R 6:70 CH/<M 0<RR1H .=UK 6:18 ;/01 10345467/8 70  06/MM1;K 48; 6:70 ;/01 70 ;1354H1; 6:1 B4I7B455Y 4;B787061H1;  ;/01@ ZM 6/ 07I J]L 4;;767/845 M4671860 T755 Q1 1861H1; 46 6:1  81I6 5/T106 ;/01 51>15 7R /85Y , M4671860 T1H1 6H1461;  MH1>7/<05Y 46 6:46 ;/01@ |
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| ./012                                                                                       | 3445//2642       | 7882190:2 ;4:9<6                                                 | =2>58?:9<6 <@ AB2/0?C           |
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| ;6C P/012  05:<988562  4C:<?2690 ;6C                                                        | R:<? 0I28:5N580M | R:<? 0I28:5N580M                                                 |                                 |
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