untitled h1
13 regulatory and operational considerations

This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable cause. Written notification, documenting the reason for study suspension or termination, will be provided by the suspending or terminating party to investigators, funding agencies, the Investigational New Drug (IND) sponsor and regulatory authorities, as applicable.  
If the study is prematurely terminated or suspended, the Principal Investigator (PI) will promptly inform study participants, the Institutional Review Board (IRB), and sponsor and will provide the reason(s) for the termination or suspension. Study participants will be contacted, as applicable, and be informed of changes to study visit schedule.  
Circumstances that may warrant termination or suspension include, but are not limited to:  
- Determination of unexpected, significant, or unacceptable risk to participants
- Demonstration of efficacy that would warrant stopping
- Insufficient compliance to protocol requirements - Data that are not sufficiently complete and/or evaluable
- Determination that the primary endpoint has been met
- Determination of futility
Study may resume once concerns about safety, protocol compliance, and data quality are addressed, and satisfy the sponsor, IRB and/or Food and Drug Administration (FDA).
untitled h1
13.2 quality assurance and quality

The clinical site will perform internal quality management of study conduct, data and biological specimen collection, documentation and completion. An individualized quality management plan will be developed to describe a site's quality management. Quality control (QC) procedures will be implemented beginning with the data entry system and data QC checks that will be run on the database will be generated. Any missing data or data anomalies will be communicated to the site(s) for clarification/resolution. Following written Standard Operating Procedures (SOPs), the monitors will verify that the clinical trial is conducted and data are generated and biological specimens are collected, documented (recorded), and reported in compliance with the protocol, International Conference on Harmonisation Good Clinical Practice (ICH GCP), and applicable regulatory requirements (e.g., Good Laboratory Practices (GLP), Good Manufacturing Practices (GMP)). The investigational site will provide direct access to all trial related sites, source data/documents, and reports for the purpose of monitoring and auditing by the sponsor, and inspection by local and regulatory authorities.  
Version Date: *11/16/2020*
untitled h1
13.3 conflict of interest policy

The independence of this study from any actual or perceived influence, such as by the pharmaceutical industry, is critical. Therefore, any actual conflict of interest of persons who have a role in the design, conduct, analysis, publication, or any aspect of this trial will be disclosed and managed. Furthermore, persons who have a perceived conflict of interest will be required to have such conflicts managed in a way that is appropriate to their participation in the design and conduct of this trial. The study leadership in conjunction with the National Cancer Institute has established policies and procedures for all study group members to disclose all conflicts of interest and will establish a mechanism for the management of all reported dualities of interest.
untitled h1
14 pharmaceutical information

This study is being conducted under a CCR-held IND: IND \#140549.
untitled h1
14.1 rhil-15 (nsc #745101)

14.1.1 Source/ Acquisition and Accountability rhIL-15 is an investigational agent supplied to investigators by the Cancer Therapy Evaluation Program (CTEP), Division of Cancer Treatment and Diagnosis (DCTD), NCI. 14.1.2 Drug Summary Information 14.1.2.1 Chemical Name or Amino Acid Sequence The 115 amino acid coding sequence of the pET28b/IL-15 cistron is as follows: MNWVNVISDLKKIEDLIQSMHIDATLYTESDVHPSCKVTAMKCFLLELQVISLESGDA SIHDTVENLIILANNSLSSNGNVTESGCKECEELEEKNIKEFLQSFVHIVQMFINTS 14.1.2.2 Other Names Recombinant Human Interleukin -15; Recombinant Human IL-15; rhIL-15 14.1.2.3 Classification Recombinant human interleukin-15 (rhIL-15) is a cytokine of the 4-alpha helix bundle family of cytokines whose mature form consists of 115 amino acids. It has two cystine disulfide cross linkages at positions Cys 42-Cys 88 and Cys 35-Cys 85. 14.1.2.4 Molecular Weight (M.W.) 12,898.8 Daltons 14.1.2.5 Mode of Action IL-15 interacts with a private receptor subunit IL- 15R alpha as well as the IL-2/IL-15R beta chain shared with IL-2 and the common gamma chain shared with IL-2, IL-4, IL-7, IL-9 and IL-21. IL-15 shares a number of biological activities with IL-2, including stimulation of the proliferation of activated CD4+, CD8+ as well as gamma-delta subsets of T cells. IL-15 also stimulates the proliferation of NK cells and acts as a co-stimulator with IL-12 to facilitate the production of Interferon-gamma and TNF-alpha.
untitled h1
14.1.3 how supplied

IL-15 is manufactured by the Biopharmaceutical Development Program (BDP) and distributed by the Pharmaceutical Management Branch (PMB) CTEP. IL-15 is supplied as a sterile, frozen liquid product in single use vials containing no preservatives. Currently, IL-15 is supplied as 147 mcg /  
Version Date: *11/16/2020* 0.3 mL (490 mcg/mL) in a 3 mL glass vial. The IL-15 is formulated in 25 mM sodium phosphate containing 0.5 M sodium chloride at a pH of 7.4.  
NOTE: IL-15 vial content may vary between lots and protocols. Use caution and consult the protocol document for specific preparation instructions when preparing each dose. 14.1.4 Preparation Vials of frozen IL-15 should be thawed at ambient room temperature. Upon thawing, the solution should be clear and colorless with no evidence of particulates or foreign matter. The infusion solutions should be mixed in a PVC bag. 14.1.5 Storage IL-15 vials should be stored at or below (-70°C). 14.1.6 Stability 14.1.6.1 Vials Stability studies of the intact vials are ongoing. 14.1.6.2 Prepared Infusion The rhIL-15 infusion solution is stable at a concentration of 1 mcg/mL with 0.1% HSA for 4 hours at controlled room temperature (15°C–30°C) prior to initiation of the 24-hour infusion or 24 hours at 2-8°C prior to initiation of the 24-hour infusion. This stability information was previously documented by the Biopharmaceutical Development Program (BDP) of Leidos Biomedical Research, Inc., the drug manufacturer.
untitled h1
14.1.7 administration

For all dose levels, the dose of rhIL-15 will be diluted in the appropriate volume of 0.1% human serum albumin (HSA) in 5% dextrose in water, USP (D5W) to reach a final rhIL-15 concentration of 1 mcg/mL (see Dilution instructions, **APPENDIX D**). The rhIL-15 infusion will be administered to the patient by continuous intravenous infusion (civ) at a dose in mcg/kg/day determined by the dose level at which the patient is enrolled. Each bag (total 5 bags over 5 days) will be infused over 24 hours using a portable ambulatory pump on the inpatient unit (cycle 1) or in the outpatient setting (cycles 2-6, if deemed appropriate by the PI) for a total of 120 hours. Bags must be changed every 24 hours. Treatment with rhIL-15 will begin within 4 hours of preparation of the infusion bag and the infusion must be completed within 24 hours from the time drug administration begins. Otherwise a new infusion bag must be prepared to complete administration of the remaining dose.  
See Appendix 3.2 for Drug Regimen, and Section **3.2.1** for supportive care measures.
untitled h1
14.1.8 toxicity

The Comprehensive Adverse Event and Potential Risks List (CAEPRs) for Recombinant Human IL-15 provides a single list of reported and/or potential adverse events (AE) associated with the 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 (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. The CAEPR does not provide frequency data; refer to the Investigator's  
Version Date: *11/16/2020* Brochure for this information. Below is the CAEPR for Recombinant Human IL-15.  
| Version 1.3, January 2, 2019*                                                                                                                                                                                                                       |                                                              |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------|
| Adverse Events with Possible                                                                                                                                                                                                                        |                                                              |
| Relationship to Recombinant Human IL-15 (CTCAE 5.0 Term)                                                                                                                                                                                            | Specific Protocol Exceptions to  Expedited Reporting (SPEER) |
| BLOOD AND LYMPHATIC SYSTEM DISORDERS Anemia                                                                                                                                                                                                         | Anemia (Gr 2)                                                |
| Bone marrow hypocellular CARDIAC DISORDERS Sinus tachycardia                                                                                                                                                                                        | Sinus tachycardia (Gr 2)                                     |
| GASTROINTESTINAL DISORDERS Abdominal pain Diarrhea Nausea                                                                                                                                                                                           | Nausea (Gr 2)                                                |
| Vomiting                                                                                                                                                                                                                                            | Vomiting (Gr 2)                                              |
| GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS Chills                                                                                                                                                                                         | Chills (Gr 2)                                                |
| Edema limbs Fatigue                                                                                                                                                                                                                                 | Fatigue (Gr 2)                                               |
| Fever                                                                                                                                                                                                                                               | Fever (Gr 2)                                                 |
| Injection site reaction INFECTIONS AND INFESTATIONS Sepsis INVESTIGATIONS Alanine aminotransferase increased Aspartate aminotransferase increased Blood bilirubin increased Creatinine increased Lymphocyte count decreased                         | Lymphocyte count decreased (Gr 2)                            |
| Lymphocyte count increased Neutrophil count decreased Platelet count decreased White blood cell decreased METABOLISM AND NUTRITION DISORDERS Hypoalbuminemia Hypophosphatemia                                                                       | Hypophosphatemia (Gr 2)                                      |
| MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS Generalized muscle weakness NERVOUS SYSTEM DISORDERS Dizziness Headache RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS Dyspnea SKIN AND SUBCUTANEOUS TISSUE DISORDERS Dry skin Erythema multiforme | Erythema multiforme (Gr 2)                                   |
| Skin and subcutaneous tissue disorders - Other (rash) VASCULAR DISORDERS Capillary leak syndrome                                                                                                                                                    |                                                              |  
Version Date: *11/16/2020*  
Adverse Events with Possible  
Relationship to Recombinant Human IL-15  
(CTCAE 5.0 Term)  
| Adverse Events with Possible                             |                                                              |
|----------------------------------------------------------|--------------------------------------------------------------|
| Relationship to Recombinant Human IL-15 (CTCAE 5.0 Term) | Specific Protocol Exceptions to  Expedited Reporting (SPEER) |
| Hypertension                                             | Hypertension (Gr 2)                                          |
| Hypotension                                              | Hypotension (Gr 2)                                           |  
*This table will be updated as the toxicity profile of the agent is revised. Updates will be distributed to all Principal Investigators at the time of revision. The current version can be obtained by contacting PIO@CTEP.NCI.NIH.GOV.  
Your name, the name of the investigator, the protocol and the agent should be included in the e-mail Adverse events reported on Recombinant Human IL-15 trials, but for which there is insufficient evidence to suggest that there was a reasonable possibility that Recombinant Human IL-15 caused the adverse event:
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Febrile neutropenia CARDIAC DISORDERS - Atrial fibrillation; Chest pain - cardiac; Palpitations; Pericardial effusion; Pericardial tamponade; Sinus bradycardia; Ventricular tachycardia GASTROINTESTINAL DISORDERS - Ascites; Constipation; Duodenal hemorrhage; Gastritis; Gastrointestinal disorders - Other (increased appetite); Ileus; Mucositis oral; Pancreatitis; Visceral arterial ischemia GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Edema face; Infusion site extravasation; Multi-organ failure; Pain IMMUNE SYSTEM DISORDERS - Autoimmune disorder INFECTIONS AND INFESTATIONS - Tooth infection; Upper respiratory infection; Urinary tract infection INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Bruising; Infusion related reaction INVESTIGATIONS - Alkaline phosphatase increased; Cardiac troponin I increased; Electrocardiogram QT corrected interval prolonged; GGT increased; INR increased; Lipase increased; Serum amylase increased; Weight gain; Weight loss METABOLISM AND NUTRITION DISORDERS - Anorexia; Dehydration; Hyperkalemia; Hypocalcemia; Hypokalemia MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Back pain; Bone pain; Muscle weakness upper limb; Myalgia; Pain in extremity NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Tumor pain NERVOUS SYSTEM DISORDERS - Dysgeusia; Peripheral sensory neuropathy; Presyncope; Vasovagal reaction PSYCHIATRIC DISORDERS - Anxiety; Psychosis REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Genital edema RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Adult respiratory distress syndrome; Bronchopulmonary hemorrhage; Cough; Hypoxia; Laryngeal inflammation; Pleural effusion; Pneumonitis; Pulmonary edema; Wheezing SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Erythroderma; Palmar-plantar erythrodysesthesia syndrome; Pruritus; Rash acneiform; Skin and subcutaneous tissue disorders - Other (skin plaques)
VASCULAR DISORDERS - Hot flashes NOTE: Recombinant Human IL-15 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  
Version Date: *11/16/2020* result in events never previously associated with either agent.
untitled h1
14.1.9 ctep information

14.1.9.1 Agent ordering and Agent Accountability NCI-supplied agents may be requested by eligible participating Investigators (or their authorized designee). The CTEP-assigned protocol number must be used for ordering all CTEP-supplied investigational agents. The eligible participating investigators must be registered with CTEP, DCTD through an annual submission of FDA Form 1572 (Statement of Investigator), NCI Biosketch, Agent Shipment Form, and Financial Disclosure Form (FDF). If there are several participating investigators, CTEP-supplied investigational agents for the study should be ordered under the name of one lead participating investigator at that institution. IL-15 may be order from PMB when a patient is being worked up for the study.  
Submit agent requests through the PMB Online Agent Order Processing (OAOP) application.  
Access to OAOP requires the establishment of a CTEP Identity and Access Management (IAM) account and the maintenance of an "active" account status, a "current" password, and active person registration status. For questions about drug orders, transfers, returns, or accountability, call or email PMB any time. Refer to the PMB's website for specific policies and guidelines related to agent management.
untitled h1
14.1.9.2 agent inventory records

The investigator, or a responsible party designated by the investigator, must maintain a careful record of the receipt, dispensing and final disposition of all agents received from the PMB using the appropriate NCI Investigational Agent (Drug) Accountability Record (DARF) available on the CTEP forms page. Store and maintain separate NCI Investigational Agent Accountability Records for each agent, strength, formulation and ordering investigator on this protocol.  
14.1.9.3 Investigator Brochure Availability The current versions of the IBs for the agents will be accessible to site investigators and research staff through the PMB OAOP application. Access to OAOP requires the establishment of a CTEP IAM account and the maintenance of an "active" account status, a "current" password and active person registration status. Questions about IB access may be directed to the PMB IB Coordinator via email.  
14.1.9.4 Useful Links and Contacts
- CTEP Forms, Templates, Documents: http://ctep.cancer.gov/forms/
- NCI CTEP Person Registration: RCRHelpDesk@nih.gov
- PMB policies and guidelines:
http://ctep.cancer.gov/branches/pmb/agent_management.htm
- PMB Online Agent Order Processing (OAOP) application:
https://ctepcore.nci.nih.gov/OAOP
- CTEP Identity and Access Management (IAM) account:
https://ctepcore.nci.nih.gov/iam/
- CTEP IAM account help: ctepreghelp@ctep.nci.nih.gov
- IB Coordinator: IBCoordinator@mail.nih.gov - PMB email: PMBAfterHours@mail.nih.gov  
Version Date: *11/16/2020*
- PMB phone and hours of service: (240) 276-6575 Monday through Friday between 8:30 am and 4:30 pm (ET)
untitled h1
14.2 mogamulizumab (kw-0761 nsc# 791064)

14.2.1 Source/ Acquisition and Accountability Mogamulizumab (Poteligeo®) is commercially available and will be purchased by the CCR and supplied to the patients enrolled on the study by the NIH Clinical Center Pharmacy Department. 14.2.2 Toxicity The Comprehensive Adverse Events 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.  
| Adverse Events with Possible                                                                                                                                                                                                                                                                                                                                                                                                                   |                                                                                    |                        |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------|------------------------|
| Relationship to KW-0761 (mogamulizumab) (CTCAE 5.0 Term) [n= 4759]                                                                                                                                                                                                                                                                                                                                                                             |                                                                                    |                        |
| Likely (>20%)                                                                                                                                                                                                                                                                                                                                                                                                                                  | Less Likely (<=20%)                                                                | Rare but Serious (<3%) |
| CARDIAC DISORDERS                                                                                                                                                                                                                                                                                                                                                                                                                              | Chest pain - cardiac Myocardial infarction Myocarditis2 Restrictive cardiomyopathy |                        |
| GASTROINTESTINAL DISORDERS Nausea GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS Fatigue Fever Flu like symptoms2 IMMUNE SYSTEM DISORDERS Allergic reaction                                                                                                                                                                                                                                                                              | Anaphylaxis3 Immune system disorders - Other (graft  versus host disease)4         |                        |
| INFECTIONS AND INFESTATIONS Infection5 INJURY, POISONING AND PROCEDURAL COMPLICATIONS Infusion related reaction3 INVESTIGATIONS Alanine aminotransferase increased2,6 Alkaline phosphatase increased2,6 Aspartate aminotransferase increased2,6 Blood bilirubin increased2,6 GGT increased2,6 Lymphocyte count decreased2 Neutrophil count decreased2 Platelet count decreased2 White blood cell decreased2 METABOLISM AND NUTRITION DISORDERS |                                                                                    |                        |  
Version **2.3, September 15, 2019**1  
Adverse Events with Possible  
Relationship to KW-0761 (mogamulizumab)  
(CTCAE 5.0 Term)  
[n= 4759]  
Likely (>20%) Less Likely (<=20%) **Rare but Serious (<3%)**  
Tumor lysis syndrome  
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS  
Arthritis2  
NERVOUS SYSTEM DISORDERS  
Peripheral motor neuropathy2  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS  
Pneumonitis2  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS  
Erythema multiforme2  
Rash maculo-papular2  
Skin and subcutaneous tissue disorders -  
Other (drug eruption, toxic skin eruption)2  
Skin hypopigmentation2  
Stevens-Johnson syndrome2 Toxic epidermal necrolysis2  
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.  
2Immune-mediated adverse reactions have been reported in patients receiving KW-0761  
(mogamulizumab). Adverse events potentially related to KW-0761 (mogamulizumab) may be manifestations of immune-mediated adverse events. In clinical trials, most immune-mediated adverse  
reactions were reversible and managed with interruptions of KW-0761 (mogamulizumab), administration  
of corticosteroids and supportive care.  
3Infusion reactions, including high-grade hypersensitivity reactions, anaphylaxis, and cytokine release  
syndrome, which have been observed following administration of KW-0761 (mogamulizumab), may  
manifest as fever, chills, shakes, itching, rash, hypertension or hypotension, or difficulty breathing during and immediately after administration of KW-0761 (mogamulizumab).  
4Acute graft-versus-host disease has been observed in patients treated with KW-0761 (mogamulizumab)  
who subsequently received hematopoeitic stem cell transplants.  
5Infection may include any of the infection sites under the INFECTIONS AND INFESTATIONS SOC. 6Symptoms of hepatic dysfunction may include Alanine aminotransferase increased, Alkaline  
phosphatase increased, Aspartate aminotransferase increased, Blood bilirubin increased, and GGT increased under the INVESTIGATIONS SOC.  
Adverse events reported on KW-0761 (mogamulizumab) trials, but for which there is insufficient evidence to suggest that there was a reasonable possibility that KW-0761 (mogamulizumab) caused the adverse event:
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Anemia; Disseminated intravascular coagulation; Febrile neutropenia; Hemolysis; Thrombotic thrombocytopenic purpura CARDIAC DISORDERS - Atrial fibrillation; Sinus tachycardia; Supraventricular tachycardia EYE DISORDERS - Retinal vascular disorder GASTROINTESTINAL DISORDERS - Abdominal pain; Cheilitis; Colitis2; Constipation; Diarrhea; Gastritis; Mucositis oral; Vomiting  
Version Date: *11/16/2020* GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Death NOS; Edema limbs; Generalized edema; Malaise; Multi-organ failure HEPATOBILIARY DISORDERS - Cholecystitis; Hepatic failure; Hepatobiliary disorders - Other (bile duct stone); Hepatobiliary disorders - Other (hepatitis)
INVESTIGATIONS - Blood lactate dehydrogenase increased2; CPK increased; Lipase increased; Serum amylase increased; Weight loss METABOLISM AND NUTRITION DISORDERS - Acidosis; Anorexia; Dehydration; Hypercalcemia; Hyperglycemia; Hyperkalemia; Hypoalbuminemia; Hypocalcemia; Hypokalemia; Hypomagnesemia; Hyponatremia; Hypophosphatemia; Metabolism and nutrition disorders - Other (diabetes mellitus)
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthralgia; Flank pain; Generalized muscle weakness; Musculoskeletal and connective tissue disorder - Other (tendonitis); Myositis NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Treatment related secondary malignancy NERVOUS SYSTEM DISORDERS - Depressed level of consciousness; Encephalopathy; Headache; Nervous system disorders - Other (altered state of consciousness); Nervous system disorders - Other (cerebellar syndrome); Paresthesia; Seizure
untitled h1
renal and urinary disorders -

RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Adult respiratory distress syndrome; Cough; Dyspnea; Hypoxia; Pleural effusion; Respiratory failure SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Dry skin; Erythroderma; Hyperhidrosis; Palmar-plantar erythrodysesthesia syndrome; Photosensitivity; Pruritus; Rash acneiform; Skin and subcutaneous tissue disorders - Other (lichenoid keratosis); Urticaria VASCULAR DISORDERS - Hypertension2; Hypotension2 Note: KW-0761 (mogamulizumab) 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. 14.2.3 Formulation and preparation Mogamulizumab is supplied as single-use 20 mg vials containing a sterile, clear, colorless solution (4 mg/mL). Mogamulizumab solution for infusion is formulated in 2.1 mmol/L sodium citrate buffer, 300 mmol/L glycine, and 0.2 mg/mL polysorbate 80 (Tween 80), pH 5.5, supplied in Type I glass vials. Mogamulizumab solution for infusion must be diluted prior to administration. Do not shake the vials. To prepare the infusion solution add the dose volume of Mogamulizumab to an infusion bag containing 0.9% Sodium Chloride Injection, USP. PVC and non-PVC (polyolefin) IV bags may be used. The final concentration of the infusion solution must be between 0.1 mg/mL to 3.0 mg/mL. 14.2.4 Stability and Storage Store intact vials between 2°C - 8°C (36°F - 46°F). Do not freeze. Protect from light by storing in the original box. If a storage temperature excursion is identified, promptly return Mogamulizumab to between 28°C and quarantine the supplies.  
Version Date: *11/16/2020* After preparation, infuse the mogamulizumab solution immediately, or store under refrigeration at 2°C to 8°C (36°F to 46°F) for no more than 4 hours from the time of infusion preparation. Do not freeze. Do not shake. 14.2.5 Administration procedures Infuse over at least 1 hour using an infusion set containing a low-protein binding 0.2 to 0.22 µm in-line filter. Do not co-administer other drugs through the same infusion line. Following the infusion, flush the IV line with normal saline. 14.2.6 Incompatibilities No incompatibilities between mogamulizumab and polyvinylchloride (PVC) or non-PVC polyolefin bags and administration sets have been observed. No formal drug interaction studies have been performed with mogamulizumab. Please refer to the package insert and PDR for full drug interactions and toxicities.  
Please refer to the mogamulizumab package insert for complete information. 1. Malpica L, Pimentel A, Reis IM, Gotuzzo E, Lekakis L, Komanduri K, et al. Epidemiology, clinical features, and outcome of HTLV-1–related ATLL in an area of prevalence in the United States. Blood Advances. 2018;2(6):607-20. 2. Shimoyama M, members of The Lymphoma Study G. Diagnostic criteria and classification of clinical subtypes of adult T-cell leukaemia-lymphoma. British journal of haematology. 1991;79(3):428-37. 3. Fuji S, Fujiwara H, Nakano N, Wake A, Inoue Y, Fukuda T, et al. Early application of related SCT might improve clinical outcome in adult T-cell leukemia/lymphoma. Bone Marrow Transplant. 2016;51(2):205--11. 4. Fujiwara H, Fuji S, Wake A, Kato K, Takatsuka Y, Fukuda T, et al. Dismal outcome of allogeneic hematopoietic stem cell transplantation for relapsed adult T-cell leukemia/lymphoma, a Japanese nation-wide study. Bone Marrow Transplant. 2017;52(3):484--8. 5. Bazarbachi A, Suarez F, Fields P, Hermine O. How I treat adult T-cell leukemia/lymphoma. Blood. 2011;118(7):1736-45. 6. Tsukasaki K, Utsunomiya A, Fukuda H, Shibata T, Fukushima T, Takatsuka Y, et al. VCAP-AMP-VECP compared with biweekly CHOP for adult T-cell leukemia-lymphoma: Japan Clinical Oncology Group Study JCOG9801. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2007;25(34):5458-64. 7. Bazarbachi A, Plumelle Y, Carlos Ramos J, Tortevoye P, Otrock Z, Taylor G, et al. Meta-analysis on the use of zidovudine and interferon-alfa in adult T-cell leukemia/lymphoma showing improved survival in the leukemic subtypes. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2010;28(27):4177-83. 8. Ishida T, Joh T, Uike N, Yamamoto K, Utsunomiya A, Yoshida S, et al. Defucosylated anti-CCR4 monoclonal antibody (KW-0761) for relapsed adult T-cell leukemia-lymphoma: a multicenter phase II study. J Clin Oncol. 2012;30(8):837--42. 9. Sharma K, Janik JE, O'Mahony D, Stewart D, Pittaluga S, Stetler-Stevenson M, et al.  
Phase II Study of Alemtuzumab (CAMPATH-1) in Patients with HTLV-1-Associated Adult Tcell Leukemia/lymphoma. Clinical cancer research : an official journal of the American Association for Cancer Research. 2017;23(1):35-42. 10. Ishida T, Fujiwara H, Nosaka K, Taira N, Abe Y, Imaizumi Y, et al. Multicenter Phase II
Study of Lenalidomide in Relapsed or Recurrent Adult T-Cell Leukemia/Lymphoma: ATLL002. J Clin Oncol. 2016;34(34):4086--93.  
11. Tobinai K, Uike N, Saburi Y, Chou T, Etoh T, Masuda M, et al. Phase II study of cladribine (2-chlorodeoxyadenosine) in relapsed or refractory adult T-cell leukemia-lymphoma. Int J Hematol. 2003;77(5):512--7. 12. Hermine O, Dombret H, Poupon J, Arnulf B, Lefrère F, Rousselot P, et al. Phase II trial of arsenic trioxide and alpha interferon in patients with relapsed/refractory adult T-cell leukemia/lymphoma. Hematol J. 2004;5(2):130--4.  
Version Date: *11/16/2020* 13. Ishitsuka K, Utsunomiya A, Katsuya H, Takeuchi S, Takatsuka Y, Hidaka M, et al. A phase II study of bortezomib in patients with relapsed or refractory aggressive adult T-cell leukemia/lymphoma. Cancer Sci. 2015;106(9):1219--23. 14. Wilcox RA. Cutaneous T-cell lymphoma: 2017 update on diagnosis, risk-stratification, and management. Am J Hematol. 2017;92(10):1085--102. 15. Duarte RF, Canals C, Onida F, Gabriel IH, Arranz R, Arcese W, et al. Allogeneic hematopoietic cell transplantation for patients with mycosis fungoides and Sézary syndrome: a retrospective analysis of the Lymphoma Working Party of the European Group for Blood and Marrow Transplantation. J Clin Oncol. 2010;28(29):4492--9. 16. Dummer R, Quaglino P, Becker JC, Hasan B, Karrasch M, Whittaker S, et al. Prospective international multicenter phase II trial of intravenous pegylated liposomal doxorubicin monochemotherapy in patients with stage IIB, IVA, or IVB advanced mycosis fungoides: final results from EORTC 21012. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2012;30(33):4091-7. 17. Whittaker S, Hoppe R, Prince HM. How I treat mycosis fungoides and Sezary syndrome. Blood. 2016;127(25):3142-53. 18. Duvic M, Hymes K, Heald P, Breneman D, Martin AG, Myskowski P, et al. Bexarotene is effective and safe for treatment of refractory advanced-stage cutaneous T-cell lymphoma: multinational phase II-III trial results. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2001;19(9):2456-71. 19. Olsen EA, Kim YH, Kuzel TM, Pacheco TR, Foss FM, Parker S, et al. Phase IIb multicenter trial of vorinostat in patients with persistent, progressive, or treatment refractory cutaneous T-cell lymphoma. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2007;25(21):3109-15. 20. Piekarz RL, Frye R, Turner M, Wright JJ, Allen SL, Kirschbaum MH, et al. Phase II multi-institutional trial of the histone deacetylase inhibitor romidepsin as monotherapy for patients with cutaneous T-cell lymphoma. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2009;27(32):5410-7.  
21. Whittaker SJ, Demierre MF, Kim EJ, Rook AH, Lerner A, Duvic M, et al. Final results from a multicenter, international, pivotal study of romidepsin in refractory cutaneous T-cell lymphoma. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2010;28(29):4485-91. 22. Prince HM, Kim YH, Horwitz SM, Dummer R, Scarisbrick J, Quaglino P, et al. Brentuximab vedotin or physician's choice in CD30-positive cutaneous T-cell lymphoma (ALCANZA): an international, open-label, randomised, phase 3, multicentre trial. Lancet (London, England). 2017;390(10094):555-66. 23. Duvic M, Pinter-Brown LC, Foss FM, Sokol L, Jorgensen JL, Challagundla P, et al. Phase 1/2 study of mogamulizumab, a defucosylated anti-CCR4 antibody, in previously treated patients with cutaneous T-cell lymphoma. Blood. 2015;125(12):1883--9. 24. Kim YH, Bagot M, Pinter-Brown L, Rook AH, Porcu P, Horwitz SM, et al. Mogamulizumab versus vorinostat in previously treated cutaneous T-cell lymphoma  
Version Date: *11/16/2020*
(MAVORIC): an international, open-label, randomised, controlled phase 3 trial. The Lancet Oncology. 2018. 25. Yoshie O. Expression of CCR4 in adult T-cell leukemia. Leukemia & Lymphoma. 2005;46(2):185-90. 26. Nakagawa M, Schmitz R, Xiao W, Goldman CK, Xu W, Yang Y, et al. Gain-of-function <em>CCR4</em> mutations in adult T cell leukemia/lymphoma. The Journal of experimental medicine. 2014;211(13):2497-505. 27. Duvic M, Pinter-Brown LC, Foss FM, Sokol L, Jorgensen JL, Challagundla P, et al. Phase 1/2 study of mogamulizumab, a defucosylated anti-CCR4 antibody, in previously treated patients with cutaneous T-cell lymphoma. Blood. 2015;125(12):1883-9. 28. Wang L, Ni X, Covington KR, Yang BY, Shiu J, Zhang X, et al. Genomic profiling of Sezary syndrome identifies alterations of key T cell signaling and differentiation genes. Nature genetics. 2015;47(12):1426-34. 29. Antoniu SA. Mogamulizumab, a humanized mAb against C-C chemokine receptor 4 for the potential treatment of T-cell lymphomas and asthma. Curr Opin Mol Ther. 2010;12(6):770-- 9. 30. Ishii T, Ishida T, Utsunomiya A, Inagaki A, Yano H, Komatsu H, et al. Defucosylated humanized anti-CCR4 monoclonal antibody KW-0761 as a novel immunotherapeutic agent for adult T-cell leukemia/lymphoma. Clin Cancer Res. 2010;16(5):1520--31. 31. Sakamoto Y, Ishida T, Masaki A, Murase T, Yonekura K, Tashiro Y, et al. CCR4 mutations associated with superior outcome of adult T-cell leukemia/lymphoma under mogamulizumab treatment. Blood. 2018:2018--02. 32. Waldmann TA. The biology of interleukin-2 and interleukin-15: implications for cancer therapy and vaccine design. Nature reviews Immunology. 2006;6(8):595-601. 33. Lugli E, Goldman CK, Perera LP, Smedley J, Pung R, Yovandich JL, et al. Transient and persistent effects of IL-15 on lymphocyte homeostasis in nonhuman primates. Blood. 2010;116(17):3238-48. 34. Sneller MC, Kopp WC, Engelke KJ, Yovandich JL, Creekmore SP, Waldmann TA, et al. IL-15 administered by continuous infusion to rhesus macaques induces massive expansion of CD8+ T effector memory population in peripheral blood. Blood. 2011;118(26):6845--8. 35. Waldmann TA, Lugli E, Roederer M, Perera LP, Smedley JV, Macallister RP, et al. Safety (toxicity), pharmacokinetics, immunogenicity, and impact on elements of the normal immune system of recombinant human IL-15 in rhesus macaques. Blood. 2011;117(18):4787-95. 36. Waldmann TA. The biology of IL-15: implications for cancer therapy and the treatment of autoimmune disorders. The journal of investigative dermatology Symposium proceedings. 2013;16(1):S28-30. 37. Conlon KC, Lugli E, Welles HC, Rosenberg SA, Fojo AT, Morris JC, et al. Redistribution, hyperproliferation, activation of natural killer cells and CD8 T cells, and cytokine production during first-in-human clinical trial of recombinant human interleukin-15 in patients with cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2015;33(1):74-82.  
Version Date: *11/16/2020* 38. Miller JS, Morishima C, McNeel DG, Patel MR, Kohrt HEK, Thompson JA, et al. A First-in-Human Phase I Study of Subcutaneous Outpatient Recombinant Human IL15 (rhIL15) in Adults with Advanced Solid Tumors. Clinical Cancer Research. 2018;24(7):1525-35. 39. Conlon KC, Dubois S, Lee C-cR, Fleisher T, Hsu JI, Waldmann TA. Abstract 1596: Phase I trial of recombinant human Interleukin 15 (rhIL-15) administered as continuous intravenous infusion (CIV) for 10 days (240 hours) in patients with refractory metastatic cancers. Cancer Research. 2017;77(13 Supplement):1596-.  
40. Miljkovic MD, Zhang M, Conlon KC, Waldmann TA. IL-15-enhanced antibodydependent cellular cytotoxicity mediated by NK cells and macrophages: Implications for immunotherapy of T-cell lymphoma [abstract]. In: Proceedings of the 2018 AACR Meeting on Advances in Malignant Lymphoma; 2018 June 22 - 26; Boston, Massachusetts: Philadelphia (PA): AACR; 2018. 41. Olsen EA, Whittaker S, Kim YH, Duvic M, Prince HM, Lessin SR, et al. Clinical End Points and Response Criteria in Mycosis Fungoides and Sézary Syndrome: A Consensus Statement of the International Society for Cutaneous Lymphomas, the United States Cutaneous Lymphoma Consortium, and the Cutaneous Lymphoma Task Force of the European Organisation for Research and Treatment of Cancer. Journal of Clinical Oncology. 2011;29(18):2598-607.  
42. Cook LB, Fuji S, Hermine O, Bazarbachi A, Ramos JC, Ratner L, et al. Revised Adult TCell Leukemia-Lymphoma International Consensus Meeting Report. Journal of Clinical Oncology. 2019. 43. Tsukasaki K, Hermine O, Bazarbachi A, Ratner L, Ramos JC, Harrington W, et al.  
Definition, Prognostic Factors, Treatment, and Response Criteria of Adult T-Cell LeukemiaLymphoma: A Proposal From an International Consensus Meeting. Journal of Clinical Oncology. 2009;27(3):453-9. 44. Khodadoust MS, Rook AH, Porcu P, Foss F, Moskowitz A, Shustov AR, et al. Pembrolizumab For Treatment Of Relapsed/Refractory Mycosis Fungoides And Sézary Syndrome: Clinical Efficacy In A CITN Multicenter Phase 2 Study. 3rd World Congress of Cutaneous Lymphomas. 2016;Abstract O-10. 45. Agresti A, Coull BA. Approximate Is Better than "Exact" for Interval Estimation of Binomial Proportions. The American Statistician. 1998;52(2):119-26. 46. Ishitsuka K, Yurimoto S, Kawamura K, Tsuji Y, Iwabuchi M, Takahashi T, et al. Safety and efficacy of mogamulizumab in patients with adult T-cell leukemia–lymphoma in Japan: interim results of postmarketing all-case surveillance. International journal of hematology. 2017;106(4):522-32.  
| 16.1                                                                                                                                                                                      | APPENDIX A: PERFORMANCE STATUS CRITERIA ECOG Performance Status Scale Karnofsky Performance Scale   |                                                              |             |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------|--------------------------------------------------------------|-------------|
| Grade                                                                                                                                                                                     | Descriptions                                                                                        | Percent                                                      | Description |
| 100                                                                                                                                                                                       | Normal, no complaints, no  evidence of disease.                                                     |                                                              |             |
| Normal activity. Fully active, able                                                                                                                                                       |                                                                                                     |                                                              |             |
| 0                                                                                                                                                                                         | to carry on all pre-disease  performance without restriction.                                       | Able to carry on normal activity;                            |             |
| 90                                                                                                                                                                                        | minor signs or symptoms of  disease. Normal activity with effort;                                   |                                                              |             |
| 80                                                                                                                                                                                        | some signs or symptoms of  disease.                                                                 |                                                              |             |
| 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                                                                                                                                                                                         | Cares for self, unable to carry on                                                                  |                                                              |             |
| 70                                                                                                                                                                                        | normal activity or to do active  work. Requires occasional assistance,                              |                                                              |             |
| 60                                                                                                                                                                                        | but is able to care for most of  his/her needs.                                                     |                                                              |             |
| 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                                                                                                                                                                                         | 50                                                                                                  | Requires considerable assistance  and frequent medical care. |             |
| 40                                                                                                                                                                                        | Disabled, requires special care  and assistance.                                                    |                                                              |             |
| In bed >50% of the time. Capable  of only limited self-care, confined  to bed or chair more than 50% of  waking hours.                                                                    |                                                                                                     |                                                              |             |
| 3                                                                                                                                                                                         | Severely disabled,                                                                                  |                                                              |             |
| 30                                                                                                                                                                                        | hospitalization indicated. Death  not imminent.                                                     |                                                              |             |
| 20                                                                                                                                                                                        | Very sick, hospitalization  indicated. Death not imminent.                                          |                                                              |             |
| 100% bedridden. Completely  disabled. Cannot carry on any  self-care. Totally confined to bed  or chair.                                                                                  |                                                                                                     |                                                              |             |
| 4                                                                                                                                                                                         | 10                                                                                                  | Moribund, fatal processes  progressing rapidly.              |             |
| 5                                                                                                                                                                                         | Dead.                                                                                               | 0                                                            | Dead.       |  
- Peripheral blood mononuclear cells (PBMCs) should be isolated by Ficoll-High-Paque Density Gradient Centrifugation.  
- The viable cells should be viably frozen and stored in liquid nitrogen.  
- The ADCC assay will be performed on the same occasion for all samples of a given patient.  
- Vials of frozen cells will be thawed using standard procedures 18 hours before the assay in accordance with our experience with normal donors.  
- 1.5 million of patient's PBMCs obtained before and on day 15 following IL-15 injection will be tested in aliquots as follows:
o Tested alone o Tested with untreated PD-L1-expressing Raji cells and with PD-L1-expressing Raji cells coated with mogamulizumab for 5 hours.  
o In addition, we may utilize an ATL cell line in addition to Raji cells. These cell populations will be stained with CD107, CD3, CD56 and CD94.  
| Global Response Score                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |                                                                                             |                         |                                           |       |         |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------|-------------------------|-------------------------------------------|-------|---------|
| Global Score                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  | Definition                                                                                  | Skin                    | Nodes                                     | Blood | Viscera |
| CR                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            | Complete disappearance of all                                                               | CR                      | All categories have CR/NI                 |       |         |
| clinical evidence of disease                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  |                                                                                             |                         |                                           |       |         |
| PR                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            | Regression of measurable                                                                    | CR                      | All categories do not have a CR/NI and no |       |         |
| disease                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       | category has a PD                                                                           |                         |                                           |       |         |
| PR                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            | No category has a PD and if any category  involved at baseline at least one has a CR  or PR |                         |                                           |       |         |
| SD                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            | Failure to attain CR, PR, or PD                                                             | PR                      | No category has a PD and if any category  |       |         |
| representative of all disease                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 | involved at baseline, no CR or PR in any                                                    |                         |                                           |       |         |
| SD                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            | CR/NI, PR, SD in any category and no  category has a PD                                     |                         |                                           |       |         |
| PD                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            | Progressive disease                                                                         | PD in any category      |                                           |       |         |
| Relapse                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       | Recurrence of disease in prior                                                              | Relapse in any category |                                           |       |         |
| CR                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            |                                                                                             |                         |                                           |       |         |
| Abbreviations: CR, complete response; NI, noninvolved; PR, partial response; PD, progressive disease;  SD, stable disease. Response in Skin Response Definition Complete response 100% clearance of skin lesions Partial response 50%-99% clearance of skin disease from baseline without new tumors (T3) in  patients with T1, T2 or T4 only skin disease Stable disease <25% increase to <50% clearance in skin disease from baseline without new  tumors (T3) in patients with T1, T2, or T4 only skin disease Progressive disease ≥25% increase in skin disease from baseline or New tumors (T3) in patients with T1, T2, or T4 only skin disease or Loss fo response: in those with complete or partial response, increase of skin  score of greater than the sum of nadir plus 50% baseline score Relapse Any disease recurrence in those with complete response Notes: |                                                                                             |                         |                                           |       |         |
untitled h1
version date 11/16/2020

16.3 APPENDIX C: GLOBAL RESPONSE SCORE AND DEFINITIONS OF RESPONSE IN SKIN,
LYMPH NODES, VISCERA, AND B**LOOD**
Notes:
Percentages refer to mSWAT score. A biopsy of normal appearing skin is unnecessary to assign a complete response. However, a skin biopsy should be performed of a representative area of the skin if there is any question of residual disease (persistent erythema or pigmentary change) where otherwise a complete response would exist. If histologic features are suspicious or suggestive of mycosis fungoides/Sézary syndrome, the response should be considered a partial response only.  
| Abbreviated Title: IL-15+Mogamulizumab  Version Date: 11/16/2020 Response in Lymph Nodes Response Definition CR All lymph nodes are now ≤1.5 cm in greatest transverse (long axis) diameter by method  used to assess lymph nodes at baseline or biopsy negative for lymphoma; in addition,  lymph nodes that were N3 classification and ≤1.5 cm in their long axis and >1 cm in  their short axis at baseline, must now be ≤1 cm in their short axis or biopsy negative for  lymphoma PR Cumulative reduction ≥50% of the SPD of each abnormal lymph node at baseline and no  new lymph node >1.5 cm in the diameter of the long axis or >1.0 cm in the diameter of  the short axis if the long axis is 1-1.5 cm diameter SD Fails to attain the criteria for CR, PR, and PD PD >50% increase in SPD from baseline of lymph nodes OR Any new node >1.5cm in the long axis or >1cm in the short axis if 1-1.5 cm in the long  axis that is proven to be N3 histologically OR Loss of response: >50% increase from nadir in SPD of lymph nodes in those with PR  (whichever occurs first) Relapse Any new lymph node >1.5 cm in the long axis in those with CR proven to be N3  histologically Abbreviations: CR, complete response; PR, partial response; SPD, sum of the maximum linear  dimension (major axis) ⨉ longest perpendicular dimension (minor axis); SD, stable disease; PD,  progressive disease. Response in Viscera Response Definition CR Liver or spleen or any organ considered involved at baseline should not be enlarged on  physical exam and should be considered normal by imaging; no nodules should be  present on imaging of liver or spleen; any post treatment mass must be determined by  biopsy to be negative for lymphoma PR >50% regression in any splenic or liver nodules, or in measurable disease (SPD) in any  organs abnormal at baseline; no increase in size of liver or spleen and no new sites of  involvement SD Fails to attain the criteria for CR, PR, and PD PD >50% increase in size (SPD) of any organs involved at baseline OR New organ involvement OR Loss of response: >50% increase from nadir in the size (SPD) of any previous organ  involvement in those with PR (whichever occurs first) Relapse New organ involvement in those with CR Abbreviations: CR, complete response; PR, partial response; SPD, sum of the maximum linear  dimension (major axis) ⨉ longest perpendicular dimension (minor axis); SD, stable disease; PD,  progressive disease.   |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
Version Date: *11/16/2020*  
Response in Blood*  
Response Definition  
CR† B0  
PR‡ >50% decrease in quantitative measurements of blood tumor burden from baseline in  
those with high tumor burden at baseline (B2)  
SD Fails to attain the criteria for CR, PR, and PD  
PD§ B0 to B2 or  
> 50% increase from baseline and at least 5,000 neoplastic cells/μL or  
Loss of response: in those with PR who were originally B2 at baseline, > 50% increase  
from nadir and at least 5,000 neoplastic cells/μL  
Relapse Increase of neoplastic blood lymphocytes to ≥ B1 in those with CR  
Abbreviations: CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease.  
* As determined by absolute number of neoplastic cells/μL  
† If a bone marrow biopsy was performed at baseline and determined to unequivocally be indicative of  
lymphomatous involvement, then to confirm a global CR where blood assessment now meets criteria  
for B0, a repeat bone marrow biopsy must show no residual disease or the response should be  
considered a PR only.  
‡ There is no PR in those with B1 disease at baseline as the difference within the range of neoplastic  
cells that define B1 is not considered significant and should not affect determination of global objective response.  
§ Whichever occurs first  
All dose preparations will be performed aseptically in a laminar flow hood in compliance with all legal requirements and in accordance with guidelines of recognized organizations. Vials of IL-15 do not contain any preservatives. 0.1% human serum albumin (HSA) in 5% dextrose in water, USP (D5W), should be used for the dilutions listed below. To prepare an IL-15 dose for Dose Level 1 (2 mcg/kg) OR Dose Level 2 (4 mcg/kg):
1. Thaw vial(s) of IL-15, 147 mcg/0.3 mL **(490 mcg/mL)** at room temperature.  
2. Using a 27-gauge needle, slowly draw up the required dose in a 1 mL syringe. Doses should be rounded to the nearest 0.01 mL.  
3. Add the calculated volume of diluted IL-15 to 0.1% HSA in D5W in a PVC or polyolefin bag.  
4. Label the bag with a 4-hour beyond-use date. The infusion may be started within 4 hours at room temperature, or within 24 hours if bag was kept at 2-8°C. The infusion must be completed within 24 hours of initiation.  
Administered dose = _______ kg (Patient's weight) X _______ mcg/kg (DL) = _______ mcg Prepared dose = _______ mcg (Administered dose) + 10 mcg (Overfill dose) = _______ mcg IL-15 volume = _______ mcg (Prepared dose)  490 mcg/mL (vial concentration) = _______ mL
Total infusion volume =
_______ mcg (Prepared dose)  1 mcg/mL (final infusion concentration) = _______ mL
Diluent volume =
_______ **mL (Total infusion volume) -** _______ **mL (IL-15 volume) =** _______ mL
Please note: The dosing examples listed below are for the 147 mcg/0.3 mL in a 3mL vial size and dilution ONLY. The following dosing chart may be used as a reference, but doses should always be re-calculated at the time of preparation. In the future, different concentrations of IL-15 may be available and doses and dilutions will need to be recalculated.  
| IL-15 volume (490 mcg/ml)                                    | Diluent volume   | Total infusion volume  (1 mcg/ml)   |        |        |        |        |
|--------------------------------------------------------------|------------------|-------------------------------------|--------|--------|--------|--------|
| DL1                                                          | DL2              | DL1                                 | DL2    | DL1    | DL2    |        |
| Patient's  weight 60 kg                                      | 0.27             | 0.51                                | 129.73 | 249.49 | 130 ml | 250 ml |
| 75 kg                                                        | 0.33             | 0.63                                | 159.67 | 309.37 | 160 ml | 310 ml |
| 90 kg                                                        | 0.39             | 0.76                                | 189.61 | 369.24 | 190 ml | 370 ml |
| 105 kg                                                       | 0.45             | 0.88                                | 219.55 | 429.12 | 220 ml | 430ml  |
| Dose Level 1 (DL1) = 2 mcg/kg, Dose Level 2 (DL2) = 4 mcg/kg |                  |                                     |        |        |        |        |
untitled h1
dose calculation for obese patients

For patients whose body mass index (BMI) is >30 kg/m2, the factor for body weight used in calculating IL-15 doses will be determined as follows:
Corrected body weight (kg) = 30 x (height [m])2  
$\mathbf{m}\mathbf{c}\mathbf{g}$ .  
  
  
Version Date: *11/16/2020* 16.5 APPENDIX E: ASSAY FOR ANTIBODIES TO RH**IL-15**
- Plates are coated with human IL-15 for 3 hours at 37°C, washed, blocked with 3% FBS
and washed again.  
- A standard curve for assay quantitation and quality control is constructed using serial dilutions of a commercial affinity purified goat anti-human IL-15 that is diluted in heatinactivated normal human serum. The standard curve samples are incubated for 2 hours at 37°C and washed.  
- Biotin conjugated IL-15 is added to each well, incubated 2 hours at 37°C, and the plates are washed.  
- Alkaline phosphatase–conjugated streptavidin is added to each well for 2 hours at 37°C
and then washed.  
- The assay is developed with the addition of diethanolamine buffer with p-Nitrophenyl Phosphatase for 1 hour at 37°C and then immediately read at 405 nm.  
- To detect antibodies to human IL-15 in test samples, serum from the test subject will be assayed in duplicate at dilutions of 1/3 and 1/9 concomitantly with the standard curve samples as above and the resultant OD obtained used to quantitate the level of antibody present.