synopsis
7.6 relapse of malignancy

The definition of relapse is based on the disease under study and should be sourced from the National Comprehensive Cancer Network guidelines. For AML and ALL, relapse following CR is defined as reappearance of leukemic blasts in the peripheral blood or the finding of >5% blasts in the BM, not attributable to another cause or extramedullary relapse. Evidence of minimal residual disease will not be sufficient to meet the definition of disease recurrence in the context of this study.
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7.7 immune reconstitution

Peripheral blood samples for immune reconstitution assays will be collected at baseline (during the Screening Period), and at Days +7, +14, +28, +56, +91, +180, +270, and +365. The peripheral blood sample will be sent to a central laboratory for analysis.
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7.8 serum immunoglobulin

Serum IgG, IgM, and IgA will be collected by a peripheral blood sample at Days +100, +180, and +365.
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7.9 bone marrow aspirate

Bone marrow aspirate will be sent to pathology and to cytogenetics during the Screening Period, on Day +21 in those subjects whose ANC is <500/µL, and as clinically indicated. Flow cytometry is required on BM aspirate.
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7.10 gvhd biomarkers

Peripheral blood samples for GvHD exploratory biomarkers will be obtained once weekly from Days +7 through Day +42, then on Day +100. Samples will be banked.
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7.11 radiologic tumor staging

If appropriate, radiologic tumor staging will be completed by the Investigator during the Screening Period.
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8 safety assessments

The safety endpoints for both the Phase 1 and Phase 2 parts of the study include the assessment of adverse events, vital signs, physical examination findings, engraftment, graft failure, chimerism, clinical laboratory assessments, and electrocardiographic data through a 12-lead ECG.
synopsis
8.1 adverse events

Any adverse event experienced between signing the ICF and prior to administration of the study conditioning regimen will be recorded in the medical history. Adverse events will be collected during Phase 1 and 2, as follows:  
- All serious adverse events (SAEs) will be recorded from Day -10 through Day +365, and only SAEs related to the infused cells (ProTmune *ex vivo* programmed mPB cells or Control mPB
cells) from Day +366 through Day +730;
- Start of conditioning regimen (Day -10) through Day +100: Adverse events associated with infusion reactions, GvHD, infections, or engraftment failure (Grades 1 through 5). All other adverse events (Grades 2 through 5). Laboratory abnormalities will only be recorded as adverse events if deemed clinically significant by the Investigator;
- From Day +100 through Day +365: Only adverse events associated with GvHD, infections, or secondary engraftment failure (Grades 1 through 5);
The details of each event will be recorded in the appropriate eCRF. An adverse event is defined as any untoward medical occurrence in a clinical investigation subject administered a pharmaceutical product, which does not necessarily have a causal relationship with this treatment. An adverse event can therefore be any unfavorable and/or unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of an investigational medicinal product, whether or not related to the investigational medicinal product. All adverse events, including observed or volunteered problems, complaints, or symptoms, are to be recorded on the appropriate eCRF. Adverse events, which include clinically significant laboratory test results, will be monitored and documented. Subjects should be instructed to report any adverse event that they experience to the Investigator. Investigators should make an assessment for adverse events at each visit and record the event on the appropriate adverse event eCRF. The following information about each adverse event should be recorded in the source documentation and in the eCRF:
- Onset and cessation dates of adverse events or SAEs,  
- Severity,
- SAE (yes or no), - Relationship to the cell product, (ProTmune *ex vivo* programmed mPB cells or Control mPB
cells). For SAEs only, relationship to conditioning regimen medications, and GvHD prophylaxis medications (tacrolimus and methotrexate) is also required.  
- Action taken in response to the event.
The Investigator will make assessments of adverse event or SAE severity and of the possible relationship to study medication(s). Wherever possible, a specific disease or syndrome rather than individual associated signs and symptoms should be identified by the Investigator and recorded on the eCRF. However, if an observed or reported sign or symptom is not considered a component of a specific disease or syndrome by the Investigator, it should be recorded as a separate adverse event on the eCRF. Additionally, the condition that led to a medical or surgical procedure (e.g., surgery, endoscopy, tooth extraction, or transfusion) should be recorded as an adverse event, not the procedure. Any medical condition already present at screening or randomization should not be reported as an adverse event unless the medical condition or signs or symptoms present at baseline changes in severity or seriousness at any time during the study. In this case, it should be reported as an adverse event. Clinically significant abnormal laboratory or other examination (e.g., ECG) findings that are detected during the study or are present at screening or randomization and significantly worsen during the study should be reported as adverse events. The Investigator will exercise his or her medical and scientific judgment in deciding whether an abnormal laboratory finding or other abnormal assessment is clinically significant. Clinically significant abnormal laboratory values occurring during the clinical study will be followed until repeat tests return to normal, stabilize, or are no longer clinically significant. Any abnormal test that is determined to be an error does not require reporting as an adverse event. If a clinically significant abnormal laboratory finding meets the definition of an adverse event, a diagnosis or any clinical signs and symptoms rather than the abnormal laboratory finding should be recorded if possible. All adverse events must be followed until resolution, until the condition stabilizes, until the event is otherwise explained or is judged by the Investigator to be no longer clinically significant, or until the subject is lost to follow-up. The Investigator is responsible for ensuring that follow-up includes any supplemental investigations necessary to elucidate as completely as practical the nature and/or causality of the adverse event. This may include additional laboratory tests or investigations, histopathological examinations, or consultation with other health care professionals. The Sponsor may request that the Investigator perform or arrange for the conduct of supplemental measurements and/or evaluations of an adverse event. If a subject dies during participation in the study or during a recognized follow-up period, then Sponsor should be provided with a copy of any post-mortem findings, including histopathology, as required.
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8.1.1 adverse (drug) reaction

All noxious and unintended responses to the study medication(s) should be considered an adverse drug reaction. "Responses" to the infused cells means that a causal relationship between the study medication(s) and an adverse event is at least a reasonable possibility, i.e. the relationship cannot be ruled out.  
8.1.2 Unexpected Adverse Drug Reaction 8.1.3 An Unexpected Adverse Drug Reaction is defined as an adverse reaction, the nature or severity of which is not consistent with the applicable product information.  
Assessment of Adverse Events by the Investigator
The Investigator will assess the severity (intensity) of each adverse event as mild, moderate, or severe, and will also categorize each adverse event as to its potential relationship to the infused cells using the categories of yes or no. The severity of all adverse events should be graded according to the NCI CTCAE version 4.0. These criteria can be found at http://ctep.cancer.gov/reporting/ctc.html. For those adverse events not listed in the NCI CTCAE, the following grading system should be used:
- Mild (CTCAE Grade 1): Transient symptoms, awareness of sign/symptom, but easily tolerated and no interference with subject's daily activities;  
- Moderate (CTCAE Grade 2): Marked signs/symptoms that interfere with subject's usual activities, but still acceptable;
- Severe (CTCAE Grade 3): Incapacitating signs/symptoms that cause considerable interference with the subject's daily activities, unacceptable;
- Life-threatening (CTCAE Grade 4): Life threatening or disabling adverse event; and
- Death (CTCAE Grade 5): Death-related adverse event.  
AEs of infections will use both the CTCAE and the Blood and Marrow Transplant Clinical Trials Network (BMT CTN, Appendix G) criteria.
synopsis
causality assessment

For this study, the Investigator should evaluate the relatedness of all adverse events to investigational study medications (ProTmune *ex vivo* programmed mPB cells or Control mPB cells). Relatedness to non-investigational study medications (conditioning medications and GvHD prophylaxis medications) is only required for SAEs. Safety monitoring for adverse events for this study begins as of the start of the conditioning regimen and will be reported as per the requirements outlined in Section 8.1. The relationship of an adverse event to the study medication(s) is (are) to be assessed according to the following definitions: No (unrelated, not related, no relation) - The time course between the administration of the study medication(s) and the occurrence or worsening of the adverse event rules out a causal relationship and another cause (concomitant drugs, therapies, complications, etc.) is suspected. Yes (related) - The time course between the administration of the study medication(s) and the occurrence or worsening of the adverse event is consistent with a causal relationship and no other cause (concomitant drugs, therapies, complications, etc.) can be identified. The definition implies a reasonable possibility of a causal relationship between the event and the study medication(s). This means that there are facts (evidence) or arguments to suggest a causal relationship. The following factors should also be considered:
- The temporal sequence from the study medication(s) administration:
The event should occur during or after the study medication(s) is administered. The length of time from the administration of the study medication(s) to the event should be evaluated in the clinical context of the event.  
- Underlying, concomitant, intercurrent diseases:
Each report should be evaluated in the context of the natural history and course of the disease being treated and any other disease the subject may have.  
- Concomitant drug:
The other drugs the subject is taking or the treatment the subject receives should be examined to determine whether any of them might be recognized to cause the event in question.  
- Known response pattern for study medication(s) administration:
Clinical and/or nonclinical data may indicate whether a particular response is likely to be a class effect.  
- Exposure to physical and/or mental stresses:
The exposure to stress might induce adverse changes in the recipient and provide a logical and better explanation for the event.
synopsis
8.2 serious adverse events

An adverse event or adverse reaction is considered serious if, in the view of either the Investigator or Sponsor, it results in any of the following outcomes:
synopsis
- death

- A life-threatening adverse event; NOTE: An adverse event or adverse reaction is considered "life-threatening" if, in view of either the Investigator or Sponsor, its occurrence places the subject at immediate risk of death. It does not include an event that, had it occurred in a more severe form, might have caused death.  
- Requires hospitalization or prolongation of existing hospitalizations; NOTE: Any hospital admission with at least 1 overnight stay will be considered an in-patient hospitalization. An emergency room visit without hospital admission will not be recorded as a SAE under this criterion, nor will hospitalization for a procedure scheduled or planned before signing of informed consent. However, unexpected complications and/or prolongation of hospitalization that occur during elective surgery should be recorded as adverse events and assessed for seriousness. Admission to the hospital for social or situational reasons (i.e., no place to stay, live too far away to come for hospital visits) will not be considered in-patient hospitalizations.  
- A persistent or significant disability/incapacity or substantial disruption of the ability to conduct normal life functions;
- A congenital anomaly/birth defect; or
- An important medical event.  
NOTE: Important medical events that may not result in death, be life-threatening, or require hospitalization may be considered an SAE when, based upon appropriate medical judgment, they may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes listed above. Examples of such medical events include allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient hospitalizations, or the development of drug dependency.
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8.3 serious adverse event reporting

All SAEs occurring from the start of the conditioning regimen (Day -10) until Day +365, and only SAEs related to infused cells (ProTmune *ex vivo* programmed mPB cells or Control mPB cells) from Day +366 through Day +730, must be reported to Medpace Clinical Safety within 24 hours of the knowledge of the occurrence (this refers to any adverse event that meets any of the aforementioned serious criteria). SAE forms must list the subject identification number and a comprehensive narrative that includes a chronological description and assessment of the event. To report the SAE, complete the SAE form electronically in the electronic data capture (EDC) system for the study. When the form is completed, Medpace Safety personnel will be notified electronically and will retrieve the form. If the event meets serious criteria and it is not possible to access the EDC system, send an email to Medpace Safety at medpacesafetynotification@medpace.com or call the Medpace SAE hotline (phone number listed below),
and fax the completed paper SAE form to Medpace (fax number listed below) within 24 hours of awareness. When the EDC system becomes available, the SAE information must be entered within 24 hours of the system becoming available. Safety Contact Information: Medpace Clinical Safety Medpace SAE hotline - USA: Telephone: +1-800-730-5779, ext. 2999 or +1-513-579-9911, ext. 2999 Facsimile: +1-866-336-5320 or +1-513-579-0444 e-mail: medpace-safetynotification@medpace.com
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follow-up reports

The Investigator must continue to follow the subject until the SAE has subsided or until the condition becomes chronic in nature, stabilizes (in the case of persistent impairment), or the subject dies. Within 24 hours of receipt of follow-up information, the Investigator must update the SAE form electronically in the EDC system for the study and submit any supporting documentation (e.g., subject discharge summary or autopsy reports) to Medpace Clinical Safety via fax or e-mail. If it is not possible to access the EDC system, refer to the procedures outlined above for initial reporting of SAEs.
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8.4 pregnancy reporting

If the subject or partner of a subject participating in the study becomes pregnant during the study, the Investigator should report the pregnancy to Medpace Clinical Safety within 24 hours of being notified. Medpace Clinical Safety will then forward the Exposure In Utero form to the Investigator for completion. The subject or partner should be followed by the Investigator until completion of the pregnancy. If the pregnancy ends for any reason before the anticipated date, the Investigator should notify Medpace Clinical Safety. At the completion of the pregnancy, the Investigator will document the outcome of the pregnancy. If the outcome of the pregnancy meets the criteria for immediate classification as an SAE (i.e., postpartum complication, spontaneous abortion, stillbirth, neonatal death, or congenital anomaly), the Investigator should follow the procedures for reporting an SAE.
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8.5 expedited reporting

The Sponsor will report all relevant information about suspected unexpected serious adverse reactions that are fatal or life-threatening as soon as possible to the Food and Drug Administration (FDA), applicable competent authorities in all the Member States concerned, and to the Central Ethics Committee, and in any case no later than 7 days after knowledge by the Sponsor of such a case, and that relevant follow-up information will subsequently be communicated within an additional 8 days. All other suspected unexpected serious adverse reactions will be reported to the FDA, applicable competent authorities concerned and to the Central Ethics Committee concerned as soon as possible but within a maximum of 15 days of first knowledge by the Sponsor. The Sponsor will also inform all Investigators as required. Expedited reporting will only be conducted for SUSARs related to ProTmune. The current ProTmune IB will be used to assess for expectedness for the purposes of serious and unexpected suspected adverse reaction (SUSAR) reporting. The ProTmune IB will be reviewed yearly and the periodicity of the review will be harmonized with the reporting period of the Development Safety Update Report.
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8.6 engraftment graft failure and

ANC and platelets from the clinical laboratory assessments will be used to evaluate engraftment.  
- Neutrophil engraftment is defined as the first date of 3 consecutive laboratory values of an ANC ≥ 0.5 x 109/L obtained on different days.  
- Platelet engraftment is defined as the first date of 3 consecutive laboratory values of platelets ≥ 20 × 109/L obtained on different days without platelet transfusions within the preceding 7 days.
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8.6.2 primary and secondary graft

Primary graft failure is defined as the subject not ever meeting the definition of neutrophil engraftment or any use of the reserve hematopoietic cell product (in Phase 1). If donor engraftment is not present through Visit Day +28 bone marrow examination and the subject's disease is not present, the subject is also considered as a primary graft failure (in the absence of relapsed disease). Secondary graft failure is defined as graft failure occurring after initial engraftment (ANC
≥500 cells/µL), including the presence of >95% recipient CD3+ or myeloid cells, re-infusion of donor cells because of permanent loss of neutrophils (<0.5 × 109/L) and/or platelets <30 × 109/L,
or >50% recipient CD3+ cells and treatment with donor lymphocyte infusion.
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8.6.3 chimerism

Neutrophil and T-cell chimerism will be assessed on the third consecutive day of ANC >500 cells/µL (neutrophil only) and on Days +28, +100, +180, and +365 (both neutrophil and T-cell). Chimerism will be measured by PCR amplification of recipient-and-donor-derived cells; which may include single nucleotide polymorphism and/or DNA microsatellites (short tandem repeats) analyses consistent with Institutional Standards. Chimerism will be measured by restriction fragment length polymorphism or microsatellite. Chimerism studies will be performed by short tandem repeats and/or flow cytometry according to local laboratory practices. When feasible, fractional chimerism (total, myeloid, lymphoid) will be performed from peripheral blood samples. If there is no evidence for donor engraftment by Day +21, then the subject will undergo BM and peripheral blood chimerism studies. If donor engraftment is not present by Day +28 BM examination, and the subject's disease is not present, the subject should be considered a primary graft failure (in the absence of relapsed disease).
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8.7 clinical laboratory evaluations

Safety laboratory tests will include hematology and serum chemistry panels. Peripheral blood samples will be collected and forwarded to either local laboratories or central laboratories for testing as described in Appendix A. The following clinical laboratory tests will be performed (the analyses of which are the minimum):  
- Hematology (CBC and when possible per Institutional practice to include a differential
(automated or manual)): RBCs, hemoglobin, hematocrit, platelets, total white blood cell, neutrophils, bands, lymphocytes, eosinophils, and monocytes. Manual differential will include blasts if present and ANC calculation; and
- Serum chemistry: includes creatinine, ALT, AST, alkaline phosphatase, blood urea nitrogen, lactate dehydrogenase, sodium, potassium, calcium, phosphorus, chloride, CO2, albumin, bilirubin (total and direct), and magnesium.
Clinical laboratory test results should be within normal limits or for certain clinical laboratory tests, within an "acceptable" range based on disease characteristics. The results will be forwarded to the Investigator for review. Any abnormalities deemed clinically significant by the Investigator will be reported as adverse events and recorded in the subject's eCRF if they meet adverse event reporting criteria (refer to Section 8.1). Any clinically significant abnormal laboratory values that persist should be followed by the Investigator. Such events should be followed until they have resolved (within normal limits or return to baseline) or the Investigator assesses them to be chronic or stable. The Investigator should file all copies of the laboratory reports in the subject's study chart. Note: Clinical laboratory testing may be performed at any time during the study if clinically indicated.
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8.8 serum pregnancy tests

Serum pregnancy tests will be performed during the Screening Period from all female subjects of child bearing potential. Pregnant females will be excluded from the study.
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8.9 vital signs

Vital signs will be recorded at study visits as described in Appendix A and will include systolic blood pressure, diastolic blood pressure, pulse rate, respiratory rate, and temperature.
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8.10 electrocardiograms

Standard supine triplicate 12-lead ECG (sequential, within 15 minutes total) will be performed by qualified technicians during the Screening Period, at Day 0 prior to HCT, and at Day +100. Electrocardiograms will be reviewed at the site for treatment of any urgent issues. The clinical significance of any ECG change must be assessed by the Investigator in the context of the subject's medical history, physical examination, and concomitant medications. The Investigator or delegated physician will review, sign, and date all ECGs. For the purposes of QTc interval calculation, QTcF is the preferred calculation.
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8.11 physical examinations

During the Screening Period, and at Subject Conditioning and Hospital Admission, a complete physical examination will be performed. The complete examination should include height, body weight, skin, head-neck, eyes-ears-nose-throat, lungs-chest, heart, abdomen, extremities, and appearance. A subset of follow-up physical examination assessments (with the exception of height) will be performed on the subject at Day 0 prior to HCT and weekly from Day +1 through Day +91, then on Days +100, +180, +270, and +365. All physical examination findings must be documented in the subject's study chart and also recorded in the appropriate eCRF.
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8.12 donor history

During the Screening Period, the following should be documented in the eCRF, including (but not limited to) donor age, sex, race or ethnicity, parity, CMV status, and blood type.
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8.13 medical history and concomitant

Significant medical history will be collected from the subject at the Screening Visit and should include (but not be limited to) demographic information, current and past medical conditions, co-morbid diseases, prior treatment history information for hematological malignancy, and medications up to 30 days prior to the Screening Visit. The medical history must be documented in the subject's study chart (the on-site source document) prior to study treatment administration and also recorded on the appropriate eCRF. Updated medical history information is to be collected at Subject Conditioning and the Hospital Admission Visit (to include any event that has occurred since the Screening Visit that could be considered clinically significant). Furthermore, any clinically significant that occurs after the ICF is signed but prior to administration of the study treatment is to be recorded as an update to the Medical History. All concomitant medication usage will be collected and recorded on the appropriate eCRF starting at Day -30 through Day +100. From Day +100 through Day +730, only concomitant medications given as TKI maintenance, or that were ongoing at the time of, and for the treatment of, an AE of GvHD, infection or secondary engraftment failure or any SAE, will be recorded.
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8.14 cardiac function

During the Screening Period, either an ECHO or MUGA scan will be obtained to assess for left ventricular ejection fraction or shortening fraction for eligibility criteria assessment by the Investigator, if not performed within 6 weeks prior to the Subject Conditioning Period, from Day -53 to Day -11.
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8.15 pulmonary function tests

Pulmonary function tests will be assessed during the Screening Period, if not performed within 6 weeks prior to the Subject Conditioning Period, from Day -53 to Day -11.
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9 statistics 9.1 analysis populations

The Intent-to-Treat (ITT) Population for Phase 1 will include all subjects who received ProTmune. The ITT Population for Phase 2 will include all randomized subjects. The ITT population will include each subject in their randomized treatment group, regardless of actual treatment received.
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9.1.2 modified intent-to-treat population

The Modified Intent-to-Treat (mITT) Population will include all subjects in the ITT Population who receive IP (defined as either ProTmune or Control mBP units). Subjects who are randomized and do not receive IP because the incoming donor mPB unit did not meet criteria for manufacturing, or because their health status deteriorated and they no longer met eligibility criteria, will be considered screen failures and are not part of mITT. Despite the exclusion of these subjects, the ITT principle would be considered preserved since the decision of whether or not to receive treatment is not expected to be influenced by knowledge of the assigned treatment and would be expected to occur equally in either treatment group. Summaries and analyses utilizing the mITT Population will include each subject in their randomized treatment group, regardless of actual treatment received.
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9.1.3 per-protocol population

The Per-Protocol (PP) Population will include all Phase 2 subjects in the mITT Population who do not have any major protocol violations deemed to impact the results as defined in the statistical analysis plan prior to locking the database.
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9.1.4 safety population

The Safety Population will include all subjects who receive IP. All safety analysis will be based on the Safety Population. Summaries and analyses utilizing the Safety Population will include each subject in the treatment group representing the actual treatment received, regardless of randomization. For example, if a single dose of ProTmune is received by a subject randomized to the control arm, the subject will be analyzed in the ProTmune arm.
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9.2 statistical methods

A Statistical Analysis Plan (SAP) will be finalized before database lock. Any changes to the methods described in the final SAP will be described and justified as needed in the clinical study report. All reporting and analyses will be conducted at the end of the study, which is defined as the date when the last subject last visit occurs or the date at which the last data point is collected for the completion of 1-year on study (Day +365), whichever occurs later. Analysis of the 2-year survival follow-up will be conducted upon completion of the Day +730 follow-up. The initial clinical study report will be completed following final analysis of the 1-year data and will be appended to include the 2-year survival data upon completion. Summary statistics will be presented by treatment group. Unless otherwise stated, continuous variables will be summarized by using the number of non-missing observations, arithmetic mean, standard deviation, median, minimum, and maximum values as descriptive statistics. Categorical variables will be summarized by using the frequency count and the percentage of subjects in each category as descriptive statistics.  
Statistical analyses will be performed using SAS® (Version 9.3, or higher).
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9.2.1 analysis of efficacy

Based on the timing from randomization to infusion of IP (defined as ProTmune or Control mPB units), a post-randomization screen failure may occur if the mPB donor collection unit fails to meet the requirements for ProTmune or Control processing (see Section 4.4). As such, the ITT population will only be used to summarize subject disposition. Efficacy analyses will be performed based on the mITT Population. Additional sensitivity analyses will be performed based on the PP Population for the primary and key secondary efficacy endpoint for Phase 2. Efficacy data from the Phase 1 part of the study and Phase 2 part of the study will be summarized separately. Summary tables will present results for each phase by treatment group. The primary efficacy endpoint is the cumulative incidence of CIBMTR Grades II through IV aGvHD through Visit Day +100 based on investigator results; death and relapse without Grades II-IV aGvHD will be considered competing risks. Subjects who are alive with no occurrence of Grade II-IV aGvHD through Visit Day +100 will be censored at their last assessment for aGvHD on or prior to Visit Day +100.  
Phase 1: Cumulative incidence curves will be constructed for the primary efficacy endpoint along with curves for death and relapse without CIBMTR Grades II-IV aGvHD as competing risks. The first day of Grades II-IV aGvHD will be used to calculate the cumulative incidence curve. The estimate of the cumulative incidence rate of Grades II-IV aGvHD by Day +100 and the associated 2-sided 95% confidence intervals will be estimated based on the cumulative incidence function with variance estimated using the Delta method.  
Phase 2: The cumulative incidence curves and estimates of the cumulative incidence rate along with the associated 2-sided 95% confidence intervals will be presented in the same manner described in Phase 1. The cumulative incidence functions for CIBMTR Grades II-IV aGvHD by Day +100 between the two treatment groups will be compared using Gray's test (Gray 1988) at a two-sided 0.05 significance level. The corresponding hazard ratio of the treatment effect along with the 95% confidence interval will be calculated using the Fine and Gray's sub-distribution hazard model (Fine and Gray 1999) with treatment and age as a covariate. Other covariates may be considered for model inclusion. The key secondary efficacy endpoint is the proportion of subjects alive without relapse and without moderate or severe cGvHD per NIH Consensus Criteria for the global severity score at Visit Day +365 using observed cases. Subjects meeting these criteria will be considered a responder.  
Phase 1: The number of subjects that are alive without relapse and without moderate or severe cGvHD at Visit Day +365 will be summarized using counts and percentages. Summaries will also include the number of subjects that are considered non-responders.  
Phase 2: The same summaries described in Phase 1 will be presented by treatment group.  
Statistical comparisons between treatment groups will be performed using a logistic regression with treatment and age as a covariate. Other covariates may be considered for model inclusion.  
Sensitivity analyses of the primary efficacy and key secondary efficacy endpoints will be repeated using the PP population. For the responder/non-responder endpoint, analyses using non-responder imputation cases will also be performed; other methods may be explored to account for missing data such as multiple imputation methods. All exploratory efficacy endpoints will be summarized descriptively by phase and treatment groups using the mITT Population, unless otherwise noted. For Phase 2, nominal 2-sided p-values (without adjustment for multiple comparisons) will be reported as a measure of the strength of association between the endpoint and the treatment effect rather than formal tests of hypotheses. Exploratory time-to-event endpoints in the presence of competing risks (e.g., aGvHD and cGvHD) will be performed using the cumulative incidence function in the same manner as the primary efficacy endpoint.  
Exploratory time-to-event endpoints will be summarized using Kaplan-Meier estimates and a twosided log-rank test to compare treatment groups. In addition, the hazard ratio along with the 95%
confidence intervals will be calculated using a Cox proportional hazards model with treatment and age as covariates. Other covariates may be considered for model inclusion.
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9.2.2 analysis of safety

The safety profile will be based on adverse events, vital signs, physical examinations, engraftment, graft failure, chimerism, clinical laboratory assessments, and ECGs. All safety analysis will be based on the Safety Population. Safety analyses in general will be descriptive and will be presented by phase and treatment group in tabular format. Categorical endpoints will be summarized using number and percentage of subjects within each category. Continuous endpoints will be summarized descriptively with summary statistics (n, mean, standard deviation, standard error, median, Q1, Q3, minimum, and maximum). A treatment-emergent adverse event (TEAE) is defined as an adverse event with a start date and time on or after the administration of investigational product. AEs that are designated as GvHDrelated events per the investigator as indicated on the eCRF are considered signs and symptoms of GvHD. GvHD-specific details are also collected on separate eCRFs to assess efficacy. As such, non-serious GvHD-related adverse events will not be included in the AE analyses and will be summarized separately; GvHD-related AEs that meet the criteria of SAEs will be included in the summaries of AEs and SAEs. The number and percentage of subjects with TEAEs will be tabulated by System Organ Class and Preferred Term for each treatment group and by severity and relationship to treatment. Adverse events leading to discontinuation of the study and serious adverse events will be summarized by treatment group. By-subject listings will also be provided for any deaths, SAEs, and adverse events leading to discontinuation of the study. Non-CMV infections are defined as bacterial, fungal, viral (excluding CMV), and parasitic infections. The number of subjects with non-CMV infections will be summarized using frequency counts and percentages overall and by System Organ Class and Preferred Term. Febrile neutropenia, as collected on the eCRF and defined by the Infectious Disease Society of America Fever and Neutropenia Guidelines Panel (Freifeld et al. 2011):  
- Fever is defined as a single oral temperature measurement of ≥38.3°C (101°F) or a temperature of ≥38.0°C (100.4°F) sustained over a 1-hour period
- Neutropenia is defined as an ANC of <0.5 × 109/L
The number of subjects with febrile neutropenia will be summarized using frequency counts and percentages. The following safety endpoints will be summarized using descriptive statistics:  
- proportion of subjects with neutrophil engraftment per CIBMTR through Visit Day +28
- proportion of subjects with platelet engraftment per CIBMTR through Visit Day +100 per CIBMTR will be summarized using
- time to neutrophil engraftment - time to platelet engraftment - proportion of subjects with primary graft failure
- proportion of subjects with secondary graft failure
Descriptive statistics will be provided for clinical laboratory data and vital signs data, presented as both actual values and changes from baseline over time. Abnormal physical examination findings will be presented in a by-subject data listing. Descriptive statistics will be provided for ECG interval data and presented as both actual values and changes from baseline. Details of any abnormalities will be included in subject listings.
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9.2.3 interim analysis

During Phase 1, the IDMC will convene to assess safety data as outlined in the IDMC Charter. At that time, the Sponsor, in consultation with and based on recommendations from the IDMC, will decide whether the study should stop or whether the Phase 2 study can begin. If the IDMC and Sponsor determine that there are no safety concerns based on Phase 1 safety data, Phase 2 study enrollment will begin. During Phase 2, the IDMC will convene according to the guidelines outlined in the IDMC Charter. There are no formal interim analyses for efficacy planned.
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9.2.4 hypotheses

The following hypothesis statements are given to provide some context to the comparisons being performed.
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primary efficacy endpoint

H0 (null hypothesis): There is no difference in the cumulative incidence of CIBMTR Grade II-IV
aGvHD (with death or relapse without CIBMTR Grade II-IV aGvHD as competing events) through Visit Day +100 between the ProTmune and Control groups.  
H1 (alternative hypothesis): There is a difference in the cumulative incidence of CIBMTR Grade II-IV aGvHD (with death or relapse without CIBMTR Grade II-IV aGvHD as competing events) through Visit Day +100 between the ProTmune and Control groups.
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key secondary efficacy endpoint

H0 (null hypothesis): There is no difference in the proportion of subjects alive without relapse and without moderate or severe cGvHD per NIH Consensus Criteria at Visit Day +365 between the ProTmune and Control groups.  
H1 (alternative hypothesis): There is a difference in the proportion of subjects alive without relapse and without moderate or severe cGvHD per NIH Consensus Criteria at Visit Day +365 between the ProTmune and Control groups. Hypothesis testing will be described in the statistical analysis plan.
synopsis
9.2.5 sample size determination

The background cumulative incidence rate of International Bone Marrow Transplant Registry (IBMTR) Grades B-D aGvHD in this population is assumed to be between 40% and 60% as reported in the literature (Jagasia et al. 2012).  
Phase 1: Allowing for a dropout rate of approximately 15%, approximately 8-12 subjects will be enrolled to include 6-10 evaluable subjects.  
Phase 2: When accounting for competing risk factors (death or relapse without aGvHD), a sample size of 80 subjects (40 subjects in each treatment group) allows for approximately 85% power to detect a reduction in the cumulative incidence rate of CIBMTR Grades II-IV aGvHD through Visit Day +100 from 55% to 25% (i.e., a hazard ratio of 0.3464) in the Control versus ProTmune treatment arms using a two-sided log-rank test at a 0.05 significance level. This calculation assumes the cumulative incidence rate for competing risk factors is 10% through Visit Day +100. Allowing for a dropout rate of approximately 10%, approximately 90 subjects will be randomized to include approximately 80 treated subjects in the mITT Population. The sample size was calculated using PASS Sample Size Software (PASS 16 Power Analysis and Sample Size Software, 2018).
synopsis
10 data management and record

Data will be recorded at the site on eCRFs and reviewed by the clinical research associate (CRA) during monitoring visits. The CRAs will verify data recorded in the EDC system with source documents. All corrections or changes made to any study data must be appropriately tracked in an audit trail in the EDC system. An eCRF will be considered complete when all missing, incorrect, and/or inconsistent data has been accounted for.
synopsis
10.1.2 computer systems

Data will be processed using a validated computer system conforming to regulatory requirements.
synopsis
10.1.3 data entry

Data must be recorded using the EDC system as the study is in progress. All site personnel must log into the system using their secure user name and password in order to enter, review, or correct study data. These procedures must comply with Title 21 of the Code of Federal Regulations (21 CFR Part 11) and other appropriate international regulations. All passwords will be strictly confidential. 10.1.4 Medical Information Coding For medical information, the following thesauri will be used:
- Medical Dictionary for Regulatory Activities for medical history and adverse events, and
- World Health Organization Drug Dictionary for prior and concomitant medications.
synopsis
10.1.5 data validation

Validation checks programmed within the EDC system, as well as supplemental validation performed via review of the downloaded data, will be applied to the data in order to ensure accurate, consistent, and reliable data. Data identified as erroneous, or data that are missing, will be referred to the investigative site for resolution through data queries. The eCRFs must be reviewed and electronically signed by the Investigator.
synopsis
10.2 record keeping

Records of subjects, source documents, monitoring visit logs, eCRFs, inventory of investigational product, regulatory documents, and other Sponsor correspondence pertaining to the study must be kept in the appropriate study files at the site. Source data is defined as all information in original records and certified copies of original records of clinical findings, observations, or other activities in a clinical study necessary for the evaluation and reconstruction of the clinical study. Source data are contained in source documents (original records or certified copies). These records will be retained in a secure file for the period as set forth in the Clinical Study Agreement. Prior to transfer or destruction of these records, the Sponsor must be notified in writing and be given the opportunity to further store such records.
synopsis
11 investigator requirements and quality

Good Clinical Practice (GCP) is an international ethical and scientific quality standard for designing, conducting, recording, and reporting studies that involve human subjects. Compliance with this standard provides public assurance that the rights, safety, and well-being of study subjects are protected, consistent with the principles that have their origin in the Declaration of Helsinki, and that the clinical study data are credible.
synopsis
11.2 institutional review board/independent ethics

The IRB/IEC will review all appropriate study documentation in order to safeguard the rights, safety, and well-being of subjects. The study will only be conducted at sites where IRB/IEC
approval has been obtained. The protocol, ProTmune IB, ICF, advertisements (if applicable),
written information given to the subjects, safety updates, annual progress reports, and any revisions to these documents will be provided to the IRB/IEC by the Investigator. Federal regulations and International Conference on Harmonisation (ICH) require that approval be obtained from an IRB/IEC prior to participation of subjects in research studies. Prior to study onset, the protocol, any protocol amendments, ICFs, advertisements to be used for subject recruitment, and any other written information regarding this study to be provided to a subject or subject's legal guardian must be approved by the IRB/IEC. No investigational product will be released to the site for dosing until written IRB/IEC authorization has been received by the Sponsor. It is the responsibility of the Sponsor or their designee (i.e., Medpace) to obtain the approval of the responsible ethics committees according to the national regulations. The study will only start in the respective sites once the respective committee's written approval has been given.
synopsis
11.3 informed consent

The ICF and any changes to the ICF made during the course of the study must be agreed to by the Sponsor or designee and the IRB/IEC prior to its use and must be in compliance with all ICH GCP, local regulatory requirements, and legal requirements. The Investigator must ensure that each study subject is fully informed about the nature and objectives of the study and possible risks associated with participation and must ensure that the subject has been informed of his/her rights to privacy. The Investigator will obtain written informed consent from each subject before any study-specific activity is performed and should document in the source documentation that consent was obtained prior to enrollment in the study. The original signed copy of the ICF must be maintained by the Investigator and is subject to inspection by a representative of the Sponsor, their representatives, auditors, the IRB/IEC and/or regulatory agencies. A copy of the signed ICF will be given to the subject.
synopsis
11.4 subject card

On enrollment in the study, the subject will receive a subject card to be carried at all times. The subject card will state that the subject is participating in a clinical research study, type of treatment, and contact details in case of an SAE.
synopsis
11.5 study monitoring requirements

It is the responsibility of the Investigator to ensure that the study is conducted in accordance with the protocol, ICH GCP, applicable regulatory requirements, the Declaration of Helsinki (for United States sites), and that valid data are entered into the eCRFs. To achieve this objective, the monitor's duties are to aid the Investigator and, at the same time, the Sponsor in the maintenance of complete, legible, well organized and easily retrievable data. Before the enrollment of any subject in this study, the Sponsor or their designee will review with the Investigator and site personnel the following documents: protocol, ProTmune IB, eCRFs and procedures for their completion, informed consent process, and the procedure for reporting SAEs. The Investigator will permit the Sponsor or their designee to monitor the study as frequently as deemed necessary to determine that data recording and protocol adherence are satisfactory. During the monitoring visits, information recorded on the eCRFs will be verified against source documents and requests for clarification or correction may be made. After the eCRF data is entered by the site, the CRA will review the data for safety information, completeness, accuracy, and logical consistency. Computer programs that identify data inconsistencies may be used to help monitor the clinical study. If necessary, requests for clarification or correction will be sent to Investigators. The Investigator and his/her staff will be expected to cooperate with the monitor and provide any missing information, whenever possible. All monitoring activities will be reported and archived. In addition, monitoring visits will be documented at the investigational site by signature and date on the study-specific monitoring log.
synopsis
11.6 disclosure of data

Data generated by this study must be available for inspection by the FDA, the Sponsor or their designee, applicable foreign health authorities, and the IRB/IEC as appropriate. Subjects or their legal representatives may request their medical information be given to their personal physician or other appropriate medical personnel responsible for their welfare. Subject medical information obtained during the study is confidential and disclosure to third parties other than those noted above is prohibited.
synopsis
11.7 retention of records

To enable evaluations and/or audits from regulatory authorities or the Sponsor, the Investigator will keep records, including the identity of all participating subjects (sufficient information to link records, e.g., CRFs and hospital records), all original signed ICFs, copies of all CRFs, SAE forms, source documents, and detailed records of treatment disposition. The records should be retained by the Investigator according to specifications in the ICH guidelines, local regulations, or as specified in the Clinical Study Agreement, whichever is longer. The Investigator must obtain written permission from the Sponsor before disposing of any records, even if retention requirements have been met. If the Investigator relocates, retires, or for any reason withdraws from the study, the Sponsor should be prospectively notified. The study records must be transferred to an acceptable designee, such as another Investigator, another institution, or to the Sponsor.
synopsis
11.8 publication policy

Following completion of the study, the data may be considered for publication in a scientific journal or for reporting at a scientific meeting. Each Investigator is obligated to keep data pertaining to the study confidential. The Investigator must consult with the Sponsor before any study data are submitted for publication. The Sponsor reserves the right to deny publication rights until mutual agreement on the content, format, interpretation of data in the manuscript, and journal selected for publication are achieved.
synopsis
11.9 financial disclosure

Investigators are required to provide financial disclosure information to the Sponsor to permit the Sponsor to fulfill its obligations under 21 CFR Part 54. In addition, Investigators must commit to promptly updating this information if any relevant changes occur during the study and for a period of 1 year after the completion of the study.
synopsis
11.10 insurance and indemnity

In accordance with the relevant national regulations, the Sponsor has taken out subject liability insurance for all subjects who have given their consent to the clinical study. This cover is designed for the event that a fatality, physical injury, or damage to health occurs during the clinical study's execution.
synopsis
11.11 legal aspects

The clinical study is submitted to the relevant national competent authorities in all participating countries to achieve a clinical trial authorization (CTA). The study will commence (i.e., initiation of study centers) when the CTA and favorable Ethics opinion have been received.
synopsis
12 study administrative information 12.1

Any amendments to the study protocol will be communicated to the Investigators by Medpace or the Sponsor. All protocol amendments will undergo the same review and approval process as the original protocol. A protocol amendment may be implemented after it has been approved by the IRB/IEC, unless immediate implementation of the change is necessary for subject safety. In this case, the situation must be documented and reported to the IRB/IEC within 5 working days.
synopsis
12.2 address list

12.2.1 Sponsor Fate Therapeutics, Inc.  
3535 General Atomics Court, Suite 200 San Diego, CA 92121 USA Telephone: 858-875-1800 Facsimile: 858-875-1843 12.2.2 Contract Research Organization Medpace, Inc. 5375 Medpace Way Cincinnati, OH 45227 USA Telephone: +1-800-730-5779 Facsimile: +1-513-579-0444 12.2.3 Drug Safety Medpace Clinical Safety 5375 Medpace Way Cincinnati, OH 45227 USA Telephone: +1-800-730-5779, ext. 2999 Facsimile: +1-866-336-5320 12.2.4 Biological Specimens Refer to the current PT-001 Laboratory Manual for a complete list of testing facilities.
synopsis
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53. Salzberger B, Bowden RA, Hackman RC, Davis C, Boeckh M. Neutropenia in allogeneic marrow transplant recipients receiving ganciclovir for prevention of cytomegalovirus disease: risk factors and outcome. Blood. 1997;90:2502-2508. Salzberger B, Bowden RA, Hackman RC, Davis C, Boeckh M. Neutropenia in allogeneic marrow transplant recipients receiving ganciclovir for prevention of cytomegalovirus disease: risk factors and outcome. Blood. 1997;90:2502-2508.  
54. Schmitz N, Eapen M, Horowitz MM, et al. Long-term outcome of patients given transplants of mobilized blood or bone marrow: A report from the International Bone Marrow Transplant Registry and the European Group for Blood and Marrow Transplantation. Blood. 2006;108:4288-4290.  
54. Schmitz N, Eapen M, Horowitz MM, et al. Long-term outcome of patients given transplants of mobilized blood or bone marrow: A report from the International Bone Marrow Transplant Registry and the European Group for Blood and Marrow Transplantation. Blood. 2006;108:4288-4290.  
55. Smith A, Howell D, Patmore R, Jack A, Roman E. Incidence of haematological malignancy by sub-type: a report from the Haematological Malignancy Research Network. British Journal of Cancer. 2011;105:1684-1692.  
55. Smith A, Howell D, Patmore R, Jack A, Roman E. Incidence of haematological malignancy by sub-type: a report from the Haematological Malignancy Research Network. British Journal of Cancer. 2011;105:1684-1692.  
56. Sorror ML, Martin PJ, Storb RF, et al. Pretransplant comorbidities predict severity of acute graft-versus-host disease and subsequent mortality. Blood. 2014;124:287-295. Sorror ML, Martin PJ, Storb RF, et al. Pretransplant comorbidities predict severity of acute graft-versus-host disease and subsequent mortality. Blood. 2014;124:287-295.  
57. Thomas ED, Storb R, Clift RA, Fefer A, Johnson FL, et al. Bone Marrow Transplantation.  
NEJM. 1975;292:895-902. Thomas ED, Storb R, Clift RA, Fefer A, Johnson FL, et al. Bone Marrow Transplantation. NEJM. 1975;292:895-902.  
58. To LB, Levesque JP, Herbert KE. How I treat patients who mobilize hematopoietic stem cells poorly. Blood. 2011;118:4530-4540. To LB, Levesque JP, Herbert KE. How I treat patients who mobilize hematopoietic stem cells poorly. Blood. 2011;118:4530-4540.  
59. Tomblyn M, Chiller T, Einsele H, et al. Guidelines for preventing infectious complications among hematopoietic cell transplantation recipients: a global perspective. Biol Blood Marrow Transplant. 2009;15:1143-1238.  
59. Tomblyn M, Chiller T, Einsele H, et al. Guidelines for preventing infectious complications among hematopoietic cell transplantation recipients: a global perspective. Biol Blood Marrow Transplant. 2009;15:1143-1238.  
60. Trimethoprim-Sulfamethoxazole (co-trimoxazole): Drug Information. Lexicomp. 2015. 60. Trimethoprim-Sulfamethoxazole (co-trimoxazole): Drug Information. Lexicomp. 2015. 61. Wagner JE, Eapen M, Kurtzberg J. One-unit versus two-unit cord-blood transplantation.  
N Engl J Med. 2015;372:288. Wagner JE, Eapen M, Kurtzberg J. One-unit versus two-unit cord-blood transplantation. N Engl J Med. 2015;372:288.  
62. Weisdorf D, Haake R, Blazar B, et al. Treatment of moderate/severe acute graft-versus-host disease after allogeneic bone marrow transplantation: an analysis of clinical risk features and outcome. Blood 1990 Feb 15;75(4):1024-30.  
62. Weisdorf D, Haake R, Blazar B, et al. Treatment of moderate/severe acute graft-versus-host disease after allogeneic bone marrow transplantation: an analysis of clinical risk features and outcome. Blood 1990 Feb 15;75(4):1024-30.  
63. Wingard JR, Hsu J, Hiemenz JW. Hematopoietic stem cell transplantation: an overview of infection risks and epidemiology. Infect Dis Clin North Am. 2010;24:257.  
63. Wingard JR, Hsu J, Hiemenz JW. Hematopoietic stem cell transplantation: an overview of infection risks and epidemiology. Infect Dis Clin North Am. 2010;24:257.  
64. Woolfrey A, Klein JP, Haagenson M, et al. HLA-C Antigen mismatches are associated with worse outcomes in unrelated donor peripheral blood stem cell transplantation. Biol Blood Marrow Transplant. 2011;17:885-892.  
64. Woolfrey A, Klein JP, Haagenson M, et al. HLA-C Antigen mismatches are associated with worse outcomes in unrelated donor peripheral blood stem cell transplantation. Biol Blood Marrow Transplant. 2011;17:885-892.  
| APPENDIX A: SCHEDULE OF PROCEDURES FOR THE PHASE 1 AND PHASE 2 PARTS OF THE STUDY Day  of  HCT Days Post-Transplant   | Early   |      |                    |    |    |    |     |     |     |     |     |     |     |     |     |     |     |     |      |      |      |      |       |    |
|-----------------------------------------------------------------------------------------------------------------------|---------|------|--------------------|----|----|----|-----|-----|-----|-----|-----|-----|-----|-----|-----|-----|-----|-----|------|------|------|------|-------|----|
| -53 to                                                                                                                | -10 to  | INST | Withdrawal  Visit3 |    |    |    |     |     |     |     |     |     |     |     |     |     |     |     |      |      |      |      |       |    |
| Study Day                                                                                                             | -11     | -1   | Policy             | 0  | +1 | +7 | +14 | +21 | +28 | +35 | +42 | +49 | +56 | +63 | +70 | +77 | +84 | +91 | +100 | +180 | +270 | +365 | +7302 |    |
| Visit window  (days)                                                                                                  | -       | -    | -                  | -  | -  | ±3 | ±3  | ±3  | ±3  | ±3  | ±3  | ±3  | ±3  | ±3  | ±3  | ±3  | ±3  | ±3  | ±3   | ±14  | ±28  | ±28  | ±28   | -  |
| Study  Procedures Informed consent                                                                                    | X       |      |                    |    |    |    |     |     |     |     |     |     |     |     |     |     |     |     |      |      |      |      |       |    |
| Inclusion and  exclusion                                                                                              | X       |      |                    |    |    |    |     |     |     |     |     |     |     |     |     |     |     |     |      |      |      |      |       |    |
| HLA typing4                                                                                                           | X       |      |                    |    |    |    |     |     |     |     |     |     |     |     |     |     |     |     |      |      |      |      |       |    |
| ECHO or  MUGA scan5                                                                                                   | X       |      |                    |    |    |    |     |     |     |     |     |     |     |     |     |     |     |     |      |      |      |      |       |    |
| Demographics                                                                                                          | X       |      |                    |    |    |    |     |     |     |     |     |     |     |     |     |     |     |     |      |      |      |      |       |    |
| Medical history                                                                                                       | X       | X    | X                  |    |    |    |     |     |     |     |     |     |     |     |     |     |     |     |      |      |      |      |       |    |
| Qualification of  mPB6                                                                                                | X       |      |                    |    |    |    |     |     |     |     |     |     |     |     |     |     |     |     |      |      |      |      |       |    |
| Karnofsky  Performance                                                                                                | X       |      |                    |    |    |    |     |     |     |     |     |     |     |     |     |     |     |     |      |      |      |      |       |    |
| Status7                                                                                                               | X       | X    | X                  | X  | X  | X  | X   | X   | X   | X   | X   | X   | X   | X   | X   | X   | X   | X   | X    | X    |      |      |       |    |
| Subject  Hospital                                                                                                     |         |      |                    |    |    |    |     |     |     |     |     |     |     |     |     |     |     |     |      |      |      |      |       |    |
| Study Period                                                                                                          | SCRN1   | COND | ADM                |    |    |    |     |     |     |     |     |     |     |     |     |     |     |     |      |      |      |      |       |    |
| Bone marrow  aspirate8                                                                                                | X       | X    |                    |    |    |    |     |     |     |     |     |     |     |     |     |     |     |     |      |      |      |      |       |    |
| Infectious  disease titers and  plasma CMV  PCR viremia9,10                                                           | X       |      |                    |    |    |    |     |     |     |     |     |     |     |     |     |     |     |     |      |      |      |      |       |    |
| Physical                                                                                                              | X       |      |                    |    |    |    |     |     |     |     |     |     |     |     |     |     |     |     |      |      |      |      |       |    |
| examination11                                                                                                         | X       | X    | X                  | X  | X  | X  | X   | X   | X   | X   | X   | X   | X   | X   | X   | X   | X   | X   | X    | X    | X    | X    | X     |    |
| Vital signs12                                                                                                         | X       | X    | X                  | X  | X  | X  | X   | X   | X   | X   | X   | X   | X   | X   | X   | X   | X   | X   | X    | X    | X    | X    |       |    |
| ECG13                                                                                                                 | X       | X    | X                  |    |    |    |     |     |     |     |     |     |     |     |     |     |     |     |      |      |      |      |       |    |
| Concomitant                                                                                                           | X       |      |                    |    |    |    |     |     |     |     |     |     |     |     |     |     |     |     |      |      |      |      |       |    |
| medications14                                                                                                         | X       | X    | X                  | X  | X  | X  | X   | X   | X   | X   | X   | X   | X   | X   | X   | X   | X   | X   | X    | X    | X    | X    | X     |    |
| Adverse events15                                                                                                      | X       | X    | X                  | X  | X  | X  | X   | X   | X   | X   | X   | X   | X   | X   | X   | X   | X   | X   | X    | X    | X    | X    |       |    |
| Pulmonary  function tests                                                                                             | X       |      |                    |    |    |    |     |     |     |     |     |     |     |     |     |     |     |     |      |      |      |      |       |    |
| Blood typing and  RBC antibody  screen                                                                                | X       | X    |                    |    |    |    |     |     |     |     |     |     |     |     |     |     |     |     |      |      |      |      |       |    |
| Hematology16                                                                                                          | X       | X    | X16                | X  | X  | X  | X   | X   | X   | X   | X   | X   | X   | X   | X   | X   | X   | X   | X    |      |      |      |       |    |  
| APPENDIX A: SCHEDULE OF PROCEDURES FOR THE PHASE 1 AND PHASE 2 PARTS OF THE STUDY (CONTINUED) Day  of  HCT Days Post-Transplant   | Early             |                                                       |                    |    |    |    |     |     |     |     |     |     |     |     |     |     |     |     |      |      |      |      |       |    |
|-----------------------------------------------------------------------------------------------------------------------------------|-------------------|-------------------------------------------------------|--------------------|----|----|----|-----|-----|-----|-----|-----|-----|-----|-----|-----|-----|-----|-----|------|------|------|------|-------|----|
| -53 to                                                                                                                            | -10 to            | INST                                                  | Withdrawal  Visit3 |    |    |    |     |     |     |     |     |     |     |     |     |     |     |     |      |      |      |      |       |    |
| Study Day                                                                                                                         | -11               | -1                                                    | Policy             | 0  | +1 | +7 | +14 | +21 | +28 | +35 | +42 | +49 | +56 | +63 | +70 | +77 | +84 | +91 | +100 | +180 | +270 | +365 | +7302 |    |
| Visit window  (days)                                                                                                              | -                 | -                                                     | -                  | -  | -  | ±3 | ±3  | ±3  | ±3  | ±3  | ±3  | ±3  | ±3  | ±3  | ±3  | ±3  | ±3  | ±3  | ±3   | ±14  | ±28  | ±28  | ±28   | -  |
| Study Procedures                                                                                                                  | Subject  Hospital |                                                       |                    |    |    |    |     |     |     |     |     |     |     |     |     |     |     |     |      |      |      |      |       |    |
| Study Period                                                                                                                      | SCRN1             | COND                                                  | ADM                |    |    |    |     |     |     |     |     |     |     |     |     |     |     |     |      |      |      |      |       |    |
| Serum chemistry17                                                                                                                 | X                 | X                                                     | X                  | X  | X  | X  | X   | X   | X   | X   | X   | X   | X   | X   | X   | X   | X   | X   | X    | X    |      |      |       |    |
| Immune  reconstitution  assays18                                                                                                  | X                 | X                                                     | X                  | X  | X  | X  | X   | X   | X   |     |     |     |     |     |     |     |     |     |      |      |      |      |       |    |
| Serum pregnancy  test19                                                                                                           | X                 |                                                       |                    |    |    |    |     |     |     |     |     |     |     |     |     |     |     |     |      |      |      |      |       |    |
| Randomization  (Phase 2 only)20                                                                                                   | X                 |                                                       |                    |    |    |    |     |     |     |     |     |     |     |     |     |     |     |     |      |      |      |      |       |    |
| CMV assessment  for pre-emptive  therapy21                                                                                        | X                 | X (ad hoc if subject is seen at an unscheduled visit) |                    |    |    |    |     |     |     |     |     |     |     |     |     |     |     |     |      |      |      |      |       |    |
| Conditioning  regimen22                                                                                                           | X                 |                                                       |                    |    |    |    |     |     |     |     |     |     |     |     |     |     |     |     |      |      |      |      |       |    |
| GvHD  prophylaxis23                                                                                                               | X                 |                                                       |                    |    |    |    |     |     |     |     |     |     |     |     |     |     |     |     |      |      |      |      |       |    |
| Admission to  hospital unit                                                                                                       | X                 |                                                       |                    |    |    |    |     |     |     |     |     |     |     |     |     |     |     |     |      |      |      |      |       |    |
| Prepare  investigational  product                                                                                                 | X                 |                                                       |                    |    |    |    |     |     |     |     |     |     |     |     |     |     |     |     |      |      |      |      |       |    |
| Transplantation                                                                                                                   | X                 |                                                       |                    |    |    |    |     |     |     |     |     |     |     |     |     |     |     |     |      |      |      |      |       |    |
| Viral assessment24                                                                                                                | X                 | X                                                     | X                  | X  | X  | X  | X   | X   | X   | X   | X   | X   | X   | X   | X   | X   | X   | X   |      |      |      |      |       |    |
| aGvHD  assessment25                                                                                                               | X                 | X                                                     | X                  | X  | X  | X  | X   | X   | X   | X   | X   | X   | X   | X   | X   | X   | X   |     |      |      |      |      |       |    |
| cGvHD  assessment26                                                                                                               | X                 | X                                                     | X                  | X  |    |    |     |     |     |     |     |     |     |     |     |     |     |     |      |      |      |      |       |    |
| Chimerism  testing27                                                                                                              | X                 | X                                                     | X                  | X  |    |    |     |     |     |     |     |     |     |     |     |     |     |     |      |      |      |      |       |    |
| Serum  immunoglobulin28                                                                                                           | X                 | X                                                     | X                  |    |    |    |     |     |     |     |     |     |     |     |     |     |     |     |      |      |      |      |       |    |
| GvHD  biomarkers29                                                                                                                | X                 | X                                                     | X                  | X  | X  | X  | X   |     |     |     |     |     |     |     |     |     |     |     |      |      |      |      |       |    |
| Survival                                                                                                                          | X                 |                                                       |                    |    |    |    |     |     |     |     |     |     |     |     |     |     |     |     |      |      |      |      |       |    |  
1. The study will consist of a Screening Period of up to 6 weeks prior to administration of conditioning regimen (subject conditioning will occur between Day -10 to Day -1). General donor history will be collected in the eCRF, including (but not limited to) donor age, sex, race or ethnicity, CMV status, and blood type. Upon completion of all screening procedures and determination of eligibility, subjects will be scheduled for administration of conditioning regimen and admission for transplant, per institutional procedures. Screening procedures must be completed within 6 weeks prior to initiation of conditioning regimen. There may be situations in which a subject is not able to begin the conditioning within 6 weeks of the study screening. In these instances, the subject may need to be re-screened.  
This will involve repeating select or all screening procedures, as advised by the Medical Monitor.  
2. The Day +730 visit will occur by conducting a telephone contact report for capture of survival status and adverse event reporting. 3. If a subject withdraws or is withdrawn from the study prior to Day 0, the subject's mPB will not be processed to a ProTmune unit, they will not be considered evaluable for any study-related endpoint analyses, and the subject will be replaced. If a subject withdraws from the study after transplantation, information regarding secondary graft failure, disease relapse, serious adverse events involving GvHD and infections, and survival outcomes will be collected on Days +180, +365, and +730 by phone.  
4. Investigator is required to verify that the subject completed HLA typing. HLA typing can be completed prior to the Screening Period. 5. During the Screening Period, either an ECHO or MUGA scan will be obtained to assess for LVEF or shortening fraction for eligibility criteria assessment by the Investigator. The results of an ECHO/MUGA performed prior to consent may be used for subject qualification as long as performed within 6 weeks prior to the Subject Conditioning Period, from Day -53 to Day -11.  
6. Qualification of mPB unit must be conducted by a Fate representative. 7. Karnofsky Performance Status will be assessed during the Screening Period, at Day 0 after HCT, and all subsequent study visits up through Day +365 (which should include, but are not limited to, weekly from Day +1 through Day +91, then on Days +100, +180, +270, and +365). If applicable, Karnofsky Performance Status will be assessed at the Early Withdrawal Visit. Refer to Appendix D for details and the grading scale.  
8. Bone marrow aspirate will be sent to pathology and to cytogenetics during the Screening Period, on Day +21 in those subjects whose ANC is <500/µL, and as clinically indicated. Flow cytometry is required on BM aspirate. The results of the bone marrow aspirate performed prior to consent may be used for subject qualification as long as performed within 6 weeks prior to the Subject Conditioning Period, from Day -53 to Day -11.  
9. All subjects will be tested for baseline CMV antibody titer (IgG/IgM) and plasma CMV viremia. This baseline testing will be performed by a central laboratory and results will be provided to the clinical site prior to the initiation of randomization.  
10. Infectious diseases screen during the Screening Period by peripheral blood sample will include titers for EBV, CMV, hepatitis panel (hepatitis A antibody, hepatitis B surface antibody, hepatitis B
surface antigen, hepatitis B core antibody, and hepatitis C antibody), BK virus, HSV, HHV-6, HIV, HTLV types I/II antibody, syphilis, and VZV. Titer testing will be done by central laboratory testing during the Screening Period.  
11. During the Screening Period, Subject Conditioning Period, and Hospital Admission, a complete physical examination will be performed. The complete examination should include height, body weight, skin, head-neck, eyes-ears-nose-throat, lungs-chest, heart, abdomen, extremities and appearance. A subset of follow-up physical examination assessments (with the exception of height) will be performed on the subject at Day 0 prior to HCT and weekly from Day +1 through Day +91, then on Days +100, +180, +270, and +365. If applicable, a follow-up physical examination assessment will be performed at the Early Withdrawal Visit. All physical examination findings must be documented in the subject's study chart and also recorded in the appropriate eCRF.  
12. Vital Signs will be obtained at the Screening Period, Subject Conditioning Period, Hospital Admission, and at the following intervals on Day 0: prior to infusion of the cells, and at 15, 30, 45, and 60 minutes after the start of infusion of the cells (Note: these are targeted collection times; protocol deviations will only be documented when a collection is missed). Vital Signs will be obtained weekly from Day +1 through Day +91, then on Days +100, +180, +270, and +365. If applicable, vital signs will be obtained at the Early Withdrawal Visit. Vital signs will include systolic blood pressure, diastolic blood pressure, pulse rate, respiratory rate, and temperature.  
13. A 12-lead triplicate ECG (sequential, within 15 minutes total) will be obtained during the Screening Period, at Day 0 (prior to HCT), and at Day +100.  
14. All concomitant medications will be recorded starting at Day -30 through Day +100. From Day +100 through Day +730, only concomitant medications given as TKI maintenance, or that were ongoing at the time of, and for the treatment of, an AE of GvHD, infection or secondary engraftment failure or any SAE, will be recorded.  
15. All SAEs will be recorded from Day -10 through Day +365, and only SAEs related to the infused cells (ProTmune ex *vivo* programmed mPB cells or Control mPB cells) from Day +366 through Day
+730. From Day -10 through Day +100: adverse events will be collected as per CTCAE 4.0 (as well as BMT CTN for infections) as follows: Adverse events associated with infusion reactions, GvHD, infections, or engraftment failure (Grades 1 through 5). All other adverse events (Grades 2 through 5). Laboratory abnormalities will only be recorded as adverse events if deemed clinically significant by the Investigator. From Day +100 through Day +365: Only adverse events associated with GvHD, infections or secondary engraftment failure (Grades 1 through 5).  
16. Peripheral blood testing for hematology (CBC and when possible per institutional practice to include a differential (automated or manual) including total white blood cells, red blood cells, hemoglobin, hematocrit, platelets, neutrophils, bands, lymphocytes, eosinophils, and monocytes; manual differential will include blasts if present and ANC calculation) will be performed once during the Screening Period, once at Hospital Admission, once at Day 0 (prior to HCT), and daily from Day +1 through Day +28 (or until the subject achieves neutrophil engraftment, whichever event occurs first), and on  
Day +35, +42, +49, +56, +63, +70, +77, +84, +100, +180, and +365. If applicable, peripheral blood testing for hematology will be performed at the Early Withdrawal Visit. Following engraftment, blood for hematology is to be collected per institutional policy. Blood samples will be collected and forwarded to the local laboratory for analysis.  
17. A peripheral blood sample for serum chemistry will be collected once during the Screening Period, once at Hospital Admission, once at Day 0 prior to HCT, and weekly from Day +1 through Day +100, then at Day +180. If applicable, a peripheral blood sample for serum chemistry will be obtained at the Early Withdrawal Visit. Serum chemistry assessment will include creatinine, blood urea nitrogen, albumin, ALT, AST, bilirubin (total and direct), alkaline phosphatase, lactate dehydrogenase, calcium, sodium, potassium, phosphorus, chloride, CO2, and magnesium.  
18. Peripheral blood samples for immune reconstitution assays will be collected at baseline (during the Screening Period), and at Days +7, +14, +28, +56, +91, +180, +270, and +365. The peripheral blood sample will be sent to a central laboratory for analysis.  
19. A serum pregnancy test will be performed for females of child-bearing potential. 20. For the Phase 2 part of the study only, after meeting eligibility and no later than Day -7, subjects will be randomized using the IWRS to either the Control arm or ProTmune arm. 21. If pre-emptive CMV therapy is being initiated per local Institutional policy at a timepoint that does not have a regularly scheduled viral assessment (e.g., at conditioning or at an unscheduled visit), 2 peripheral blood samples (1 blood sample to be utilized locally, per institutional policy as required, at the site for subject management and 1 blood sample for central laboratory testing) will be collected for CMV assessments of DNA by quantitative PCR prior to starting the preemptive therapy.  
22. The conditioning regimen will be administered to subject per Section 3.4. 23. GvHD prophylaxis will be initiated per Section 3.4. 24. Two peripheral blood samples at each testing time point (1 blood sample to be utilized locally at the site for subject management and 1 blood sample for central laboratory testing) will be collected for viral assessments of DNA by quantitative PCR for EBV, CMV, HHV-6, and BK virus weekly from Days +7 through Day +100, and at Days +180, +270, and +365. For CMV assessment: Assessment of infection will be performed based on the NCI CTCAE and the BMT CTN Definitions. Study sites will monitor CMV viremia using local assays and frequencies as determined by local practices for inpatient and out-patient care. Therefore, if a blood sample is being drawn for a CMV PCR at a local virology laboratory, a sample must also be drawn at the same time and sent to the central virology laboratory for a CMV PCR result. If applicable, a peripheral blood sample for CMV assessment will be obtained at the Early Withdrawal Visit.  
25. Clinical and laboratory assessments of aGvHD will be performed weekly from Day +1 through Day +100, and on Day +180. If applicable, aGvHD assessments will be performed at the Early Withdrawal Visit. Acute GvHD assessments (incidence and maximum severity) of Grades I through IV aGvHD of the skin, liver, and gut as per the CIBMTR aGvHD Grading Scale (Appendix E) will be performed.  
26. Chronic GvHD assessments of mild, moderate, or severe cGvHD as per NIH Consensus Criteria for cGvHD (Appendix F) will be performed on Days +180, +270, and +365. If applicable, cGvHD
assessments will be performed at the Early Withdrawal Visit.  
27. Neutrophil and T-cell chimerism will be assessed on the third consecutive day of ANC >500 cells/µL (neutrophil only) and on Days +28, +100, +180, and +365 (both neutrophil and T-cell). Chimerism will be measured by PCR amplification of recipient-and-donor-derived cells; which may include single nucleotide polymorphism and/or DNA microsatellites (short tandem repeats) analyses consistent with Institutional Standards. Chimerism will be measured by restriction fragment length polymorphism or microsatellite. Chimerism studies will be performed by short tandem repeats and/or flow cytometry according to local laboratory practices. When feasible, fractional chimerism (total, myeloid, lymphoid) will be performed from peripheral blood samples. If there is no evidence for donor engraftment by Day +21, then the subject will undergo BM and peripheral blood chimerism studies. If donor engraftment is not present by Day +28 BM examination, and the subject's disease is not present, the subject should be considered a primary graft failure (in the absence of relapsed disease).  
28. Serum IgG, IgM, and IgA will be collected by a peripheral blood sample at Days +100, +180, and +365. 29. Peripheral blood samples for GvHD exploratory biomarkers will be obtained once weekly from Days +7 through Day +42, then on Day +100. Samples will be banked. ADM = Admission; aGvHD = Acute graft-versus-host disease; ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST = aspartate aminotransferase; BM = Bone marrow; BMT CTN = Blood and Marrow Transplant Clinical Trials Network; CBC = Complete blood count; cGvHD = Chronic graft-versus-host disease; CMV = Cytomegalovirus; CO2 = Carbon dioxide; COND = Conditioning; CTCAE = Common Terminology Criteria for Adverse Events; DNA = Deoxyribonucleic acid; EBV = Epstein-Barr Virus; ECG = Electrocardiogram; ECHO = Echocardiogram; eCRF = Electronic case report form; GvHD = Graft-versus-host disease; HCT = Hematopoietic cell transplantation; HSV = Herpes simplex virus; HHV-6 = Human herpes virus 6; HIV = Human immunodeficiency virus; HLA = Human leukocyte antigen; HTLV = Human T-cell lymphotropic virus; Ig = Immunoglobulin; INST = Institutional; LVEF = Left ventricular ejection fraction; mPB = Mobilized peripheral blood; MUGA = Multiple gated acquisition; NCI = National Cancer Institute; NIH = National Institutes of Health; SAE = serious adverse event; SCRN = Screening; PCR = Polymerase chain reaction; VZV = Varicella zoster virus.
synopsis
appendix b study design schematic

Non-Randomized Subjects N = approximately 6 to 10 treated subjects Subjects must have an available 8/8 HLA-A, -B, -C,
and -DRB1-matched unrelated mPB donor.  
Screening and Subject Conditioning Screening Period: Day -53 to Day -11 (up to 6 weeks prior to the Subject Conditioning Period)
Subject Conditioning Period: Day -10 to Day -1 The conditioning regimen will be administered as required per the protocol.
synopsis
conditioning regimens

- The conditioning regimen will include preparative regimens of fludarabine and busulfan
(FluBu4); busulfan and cyclophosphamide; cyclophosphamide and TBI; TBI and etoposide; or fludarabine and melphalan (FluMel 140).
synopsis
gvhd prophylaxis regimen

- Methotrexate (15 mg/m2on Day +1 after hematopoietic stem cell infusion and 10 mg/m2 on Days +3, +6, and +11), and
- Tacrolimus (0.02 mg/kg every 24 hours as an IV infusion or 0.03 mg/kg orally beginning on Day -2, adjusted to target dose level of 5 to 15 ng/mL. Taper starting at Day +100).  
Hospital Admission: Per Institutional Policy Study Treatment Administration: Day 0 (Day of HCT)
One unit of ProTmune *ex vivo* programmed mPB cells as the cell source for the HCT procedure.  
Post-Transplant Follow-Up: After HCT up through Day +730 Comprised of post-transplant assessments and post-transplant weekly visits through Day +100, intermittent visits through Day +365 and a telephone call on Day +730.  
CIBMTR = Center for International Blood and Marrow Transplant Research; GvHD = Graft-versus-host disease; HLA = Human Leukocyte Antigen; HCT = Hematopoietic cell transplant; IV = intravenous; mPB = Mobilized peripheral blood; TBI = Total body irradiation.
synopsis
appendix c flow schematic for

*Comprised of post-transplant assessments and post-transplant weekly visits through Day +100, intermittent visits through Day +365 and a telephone call on Day +730. aGvHD = Acute graft-versus-host disease; CMV = Cytomegalovirus; EAC = Endpoint Adjudication Committee; ECG = Electrocardiogram; GvHD = Graft-versus-host disease; HLA = Human Leukocyte Antigen; HCT = Hematopoietic cell transplant; IDMC = Independent Data Monitoring Committee; mPB = Mobilized peripheral blood.  
| Antigen; HCT = Hematopoietic cell transplant; IDMC = Independent Data Monitoring Committee; mPB = Mobilized peripheral blood. An IDMC will convene to assess preliminary safety data  as outlined in the IDMC Charter. At that time, the  Sponsor, in consultation with and based on  recommendations from the IDMC, will decide whether the  study should stop or whether the Phase 2 study can begin. One unit of  ProTmune  ex vivo  programmed  mPB cells as  the cell  source for the  HCT  procedure. Conditioning Regimen per  protocol. GvHD Prophylaxis Regimen per  protocol. The study will utilize an EAC to adjudicate the aGvHD  endpoint at Day +100 and Day +180 in accordance with  the EAC charter. Post-Transplant  Assessments*   |                                                                                      |                                             |                                                                                                                                                                                                                                                                                        |           |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------|---------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------|
| Day -53                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | Day -10                                                                              | Day 0                                       | Day +365                                                                                                                                                                                                                                                                               | Day +730* |
| Screening                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             | 2-Year Follow- up                                                                    |                                             |                                                                                                                                                                                                                                                                                        |           |
| Period                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                |                                                                                      |                                             |                                                                                                                                                                                                                                                                                        |           |
| (Day -53 to                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           |                                                                                      |                                             |                                                                                                                                                                                                                                                                                        |           |
| Day -11; up to 6 weeks  prior to the  Conditioning Period)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            | Conditioning Period (Day -10 to  Day -1; up to 9 days  prior to Hospital  Admission) | Hospital  Admission (Institutional  Policy) | Key Assessments: - Adverse event monitoring.  - Karnofsky Performance Status. - Acute GvHD assessments. - Chronic GvHD assessments. - Peripheral blood monitoring for safety panels, viral  monitoring, immune reconstitution, chimerism,  serum immunoglobulins, and GvHD exploratory |           |
| Day of  HCT                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           | Post-Transplant                                                                      | Study Completion                            |                                                                                                                                                                                                                                                                                        |           |
| Follow-up                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             |                                                                                      |                                             |                                                                                                                                                                                                                                                                                        |           |
| Key Assessments: - ECG and safety panels  on Day 0 prior to HCT.  - Adverse event  monitoring (starting at                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            |                                                                                      |                                             |                                                                                                                                                                                                                                                                                        |           |
| Key Assessments: - Investigator is required to verify that the  subject completed HLA typing.  - Infectious disease titers and CMV                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    |                                                                                      |                                             |                                                                                                                                                                                                                                                                                        |           |  
Key Assessments:  
- ECG and safety panels  
on Day 0 prior to HCT.  
- Adverse event  
monitoring (starting at Conditioning).  
- Karnofsky Performance  
Status.  
Key Assessments:  
- Investigator is required to verify that the  
subject completed HLA typing.  
- Infectious disease titers and CMV  
viremia.  
- Peripheral blood baseline sample for  
immune reconstitution assays.  
| APPENDIX D: KARNOFSKY PERFORMANCE STATUS SCALE General Category Index                                                                                                                         | Specific Criteria                                                                |                                                                    |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------|--------------------------------------------------------------------|
| Able to carry on normal activity; no                                                                                                                                                          | 100                                                                              | Normal; no complaints; no evidence of                              |
| special care needed.                                                                                                                                                                          | disease.                                                                         |                                                                    |
| 90                                                                                                                                                                                            | Able to carry on normal activity; minor  signs or symptoms of disease.           |                                                                    |
| 80                                                                                                                                                                                            | Normal activity with effort; some signs  or symptoms of disease.                 |                                                                    |
| Unable to work; able to live at home  and care for most personal needs;  varying amount of assistance needed.                                                                                 | 70                                                                               | Cares for self; unable to carry on  normal activity or to do work. |
| 60                                                                                                                                                                                            | Requires occasional assistance from  others but is able to care for most  needs. |                                                                    |
| 50                                                                                                                                                                                            | Requires considerable assistance from  others and frequent medical care.         |                                                                    |
| Unable to care for self; requires  institutional or hospital care or  equivalent; diseases may be rapidly  progressing.                                                                       | 40                                                                               | Disabled; requires special care and  assistance.                   |
| 30                                                                                                                                                                                            | Severely disabled; hospitalization  indicated; death not imminent.               |                                                                    |
| 20                                                                                                                                                                                            | Very sick; hospitalization necessary;  active supportive treatment necessary.    |                                                                    |
| 10                                                                                                                                                                                            | Moribund.                                                                        |                                                                    |
| 0                                                                                                                                                                                             | Dead                                                                             |                                                                    |
| Source: Mor V, Laliberte L, Morris JN, Wieman M. The Karnofsky Performance Status Scale. An examination of its reliability and validity in  a research setting. Cancer. 1984;53(9):2002-2007. |                                                                                  |                                                                    |
synopsis
appendix e acute gvhd scoring

| Stage                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         | Skin                     | Liver                | Gut                                           |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------|----------------------|-----------------------------------------------|
| 1                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             | Rash on <25% of skina    | Bilirubin 2-3 mg/dlb | Diarrhea > 500 ml/dayc or  persistent nausead |
| 2                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             | Rash on 25-50% of skin   | Bilirubin 3-6 mg/dl  | Diarrhea >1000 ml/day                         |
| 3                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             | Rash on >50% of skin     | Bilirubin 6-15 mg/dl | Diarrhea >1500 ml/day                         |
| 4                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             | Generalized erythroderma | Bilirubin >15 mg/dl  | Severe abdominal pain with or  without ileus  |
| with bullous formation                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        |                          |                      |                                               |
| Grade e I                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     | Stage 1-2                | None                 | None                                          |
| II                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            | Stage 3 or               | Stage 1 or           | Stage 1                                       |
| III                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           | --                       | Stage 2-3 or         | Stages 2-4                                    |
| IV f                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          | Stage 4                  | Stage 4              | --                                            |
| a Use "Rule of Nines" or burn chart to determine extent of rash. b Range given as total bilirubin. Downgrade one stage if an additional cause of elevated bilirubin has been documented. c Volume of diarrhea applies to adults. For pediatric subjects, the volume of diarrhea should be based on body surface area. Downgrade one  stage if an additional cause of diarrhea has been documented. d Persistent nausea with histologic evidence of GvHD in the stomach or duodenum. e Criteria for grading given as minimum degree of organ involvement required to confer that grade. f Grade IV may also include lesser organ involvement with an extreme decrease in performance status.  Source: CIBMTR Forms Manual: Post-TED (Form2450); A00425 version 2.0 (8/01/2012) |                          |                      |                                               |  
| APPENDIX F: NIH CONSENSUS CRITERIA FOR CHRONIC GVHD Performance Score: SCORE 0 SCORE 1 SCORE 2                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  | SCORE 3                                                                                                                            |                                                                                                                                                                                                      |                                                                                                                                            |                                                                                                                             |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------|
| KPS, ECOG LPS                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   | Asymptomatic  and fully active  (ECOG 0; KPS  or LPS 100%).                                                                        | Symptomatic, fully  ambulatory, restricted  only in physically  strenuous activity  (ECOG 1, KPS or LPS  80-90%).                                                                                    | Symptomatic,  ambulatory, capable of  selfcare, >50% of  waking hours out of bed  (ECOG 2, KPS or LPS  60-70%).                            | Symptomatic, limited  self-care, >50% of  waking hours in bed  (ECOG 3-4, KPS or  LPS <60%).                                |
| Skin Clinical features: - Maculopapular rash - Lichen planus-like  features - Papulosquamous  lesions or ichthyosis - Hyperpigmentation - Hypopigmentation - Keratosis pilaris - Erythema - Erythroderma  - Poikiloderma - Sclerotic features - Pruritus - Hair involvement - Nail involvement                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  | No symptoms.                                                                                                                       | <18% BSA with disease  signs but NO sclerotic  features.                                                                                                                                             | 19-50% BSA OR involvement with  superficial sclerotic  features "not  hidebound" (able to  pitch).                                         | >50% BSA OR deep  sclerotic features  "hidebound" (unable to  pinch) OR impaired  mobility, ulceration or  severe pruritus. |
| Mouth                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           | No symptoms.                                                                                                                       | Mild symptoms with  disease signs but not  limiting oral intake  significantly.                                                                                                                      | Severe symptoms with  disease signs on  examination with major  limitation of oral intake.                                                 |                                                                                                                             |
| Eyes Mean tear test (mm): - >10 - 6-10 - ≤5  - Not done                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         | Moderate symptoms  with disease signs with partial limitation of oral  intake.                                                     | Severe dry eye  symptoms significantly  affecting ADL (special  eyeware to relieve pain)  OR unable to work  because of ocular  symptoms OR loss of  vision caused by  keratoconjunctivitis  sicca.  |                                                                                                                                            |                                                                                                                             |
| GI Tract                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        | No symptoms.                                                                                                                       | Symptoms such as  dysphagia, anorexia,  nausea, vomiting,  abdominal pain or  diarrhea without  significant weight loss  (<5%).                                                                      |                                                                                                                                            |                                                                                                                             |
| No symptoms.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    | Mild dry eye symptoms  not affecting ADL  (requiring eyedrops  ≤3 × per day) OR asymptomatic signs of  keratoconjunctivits  sicca. | Moderate dry eye  symptoms partially  affecting ADL  (requiring drops  >3 × per day or punctal  plugs), WITHOUT vision impairment. Symptoms associated  with mild to moderate  weight loss  (5-15%). | Symptoms associated  with significant weight  loss >15%, requires  nutritional supplement  for most calorie needs  OR esophageal dilation. |                                                                                                                             |
| *AP may be elevated in growing children, and not reflective of liver dysfunction.  †Pulmonary scoring should be performed using both the symptom and pulmonary function testing (PFT) scale whenever possible. When  discrepancy exists between pulmonary symptom or PFT scores the higher value should be used for final scoring. Scoring using the Lung  Function Score (LFS) is preferred, but if DLCO is not available, grading using FEV1 should be used. The LFS is a global assessment of lung  function after the diagnosis of bronchiolitis obliterans has already been established [29]. The percent predicted FEV1 and DLCO (adjusted for  hematocrit but not alveolar volume) should be converted to a numeric score as follows: >80% = 1; 70-79% = 2; 60-69% = 3; 50-59% = 4;  40-49% = 5; =40% = 6.  The LFS = FEV1 score = DLCO score, with a possible range of 2-12.  ADL = activities of daily living; ALT = alanine aminotransferase; AP = alkaline phosphatase; AST = aspartate aminotransferase; BSA = body |                                                                                                                                    |                                                                                                                                                                                                      |                                                                                                                                            |                                                                                                                             |  
| APPENDIX F: NIH CONSENSUS CRITERIA FOR CHRONIC GVHD (CONTINUED) Performance Score: SCORE 0 SCORE 1 SCORE 2 SCORE 3 Liver Normal LFT. Elevated Bilirubin,  Bilirubin  AP*, AST or ALT. >3 mg/dl or Bilirubin,  enzymes 2-5 × ULN. Bilirubin or enzymes  >5 × ULN. Lungs† No symptoms. Mild symptoms  (shortness of breath  after climbing 1 flight  of steps). Moderate symptoms  (shortness of breath  after walking on flat  ground). Severe symptoms  (shortness of breath at  rest; requiring 02).  FEVI - FEV1  >80% OR LFS=2 - FEV1 60-79% OR LFS 3-5  - FEV1 40-59%  OR LFS 6-9  - FEVI ≤39% OR LFS 10-12 DLCO Joints and Fascia No symptoms. Mild tightness of arms  or legs, normal or mild  decreased range of  motion (ROM) AND not affecting ADL. Tightness of arms or  legs OR joint  contractures, erythema  thought due to fasciitis,  moderate decrease  ROM AND mild to  moderate limitation of  ADL. Contractures WITH significant decrease of  ROM AND significant  limitation of ADL  (unable to tie shoes, button shirts, dress self,  etc.) Genital Tract No symptoms. Symptomatic with mild  signs on examination  AND no effect on  coitus and minimal  discomfort with  gynecologic exam. Symptomatic with  moderate signs on  examination AND with  mild dyspareunia or  discomfort with  gynecologic exam. Symptomatic WITH  advanced signs  (stricture, labial  agglutination or severe  ulceration) AND severe  pain with coitus or  inability to insert  vaginal speculum. Other indicators, clinical manifestations or complications related to chronic GvHD (check all that apply and assign a  score to its severity (0-3) based on its functional impact where applicable (none - 0, mild - 1, moderate - 2, severe - 3): - Esophageal stricture or web  - Ascites (serositis) - Myasthenia Gravis - Polymyositis - Platelets >100,000/µl - Pericardial Effusion - Nephrotic syndrome - Cardiomyopathy - Cardiac conduction defects - Progressive onset - Pleural Effusion(s) - Peripheral Neuropathy - Eosinophilia >500µl - Coronary artery involvement *AP may be elevated in growing children, and not reflective of liver dysfunction.  †Pulmonary scoring should be performed using both the symptom and pulmonary function testing (PFT) scale whenever possible. When  discrepancy exists between pulmonary symptom or PFT scores the higher value should be used for final scoring. Scoring using the Lung  Function Score (LFS) is preferred, but if DLCO is not available, grading using FEV1 should be used. The LFS is a global assessment of lung  function after the diagnosis of bronchiolitis obliterans has already been established [29]. The percent predicted FEV1 and DLCO (adjusted for  hematocrit but not alveolar volume) should be converted to a numeric score as follows: >80% = 1; 70-79% = 2; 60-69% = 3; 50-59% = 4; 40- 49% = 5; =40% = 6.  The LFS = FEV1 score = DLCO score, with a possible range of 2-12.  ADL = activities of daily living; ALT = alanine aminotransferase; AP = alkaline phosphatase; AST = aspartate aminotransferase; BSA = body  surface area; DLCO = diffusing capacity of the lung; ECOG = Eastern Cooperative Oncology Group; GvHD = graft-versus-host disease;  KPS = Karnofsky Performance Status; LPS = Lansky Performance Status; LFTs = liver function tests; ULN = upper limit of normal. Source: Filipovich AH, Weisdorf D, Pavletic S, et al. National Institutes of Health consensus development project on criteria for clinical trials in  chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant. 2005;11(12):945-956.   |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
synopsis
appendix f nih consensus criteria

Elements included in the proposed global scoring system include both the number of organs or sites involved and the severity within each affected organ (note that performance status scoring is not incorporated into the global scoring system). The global descriptions of mild, moderate, and severe were chosen to reflect the degree of organ impact and functional impairment due to chronic GVHD. Although scoring is often used at the time of initial diagnosis, evaluating the clinical score periodically during the course of chronic GVHD may revise prognostic expectations and better describe the current severity of chronic GVHD. Note that the global scoring system can be applied only after the diagnosis of chronic GVHD is confirmed by either (1) the presence of a diagnostic feature or, if a diagnostic feature is not present, (2) at least 1 distinctive manifestation of chronic GVHD with the diagnosis supported by histologic, radiologic, or laboratory evidence of GVHD from any site.  
Mild chronic GVHD involves only 1 or 2 organs or sites (except the lung: see below), with no clinically significant functional impairment (maximum of score 1 in all affected organs or sites).  
Moderate chronic GVHD involves (1) at least 1 organ or site with clinically significant but no major disability (maximum score of 2 in any affected organ or site) or (2) 3 or more organs or sites with no clinically significant functional impairment (maximum score of 1 in all affected organs or sites). A lung score of 1 will also be considered moderate chronic GVHD.  
Severe chronic GVHD indicates major disability caused by chronic GVHD (score of 3 in any organ or site). A lung score of 2 or greater will also be considered severe chronic GVHD.  
Source: Filipovich AH, Weisdorf D, Pavletic S, et al. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant. 2005;11(12):945-956.  
| DEFINITION                                                                                                                                                                                                                                                                                                                                                                                   |                                                                                                                                                                                                               |                                                                                                                                                                                                                                                                      |                      |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------|
| Type of  Infection/Severity Grade                                                                                                                                                                                                                                                                                                                                                            | Grade 1                                                                                                                                                                                                       | Grade 2                                                                                                                                                                                                                                                              | Grade 3              |
| Bacterial infections                                                                                                                                                                                                                                                                                                                                                                         | Bacterial focus NOS  requiring no more than  14 days of therapy for  treatment (e.g., urinary  tract infection).                                                                                              | Bacteremia (except CoNS)                                                                                                                                                                                                                                             | Bacteremia with deep |
| without severe sepsis.*                                                                                                                                                                                                                                                                                                                                                                      | organ involvement (e.g.,  with new or worsening  pulmonary infiltrates;  endocarditis).                                                                                                                       |                                                                                                                                                                                                                                                                      |                      |
| Coag Neg Staph (S. epi),  Corynebacterium, or  Proprioniobacterium  bacteremia.                                                                                                                                                                                                                                                                                                              | Bacterial focus with  persistent signs, symptoms,  or persistent positive  cultures requiring greater  than 14 days of therapy.                                                                               | Severe sepsis with  bacteremia.                                                                                                                                                                                                                                      |                      |
| Cellulitis responding to  initial therapy within  14 days.                                                                                                                                                                                                                                                                                                                                   | Cellulitis requiring a  change in therapy due to  progression. Localized or diffuse  infections requiring  incision with or without  drain placement. Any pneumonia  documented or presumed  to be bacterial. | Fasciitis requiring  debridement. Pneumonia requiring  intubation.                                                                                                                                                                                                   |                      |
| C. Difficile toxin  positive stool with  diarrhea <1 L without  abdominal pain (child  <20 mL/kg).                                                                                                                                                                                                                                                                                           | C. Difficile toxin positive  stool with diarrhea ≥1 L  (child ≥20 ml/kg) or with  abdominal pain                                                                                                              | C. Difficile toxin positive  stool with toxic dilation  or renal insufficiency  with/without diarrhea                                                                                                                                                                |                      |
| Fungal infections                                                                                                                                                                                                                                                                                                                                                                            | Superficial candida  infection (e.g., oral  thrush, vaginal  candidiasis).                                                                                                                                    | Candida esophagitis                                                                                                                                                                                                                                                  | Fungemia including   |
| (biopsy proven).                                                                                                                                                                                                                                                                                                                                                                             | Candidemia.                                                                                                                                                                                                   |                                                                                                                                                                                                                                                                      |                      |
| -                                                                                                                                                                                                                                                                                                                                                                                            | Proven or probable fungal  sinusitis confirmed  radiologically without  orbital, brain, or bone  involvement.                                                                                                 | Proven or probable  invasive fungal infections  (e.g., Aspergillus, Mucor,  Fusarium, Scedosporium).                                                                                                                                                                 |                      |
| -                                                                                                                                                                                                                                                                                                                                                                                            | -                                                                                                                                                                                                             | Disseminated infections  (defined as multifocal  pneumonia, presence of  urinary or blood antigen,  and/or CNS involvement)  with Histoplasmosis,  Blastomycosis,  Coccidiomycosis, or  Cryptococcus. Pneumonocystis jiroveci pneumonia (regardless of  PaO2 level). |                      |
| * For definition of sepsis, see source document. CMV = Cytomegalovirus; CNS = Central nervous system; EBV = Epstein-Barr virus; HHV-6 = Human herpesvirus 6; PTLD  = Posttransplant Lymphoproliferative Disease; VZV = Varicella zoster virus. Source: Blood and Marrow Transplant Clinical Trials Network Technical Manual of Procedures, Appendix 4-A. Version 3.0,  dated March 19, 2013. |                                                                                                                                                                                                               |                                                                                                                                                                                                                                                                      |                      |  
| DEFINITION (CONTINUED)                                                                                                                                                                                                                                                                                                                                                                       |                                                                                                                                                                  |                                                                                               |                                                                  |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------|------------------------------------------------------------------|
| Type of  Infection/Severity Grade                                                                                                                                                                                                                                                                                                                                                            | Grade 1                                                                                                                                                          | Grade 2                                                                                       | Grade 3                                                          |
| Viral Infections                                                                                                                                                                                                                                                                                                                                                                             | Mucous HSV infection                                                                                                                                             | -                                                                                             | -                                                                |
| Dermatomal Zoster                                                                                                                                                                                                                                                                                                                                                                            | VZV infection with 3 or                                                                                                                                          | Severe VZV infection                                                                          |                                                                  |
| more dermatomes.                                                                                                                                                                                                                                                                                                                                                                             | (coagulopathy or organ  involvement).                                                                                                                            |                                                                                               |                                                                  |
| Asymptomatic CMV  viremia untreated or a  CMV viremia with viral  load decline by at least  2/3 of the baseline value  after 2 weeks therapy.                                                                                                                                                                                                                                                | Clinically active CMV  infection (e.g., symptoms,  cytopenias) or CMV  viremia not decreasing by  at least 2/3 of the baseline  value after 2 weeks of  therapy. | CMV end-organ  involvement  (pneumonitis, enteritis,  retinitis).                             |                                                                  |
| EBV reactivation not                                                                                                                                                                                                                                                                                                                                                                         | EBV reactivation                                                                                                                                                 |                                                                                               |                                                                  |
| treated with rituximab.                                                                                                                                                                                                                                                                                                                                                                      | requiring institution of  therapy with rituximab.                                                                                                                | EBV PTLD                                                                                      |                                                                  |
| Adenoviral conjunctivitis  asymptomatic viruria,  asymptomatic stool  shedding, and viermia not  requiring treatment.                                                                                                                                                                                                                                                                        | Adenoviral upper  respiratory infection,  viremia, or symptomatic  viruria requiring  treatment.                                                                 | Adenovirus with  end-organ involvement  (except conjunctivitis and  upper respiratory tract). |                                                                  |
| Asymptomatic HHV-6  viremia untreated or an  HHV-6 viremia with a  viral load decline by at  least 0.5 log after 2 weeks  of therapy.                                                                                                                                                                                                                                                        | Clinically active HHV-6  infection (e.g., symptoms,  cytopenias) or HHV-6  viremia without viral load  decline 0.5 log after 2  weeks of therapy.                | -                                                                                             |                                                                  |
| BK viremia or viruria  with cystis not requiring  intervention.                                                                                                                                                                                                                                                                                                                              | BK viermia or viruria  with clinical consequence  requiring prolonged  therapy and/or surgical  intervention.                                                    | -                                                                                             |                                                                  |
| Viremia (virus not  otherwise specified) not  requiring therapy.                                                                                                                                                                                                                                                                                                                             | Any viremia (virus not  otherwise specified)  requiring therapy.                                                                                                 | -                                                                                             |                                                                  |
| -                                                                                                                                                                                                                                                                                                                                                                                            | Enterocolitis with enteric                                                                                                                                       | -                                                                                             |                                                                  |
| viruses.                                                                                                                                                                                                                                                                                                                                                                                     |                                                                                                                                                                  |                                                                                               |                                                                  |
| -                                                                                                                                                                                                                                                                                                                                                                                            | Symptomatic upper tract                                                                                                                                          | Lower tract respiratory                                                                       |                                                                  |
| respiratory viruses.                                                                                                                                                                                                                                                                                                                                                                         | viruses.                                                                                                                                                         |                                                                                               |                                                                  |
| -                                                                                                                                                                                                                                                                                                                                                                                            | -                                                                                                                                                                | Any viral encephalitis or  meningitis.                                                        |                                                                  |
| Parasitic infections                                                                                                                                                                                                                                                                                                                                                                         | -                                                                                                                                                                | -                                                                                             | CNS or other organ  toxoplasmosis Strongyloides  hyperinfection. |
| * For definition of sepsis, see source document. CMV = Cytomegalovirus; CNS = Central nervous system; EBV = Epstein-Barr virus; HHV-6 = Human herpesvirus 6;  PTLD = Posttransplant Lymphoproliferative Disease; VZV = Varicella zoster virus. Source: Blood and Marrow Transplant Clinical Trials Network Technical Manual of Procedures, Appendix 4-A. Version 3.0,  dated March 19, 2013. |                                                                                                                                                                  |                                                                                               |                                                                  |  
| DEFINITION (CONTINUED)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        |                                                                       |                                                         |         |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------|---------------------------------------------------------|---------|
| Type of  Infection/Severity Grade                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             | Grade 1                                                               | Grade 2                                                 | Grade 3 |
| Nonmicrobiologically                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          | Uncomplicated fever with                                              |                                                         |         |
| defined infections                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            | negative cultures  responding within 14 days                          | -                                                       | -       |
| Clinically documented  infection not requiring  inpatient management                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          | Pneumonia or  bronchopneumonia not  requiring mechanical  ventilation | Any acute pneumonia  requiring mechanical  ventillation |         |
| -                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             | Typhlitis                                                             | -                                                       |         |
| -                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             | -                                                                     | Severe sepsis* without an  identified organism          |         |
| Recurrence Intervals to Determine Whether an Infection is the Same or New: 1. CMV, HSV, EBV, HHV-6: 2 months (<60 days) 2. VZV, HZV: 2 weeks (<14 days) 3. Bacterial, non-C. difficile: 1 week (<7 days) 4. Bacterial, C. difficile: 1 month (<30 days) 5. Yeast: 2 weeks (<14 days) 6. Molds: 3 months (<90 days) 7. Helicobacter: 1 year (<365 days) 8. Adenovirus, Enterovirus, Influenza, RSV, Parainfluenza, Rhinovirus: 2 weeks (<14 days) 9. Polyomavirus (BK virus): 2 months (<60 days) * For definition of sepsis, see source document. CMV = Cytomegalovirus; CNS = Central nervous system; EBV = Epstein-Barr virus; HHV-6 = Human herpesvirus 6; PTLD  = Posttransplant Lymphoproliferative Disease; VZV = Varicella zoster virus. Source: Blood and Marrow Transplant Clinical Trials Network Technical Manual of Procedures, Appendix 4-A. Version 3.0,  dated March 19, 2013. |                                                                       |                                                         |         |
synopsis
appendix h study design schematic

N = approximately 90 subjects randomized to achieve 80 treated Subjects must have an available 8/8 HLA-A, -B, -C, and -DRB1-matched unrelated mPB donor.  
Eligible subjects will be randomly assigned in a 1:1 ratio to receive either unmanipulated mPB cells (control arm) or ProTmune *ex vivo* programmed mPB cells (experimental arm) and will be stratified by CMV status.  
Screening and Subject Conditioning Screening Period: Day -53 to Day -11 (up to 6 weeks prior to the Subject Conditioning Period)
Subject Conditioning Period: Day -10 to Day -1 The conditioning regimen will be administered as required per the protocol.  
Conditioning Regimen:
- The conditioning regimen will include preparative regimens of fludarabine and busulfan (FluBu4);
busulfan and cyclophosphamide; cyclophosphamide and TBI; TBI and etoposide; fludarabine and melphalan (FluMel 140)  
  
 GvHD Prophylaxis Regimen:
- Methotrexate (15 mg/m2 on Day +1 after hematopoietic cell infusion and 10 mg/m2 on Days +3,
+6, and +11), and
- Tacrolimus (0.02 mg/kg every 24 hours as an IV infusion or 0.03 mg/kg orally beginning on Day
-2, adjusted to target dose level of 5 to 15 ng/mL. Taper starting at Day +100).  
Hospital Admission: Per Institutional Policy Study Treatment Administration: Day 0 (Day of HCT)  
  
One unit of unmanipulated mPB cells as the cell source for the HCT procedure  
| Post-Transplant Follow-Up: after HCT up through  Day +730 Comprised of post-transplant assessments and  post-transplant weekly visits through Day +100,  intermittent visits through Day +365 and a  telephone call on Day +730.   |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
Study Treatment Administration: Day 0 (Day of HCT)  
  
  
  
  
  
  
One unit of ProTmune *ex vivo* programmed mPB cells as the cell source for the HCT procedure  
| Post-Transplant Follow-Up: after HCT up through Day +730 Comprised of post-transplant assessments and  post-transplant weekly visits through Day +100,  intermittent visits through Day +365 and a  telephone call on Day +730.   |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
  
  
CIBMTR = Center for International Blood and Marrow Transplant Research; GvHD = Graft-versus-host disease; HLA = Human Leukocyte Antigen; HCT = Hematopoietic cell transplant; IV = Intravenous; mPB = Mobilized peripheral blood; TBI = Total body irradiation