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events that count toward an

The following events may or may not meet the definition of a reportable event; however they will be reported to the University of Minnesota Primary Clinical Research Coordinator or designee as counting toward an early study stopping rule (refer to Section 14). These will be monitored throughout stage 1 of the study by treatment arm.  
- Selected Grade 3 non-hematologic events o diarrhea o colitis o **pneumonitis**
o transaminitis o myocarditis o adrenal insufficiency o **rash that does**
resolve to grade ≤2 in 1 week o **cystitis**
- **Any new onset of graft versus host disease** - **Any Grade 4 or 5 non-hematologic adverse event** - **Any adverse events requiring discontinuation of any study drug**  
11.3 Required Reporting FDA, IRB, and Masonic **Cancer Center's SAE**  
Coordinator  
| Coordinator                                                                                                                                        | Submission                                   |             |             |             |
|----------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------|-------------|-------------|-------------|
| Agency                                                                                                                                             | Criteria for reporting                       | Timeframe   | Form to     | address/fax |
| Use                                                                                                                                                | numbers                                      |             |             |             |
| Events requiring prompt reporting including, but not limited to                                                                                    | Within 5                                     |             |             |             |
| unanticipated death of a locally enrolled subject(s); new or                                                                                       | business                                     |             |             |             |
| increased risk; any adverse event that require a change to the                                                                                     | days of                                      |             |             |             |
| protocol or consent form or any protocol deviation that                                                                                            | event                                        |             |             |             |
| resulting in harm. refer to  http://www.research.umn.edu/irb/guidance/ae.html#.VC7xraI0sh  discovery                                               | Report  Form                                 | irb@umn.edu |             |             |
| U of MN  IRB                                                                                                                                       | Per current IRB                              |             |             |             |
| Protocol or Subject Deviations                                                                                                                     | reporting requirements  As soon as  possible  but no later  than 7  CalendarDays UMCC  SAE                                              |             |             |             |
| Unexpected and fatal or life threatening suspected adverse  reaction                                                                               | Submit as an  amendment                      |             |             |             |
| 1) Serious and unexpected suspected adverse reaction or 2)                                                                                         | to IND with                                  |             |             |             |
| increased occurrence of serious suspected adverse                                                                                                  | copy to BMS                                  |             |             |             |
| reactions over that listed in the protocol or investigator  brochure or 3) findings from other sources (other studies, animal or in vitro testing) | As soon as  possible  but no later  than 15  CalendarDays                                              |             |             |             |
| FDA                                                                                                                                                | Submit as  part of the  IND annual  report   |             |             |             |
| At time of                                                                                                                                         | Summary                                      |             |             |             |
| All other events per CFR 312.33                                                                                                                    | IND annual                                   | format      |             |             |
| report                                                                                                                                             |                                              |             |             |             |
| BMS                                                                                                                                                | Refer to Section 11.4                        |             |             |             |
| Cancer  Center                                                                                                                                     | Any event that counts toward a stopping rule | Upon        | Event  Form | n/a         |
| SAE                                                                                                                                                | reporting                                    |             |             |             |
| Coordinator                                                                                                                                        |                                              |             |             |             |  
In each IND safety report, the sponsor must identify all IND safety reports previously submitted to the FDA concerning a similar suspected adverse reaction and must analyze the significance of the suspected adverse reaction in light of the previous, similar reports or other relevant information.  
The SAE Coordinat**or will provide the Masonic Cancer Center's Data and Safety**
Monitoring Council (DSMC) with the SAE in an appropriate format depending on the individual SAE (as reported or in a summary format).
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11.4 additional bms requirements for

The collection of non-serious AE (AE that is not an SAE) information should begin at initiation of study drug. All non-serious adverse events (not only those deemed to be treatment-related) should be collected continuously during the treatment period and for a minimum of 30 days following the last dose of study treatment.  
Non-serious AEs should be followed to resolution or stabilization, or reported as SAEs if they become serious. Follow-up is also required for non-serious AEs that cause interruption or discontinuation of study drug and for those present at the end of study treatment as appropriate.
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laboratory test abnormalities

All laboratory test results captured as part of the study should be recorded following institutional procedures. Test results that constitute SAEs should be documented and reported as such.  
The following laboratory abnormalities should be documented and reported appropriately:
- **any laboratory test result that is clinically significant or meets the definition**
of an SAE
- **any laboratory abnormality that required the subject to have study drug**
discontinued or interrupted
- **any laboratory abnormality that required the subject to receive specific**
corrective therapy.
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other safety considerations

Any significant worsening noted during interim or final physical examinations, electrocardiograms, x-rays, and any other potential safety assessments, whether or not these procedures are required by the protocol, should also be recorded as a non-serious or serious AE, as appropriate, and reported accordingly.
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serious adverse events (saes)

BMS requires monitoring for Serious Adverse Events (SAEs) that occur following the subject's written consen**t to participate in the study through 100 days of**
discontinuation of dosing.
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12 study data collection and

This study will collect regulatory and clinical data using University of Minnesota CTSI's instance of OnCore® **(Online Enterprise Research Management**
Environment).  
The Oncore database resides on dedicated secure and PHI compliant hardware consisting of 3 physical servers: dev, DR, and production. The dev server is located in the University of Minnesota (UMN) datacenter (WBOB) and houses six database instances (test, train, sandbox, mcc reports, oncdm, and vendor) that are backed up locally because the data is refreshed from Oncore production data. The production server is located in the UMN datacenter (WBOB). All the data servers are managed by the Academic Health Center - **Information Systems**
(AHC-IS) virtual servers which utilize clustered infrastructure to provide real-time failover of virtual servers. This real-time clustering is physically limited to the UMN data center. All relevant AHC IS procedures related for PHI compliant servers (as required by the Center of Excellence for HIPAA Data) apply to Oncore databases.  
The integrated data will be stored in PHI compliant servers managed by AHC IS
with access given to those authorized users in the Clinical and Translation Science Institute Informatics team (CTSI BPIC and MCC CISS). The data will be integrated and extracted to researchers through the CTSI Informatics team and will be delivered through secure and compliant mechanisms (e.g. AHC IE data shelter, BOX, sftp, etc). If data de-identification is needed, then compliant AHC IE data de-identification tools will be used. The informatics team will grant the IRB approved study team members access to data.  
Additional immune monitoring data about correlative laboratory samples generated by the Masonic Cancer Center Translational Therapy Laboratory (TTL) from the protocol-directed correlative research samples is stored in their Laboratory Information Management System (LIMS). The LIMS database application is also stored on a production server located in the UMN datacenter (WBOB) and is managed by the Academic Health Center Key study personnel are trained on the use of OnCore and will comply with protocol specific instructions embedded within the OnCore.
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12.2 case report forms

Participant data will be collected using protocol specific electronic case report forms (e-CRF) developed within OnCore based on its library of standardized forms. The e-**CRF will be approved by the study's Principal Investigator and the**
Biostatistician prior to release for use. The Primary Clinical Research Coordinator or designee will be responsible for registering the patient into OnCore at time of study entry, completing e-CRF based on the patient specific calendar, and updating the patient record until patient death or end of required study participation.
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12.3 data and safety monitoring

The study's Data and Safety Monitoring Plan will be in compliance with the University of Minnesota Masonic Cancer Center's Data & Safety Monitoring Plan (DSMP), which can be accessed at http://z.umn.edu/dmsp  
For the purposes of data and safety monitoring, this study is classified as high risk (investigator initiated). Therefore the following requirements will be fulfilled:
- **The Masonic Cancer Center Data and Safety Monitoring Council (DSMC) will**
review the study's progress at least quarterly.  
- **The PI will comply with at least twice yearly monitoring of the project by the**
Masonic Cancer Center monitoring services.  
- **The PI will oversee the submission of all reportable adverse events per the**
definition of reportable in Section 11.3 **to the Masonic Cancer Center's SAE**
Coordinator, the University of Minnesota IRB, and the FDA.
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ind annual reports

In accordance with regulation 21 CFR § 312.33, the Sponsor-Investigator will submit a progress report annually. The report will be submitted within 60 days of the anniversary date that the IND went into effect.
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12.4 monitoring

The IND sponsor/investigator will permit study-related monitoring, audits, and inspections by the Masonic Cancer Center or their designee, IRB, government regulatory bodies, and University of Minnesota compliance groups. All study related documents (e.g. source documents, regulatory documents, data collection instruments, study data, etc.) will be made available. The S/I will ensure the capability for inspections of applicable study-related facilities (e.g. pharmacy, diagnostic laboratory, etc.) will be available for trial related monitoring, audits, or regulatory inspections.
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12.5 record retention

The investigator will retain study records including source data, copies of case report form, consent forms, HIPAA authorizations, and all study correspondence in a secured facility for at least 6 years after the study file is closed with the IRB and FDA.  
In addition, the Clinical Trials Office (CTO) will keep a master log of all patients participating in the study with sufficient information to allow retrieval of the medical records for that patient.  
Please contact the CTO before destroying any study related records.
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13 endpoints primary endpoint

Secondary endpoints:
Overall response rate (ORR) at 42 days from start of treatment defined as:
- **ORR = [\# CR/PR/HI for MDS] + [\# CR + CRi + CRp + PR for AML] at day 42**
divided by number of evaluable patients enrolled in study (Appendix II - **R-IPSS**
Criteria for MDS, Appendix III - **Modified Response Criteria for AML)**
Progression free survival (PFS) at 6 months
- **PFS is defined as the time (in months) from treatment start date to the date of**
progression or death, whichever occurs first. Patients who do not progress nor die will be censored on their last tumor assessment date. Patients who have no post-treatment tumor assessment, will be censored on their treatment start date.  
6-month PFS rate will be estimated using the Kaplan-Meier method.  
Overall survival (OS) at 6 months
- **OS is defined as the time (in months) from treatment start date to death date.**
Patients who do not die will be censored on their last known alive date. 6-month OS rate will be estimated using the Kaplan-Meier method.
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14 statistical considerations 14.1 study

This is a phase I trial which includes a randomized pilot sub-study of two dosing arms of cyclophosphamide in combination with Nivolumab and N-803. **The** primary objective is safety and the secondary objective is efficacy, as defined by overall response rate. **The study will consist of relapsed/refractory AML and**
higher-risk MDS.  
The primary endpoint of the trial is to determine the appropriate dosing arm for phase 2 study based on safety and toxicity profile. The secondary endpoints include ORR at day 42, OS at six months and PFS at six months. Exploratory endpoints include correlation of immune checkpoint ligands PD-L1 and TIM-3 on leukemic cells with response to treatment, and evaluation of subsets of T-cell, NK cell, MDSCs, and DCs in bone marrow and peripheral blood during treatment.  
By September 2019, there were 12 patients enrolled on Arm 1 and Arm 2 who received treatment with combination of nivolumab and cyclophosphamide daily or weekly. The previous treatment Arms 1 and 2 are closed due to no patients obtaining complete response and 4 patients receiving <1 cycle of treatment due to disease progression. These 12 subjects in Arms 1 and 2 will be analyzed separately for safety and efficacy from Arms 3 and 4.  
Arms 3 and 4 will enroll 20 patients with addition of N-803 to treatment plan.  
Patients will be randomized to Arm 3 (CTX 50mg daily + nivolumab 360 mg q3week + SC N-803 10 ug/kg q3week) and Arm 4 (CTX 350 mg PO q7 days+ nivolumab 360 mg q3week + SC N-803 10 ug/kg q3week) with 10 subjects in each arm. Continuous stopping rule will be used to monitor excessive toxicity for each arm. If one arm is terminated by the toxicity stopping rule, all subsequent patients will be assigned to the other arm if it is not terminated by the toxicity stopping rule to continue enrollment of up to 20 patients. If both arms succeed, then for future studies, selection of one of the two products will be based on evaluation of tolerability, clinical benefit as assessed by hematologic improvement and blast reduction, and immunological parameters. Immune stimulation will be assessed as decrease in T-regulatory cells and MDSCs, and increase in cytotoxic T-cells and differentiated NK cells.  
1. A randomized comparison of two CTX treatments (CTX 50mg daily +
nivolumab 360 mg q3week + N-803 10 ug/kg SC q3week vs. CTX 350 mg PO q7 days+ nivolumab 360 mg q3week + N-803 10 ug/kg SC q3week) using 10 patients in each Arm.  
2. 20 patients available for assessment of day 42 overall response for the entire study population.
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14.2 data analysis plan

Only subjects enrolled after addition of N-803 to treatment protocol will be included in the data analysis. The endpoints of OR and toxicity rate will be estimated by simple proportion with 95% confidence intervals. All toxicity and safety assessments will be presented in the data listings and summarized with descriptive statistics.  
The endpoints of overall survival (OS) and progression-free survival (PFS) at six months will be estimated by Kaplan-Meier curves.[70] Other correlative endpoints will be described with simple descriptive statistics such as medians, ranges, interquartile ranges, proportions, charts and plots. Logistic regression will be the primary method to compare the PD-L1 and Galectin-9 expression with response.  
Groups that will be considered for comparison include: AML vs. MDS, high vs.  
low blast count at time of study enrollment, high, intermediate, or low disease risk by cytogenetic and molecular subtype, high vs. low total peripheral lymphocyte count, high vs. low immune cell subsets in blood and bone marrow at time of study enrollment, younger vs. older age, number of prior treatments, high vs. low PD-L1 expression, and prior transplant vs. no transplant.  
P-values for subgroup analyses will be adjusted for multiplicity.  
All analyses will be conducted using SAS software 9.4 (SAS Institute Inc., Cary, NC). Results will be deemed statistically significant at the 0.05 significance level unless otherwise specified.
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14.3 sample size justification

This phase I study for the secondary endpoint of overall response uses pooled efficacy analysis. Based on this design, patients from both arms will be analyzed for efficacy analysis. Up to 20 patients will be used which is sufficient to maintain an overall type I error of 5% **while providing 80% statistical power. The maximum** number of the patients will be 20 and the minimum number of patients will be 18 to maintain statistical power of 77% if patients become unevaluable or withdraw from study.  
| Sample Size   | Power   |
|---------------|---------|
| 18            | 77%     |
| 20            | 80%     |
| 24            | 85%     |  
24 85%  
This is based on our null hypothesis of ≤10% ORR versus the alternative hypothesis of ORR ≥32%.  
The accrual will start after amendment to add N-803 to treatment protocol is implemented. The 12 patients enrolled by September 2019 treated without N803 will be analyzed separately. A patient will be considered unevaluable for the primary endpoint and replaced if unable to complete ≥1 cycle of nivolumab and cyclophosphamide. If patient receives ≥1 cycle of n**ivolumab and**
cyclophosphamide and follow up is not discontinued prior to 42 days for reasons other than progression or death, they will be considered evaluable.  
ORR will be analyzed using the evaluable patient population. PFS and OS will be analyzed using the all treated patient population.
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14.4 early study stopping rule

Continuous stopping rules are in place to stop the study in case there are excessive complications. In the case that the boundaries are crossed, the Principal Investigator will be notified who will report it to the Masonic Cancer Center Data Safety Monitoring Committee and Bristol Myers Squibb. The protocol will be reviewed to determine if the protocol should be terminated. Stopping rules were developed using Pocock stopping boundaries.[71] **The** stopping rules will be applied separately for each platform.
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early stopping rule for each

The goal is to construct a boundary based on selected Grade 3 non-hematologic events that result in the permanent discontinuation of study drugs, new onset of GVHD, and grade 4-5 non-hematologic toxicities (CTCAE v4.03) such that the probability of early stopping is at most 10% if the toxicity rate is equal to 15% and our sample size is 10. With these stipulations, the study will be stopped if there are events in 2 out of 2, 3 out of 6, 4 at any time within a 60 day follow-up time period. If the actual probability of failure is 40% or 50%, the probability of reaching the boundary will be 66% or 85%. The stopping rule will be applied to Arm 3 and 4 separately.
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15 ethical and regulatory considerations

The study will be conducted in accordance with the appropriate regulatory requirement(s). Essential clinical documents will be maintained to demonstrate the validity of the study and the integrity of the data collected. Master files should be established at the beginning of the study, maintained for the duration of the study and retained according to the appropriate regulations.
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15.2 ethical considerations

The study will be conducted in accordance with ethical principles founded in the Declaration of Helsinki. The IRB will review all appropriate study documentation in order to safeguard the rights, safety and well-being of the patients. The study will only be conducted at sites where IRB approval has been obtained. The protocol, informed consent, written information given to the patients, safety updates, annual progress reports, and any revisions to these documents will be provided to the IRB by the investigator.
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15.3 informed consent

All potential study participants will be given a copy of the IRB-approved Consent to review. The investigator or designee will explain all aspects of the study in lay language and answer all questions regarding the study. If the participant decides to participate in the study, he/she will be asked to sign and date the consent document. Patients who refuse to participate or who withdraw from the study will be treated without prejudice.
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16 references

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Metronomic cyclophosphamide regimen selectively depletes CD4 +CD25+ regulatory T cells and restores T and NK effector functions in end stage cancer patients. Cancer Immunol Immunother 2007;56:641–**8. doi:10.1007/s00262006-**
0225-8.  
[42] Lutsiak MEC, Semnani RT, Pascalis R De, Kashmiri SVS, Sabzevari H, Dc W,
et al. Inhibition of CD4+ 25+ T regulatory cell function implicated in enhanced immune response by low-dose cyclophosphamide. Blood 2005;105:2862–8.  
doi:10.1182/blood-2004-06-2410.  
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Cyclophosphamide synergizes with type I interferons through systemic dendritic cell reactivation and induction of immunogenic tumor apoptosis. Cancer Res 2011;71:768–**78. doi:10.1158/0008-5472.CAN-10-2788.**
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Cyclophosphamide induces differentiation of Th17 cells in cancer patients.  
Cancer Res 2011;71:661–**5. doi:10.1158/0008-5472.CAN-10-1259.**
[45] Ge Y, Domschke C, Stoiber N, Schott S, Heil J, Rom J, et al. Metronomic cyclophosphamide treatment in metastasized breast cancer patients: Immunological effects and clinical outcome. Cancer Immunol Immunother 2012;61:353–**62. doi:10.1007/s00262-011-1106-3.**
[46] Lord R, Nair S, Schache A, Spicer J, Somaihah N, Khoo V, et al. Low Dose Metronomic Oral Cyclophosphamide for Hormone Resistant Prostate Cancer: A
Phase II Study. J Urol 2007;177:2136–**40. doi:10.1016/j.juro.2007.01.143.**
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[48] Hermans IF, Chong TW, Palmowski MJ, Harris AL, Cerundolo V. Synergistic Effect of Metronomic Dosing of Cyclophosphamide Combined with Specific Antitumor Immunotherapy in a Murine Melanoma Model. Cancer Res 2003;63:8408–**13.**
[49] Salem ML, Kadima AN, El-Naggar S a, Rubinstein MP, Chen Y, Gillanders WE,
et al. Defining the ability of cyclophosphamide preconditioning to enhance the antigen-specific CD8+ T-cell response to peptide vaccination: creation of a beneficial host microenvironment involving type I IFNs and myeloid cells. J
Immunother 2007;30:40–**53. doi:10.1097/01.cji.0000211311.28739.e3.**
[50] Weir GM, Hrytsenko O, Quinton T, Berinstein NL, Stanford MM, Mansour M.  
Anti-PD-1 increases the clonality and activity of tumor infiltrating antigen specific T cells induced by a potent immune therapy consisting of vaccine and metronomic cyclophosphamide. J Immunother Cancer 2016;4:68.  
doi:10.1186/s40425-016-0169-2.  
[51] Buckstein R, Kerbel RS, Snaked Y, Nayar R, Foden C, Turner R, et al.  
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effective and safe therapy in patients with relapsed and refractory aggressive histology non-**Hodgkin's lymphoma. Clin Cancer Res 2006;12:5190–**8.  
doi:10.1158/10780432.CCR-06-0474.  
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implications for clinical cancer therapy. Cancer Chemother Pharmacol 2016;78:661–**71. doi:10.1007/s00280-016-3152-1.**
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[54] Penel N, Adenis A, Bocci G. Cyclophosphamide-based metronomic chemotherapy: After 10 years of experience, where do we stand and where are we going? Crit Rev Oncol Hematol 2012;82:40–**50.**
doi:10.1016/j.critrevonc.2011.04.009.  
[55] Hussong JW, Rodgers GM, Shami PJ. Evidence of increased angiogenesis in patients with acute myeloid leukemia. Blood 2000;95:309–**13.**
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[58] Cheever MA. Twelve immunotherapy drugs that could cure cancers. Immunol Rev 2008;222:357–**68. doi:10.1111/j.1600-065X.2008.00604.x.**
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doi:10.1073/pnas.0610115104.  
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doi:10.4049/jimmunol.0901244.  
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doi:10.1016/j.cyto.2011.09.028.  
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et al. First-in-human Phase 1 Clinical Study of the IL-15 Superagonist Complex ALT-803 to Treat Relapse after Transplantation. Blood 2018:blood-201712823757. doi:10.1182/blood-2017-12-823757.  
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[66] Curti A, Trabanelli S, Onofri C, Aluigi M, Salvestrini V, Ocadlikova D, et al. Indoleamine 2,3-dioxygenase-expressing leukemic dendritic cells impair a leukemia-specific immune response by inducing potent T regulatory cells.  
Haematologica 2010;95:2022–**30. doi:10.3324/haematol.2010.025924.**
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Circulating myeloid and lymphoid precursor dendritic cells are clonally involved in myelodysplastic syndromes. Leukemia 2004;18:1451–6.  
doi:10.1038/sj.leu.2403430.  
[68] Mohty M, Jarrossay D, Lafage-Pochitaloff M, Zandotti C, Brière F, de Lamballeri XN, et al. Circulating blood dendritic cells from myeloid leukemia patients display quantitative and cytogenetic abnormalities as well as functional impairment.  
Blood 2001;98:3750–**6. doi:10.1182/blood.V98.13.3750.**
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Revised Recommendations of the International Working Group for diagnosis, standardization of response criteria, treatment outcomes, and reporting standards for therapeutic trials in acute myeloid leukemia. J Clin Oncol 2003;21:4642–**9. doi:10.1200/JCO.2003.04.036.**
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25. doi:10.1182/blood-2005-10-4149.
untitled h1
appendix i - ecog performance

GRADE ECOG PERFORMANCE STATUS  
0 Fully active, able to carry on all pre-disease performance without restriction 3 Capable of only limited selfcare; confined to bed or chair more than 50% of waking hours  
  
  
 4 Completely disabled; cannot carry on any selfcare; totally confined to bed or chair  
  
5 Dead
*Oken M, Creech R, Tormey D, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group.**Am J Clin**
Oncol. **1982;5:649-655.**  
| 1   | Restricted in physically strenuous activity but ambulatory and able to carry out work of a light  or sedentary nature, e.g., light house work, office work   |
|-----|--------------------------------------------------------------------------------------------------------------------------------------------------------------|
| 2   | Ambulatory and capable of all selfcare but unable to carry out any work activities; up and  about more than 50% of waking hours                              |  
Appendix II - Revised International Prognostic Scoring System
(R-IPSS) Criteria for MDS  
| Prognostic  Variable   | 0              | 0.5       | 1       | 1.5   | 2      | 3     | 4   |
|------------------------|----------------|-----------|---------|-------|--------|-------|-----|
| Very                   | Intermedia  te | Poor      | Very    |       |        |       |     |
| Cytogenetics           | good           | -         | Good    | -     | Poor   |       |     |
| > 2%-<                 |                |           |         |       |        |       |     |
| BM blast %             | ≤ 2%           | -         | 5%      | -     | 5%-10% | > 10% | -   |
| Hemoglobin             | ≥ 10           | -         | 8 to 10 | <8    | -      | -     | -   |
| Platelets              | ≥  100         | 50-  <100 | < 50    | -     | -      | -     | -   |
| ANC                    | ≥ 0.8          | < 0.8     | -       | -     | -      | -     | -   |  
Cytogenetic Prognostic subgroups  
Very Good -Y, del(11q)  
| Cytogenetic Prognostic subgroups  Very Good   | -Y, del(11q)                                                                     |
|-----------------------------------------------|----------------------------------------------------------------------------------|
| Good                                          | Normal, del(5q), del(12p), del(20q), double including del(5q)                    |
| Intermediate                                  | del(7q), +8, +19, i(17q), any other single or double independent clones          |
| Poor                                          | -7, inv(3)/t(3q)/del(3q), double including -7/del(7q), complex: 3  abnormalities |
| Very poor                                     | Complex: >3 abnormalities                                                        |  
Poor -7, inv(3)/t(3q)/del(3q), double including -7/del(7q), complex: 3  
abnormalities  
Very poor Complex: >3 abnormalities  
| Risk category   | Risk score   |
|-----------------|--------------|
| Very low        | ≤ 1.5        |
| Low             | > 1.5-3      |
| Intermediate    | > 3-4.5      |
| High            | > 4.5-6      |
| Very high       | > 6          |  
Very high > 6
appendix iii - response criteria
appendix i - ecog performance

Response to treatment will be defined per modified criteria as outlined below.[72][73]
appendix iii - response criteria
complete remission

For subjects to be classified as being in CR, they must have bone marrow regenerating normal hematopoietic cells and achieve a morphologic leukemia-free state and must have an ANC > 1 x 109**/L and platelet count ≥**
100 x 109**/L and normal marrow differential with**
< 5% blasts, and they will be RBC and platelet transfusion independent (defined as 1 week without RBC
transfusion and 1 week without platelet transfusion). There should be no evidence of extramedullary leukemia.
appendix iii - response criteria
complete remission with incomplete platelet

For subjects to be classified as being in CRp, they must achieve CR except for incomplete platelet recovery
(<100 x 109**/L).**
appendix iii - response criteria
complete remission with incomplete hematologic

For subjects to be classified as being in CRi, they must fulfill all the criteria for CR except for incomplete hematological recovery with residual neutropenia <1 x 109**/L with or without complete platelet recovery. RBC**
and platelet transfusion independence is not required.
appendix iii - response criteria
partial remission (pr)

For subjects to be classified as being in PR, they must have ≥50% bone marrow blast reduction or decrease to 5 to 25%.
appendix iii - response criteria
hematologic improvement (hr)

For subjects to be classified as having HI, they must have pre-treatment hemoglobin of <11 g/dL, platelets of
<100 x 109/L, and absolute neutrophil count < 1000 cells/mm3**. They should have improvement in hemoglobin**
by ≥1.5 g/dL, platelets by ≥30 x 109/L, and neutrophil count by 100% or 500 cells/mm3**. Responses should be**
sustained for at least 4 weeks.
appendix iii - response criteria
appendix iv - gvhd grading

Consensus Clinical Stage and Grade of Acute GVHD (Glucksberg *et al*, 1974; Thomas *et al***, 1975,**
Przepiorka *et al*, 1995)  
| Stage                 | Skin                  | Liver               | Lower               | Upper              |
|-----------------------|-----------------------|---------------------|---------------------|--------------------|
| G Gastrointestinal    | G Gastrointestinal    |                     |                     |                    |
| Tract                 | Tract                 |                     |                     |                    |
| 1                     | Maculopapular         | Bilirubin 2.0 - 3.0 | Diarrhea 500 - 1000 | No protracted      |
| rash <25% of          | mg/dl                 | mL/day or 280 - 555 | nusea and           |                    |
| body surface          | mL/m²                 | vomiting            |                     |                    |
| 2                     | Maculopapular         | Bilirubin 3.1 - 6.0 | Diarrhea 1000 -     | Persistent nausea, |
| rash 25-50%           | m/dl                  | 1500 mL/day or 556  | vomiting or         |                    |
| body surface          | - 833 mL/m²           | anorexia            |                     |                    |
| 3                     | Generalized           | Bilirubin 6.1 -     | Diarrhea >1500      |                    |
| erythroderma          | 15.0 mg/dl            | mL/day or >833      |                     |                    |
| mL/m²                 |                       |                     |                     |                    |
| 4                     | Generalized           | Bilirubin > 15      | Severe abdominal    |                    |
| pain, with or without |                       |                     |                     |                    |
| erythroderma with     | mg/dl                 |                     |                     |                    |
| bullous formation     | ileus, or stool with  |                     |                     |                    |
| and                   | frank blood or melena |                     |                     |                    |
| desquamation          |                       |                     |                     |                    |
appendix iii - response criteria
university of minnesota acute gvhd

| Acute   | GVHD Skin Stage   | Liver Stage   | Lower GI Stage Upper GI   |    |
|---------|-------------------|---------------|---------------------------|----|
| Grade   | Stage             |               |                           |    |
| 1-2     | 0                 | 0             | 0                         |    |
| l       |                   |               |                           |    |
| l       | 3                 | 1             | 1                         | 1  |
| =       | 2-4               | 2-3           |                           |    |
| IV      | 4                 | 4             |                           |    |  
Each column identifies minimum criteria for organ grade.  
.  
Each grade is based on maximum stage for each individual organ involved
.  
e.g. Grade II = skin stage 3 and/or liver stage 1 and/or gut stage 1 and/or UGI stage 1
appendix iii - response criteria
late acute and chronic gvhd

Late acute and chronic GVHD will be assessed using the National Institutes of Health (NIH) Consensus Criteria.  
Patient ID:
Date of late acute or chronic CVHD diagnosis (mm/dd/yyy) // Onset of chronic CVHD was:
- Progressive (acute GVHD progressed directly to chronic GVHD)
o Interrupted (acute GVHD resolved, then chronic GVHD developed)
e De novo (acute GVHD never developed)
©
Chronic GVHD flare (symptoms reactivated within 30 days of drug tapering or discontinuation)
appendix iii - response criteria
karnofsky performance status

© 100 Normal, no complaints; no evidence of disease 0 90 Able to carry on normal activity, minor signs or symptoms of disease o 80 Normal activity with effort; some signs or symptoms of disease 70 70 Cares for self; unable to carry on normal activity or do active work 60 Requires occasional assistance, but is able to care for most of his/her needs 550 Requires considerable assistance and frequent medical care 00 40 Disabled; requires special care and assistance
. 30 Severely disabled; hospitalization is indicated. Death not imminent e 20 Very Sick, hospitalization necessary, active supportive treatment
🙂 necessary  10 Moribund, fatal processes, progressing rapidly  © 0 Dead
appendix iii - response criteria
diagnosis was based on

O Histologic evidence / biopsy proven Clinical evidence
✔ Both ✓ Unknown
appendix iii - response criteria
organ/system involvement (check if yes)

✔Sclerosis of skin Other skin or hair involvement (rash, ulcers, pruritus or itching, dyspigmentation, alopecia, lichenoid skin changes, etc)
O Eyes (xerophthalmia (dry eyes), abnormal Schirmer's test, abnormal slit lamp, corneal erosion / conjunctivitis, etc)  
Mouth (lichenoid changes, mucositis / ulcers, erythema, etc)
© Bronchiolitis obliterans Other lung involvement Organ/System Involvement (check if yes)
Gastrointestinal tract (esophageal involvement, chronic nausea / vomiting, chronic diarrhea, malabsorption, abdominal pain / cramps, etc)
© Liver O Genitourinary tract (vaginitis / stricture, etc) - Musculoskeletal (arthritis, contractures, myositis, myasthenia, etc) - Thrombocytopenia (< 100 x 10^9/L)
✓ Eosinophilia
✓ Autoantibodies Other hematologic involvement
© Serositis
✓ Weight loss Other organ involvement from chronic GVHD Specify other organ:
Ref: Jagasia MH, Greinix HT, Arora M. National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: The 2014 Diagnosis and Staging Working Group Report. Biol Blood Marrow Transplant. 2015 March; 21(3): 389–
appendix v - n-803 targeted
organ/system involvement (check if yes)

Patient Initials: _______ Date of Assessment: _________ **Assessment Time point:**  
_________  
| _________  Toxicity Grade 0                     | Grade 1                                                                             | Grade 2                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 | Grade 3                                                                                                                                                                | Grade 4                                                               |                                |
|-------------------------------------------------|-------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------|--------------------------------|
| None                                            | Tenderness with or  without associated  symptoms (e.g., warmth,  erythema, itching) | Pain; lipodystrophy; edema;                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             | Ulceration or necrosis; severe                                                                                                                                         |                                                                       |                                |
| phlebitis                                       | tissue damage; operative  intervention indicated                                    | Life-threatening consequences;  urgent intervention indicated                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           |                                                                                                                                                                        |                                                                       |                                |
| N-803 Injection  site reaction                  | None or no                                                                          | Shortness of breath with                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                | Shortness of breath with minimal                                                                                                                                       | Shortness of breath at rest; limiting  Life-threatening consequences; |                                |
| Dyspnea                                         | change                                                                              | moderate exertion                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       | exertion; limiting instrumental ADL                                                                                                                                    | self care ADL                                                         | urgent intervention indicated  |
| None                                            | ………………                                                                              | Decreased O2 saturation with  exercise (e.g., pulse oximeter <                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          |                                                                                                                                                                        |                                                                       |                                |
| Hypoxia                                         | 88%) intermittent supplemental  oxygen                                              | Decreased oxygen saturation at  rest (e.g., pulse oximeter < 88% or  PaO2 ≤ 55 mm Hg)  Life-threatening airway  compromise; urgent intervention  indicated (e.g., tracheotomy or  intubation)                                                                                                                                                                                                                                                                                                                                                                                                                                           |                                                                                                                                                                        |                                                                       |                                |
| None                                            | 38.0 - 39.0◦ C (100.4 -                                                             | > 39.0 - 40.0◦C (102.3 - 104.0◦F)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       | > 40.0 ◦ C (>104.0◦ F) for ≤ 24 hrs                                                                                                                                    | > 40.0 ◦ C (>104.0◦ F) for > 24                                       |                                |
| Fever                                           | 102.2◦ F)                                                                           | hrs                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     |                                                                                                                                                                        |                                                                       |                                |
| None                                            | Mild sensation of cold;                                                             | Moderate tremor of the entire body;                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     | Severe or prolonged, not                                                                                                                                               | ………………………                                                             |                                |
| Chills                                          | shivering; chattering of teeth narcotics indicated                                  | responsive to narcotics                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 |                                                                                                                                                                        |                                                                       |                                |
| None                                            | Pre-hypertension (systolic  BP 120 - 139 mm Hg or  diastolic BP 80 - 89 mm  Hg)     | Stage 1 hypertension (systolic BP  140 - 159 mm Hg or diastolic BP 90  99 mm Hg); medical intervention  indicated; recurrent or persistent ≥  24 hrs); symptomatic increase by  >20 mm Hg (diastolic) or to >140/90  mm Hg if previously WNL;  monotherapy indicated.  Stage 2 hypertension (systolic BP  ≥ 160 mm Hg or diastolic BP ≥ 100  mm Hg); medical intervention  indicated; more than one drug or  more intensive therapy than  previously used indicated.  Life-threatening  consequences (e.g., malignant  hypertension, transient or  permanent neurologic deficit,  hypertensive crisis); urgent  intervention indicated. |                                                                                                                                                                        |                                                                       |                                |
| Hypertension                                    | None                                                                                | Asymptomatic, intervention  Non-urgent medical intervention                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             | Medical intervention or                                                                                                                                                | Life-threatening and urgent                                           |                                |
| Hypotension                                     | not indicated                                                                       | indicated                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | hospitalization indicated                                                                                                                                              | intervention indicated                                                |                                |
| None                                            | Localized to dependent  areas, no disability or                                     |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |                                                                                                                                                                        |                                                                       |                                |
| Edema                                           | functional impairment                                                               | Moderate localized edema and  intervention indicated; limiting  instrumental ADL                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        | Severe localized edema and  intervention indicated; limiting self  care ADL                                                                                            | ………………………                                                             |                                |
| None                                            | Asymptomatic; clinical or  diagnostic observations                                  |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |                                                                                                                                                                        |                                                                       |                                |
| Pneumonitis                                     | only; intervention not  indicated                                                   | Symptomatic; medical intervention  indicated; limiting instrumental  ADL                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                | Severe symptoms; limiting self care  Life-threatening respiratory  ADL; oxygen indicated  compromise; urgent intervention  indicated (e.g. intubation or  tracheotomy) |                                                                       |                                |
| None                                            | Mild pain                                                                           | Moderate pain; limiting instrumental  Severe pain; limiting self care                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   | ………………………                                                                                                                                                              |                                                                       |                                |
| Headache                                        | ADL                                                                                 | ADL                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     |                                                                                                                                                                        |                                                                       |                                |
| Confusion  (Altered Mental  Status)             | None                                                                                | Mild disorientation                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     | Moderate disorientation; limiting                                                                                                                                      | Severe disorientation; limiting self                                  | Life-threatening consequences; |
| instrumental ADL                                | care ADL                                                                            | urgent intervention indicated                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           |                                                                                                                                                                        |                                                                       |                                |
| Rash (outside of  the injection site  reaction) | None                                                                                | Covering < 10% body                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     | Covering 10-30% body surface area  >30% body surface area (BSA)                                                                                                        | Generalized                                                           | exfoliative,                   |
| surface area (BSA)                              | (BSA)                                                                               | ulcerative, or bullous dermatitis                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       |                                                                                                                                                                        |                                                                       |                                |
| None                                            | Mild change in gait (eg,  wide-based, limping or                                    |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |                                                                                                                                                                        |                                                                       |                                |
| Gait Disturbance                                | hobbling)                                                                           | Moderate change in gait (eg,  widebased, limping or hobbling);  assistance device indicated; limiting  instrumental ADL  Disabling; limiting self care ADL                                                                                                                                                                                                                                                                                                                                                                                                                                                                              | ………………………                                                                                                                                                              |                                                                       |                                |
|                                                 |                                                                                     |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |                                                                                                                                                                        |                                                                       |                                |  
Person Completing Form: ADL = activities of daily living
appendix vi - n-803 injection
organ/system involvement (check if yes)

The Diary is to be completed by the patient as a self-assessment in association with each dose of N-803. A new diary must be started for each N-803 injection. If the injection reaction has not resolved by Day 6 post-injection, continue to collect information on page 2 based on the days from that injection. For inpatients, the diary is completed by study personnel.  
|                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                |                               |                             |                                |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------|-----------------------------|--------------------------------|
| May 12, 2021                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   | Page 74 of 77                 | CPRC #2017LS116             |                                |
| Patient Number*                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                | Date of Study Drug Injection* | ________/_________/________ | *To be completed by the  site. |
| Please answer all questions below daily for 7 days, beginning with day of treatment. Be sure to bring back this completed diary to  your next clinic visit.  Day of Study  Drug Injection  ____/____/_________  Day 1  Post Injection  ____/____/_________ Day 2  Post Injection  ____/____/_________  Day 3  Post Injection  ____/____/_________ Day 4  Post Injection  ____/____/________ Day 5  Post Injection  ___/___/________ Day 6  Post Injection  ____/____/_________ Instructions  Yes No  Yes No  Yes No  Yes No  Yes No  Yes No  Yes No  1. Is there redness  at the injection site?  Check: Yes  or No  If yes, measure longest  diameter in cm  ________cm  ________cm  ________cm  ________cm  ________cm  ________cm  ________cm  2. Is there firmness  or  swelling at the  injection site? Check:  Yes or No Yes No Yes No Yes No Yes No Yes No Yes No Yes No  Check the pain  and/or itch  box if present  And tell us if the pain  and/or itching is mild,  moderate or severe   Pain  Itch  Mild Mild  Mod Mod   Pain  Itch  Mild Mild  Mod Mod   Pain  Itch  Mild Mild  Mod Mod   Pain  Itch  Mild Mild  Mod Mod   Pain  Itch  Mild Mild  Mod Mod   Pain  Itch  Mild Mild  Mod Mod   Pain  Itch  Mild Mild  Mod Mod  3. Have you  experienced any  pain or itching at  the injection site? Severe Severe Severe Severe Severe Severe Severe Severe Severe Severe Severe Severe Severe Severe Yes No  Name(s):  Yes No  Name(s):  Yes No  Name:  Yes No  Name:  Yes No  Name:  Yes No  Name:  Yes No  Name: 4. Have you taken  or applied any  medication for  injection site pain  or itching? Check: Yes  or No  Provide name of  medication(s) |                               |                             |                                |
appendix vi - n-803 injection
hm2017-33 nivolumab and oral ctx

| Check: Yes                                                               | IYes DNo                                                      | □ Yes □ No   | □ Yes □ No   | IYes □ No   | □ Yes □ No   | □ Yes □ No   | ■Yes □ No   |       |
|--------------------------------------------------------------------------|---------------------------------------------------------------|--------------|--------------|-------------|--------------|--------------|-------------|-------|
| 5. Have you                                                              | or No                                                         | Mild         | Mild         |             |              |              |             |       |
| Mild                                                                     | Mild                                                          | Mild         | Mild         | Mild        |              |              |             |       |
| If yes, circle the worse                                                 |                                                               |              |              |             |              |              |             |       |
| experienced any                                                          | Moderate                                                      | Moderate     | Moderate     | Moderate    | Moderate     | Moderate     | Moderate    |       |
| severity of the chills:                                                  |                                                               |              |              |             |              |              |             |       |
| chills?                                                                  | Severe                                                        | Severe       | Severe       | Severe      | Severe       | Severe       | Severe      |       |
| mild, moderate or severe                                                 | □ Yes □ No                                                    | □ Yes □ No   | □ Yes  □ No  | □ Yes □ No  | □ Yes  □ No  | □Yes □ No    |             |       |
|                                                                          |                                                               |              |              |             |              |              |             |       |
| 6. Record your                                                           | Check: Yes                                                    | °F           | °F           | oF          | °F           | °F           | °F          | °F    |
| daily temperature                                                        | or No                                                         |              |              |             |              |              |             |       |
| upon waking                                                              | If your temperature is                                        |              |              |             |              |              |             |       |
| 101°F for more than 24                                                   |                                                               |              |              |             |              |              |             |       |
| (do not drink anything 5                                                 | hours notify your study.                                      | Time:        | Time:        | Time:       | Time:        | Time:        | Time:       | Time: |
| minutes before taking your                                               |                                                               |              |              |             |              |              |             |       |
| temperature)                                                             | doctor or research staff.                                     | A            | A            | AM          | A            | A            |             |       |
| AM / PM                                                                  | / PM                                                          | / PM         | / PM         | / PM        | / PM         | AM / PM      |             |       |
| Grading Injection Site Pain or Itching                                   | Grading Chills                                                |              |              |             |              |              |             |       |
| Mild - Noticeable, does not interfere with activity                      | Mild - Mild sensitive of cold, shivering, chattering of teeth |              |              |             |              |              |             |       |
| Moderate - Interferes with activity, limiting activities of daily living | Moderate - Moderate tremor of entire body, medication taken   |              |              |             |              |              |             |       |  
Severe - Severely limiting self-care activities of daily living, incapacitating Severe - Prolonged or severe, does not respond to medication  
| Page 2 - Please continue to complete for Injection Site Reaction if ongoing after page 1 has been filled out.  Patient Number* Date of Study Drug Injection* ________/_________/________                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   | *To be completed by the  site.   |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------|
| Complete daily for 7 days or until the injection site has resolved (returned to normal) . Please bring back this completed diary to  your next clinic visit.  Day 7  Instructions  Post Injection ____/____/_________  Day 8  Post Injection  ____/____/_________ Day 9  Post Injection  ____/____/_________  Day 10  Post Injection  ____/____/_________ Day 11  Post Injection  ____/____/________ Day 12  Post Injection  ___/___/________ Day 13  Post Injection  ____/____/_________ Yes No  Yes No  Yes No  Yes No  Yes No  Yes No  Yes No  Check:  Yes or No  If yes, measure longest  diameter in cm  1. Is there redness  at the injection  site?  ________cm  ________cm  ________cm  ________cm  ________cm  ________cm  ________cm  2. Is there  firmness or  swelling at the  injection site? Check:  Yes or No Yes No Yes No Yes No Yes No Yes No Yes No Yes No  Check the pain  and/or itch  box if present  And tell us if the pain  and/or itching is mild,  moderate or severe   Pain  Itch  Mild Mild  Mod Mod   Pain  Itch  Mild Mild  Mod Mod   Pain  Itch  Mild Mild  Mod Mod   Pain  Itch  Mild Mild  Mod Mod   Pain  Itch  Mild Mild  Mod Mod   Pain  Itch  Mild Mild  Mod Mod   Pain  Itch  Mild Mild  Mod Mod  3. Have you  experienced any  pain or itching at  the injection site? Severe Severe Severe Severe Severe Severe Severe Severe Severe Severe Severe Severe Severe Severe Yes No  Name(s):  Yes No  Name(s):  Yes No  Name:  Yes No  Name:  Yes No  Name:  Yes No  Name:  Yes No  Name:  4. Have you taken  or applied any  medication for  injection site pain  or itching? Check:  Yes or No  Provide name of  medication(s)  Grading Injection Site Pain or Itching  Mild - Noticeable, does not interfere with activity |                                  |  
Grading Injection Site Pain or Itching Mild - Noticeable, does not interfere with activity Moderate - Interferes with activity, limiting activities of daily living Severe - Severely limiting self-care activities of daily living, incapacitating HM2017-33: Nivolumab and Oral CTX in Relapsed/Refractory AML and Higher-Risk MDS