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5. 2.2.1. 3 sa m

Barc o d e d s a m ples are st ore d i n b arc o d e d b o x es i n a l o c k e d fre e z er at eit h er 2 0 or 8 0 C  
a c c or di n g t o sta bilit y re q uire m e nts. T h es e fre ez ers are l o c ate d o ns ite i n t h e B P C a n d off site at N CI  
Fre d eric k Ce ntral Re p osit or y Ser vic es i n Fre d eric k, M D. Visit ors t o t h e la b orat or y are re q uire d to b e a c c o m p a nie d b y la b orat or y staff at all ti m es. Access to stored clinical samples is restricted. Samples will be stored until requested by a researcher named on the protocol. All requests are monitored and tracked in LABrador. All researchers are required to sign a form stating that the samples are only to be used for research purposes associated with this trial (as per the IRB-approved protocol) and that any unused samples must be returned to the BPC. It is the responsibility of the NCI Principal Investigator to ensure that the samples requested are being used in a manner consistent with IRB approval. Following completion of this study, samples will remain in storage as detailed above. Access to these samples will only be granted following IRB approval of an additional protocol, granting the rights to use the material. If, at any time, a patient withdraws from the study and does not wish for their existing samples to be utilized, the individual must provide a written request. Following receipt of this request, the samples will be destroyed.
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5.2.3 sample storage tracking and

Samples received by the Surgery Branch research lab will be tracked using password protected web-based NCI database Lab matrix. All specimens will be tracked for date of receipt in the Surgery Branch lab, date analyzed, date returned to the originating hospital and/or date destroyed. Specimens will be stored in a locked laboratory cabinet or refrigerators in a locked research lab. All specimens will be entered into Lab matrix with identification and storage location. Access to the stored specimens will be restricted. Access to Lab matrix will be granted upon PI approval only. It is the responsibility of the NCI PI to ensure that the specimens are being used and stored in a manner consistent with IRB approval. All samples are stored in monitored freezers/refrigerators in 3NW NCI-SB laboratories at specified temperatures with alarm systems in place.
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5.2.4 protocol completion/sample destruction all

If the patient withdraws consent, the participant's data will be excluded from future distributions, but data that have already been distributed for approved research use will not be able to be retrieved. The PI will record any loss or unanticipated destruction of samples as a deviation. Reports will be made per the requirements of section 7.2.
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6 data collection and evaluation

The PI will be responsible for overseeing entry of data into an in-house password protected electronic system, C3D and ensuring data accuracy, consistency and timeliness. The principal investigator, associate investigators/research nurses and/or a contracted data manager will assist with the data management efforts. All data obtained during the conduct of the protocol will be kept in secure network drives or in approved alternative sites that comply with NIH security standards. Primary and final analyzed data will have identifiers so that research data can be attributed to an individual human subject participant. All ongoing AEs, including clinically significant abnormal findings on laboratory evaluations, regardless of severity, will be followed until return to baseline or stabilization of event. Document AEs from the first study intervention, Study Day 1, through the end of treatment. Beyond 30 days after the last intervention, only adverse events which are serious and related to the study intervention need to be recorded. An abnormal laboratory value will be considered an AE if the laboratory abnormality is characterized by any of the following:
End of study procedures: Data will be stored according to HHS, FDA regulations and NIH
Intramural Records Retention Schedule as applicable.  
Loss or destruction of data: Should we become aware that a major breach in our plan to protect subject confidentiality and trial data has occurred, this will be reported expeditiously per requirements in section **7.2.1**.
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6.1.1 adverse event recording

- Grade 1 adverse events will not be recorded.  
- Grade 2 adverse events that will be recorded:
a. Adverse events regardless of attribution will be recorded for the first year after the infusion.  
b. Unexpected events that are possibly, probably, or definitely related to the research will be recorded after the first year.  
- All grade 3, 4, and 5 adverse events will be recorded regardless of attribution. - All serious events regardless of attribution
- Results in discontinuation from the study - Is associated with clinical signs or symptoms - Requires treatment or any other therapeutic intervention - Is associated with death or another serious adverse event, including hospitalization. - Is judged by the Investigator to be of significant clinical impact - If any abnormal laboratory result is considered clinically significant, the investigator will provide details about the action taken with respect to the test drug and about the patient's outcome.
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6.2 data sharing plans 6.2.1

I will share human data generated in this research for future research as follows: x__ Coded, linked data in an NIH-funded or approved public repository.  
_x__ Coded, linked data in BTRIS (automatic for activities in the Clinical Center)
_x__ Coded, linked or identified data with approved outside collaborators under appropriate agreements.
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how and where will the

Data will be shared through: x__ An NIH-funded or approved public repository. Insert name or names: ClinicalTrials.gov.  
_x__ BTRIS (automatic for activities in the Clinical Center) _x__ Approved outside collaborators under appropriate individual agreements. _x__ Publication and/or public presentations.
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when will the data be

_x__ Before publication.  
_x__ At the time of publication or shortly thereafter.  
6.3 **GENOMIC DATA SHARING PLAN**
Genomic data will not be generated.
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6.4 response criteria

Responses will be categorized by using the International Uniform Response Criteria for Multiple myeloma 2016 updated version.(155) Multiple myeloma staging will be conducted at the 2 week follow-up appointment and at each subsequent follow-up appointment. The appropriate staging studies will need to be determined for each patient because of the variability in multiple myeloma.
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6.4.1 important considerations on response

- Response criteria for all categories and subcategories of response except CR and sCR are applicable only to patients who have 'measurable' disease by at least one of the three measurements as defined below
- All responses must be confirmed to be stable in two evaluations made at any time.  
6.4.1.1 Definition of measurable disease(24)
Any one or combination of these abnormalities defines measurable disease:  
- Serum M-protein greater or equal to 0.6 g/dL (6 g/L). - Urine M-protein greater or equal to 200 mg/24 h.  
- Serum FLC assay: involved FLC level greater or equal to10 mg/dL (100 mg/L) provided serum FLC ratio is abnormal.  
- Presence of a biopsy-proven plasmacytoma 6.4.1.2 Laboratory tests for measurement of M-protein
- Serum M-protein level is quantitated using densitometry on SPEP except in cases where the SPEP is felt to be unreliable such as in patients with IgA monoclonal proteins migrating in the beta region. If SPEP is not available or felt to be unreliable (e.g., in some cases of IgA myeloma) for routine M-protein quantitation during therapy, then quantitative immunoglobulin levels on nephelometry or urbidometry can be accepted. However, this must be explicitly reported, and only nephelometry can be used for that patient to assess response and SPEP and nephelometric values cannot be used interchangeably.  
- Urine M-protein measurement is estimated using 24-h UPEP only. (Random or 24 h urine tests measuring kappa and lambda light chain levels are not reliable and are not recommended)
6.4.1.3 Suggested follow-up to meet response criteria
- Patients with measurable disease by both SPEP and UPEP need to be followed by both SPEP and UPEP for response assessment and categorization;
- Except for assessment of sCR, CR, and VGPR, patients with "measurable disease" restricted to the SPEP will need to be followed routinely only by SPEP;
- Patients with "measurable disease" restricted to the UPEP will need to be followed routinely only by UPEP;
- Patients with "measurable disease" in either SPEP or UPEP or both will be assessed for response only based on these two tests and not by the FLC assay;
- FLC response criteria are only applicable to patients without measurable disease in the serum or urine, and to fulfill the requirements of the category of sCR;
- Bone marrow is required only for categorization of CR - For good clinical practice patients should be periodically screened for light chain escape with UPEP or serum FLC assay.  
- Plasmacytomas can be staged at baseline and followed for response with CT scans or MRI
scans by measuring target lesions with the sums of the products of the diameters method. For purposes of defining CR, masses greater than 1.5 cm will be considered abnormal.
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6.4.2 international myeloma working group

6.4.2.1 Stringent Complete Remission (sCR)  
- CR as defined below plus o Normal FLC ratio and o Absence of clonal cells in bone marrow by immunohistochemistry or immunofluorescence or flow cytometry (only1 bone marrow evaluation is needed).  
6.4.2.2 Complete Remission (CR)
- Negative immunofixation on the serum and urine and
- Disappearance of any soft tissue plasmacytomas and
- 5% or less plasma cells in bone marrow (only 1 bone marrow evaluation is needed) - No evidence of progressive or new bone lesions if radiographic studies were performed
- **Both** serum and urine immunofixation must be carried out and be negative regardless of the size of baseline M-protein in the serum or urine;
- Patients with negative UPEP values pretreatment still require UPEP testing to confirm CR
and exclude light chain or Bence–Jones escape 6.4.2.3 Very Good Partial Remission (VGPR)
- Serum and urine M-protein detectable by immunofixation but not on electrophoresis or
- 90% or greater reduction in serum M-protein **plus** urine M-protein level <100mg per 24 h
- No evidence of progressive or new bone lesions if radiographic studies were performed
(X-Rays not required in absence of clinical indication)
- 90% decrease in the sum of the products of the diameters of soft tissue plasmacytomas is required.  
6.4.2.4 Partial Remission (PR)
- 50% or greater reduction of serum M-protein and
- 90% or greater reduction in 24-h urinary M-protein (or to less than 200mg per 24 h) and
- 50% or greater reduction in the size of soft tissue plasmacytomas, if present at baseline - No evidence of progressive or new bone lesions if radiographic studies were performed
(X-Rays not required in absence of clinical indication)
Only if the serum and urine M-protein are not measurable (as per definition in section 6.4.1.1),
- 50% or greater decrease in the difference between involved and uninvolved FLC levels is required (in lieu of the serum and urine M-protein criteria).  
- If serum and urine M-protein are not measurable and serum FLC assay is also not measurable, 50% or greater reduction in plasma cells is required in lieu of M-protein evaluation (provided baseline bone marrow plasma cell percentage was 30% or greater)
6.4.2.6 Stable Disease (SD)
(X-Rays not required in absence of clinical indication) Comments: To be considered a CR,
- Not meeting criteria for CR, VGPR, PR or progressive disease
(Not recommended for use as an indicator of response; stability of disease is best described by providing the time to progression estimates)  
- All response categories require two consecutive assessments made at any **time** before the institution of any new therapy;
- Confirmation with repeat bone marrow biopsy not needed. - Presence/absence of clonal cells is based upon the κ/λ ratio. An abnormal κ/λ ratio by immunohistochemistry and/or immunofluorescence requires a minimum of 100 plasma cells for analysis. An abnormal ratio reflecting presence of an abnormal clone is κ/λ ration of greater than 4:1 or less than 1:2.  
6.4.2.7 Progressive Disease (PD)a
Requires one or more of the following:
- Increases of greater or equal to 25% from the lowest post-treatment (nadir) value in  
o Serum M-component (minimum absolute increase of 0.5g/dL) or o Urine M-component (minimum absolute increase of 200mg/24h) or o Only in patients without measurable M-protein, percentage of bone marrow plasma cells (minimum absolute percentage of 10%)
o Only in patients without measurable serum and urine M-protein levels: The difference between involved and uninvolved FLC levels. The absolute increase must be >10 mg/dL. The FLC ratio must be abnormal.  
- Definite development of new bone lesions or clear increase in size of one or more bone lesion(s) (must be 50% or greater increase of a lesion at least 1 cm in longest length at nadir) on CT scan or new lesion 1.5 cm or larger on CT scan.  
- 50% or more increase in the sum of the products of the diameters of multiple soft tissue plasmacytomas or 50% or more increase in the size of a single soft tissue plasmacytoma.
- Development of hypercalcemia solely attributable to the disease (corrected serum calcium >11.5 mg/dL)
aAll relapse categories require 2 consecutive assessments made at any time before classification as relapse or progression or institution of a new therapy.
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6.4.3 minimal residual disease (mrd)

Flow MRD-negative-Absence of aberrant clonal plasma cells in the bone marrow by flow cytometry using EuroFlow standard operating procedures or equivalent(which includes NCI
Dept. of Pathology multicolor flow); must have sensitivity of one in 105 nucleated cells.  
Sequencing MRD-negative-absence of clonal plasma cells by next generation sequencingon bone marrow aspirate with a method with sensitivity of 1 in 105 nucleated cells.  
Imaging plus MRD-negative-MRD negativity as defined by NGF or NGS plus disappearance of every area of increased tracer uptake found at baseline or a preceding PET/CT or decrease to less than mediastinal blood pool SUV or decrease to less than that of surrounding normal tissue.
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6.5 toxicity criteria

The following adverse event management guidelines are intended to ensure the safety of each patient while on the study. The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for AE reporting. All appropriate treatment areas should have access to a copy of the CTCAE version 5.0. A copy of the CTCAE version 5.0 can be downloaded from the CTEP web site (http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm).
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7 nih reporting requirements/data and

Please refer to definitions provided in Policy 801: Reporting Research Events found here.
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7.2 ohsrp office of compliance

Please refer to the reporting requirements in Policy 801: Reporting Research Events and Policy 802 Non-Compliance Human Subjects Research found here. Note: Only IND Safety Reports that meet the definition of an unanticipated problem will need to be reported per these policies.
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7.2.2 irb requirements for pi

Please refer to the reporting requirements in Policy 801: Reporting Research Events found here.
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7.3 nci clinical director reporting

Problems expeditiously reported to the OHSRP in iRIS will also be reported to the NCI Clinical Director. A separate submission is not necessary as reports in iRIS will be available to the Clinical Director. In addition to those reports, all deaths that occur within 30 days after receiving a research intervention should be reported via email to the Clinical Director unless they are due to progressive disease. To report these deaths, please send an email describing the circumstances of the death to Dr. Dahut at NCICCRQA@mail.nih.gov within one business day of learning of the death.
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7.4 institutional biosafety committee (ibc)reporting

The Principal Investigator (or delegate) will notify IBC of any unexpected fatal or life-threatening experience associated with the use of CAR-SLAMF7 T cells as soon as possible but in no event later than 7 calendar days of initial receipt of the information. Serious adverse events that are unexpected and associated with the use of the CAR-SLAMF7 -expressing T cells, but are not fatal or life-threatening, must be reported to the NIH IBC as soon as possible, but not later than 15 calendar days after the investigator's initial receipt of the information. Adverse events may be reported by using the FDA Form 3500a.
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7.4.2 annual reports to ibc

Within 60 days after the one-year anniversary of the date on which the IBC approved the initial protocol, and after each subsequent anniversary until the trial is completed, the Principal Investigator (or delegate) shall submit the information described below. Alternatively, the IRB continuing review report can be sent to IBC in lieu of a separate report. Please include the IBC protocol number on the report. 7.4.2.1 Clinical Trial Information A brief summary of the status of the trial in progress or completed during the previous year. The summary is required to include the following information:
- the title and purpose of the trial  
- clinical site
- the Principal Investigator - clinical protocol identifiers participant population (such as disease indication and general age group, e.g., adult or pediatric);
- the total number of participants planned for inclusion in the trial; the number entered into the trial to date whose participation in the trial was completed; and the number who dropped out of the trial with a brief description of the reasons
- the status of the trial, e.g., open to accrual of subjects, closed but data collection ongoing, or fully completed,
- if the trial has been completed, a brief description of any study results.  
7.4.2.2 Progress Report and Data Analysis
Information obtained during the previous year's clinical and non-clinical investigations, including:  
- a narrative or tabular summary showing the most frequent and most serious adverse experiences by body system
- a summary of all serious adverse events submitted during the past year - a summary of serious adverse events that were expected or considered to have causes not associated with the use of the gene transfer product such as disease progression or concurrent medications
- if any deaths have occurred, the number of participants who died during participation in the investigation and causes of death
- a brief description of any information obtained that is pertinent to an understanding of the gene transfer product's actions, including, for example, information about dose-response, information from controlled trials, and information about bioavailability.
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7.5 nih required data and

The clinical research team will meet on a regular weekly basis when patients are being actively treated on the trial to discuss each patient. Decisions about dose level enrollment and dose escalation if applicable will be made based on the toxicity data from prior patients. All data will be collected in a timely manner and reviewed by the principal investigator. Events meeting requirements for expedited reporting as described in section **7.2.1**will be submitted within the appropriate timelines.  
The principal investigator will review adverse event and response data on each patient to ensure safety and data accuracy. The principal investigator will personally conduct or supervise the investigation and provide appropriate delegation of responsibilities to other members of the research staff.
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7.5.2 safety monitoring committee (smc)

This protocol will require oversight from the Safety Monitoring Committee (SMC). Initial review will occur as soon as possible after the annual NIH Intramural IRB continuing review date. Subsequently, each protocol will be reviewed as close to annually as the quarterly meeting schedule permits or more frequently as may be required by the SMC. For initial and subsequent reviews, protocols will not be reviewed if there is no accrual within the review period. Written outcome letters will be generated in response to the monitoring activities and submitted to the Principal investigator and Clinical Director or Deputy Clinical Director, CCR, NCI.
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8 sponsor safety reporting 8.1

Any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An adverse event (AE) can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product (ICH E6 (R2))
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8.1.2 serious adverse event (sae)

An adverse event or suspected adverse reaction is considered serious if in the view of the investigator or the sponsor, it results in any of the following:
- Death,  
- A life-threatening adverse event (see 8.1.3) - Inpatient hospitalization or prolongation of existing hospitalization o A hospitalization/admission that is pre-planned (i.e., elective or scheduled surgery arranged prior to the start of the study), a planned hospitalization for pre-existing
condition, or a procedure required by the protocol, without a serious deterioration in health, is not considered a serious adverse event.  
o A hospitalization/admission that is solely driven by non-medical reasons (e.g.,
hospitalization for patient convenience) is not considered a serious adverse event.  
o Emergency room visits or stays in observation units that do not result in admission to the hospital would not be considered a serious adverse event. The reason for seeking medical care should be evaluated for meeting one of the other serious criteria.  
- Persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions
- A congenital anomaly/birth defect. - Important medical events that may not result in death, be life-threatening, or require hospitalization may be considered a serious adverse drug experience when, based upon appropriate medical judgment, they may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition.
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8.1.3 life-threatening

An adverse event or suspected adverse reaction is considered "life-threatening" if, in the view of either the investigator or sponsor, its occurrence places the patient or subject at immediate risk of death. It does not include an adverse event or suspected adverse reaction that, had it occurred in a more severe form, might have caused death. (21CFR312.32)
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8.1.4 severity

The severity of each Adverse Event will be assessed utilizing the CTCAE version 5.0.
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8.1.5 relationship to study product

All AEs will have their relationship to study product assessed using the terms: related or not related.  
- Related - There is a reasonable possibility that the study product caused the adverse event.  
Reasonable possibility means that there is evidence to suggest a causal relationship between the study product and the adverse event.  
- Not Related - There is not a reasonable possibility that the administration of the study product caused the event.
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8.2 assessment of safety events

AE information collected will include event description, date of onset, assessment of severity and relationship to study product and alternate etiology (if not related to study product), date of resolution of the event, seriousness and outcome. The assessment of severity and relationship to the study product will be done only by those with the training and authority to make a diagnosis and listed on the Form FDA 1572 as the site principal investigator or sub-investigator. AEs occurring during the collection and reporting period will be documented appropriately regardless of relationship. AEs will be followed through resolution. SAEs will be:  
- Assessed for severity and relationship to study product and alternate etiology (if not related to study product) by a licensed study physician listed on the Form FDA 1572 as the site principal investigator or sub-investigator.  
- Recorded on the appropriate SAE report form, the medical record and captured in the clinical database.  
- Followed through resolution by a licensed study physician listed on the Form FDA 1572 as the site principal investigator or sub-investigator.
For timeframe of recording adverse events, please refer to section **6.1.** All serious adverse events recorded from the time of first investigational product administration must be reported to the sponsor.
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8.3 reporting of serious adverse

Any AE that meets a protocol-defined serious criterion or meets the definition of Adverse Event of Special Interest that require expedited reporting must be submitted immediately (within 24 hours of awareness) to OSRO Safety using the CCR SAE report form. All SAE reporting must include the elements described in section 8.2. SAE reports will be submitted to the Center for Cancer Research (CCR) at: OSROSafety@mail.nih.gov and to the CCR PI and study coordinator. CCR SAE report form and instructions can be found at: https://ccrod.cancer.gov/confluence/pages/viewpage.action?pageId=157942842 Following the assessment of the SAE by OSRO, other supporting documentation of the event may be requested by the OSRO Safety and should be provided as soon as possible.
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8.4 safety reporting criteria to

All events listed below must be reported in the defined timelines to CCRsafety@mail.nih.gov. The CCR Office of Regulatory Affairs will send all reports to the manufacturer as described below.  
Rimiducid is provided under NCI CTA\# 01096-18 with Bellicum Pharmaceuticals Inc. Data sharing with Bellicum Pharmaceuticals Inc. must be carried out as follows:  
- An annual report of all patients receiving Rimiducid. This report will consist of a brief summary of each patient's Grade 2 or greater adverse events and multiple myeloma responses after the date of Rimiducid administration (report to Paul Woodard, MD of Bellicum, Inc. at pwoodard@bellicum.com).  
- Communications with the FDA related to Rimiducid must be shared within 10 calendar days. Report to this email address: BellicumSafety@pharmalex.com. Also send to Paul Woodard, MD of Bellicum, Inc. at pwoodard@bellicum.com.  
- Pregnancies must be reported to BellicumSafety@pharmalex.com. Also send a copy to Paul Woodard, MD of Bellicum, Inc. at pwoodard@bellicum.com.
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8.4.2 reporting by study team

- SAEs possibly or definitely related to Rimiducid must be reported within 24 hours of the sponsor becoming aware of the SAE. Study team will report to this email address: BellicumSafety@pharmalex.com. Back-up reporting is to this phone number: 1-617315-4825. Also, report to Paul Woodard, MD of Bellicum, Inc. at pwoodard@bellicum.com.  
- Any use of Rimiducid must be reported within 3 calendar days and must include the following (report to Paul Woodard, MD of Bellicum, Inc. at pwoodard@bellicum.com.) by Principal Investigator:
o Patient age, sex, malignancy, brief history including indication for Rimiducid o Dose of CAR T cells received by the patient and percentage of infused cells expressing the CAR
o Blood CAR T-cell levels before and after Rimiducid administration (may take longer than 3 days to obtain these results).  
o Blood cytokine levels before and after Rimiducid administration (may take longer than 3 days to obtain these results).  
o Timing and nature of Grade 2 or greater AEs within the first 3 days after Rimiducid administration.
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8.5 reporting pregnancy 8.5.1 maternal

If a patient becomes pregnant during the study, the study treatment should be discontinued immediately, and the pregnancy reported to the Sponsor no later than 24 hours of when the Investigator becomes aware of it. The Investigator should notify the Sponsor no later than 24 hours of when the outcome of the Pregnancy become known, Pregnancy itself is not regarded as an SAE. However, congenital abnormalities or birth defects and spontaneous miscarriages that meet serious criteria (section 8.1.2) should be reported as SAEs. The outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, or congenital abnormality) should be followed up and documented.
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8.5.2 paternal exposure

Male patients should refrain from fathering a child or donating sperm during the study and for 4 months after the last dose of receiving protocol treatment. Pregnancy of the patient's partner is not considered to be an AE. However, the outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, or congenital abnormality) occurring from the date of the first dose until (*120 days)* after the last dose should, if possible, be followed up and documented.
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8.6 regulatory reporting for studies

Following notification from the investigator, CCR, the IND sponsor, will report any suspected adverse reaction that is both serious and unexpected in expedited manner to the FDA in accordance to 21 CFR 312.32. CCR will report an AE as a suspected adverse reaction only if there is evidence to suggest a causal relationship between the study product and the adverse event. CCR will notify FDA and all participating investigators (i.e., all investigators to whom the sponsor is providing drug under its INDs or under any investigator's IND) in an IND safety report of potential serious risks from clinical trials or any other source, as soon as possible, in accordance to 21 CFR Part 312.32. All serious events will be reported to the FDA at least annually in a summary format.
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9 clinical monitoring

As a sponsor for clinical trials, FDA regulations require the CCR to maintain a monitoring program. The CCR's program allows for confirmation of: study data, specifically data that could affect the interpretation of primary and secondary study endpoints; adherence to the protocol, regulations, ICH E6, and SOPs; and human subjects protection. This is done through independent verification of study data with source documentation focusing on:  
- Informed consent process - Eligibility confirmation - Drug administration and accountability
- Adverse events monitoring
- Response assessment.
The monitoring program also extends to multi-site research when the CCR is the coordinating center.  
This trial will be monitored by personnel employed by a CCR contractor. Monitors are qualified by training and experience to monitor the progress of clinical trials. Personnel monitoring this study will not be affiliated in any way with the trial conduct.
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10 statistical considerations 10.1 statistical

The primary endpoint of this trial is to determine the safety of administering CAR-expressing T cells to patients with multiple myeloma. The primary approach for assessing this endpoint will be through a dose escalation. Exploratory objectives of this trial are to measure any anti-malignancy effect that might occur, to assess the feasibility of administering CAR-expressing T cells, and to measure persistence, function, and gene expression of CAR-expressing T cells. In addition, the efficacy of Rimiducid at inducing apoptosis of the SLAMF7 expressing CAR T cells and mitigating toxicity including severe infections will be assessed.
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10.2 sample size determination

The sample size of this clinical trial will be determined by the requirements of the dose-escalation scheme. A maximum of 24 treated patients will be needed to complete the dose escalation scheme, and an additional 12-patient expansion group will be treated at the MTD. The 12-patient expansion group to better characterize the MTD is needed because of the substantial variability between patients receiving infusions of CAR T cells. The total number of treated patients will be a maximum of 36. The trial uses a dose-escalation design, with 4 dose levels and a -1 dose level if needed. The number of CAR+ T cells transferred for each dose level is as follows: Dose level -1 0.3x106 CAR+ T cells per kg of recipient bodyweight  
Dose level 1 0.66x106 CAR+ T cells per kg of recipient bodyweight Dose level 2 2.0x106 CAR+ T cells per kg of recipient bodyweight Dose level 3 6.0x106 CAR+ T cells per kg of recipient bodyweight Dose level 4 12.0x106 CAR+ T cells per kg of recipient bodyweight
If sufficient cells cannot be grown to meet the criteria for the assigned dose level, the patient will receive the dose of cells called for by one dose level lower than the assigned dose level. If sufficient cells cannot be grown to meet the dose requirement called for one dose level lower than the assigned dose level, the treatment will be aborted. If a DLT occurs in an additional patient entered at a lower dose due to cell growth limitations, accrual will continue at this level as described in the dose-escalation scheme in section 3.1.4. Accrual will be halted at the higher level until accrual at the lower level is complete as described above. Should none of the first 3 patients treated on a dose level experience a DLT, the first patient can be infused on the next higher dose level after a 28-day delay following CAR T-cell infusion of the third patient. Should 1 of 3 patients experience a DLTat a particular dose level, three more patients would be treated at that dose level. If 1/6 patients have a DLT at a particular dose level, the first patient can be infused on the next higher dose level after a 28-day delay following CAR T-cell infusion of the 6th patient.If a level with 2 or more DLTs in 3-6 patients has been identified, 3 additional patients will be accrued at the next-lowest dose for a total of 6, in order to further characterize the safety of the MTD. The MTD is the dose at which a maximum of 1 of 6 patients has a DLT. After a MTD is defined, additional patients can be treated on this trial: up to 12 total additional recipients can be treated after a MTD is established in order to better define safety and toxicity at that dose level. If cell growth limitations preclude administration of the maximum tolerated dose to a patient in the expansion group, the patient will receive as many cells as possible up to the MTD. DLTs that occur in patients receiving a repeat treatment will not affect the dose escalation because no retreatments will be allowed until the optimal CAR T-cell dose is established. Use of Rimiducid will be recorded and used in descriptive statistics.
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10.3 populations for analyses

Toxicity Analysis:All patients will be evaluable for toxicity from the time of Anti-SLAMF7-CAR T cell infusion. Toxicity data will be collected for all patients. Response Analysis - Intention to treat: any subjects who enroll onto the trial and provide consent and who receive at least one cycle of treatment will be included in analyses dataset.
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10.4 statistical analyses 10.4.1 general

This is a standard 3+3 dose escalation study. Toxicity data will be obtained and used to determine the MTD of the treatment.
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10.4.2 analysis of the primary

The toxicity obtained on each patient will be determined and used to report the number of patients at each dose level who experience a DLT, following standard phase I procedures.
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10.4.4 safety analyses

The study will determine the toxicity experienced on each patient enrolled on the trial and report this by dose level.
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10.4.5 baseline descriptive statistics

None will be provided in a formal manner; brief descriptions may be incorporated in a final report.
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10.4.6 planned interim analyses

Toxicity will be evaluated at each dose level as the patients accrue to the trial. Stopping criteria are described in section 3.8.
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10.4.9 exploratory analyses

The degree of persistence of CAR-transduced T cells will be evaluated by a quantitative measure (flow cytometry and/or quantitative PCR) in all patients. Serum cytokine levels are other important exploratory assessments. Anti-malignancy effects will be measured by clinical response and categorized according to the International Uniform Response Criteria for Multiple Myeloma (Section 6.4). The clinical multiple myeloma responses will be interpreted cautiously in the context of a pilot study which may be used to guide parameters for study in future protocols if warranted. Efficacy of Rimiducid will be assessed by resolution of clinical toxicity and by evaluating elimination of CAR+ T cells by monitoring blood CAR T-cell levels by qPCR and/or flow cytometry. All other evaluations of exploratory objectives will be performed using exploratory techniques. No formal adjustment for multiple comparisons will be used since the evaluations are being done to generate hypotheses. Exploratory assessments will include analysis for associations between clinical outcomes such as severity of toxicity and serum cytokine levels or severity of toxicity and blood CAR T-cell levels. Parametric and nonparametric tests will be used as appropriate.
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11 collaborative agreements 11.1 clinical

Rimiducid is provided under a Clinical Trial Agreement (CTA) NCI CTA\# 01096-18 with Bellicum Pharmaceuticals Inc.
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12 human subjects protections 12.1

- The patients to be entered in this protocol have multiple myeloma which is an almost always incurable disease; moreover, patients will have progressive or relapsed myeloma despite at least 3 prior therapies. These patients have limited life expectancies. Subjects from both sexes and all racial/ethnic groups are eligible for this study if they meet the eligibility criteria. To date, there is no information that suggests that differences in disease response would be expected in one group compared to another. Efforts will be made to extend accrual to a representative population, but in this preliminary study, a balance must be struck between patient safety considerations and limitations on the number of individuals exposed to potentially toxic and/or ineffective treatments on the one hand and the need to explore gender and ethnic aspects of clinical research on the other hand. If differences in outcome that correlate to gender or to ethnic identity are noted, accrual may be expanded, or a follow-up study may be written to investigate those differences more fully.  
- MM remains an incurable disease despite recent advances in therapy. - Over the last 40 years and throughout the most recent era of improved therapy with novel agents, the depth of the disease response to therapy (including T- cells targeting B-cell maturation antigen) has remained the single most predictive factor for event free and overall survival in MM
- Therefore, improving the rate and depth of responses remains a high priority for clinical research in MM.  
- This justifies the enrollment of all subjects with MM eligible for T- cells targeting B-cell maturation antigen in this phase I/II study in an attempt to improve the clinical outcome while feasibility and safety are being evaluated.  
- The upper age limit of this protocol will be 73 years of age. CAR T-cell therapies often result in patients being admitted to intensive care units due to cytokine-release syndrome. These critically ill patients often need vasopressor drugs and occasionally need mechanical
ventilation among other intensive care interventions. The mortality of critically-ill patients progressively increases with age above 20 years as shown in the Acute Physiology and Chronic Health Evaluation (APACHE) IV: Hospital mortality assessment for today's critically ill patients.(156) Because mortality of critically-ill patients reaches >10% at age 70 (Table 6 of the cited paper). Because CAR toxicity is very unpredictable and based on my extensive past experience treating patient with CAR T cells on phase I clinical trials, I choose to not enroll patients over the age of 73.
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12.2 participation of children

Children will not be enrolled on this study. Multiple myeloma is extremely uncommon in children; moreover, since the efficacy of this experimental procedure is unknown, it does not seem reasonable to expose children to this risk without further evidence of benefit.
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12.3 participation of subjects unable

Adults unable to give consent are excluded from enrolling in the protocol. However, re-consent may be necessary and there is a possibility, though unlikely, that subjects could become decisionally impaired. For this reason and because there is a prospect of direct benefit from research participation (section 10.4 ), all subjects will be offered the opportunity to fill in their wishes for research and care, and assign a substitute decision maker on the "NIH Advance Directive for Health Care and Medical Research Participation" form so that another person can make decisions about their medical care in the event that they become incapacitated or cognitively impaired during the course of the study. Note: The PI or AI will contact the NIH Ability to Consent Assessment Team (ACAT) for evaluation as needed for the following: an independent assessment of whether an individual has the capacity to provide consent; assistance in identifying and assessing an appropriate surrogate when indicated; and/or an assessment of the capacity to appoint a surrogate. For those subjects that become incapacitated and do not have pre-determined substitute decision maker, the procedures described in NIH HRPP SOP 14E for appointing a surrogate decision maker for adult subjects who are (a) decisionally impaired, and (b) who do not have a legal guardian or durable power of attorney, will be followed.
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12.4 evaluation of benefits and

The experimental treatment has a chance to provide clinical benefit though this is unknown. A goal of this study is to improve upon the number of patients who may benefit from adoptive cell therapy by using genetically modified T-cells. This clinical trial is being performed to evaluate a genetically-modified T-cell therapy for multiple myeloma, which is an almost always incurable disease.(21) Only patients with multiple myeloma who have persisting or relapsed myeloma despite at least 3 prior lines of therapy will be enrolled. The risks of the study fall into six categories. The first category is chemotherapy-related toxicity that could cause cytopenias. As with any chemotherapy that causes neutropenia and thrombocytopenia, this chemotherapy could cause toxicities such as infections and bleeding. The second category of toxicity is cytokine-release-type toxicities such as high fevers, tachycardia, transient abnormalities of liver function and hypotension. These cytokine-release-type toxicities have been detected in other clinical trials of CAR T cells during the first two weeks after antiCD19 CAR T cells and anti-BCMA CAR T cells were infused.(4, 5, 134)
A third category of potential toxicities are neurological toxicities such as delirium, obtundation, myoclonus, seizures, headache and transient focal neurological toxicities including aphasia and focal paresis. In previous anti-CD19 CAR trials, cytokine-release toxicities and neurological toxicities have been limited in duration with toxicities generally resolving within 2 days to 3 weeks.(5, 41, 74, 135, 136) In the NCI anti-BCMA trial, neurologic toxicities were limited to confusion or delirium in the setting of high fevers and one case of encephalopathy and muscle weakness of all extremities consistent with critical illness polyneuropathy/polymyopathy.(5) In most cases, these toxicities have been transient with toxicities generally resolving within 2 days to 2 weeks.  
The fourth category of toxicity is direct damage to normal tissues by the CAR T cells. This could happen because of unexpected cross-reactivity of the anti-SLAMF7 CAR with proteins other than SLAMF7 in vivo. This trial will be one of the first in human trials testing anti-SLAMF7 CAR T cells in patients with multiple myeloma who have failed at least three previous lines of therapy. Although SLAMF7 is highly expressed in almost all cases of MM it has very limited or absent expression on normal tissues aside from leukocytes.(9, 10, 110, 112, 113) Hematopoietic stem cells do not express SLAMF7.(111) SLAMF7 is not expressed on the surface of normal organ epithelial tissue such as lung, kidney, stomach, brain, breast, spleen, prostate, skeletal muscle, testis, liver, ovary, heart, thymus and small intestine epithelial tissue.(9) We have performed extensive testing of the MSGV-iCasp9-Luc90CD828Z CAR T cells by culturing them with a variety of human cell lines and have not seen recognition of cell lines that did not express SLAMF7. In addition, we did not find any evidence of cross-reactivity in our cell line data or immunohistochemistry data from the NIH Department of Pathology. A fifth category of toxicity that may be caused by anti-SLAMF7 CAR T cells is impairment of normal immunity because SLAMF7 is expressed on leukocytes such as CD8+ T cells, natural killer
(NK) cells, B cells, plasma cells, some monocytes, NKT cells, and some dendritic cells.(5, 9, 10, 110, 112, 113) NK cell deficiencies are associated with severe, potentially life-threatening viral infections caused typically by benign members of the Herpesviridae (VZV, HSV, CMV, EBV)
and Papillomaviridae (HPV) families.(137) Additionally, NK cells have potent cytotoxic activity against malignant cells and NK cell defects are linked to ineffective tumor surveillance and clearance. We have included a suicide gene in this trial in large part to allow elimination of antiSLAMF7 CAR T cells in case depletion of recipient immune cells leads to infections. Greater detail about the depletion of leukocyte subsets is provided below. Finally, genotoxicity is a theoretical risk of any type of integrating gene therapy. To our knowledge, genotoxicity, such as occurrence of a replication-competent retroviruses or transformation of T cells caused by insertional mutagenesis has never occurred in a clinical trials of T-cell gene therapies.(43, 44) The specific gene therapy vector backbone, MSGV1, proposed for use in this clinical trial has been used in hundreds of patients over the past 13+ years by our group and others.(4, 33, 138, 139) The potential benefits to subjects enrolling on this trial include the possibility that the CAR T cells can cause a significant anti-myeloma effect. Many patients enrolled on trials of anti-CD19 CAR T cells and anti-BCMA CAR T cells obtained complete remissions of their advanced malignancies; there is a chance that recipients of the CAR T cells that are being evaluated in this protocol could derive a direct benefit from participation in this trial. Patients might also derive a benefit from knowing that they are contributing to the development of new cellular therapies for cancer by aiding in the development of new therapies might help future patients. Because all patients in this protocol have advanced multiple myeloma and limited life expectancies the potential benefit is thought to outweigh the potential risks. It is also anticipated that this study will provide scientific information relevant to tumor immunotherapy. The risks associated with biopsies are pain and bleeding at the biopsy site. In order to minimize pain, local anesthesia will be used. Rarely, there is a risk of infection at the sampling site.
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12.4.1 risks of exposure to

The procedures for performing the CT scans will follow clinical policies, no special procedures apply to these additional assessments for research purposes. In summary, subjects may receive additional radiation exposure from up to seven (7) CT neck +CAP, two (2) CTGuided biopsies and three (3)18FDG-PET/CT scans in the first year of the study.  
The total additional radiation dose for research purposes will be approximately 15.6 rem in the first year of the study. Being exposed to too much radiation can cause harmful side effects such as an increase in the risk of cancer. Most patients will obtain much less than the maximum levels of radiation exposure since CT scans will only be carried out in patients who have measurable plasmacytomas after baseline assessment. In addition, CT imaging will be modified based on plasmacytoma locations. For example, many patients will not receive any post-infusion neck CTs since many patients do not have baseline neck involvement with myeloma. Most activity of CAR T cells occurs in the first 3 months after infusion, so we need to assess the onset of myeloma responses carefully during this time-period. Note that our imaging practices are similar to those in the largest multicenter anti-BCMA CAR study, the bb2121 trial .(157) The radiation exposure on this study is in fact, less than what is outlined in the Raje et al. study.
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12.5 consent process and documentation

The informed consent document will be provided to the participant or consent designee(s) (e.g., the parent/guardian if participant is a minor, legally authorized representative [LAR] if participant is an adult unable to consent) for review prior to consenting. A designated study investigator will carefully explain the procedures and tests involved in this study, and the associated risks, discomforts and benefits. In order to minimize potential coercion, as much time as is needed to review the document will be given, including an opportunity to discuss it with friends, family members and/or other advisors, and to ask questions of any designated study investigator. A signed informed consent document will be obtained prior to entry onto the study. The initial consent process as well as re-consent, when required, may take place in person in a private area (e.g., clinic consult room) or remotely (e.g., via telephone or other NIH approved remote platforms) per discretion of the designated study investigator and with the agreement of the participant/consent designee(s). Permission for additional biopsies for research will be obtained from patients at the time of the biopsy procedure. The research nurse, Principal Investigator or his designee is responsible for obtaining written informed consent from the patient.
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13 pharmaceutical information

Note: The commercial drugs used in this study will not alter labelling of the FDA approved drugs and nor does the investigation involve a route of administration or dosage level in use in a patient population or other factor that significantly increases the risks (or decreases the acceptability of the risks) associated with the use of the drug product.
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13.1 retroviral vector containing the

The retroviral vector supernatant (MSGV1-IC9-Luc90CD828Z) (encoding a CAR directed against SLAMF7 with the iCasp9 suicide gene system was prepared and preserved following cGMP conditions in the University of Cincinnati Medical Center Vector Production Facility. The retroviral vector utilizes the MSGV retroviral vector backbone including the 5' LTR from the murine stem cell virus (promoter), packagingsignal including the splicing donor (SD) and splicing acceptor sites, the anti-SLAMF7 CAR protein containing a signal peptide from human CD8alpha signal sequence, a single-chain variable fragment antigen recognition domain derived from the murine Luc90 antibody, CD8-alpha (hinge and transmembrane domains), CD28 (cytoplasmic region), and CD3-zeta (cytoplasmic region), followed by the murine stem cell virus 3'LTR.  
The supernatant will be stored at –80oC or shipped on dry ice and stored in the Dept. of Transfusion Medicine, NIH or at Fisher Biosciences, Rockville, MD. Both storage facilities are equipped with around-the-clock temperature monitoring. There will be no re-use of the same unit of supernatant for different patients. Retroviral titer has been shown to be stable after immediate thawing and immediate use. Handling of the vector should follow the guidelines of Biosafety Level-2 (BSL2). The specific guidelines for Biosafety Level-2 (BSL-2) can be viewed at http://bmbl.od.nih.gov/sect3bsl2.htm
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13.1.2 source

After cells are obtained by apheresis, further cell processing to generate CAR-expressing T cells will occur in the DTM according to standard operating procedures (SOPs). Either freshlycollected cells or cryopreserved cells can be used to initiate the cell-preparation process.
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13.1.3 toxicities

Please refer to section 1.2.13.  
13.1.4 **Administration procedures:**
Please see section 3.3 3.1.4.Potential Drug Interactions There are no known drug interactions.
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13.2 commercialagents

Please refer to the US approved package insert for the full prescribing information here:
http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.DrugDetails
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13.2.1 cyclophosphamide 13.2.1.1 source

Cyclophosphamide will be purchased by the NIH Clinical Center Pharmacy Department from commercial sources and is supplied as a lyophilized powder in various vial sizes. 13.2.1.2 Administration procedures The cyclophosphamide used in this regimen will be given as Intravenous infusion over 30 minutes.
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13.2.2 fludarabine 13.2.2.1 source

Fludarabine monophosphate will be purchased by the NIH Clinical Center Pharmacy Department from commercial sources and is supplied as a white, lyophilized powder. Each vial contains 50 mg of fludarabine phosphate, 50 mg of mannitol, and sodium hydroxide to adjust pH. Fludarabine is stored at room temperature. 13.2.2.2 Administration procedures Fludarabine is administered as an IV infusion in 100 mL 0.9% sodium chloride, USP over 30 minutes.
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13.3.2 toxicity

No serious adverse events occurred during the Phase 1 study in volunteers.(122) The incidence of adverse events was very low following each treatment, with all adverse events being mild in severity. Only one adverse event was considered possibly related to AP1903. This was an episode of vasodilatation, described as "facial flushing" for 1 volunteer at the 1.0 mg/kg AP1903 level. This event occurred at 3 minutes after the start of infusion and resolved after 32 minutes' duration. All other adverse events reported during the study were considered by the investigator to be unrelated or to have improbable relationship to the study drug. These events included chest pain, flu syndrome, halitosis, headache, injection site pain, vasodilatation, increased cough, rhinitis, rash, gum hemorrhage, and ecchymosis.(122)
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13.3.3 formulation and preparation

This information is from the Rimiducid "Guidance for Investigators" from Bellicum, Inc. The Rimiducid for Injection is packaged in 3 ml Type 1 clear glass serum vials. The contents of each vial are composed of the labeled content 10 mg (2 ml) of Rimiducid drug substance dissolved in a sterile, endotoxin free, 25% Solutol HS 15/Water for Injection solution at an Rimiducid concentration of 5 mg/ml and at pH 5.0 - 7.5. Each vial is stoppered with a Teflon© coated serum stopper and a yellow flip-off seal. The primary product label (applied directly to the vial) for Rimiducid for Injection will contain the following information: product name, Rimiducid for Injection; the manufacturer's lot number; product concentration, 5 mg/ml; volume of solution available in the vial; total Rimiducid contents of the vial (10 mg); a statement, "For IV Infusion Following Dilution, contains no preservatives" and the IND notation, "Caution: New Drug-Limited by Federal Law to Investigational Use". The product will be labeled according to the requirement of each competent authority.  
Rimiducid is formulated in 25% Solutol HS 15, a non-ionic surfactant. Prior to administration, rimiducid is diluted in normal saline, which may lead to the formation of micro-micelles. Micelles of polyethoxylated pharmaceutical surfactants, such as Solutol, are known to activate complement, leading to anaphylactoid-like reactions or pseudoallergy. Such responses may be the result of the activation of mast cell and subsequent degranulation (Szebeni 2001).  
Bellicum recommends that patients are pre-medicated using standard procedures for the prevention of infusion reactions prior to administration of rimiducid. Such pre-treatment regimens would typically be administered thirty minutes to one hour prior to the infusion of rimiducid.  
Rimiducid for Injection must be warmed to room temperature prior to dilution. Drug interactions: Rimiducid is an investigational new drug and while there are no known verified drug interactions, investigators should be aware that potential unknown interactions and adverse effects may occur. It should be noted that rimiducid is an inhibitor of CYP3A4 and CYP2C8 and therefore, co-administration of rimiducid with other substrates of CYP3A4 and CYP2C8 could lead to elevated concentrations of these concomitant medications. However, a drug/drug interaction study was conducted to evaluate the potential interaction of rimiducid with substrates of CYP3A4 using the probe midazolam. This study indicated that following a single IV dose of 0.5 mg/kg or less, rimiducid is unlikely to alter the clearance of co-administered CYP3A4 substrates.  
Rimiducid was tested in normal, healthy people at doses 2.5-fold greater than those used in the clinical trials using gene modified cells (CovanceStudy No. 1711-1). A side effect noted was facial flushing (redness) in one person. Although not observed in patients to date, rimiducid was associated with modest elevations of hepatic transaminases, bilirubin and alkaline phosphatase in the acute and subacute non-human primate study. It is possible that other side effects may occur.  
In the Bellicum BP-PC-001 trial, one patient exhibited an adverse event of cytokine mediated release or hypersensitivity like reaction upon infusion of rimiducid and one patient experienced urticaria and flushing, which resolved with antihistamine administration. None of these AEs were considered serious. Rimiducid for Injection is incompatible with materials containing plasticizer or DEHP and materials sterilized with ethylene oxide. Rimiducid (AP1903) with iCasp9 Switch suspected **unexpected serious adverse reaction**
(SUSARs): Currently, no SUSARs have been reported under this program. For regulatory reporting purposes, there are currently no adverse events expected.  
The Rimiducid for Injection vials must be stored at 5°C ± 3°C (41°F ± 5°F) in a limited access, qualified refrigerator, preferably without light (but not required to protect from light). Prior to administration, the calculated dose will be diluted to 100 mL in 0.9% normal saline for infusion.(121, 122)
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13.3.4 administration procedures

For use, the Rimiducid will be diluted prior to administration. Rimiducid is administered via I.V. infusion at the target dose diluted in normal saline with volume as appropriate for age of patient to be administered over 2 hours, using a DEHP-free saline bag and solution set. Rimiducid for Injection (0.4 mg/kg) in a total volume of 100 ml of Rimiducid plus normal saline will be administered via IV infusion over 2 hours, using a non-DEHP, non-ethylene oxide sterilized infusion set and an infusion pump. For patients <50 kg or >150 kg, a volume of administration of Rimiducid different than 100 mL is allowed (121, 122)
Note: Recommendations include premedication per institutional standards (acetaminophen and antihistamine) 30 minutes prior to infusion for prevention of potential hypersensitivity to the Solutol HS 15 or rimiducid. Dose reduction for renal impairment: Rimiducid is thought to be cleared by non-renal means. Dose adjustments for hepatic or renal insufficiency have not been established.
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14 references

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15 appendices 15.1 appendix aperformance

| Grade                                                                                                                                                                             | Descriptions                                                                                                         |                                                |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------|------------------------------------------------|
| 0                                                                                                                                                                                 | Normal activity.                                                                                                     | Fully active, able to carry on all pre-disease |
| performance without restriction. Symptoms, but ambulatory. Restricted in physically strenuous activity,  but ambulatory and able to carry out work of a light or sedentary nature |                                                                                                                      |                                                |
| 1                                                                                                                                                                                 | (e.g., light housework, office work). In bed <50% of the time. Ambulatory and capable of all self-care, but          |                                                |
| 2                                                                                                                                                                                 | unable to carry out any work activities. Up and about more than 50% of  waking hours.                                |                                                |
| 3                                                                                                                                                                                 | In bed >50% of the time. Capable of only limited self-care, confined to  bed or chair more than 50% of waking hours. |                                                |
| 4                                                                                                                                                                                 | 100% bedridden. Completely disabled. Cannot carry on any self-care.  Totally confined to bed or chair.               |                                                |
| 5                                                                                                                                                                                 | Dead.                                                                                                                |                                                |  
* As published in Am. J. Clin. Oncol.: Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 1982.
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15.2 appendix b data collection

All of the following elements will be recorded in the C3D database:
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a. patient enrollment

- Date of birth, age, gender, race, ethnicity - Height - Weight - ECOG - Date of original diagnosis - Plasmacytoma present: Yes or No - Tumor Histology and date of confirmation - SLAMF7 expression by tumor type of tissue studied and date of confirmation - Date of Informed Consent signature, consent version and date of registration
- Baseline History/Physical - Baseline Symptoms
- Prior therapy
- Prior radiation
- Prior Bone Marrow Biopsy that includes the percent of plasma cells and SLAMF7 results
- Findings of consultations done at screening
untitled h1
b. study drug administration and

- Dates anti-SLAMF7-CAR-transduced T cells given - Dose level, actual dose in CAR+ T cells/kg, schedule and route given - Height, weight, and body surface area at start of each course
- Response assessment for each restaging performed
- Concomitant medications will not be collected in C3D
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c. laboratory and diagnostic test

1. All Clinical laboratory and diagnostic test results done at screening and until day 30 post infusion with the following exceptions: Diagnostic tests which are not specified in the protocol, and if the results are not needed to document the start or end of an adverse event that requires reporting. Serologies such as CMV, HSV, EBV, toxoplasmosis, adenovirus, TTV data that were not need for eligibility will not be collected.  
2. All staging studies including serum protein electrophoresis, urine protein electrophoresis, serum free light chains, bone marrow biopsy reports, flow cytometry reports, serum immunoglobulin reports including beta-2 microglobulin, complete blood count and differential reports, serum creatinine reports, TBNK
results, serum protein, urine albumin, serum calcium (including ionized), ESR and CRP results. MRI, X-ray, and CT scan results will only be reported if they were used for staging.
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e. tumor response and measurements

- Restaging studies performed at protocol specified time points and as clinically indicated .  
- Any physical exam findings will be collected as Adverse Events and labs results.
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f. off study

- Date and reason for off study
- Date and cause of death - Autopsy findings if available
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15.3 appendix c guidelines for

Infusions of CAR T cells are often complicated by significant acute toxicities in the first 2 to 3 weeks after the infusion. In many cases the toxicities correlate with serum inflammatory cytokine levels. The toxicities most often experienced by patients receiving infusions of CAR T cells include, but are not limited to, tumor lysis syndrome, fever, fatigue, hypotension, tachycardia, acute renal failure, and neurological toxicities such as aphasia, ataxia, headache, somnolence, and coma. Fever is usually the first toxicity to occur. Note these are guidelines that might require modification based on clinical circumstances of each patient, and failure to exactly follow these guidelines is not a protocol deviation or violation. Administration of corticosteroids should be avoided if possible, to avoid killing or impairing the function of the CAR T cells.
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general supportive care guidelines

1. All patients with significant malignancy burdens and without a contradiction such as allergy should be started on allopurinol at the time of the start of the chemotherapy conditioning regimen or 1 day before the CAR T cell infusion. The suggested allopurinol dose is 200 to 300 mg/day with a possible loading dose of 300 to 400 mg.  
2. Vital signs should be checked a minimum of every 4 hours during hospitalization. Increasing the time interval between vital sign checks for patient convenience or other reasons should be avoided.  
3. Strict ins and outs should be recorded on all patients. 4. As a minimum, keep hemoglobin greater than 8.0 g/dL and platelets greater than 20K/microliter.  
5. Administer fresh frozen plasma (FFP) for a PTT 1.5-fold or more above the upper limit of normal.  
6. For patients with an increased PTT, check the fibrinogen level and keep the fibrinogen level above 100 mg/dL with cryoprecipitate.  
7. Fevers should be treated with acetaminophen and comfort measures. NSAIDs and corticosteroids should be avoided.  
8. Patients with a heart rate persistently higher than 115/minute and fever should have vital signs checked every 2 hours.  
9. Patients who are neutropenic and febrile should be receiving broad-spectrum antibiotics. 10. Avoid meperidine due to seizure risk. 11. Minimize benzodiazepine use to avoid aggravating delirium.
12. Patients on this protocol will be placed on strict fall precautions including instructions to get out of bed only with assistance under the following conditions:
1. Any history of syncope or near-syncope within 1 month before CAR T-cell infusion or any time after CAR T-cell infusion.  
2. Any blood pressure reading of less than 100 mm Hg systolic blood pressure after antiCD19 CAR T-cell infusion if 100 mm Hg is lower than the patients baseline systolic blood pressure.  
3. Heart rate greater than 100 beats per minute.  
13. Any patient with syncope, near-syncope, or light-headedness will have orthostatic blood pressure and heart rate checked and receive intravenous fluids as appropriate. These patients will also receive an ECG.  
14. A CBC will be obtained twice daily while the patient is inpatient. If the absolute neutrophil count becomes less than 500/microliter, Filgrastim will be initiated at a dose of 300 micrograms daily for patients under 70 kg in weight and a dose of 480 micrograms daily for patients over 70 kg in weight only in patients with absolute neutrophil counts less than 500/microliter. Filgrastim will be discontinued as soon as the absolute neutrophil count recovers to 2000/microliter.  
15. Hypotension is a common toxicity requiring intensive care unit (ICU) admission. In general patients should be kept well-hydrated. Maintenance I.V. fluids (normal saline (NS) should be started on most patients with high fevers especially if oral intake is poor or the patient has tachycardia. I.V. fluids are not necessary for patients with good oral intake and mild fevers. For patients who are not having hypotension or tumor lysis syndrome, a generally even fluid balance should be strived for after allowing for insensible fluid losses in patients with high fevers. The baseline systolic blood pressure is defined for this protocol as the average of all systolic blood pressure readings obtained during the 24 hours prior to the CAR T-cell infusion. The first treatment for hypotension is administration of IV NS boluses.
- Patients with a systolic blood pressure that is less than 80% of their baseline blood pressure and **less than 100 mm Hg should receive a 1 L NS bolus.**
- **Patients with a systolic blood pressure less than 90 mm Hg should receive a 1 L**
NS bolus regardless of baseline blood pressure.  
These I.V. fluid management suggestions may need to be modified based on the clinical characteristics of individual patients such as pulmonary status, cardiac function, edema and other factors.  
16. Patients receiving more than 1 fluid bolus for hypotension should have a stat EKG and troponin, and a cardiac echocardiogram as soon as possible.
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icu transfer

Patients should be transferred to the ICU after consultation with the ICU physicians under these circumstances. Patients not meeting these criteria could also require ICU admission at the discretion of the clinical team caring for the patient.  
- Systolic blood pressure less than 75% the patient's baseline blood pressure and less than 100 mm Hg after administration of a 1L NS bolus.  
- Anytime the systolic blood pressure is less than 90 mm Hg after a 1L NS bolus. - Continuous tachycardia with a heart rate higher than 125 beats per minute on at least 2 occasions separated by 2 hours.  
- Oxygen requirement of more than a 4L standard nasal cannula 1. All patients transferred to the ICU for hypotension or tachycardia should have a stat EKG
and a cardiac echocardiogram within 6 hours of the time of transfer.  
2. Patients with hypotension not responding to IV fluid resuscitation should be started on norepinephrine at doses called for by standard ICU guidelines.  
3. Patients should have a cardiac echocardiogram and an EKG within 6 hours of starting norepinephrine.  
4. Patients in the ICU should get twice-daily labs (CBC with differential, acute care panel, mineral panel, hepatic panel, uric acid, LDH. Patients in the ICU should also get a daily troponin level).  
5. Patients receiving vasopressors should have a cardiac echocardiogram at least every other day.
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immunosuppressive drug administration

In general, immunosuppressive drugs are administered in a stepwise escalation based on toxicity severity. The first immunosuppressive drug administered is usually tocilizumab. If toxicity does not improve after tocilizumab, treatment progresses to intermediate-dose or high-dose methylprednisolone. For certain severe toxicities listed below, high-dose methylprednisolone must be given immediately.
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tocilizumab administration

Tocilizumab should be administered under the following circumstances if the listed disorders are thought to be due to cytokine release from CAR T cells. Tocilizumab is administered at a dose of **8 mg/kg** in patients weighing 30 kg or more, infused IV over 1 hour (dose should not exceed 800 mg); it may be infused up to three additional times if there is no clinical improvement in signs and symptoms after the first dose. The interval between consecutive doses should be at least 8 hours.  
- Left ventricular ejection fraction less than 45% by echocardiogram - Creatinine greater than 2-fold higher than the most recent level prior to CAR T-cell infusion
- Norepinephrine requirement at a dose greater than 3 µg/minute for 36 hours since the first administration of norepinephrine.  
- Requirement of 5 mcg/minute or more of norepinephrine to maintain systolic blood pressure greater than 90 mm Hg.  
- Oxygen requirement of 40% or greater fraction of inspired oxygen (FIO2) to maintain oxygen saturation of >92%.  
- Subjective significant dyspnea and respiratory rate greater than 25 for 2 hours or more.  
- PTT or INR>2x upper limit of normal
- Bleeding possibly related to cytokine-release syndrome - Creatine kinase greater than 5x upper limit of normal
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intermediate-dose methylprednisolone for toxicities not

1. Give methylprednisolone 50 mg every 6 hours for any of the toxicities under "Tocilizumab administration" above that don't improve after tocilizumab administration.
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high-dose methylprednisolone should be given

1. Give methylprednisolone 200 mg every 6 hours for systolic blood pressure that is less than 90 mm Hg while the patient is on 15 mcg/minute or higher doses of norepinephrine. If the patient has not had tocilizumab, give 8 mg/kg of tocilizumab along with the methylprednisolone.  
2. Give methylprednisolone 200 mg every 6 hours for hypotension requiring 15 mcg/minute or more of norepinephrine continuously for 8 hours or more. If the patient has not already had tocilizumab, administer 8 mg/kg tocilizumab in addition to methylprednisolone.  
3. Give methylprednisolone 200 mg every 6 hours for any left ventricular ejection fraction 30%
or less. If the patient has not already had tocilizumab, administer 8 mg/kg tocilizumab in addition to methylprednisolone.  
4. Give methylprednisolone 200 mg every 6 hours for any situation in which pulmonary toxicity makes mechanical ventilation likely to be required within 4 hours. If the patient has not had tocilizumab, administer 8 mg/kg tocilizumab in addition to methylprednisolone.  
5. In life-threating toxicity not improving after 200 mg of methylprednisoloneRimiducid should be administered, 1000 mg of methylprednisolone can be considered.
In general, stop corticosteroid use when toxicity improves to a tolerable level. For example, in patients with hypotension, stop methylprednisolone 6 to 12 hours after vasopressors are no longer needed.
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neurological toxicity

1. All patients with neurological toxicities other than somnolence and delirium should get a neurology consult.  
2. All patients with significant neurological toxicity should get an MRI of the brain. 3. All patients with significant neurological toxicity should get a lumbar puncture after MRI if it is safe to perform a lumbar puncture.  
4. CARTOX-10 scale (Appendix E) will be administered daily in patients and used to monitor for aphasia/dysphasia in patients.  
5. The following patients should receive dexamethasone 10 mg intravenously every 6 hours until the toxicities improve. Note: for seizures administer standard seizure therapies in addition to dexamethasone. For patients already getting higher doses of corticosteroids for CAR-related toxicity, it is not necessary to add dexamethasone 10 mg every 6 hours. Stop dexamethasone as soon as toxicity improves to a tolerable level; the duration of dexamethasone use will need to be determined on a patient to patient basis. Tocilizumab is possibly not effective for neurological toxicity, so it should not be given when patients have isolated neurological toxicity. Tocilizumab may be concurrently given with steroids if the patient has evidence of CRS in addition to neurological toxicity
1. Inability of patient to follow simple commands such as "squeeze my fingers".  
2. Any generalized seizure
3. Somnolence severe enough to potentially limit airway protection 4. Obtundation and stupor 5. Ataxia severe enough to preclude ambulation 6. Disorientation to person or place that persists longer than 48 hours 7. Neurologic toxicity lasting more than 2 hours that is severe enough to interfere with activities of daily living (ADLs)  
8. Cerebral edema
15.4 **APPENDIX D: INFUSION INSTRUCTIONS**
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equipment

Primary IV tubing (2)
Secondary IV tubing (1) NS (sodium chloride 0.9%) 250cc bags (2) IV infusion pump Gloves  
| Steps:                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       | Key Points:                                                                       |    |                                                                      |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------|----|----------------------------------------------------------------------|
| 1.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           | The RN will be informed of the  approximate time of cell arrival at  the bedside. | -  | Premeds are acetaminophen 650 mg PO and  diphenhydramine 12.5 mg IV. |
| 2. Verify the physician orders: - to administer the cells - for the date of administration - for premedication orders  - protocol number 3. Verify that the protocol consent has been  signed  4. Ensure that emergency and monitoring  equipment are available in the patient's  room: - oxygen - suction - vital sign monitor with pulse oximeter  and thermometer  5. Provide patient education covering  infusion procedure, potential complications  and associated symptoms to report. |                                                                                   |    |                                                                      |  
| 7. Measure and record baseline vital signs,  respiratory and circulatory assessments. 8. Verify the patency of the patient's IV                                                                                                                                                                                                    | A central venous access device such as a non-valved                                                                                                                                                                                                                                        |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| access.                                                                                                                                                                                                                                                                                                                            | PICC line should be used.                                                                                                                                                                                                                                                                  |
| 9. Hang a primary line of 250cc NS at a kvo  rate - NEW bag and NEW tubing.                                                                                                                                                                                                                                                        | This will be the dedicated NS line for infusing the  cells. Under no circumstances are any other  substances to be infused into the line.                                                                                                                                                  |
| This MUST be ready and infusing prior to  the cells being delivered to the unit.                                                                                                                                                                                                                                                   | Cell death occurs quickly - the infusion must be  initiated immediately.                                                                                                                                                                                                                   |
| The patient's primary IV hydration can  infuse via a separate lumen while the cells  are infusing, but NO MEDs should be administered during this time.                                                                                                                                                                            | Do not infuse medication during the cell infusion. If  emergency meds must be administered, use the  hydration or emergency NS IV line.                                                                                                                                                    |
| Have a second bag of 250cc NS and tubing  ready as an emergency line.                                                                                                                                                                                                                                                              | This will be the emergency IV solution and can be  used for medication administration. Do not use an inline filter for cells.                                                                                                                                                              |
| 10.                                                                                                                                                                                                                                                                                                                                | The primary RN will be notified                                                                                                                                                                                                                                                            |
| approximately 10 minutes before the cells  arrive on the unit. The cells will be hand  delivered to the bedside.                                                                                                                                                                                                                   | It is critical to be at the bedside awaiting the arrival  of the cells for infusion; have baseline VS,  assessment, and IV lines hooked up when the cells  arrive. Cell death occurs as soon as the cells are  removed from the laboratory. Initiate the infusion  as quickly as possible. |
| It is critical to be at the bedside awaiting the  arrival of the cells for infusion.  12. Prior to spiking the cell bag, two RNs  will perform the identification procedure.  Both RNs must have their names charted in  the CRIS cellular therapy flow sheet 13. Infuse the cells by INFUSION PUMP or syringe over 20-30 minutes. | This prevents the cells from clumping in the bag.                                                                                                                                                                                                                                          |
| a. Piggyback the cells into the dedicated  NS line; use the backflush technique  to prime the line. b. While the cells are infusing, gently agitate the bag of cells every few  minutes. When the cell bag is  empty, backflush NS to rinse the bag                                                                                |                                                                                                                                                                                                                                                                                            |  
| and infuse this at the same rate as the  cells; rinse bag until NS runs clear.                                                                                                                                                                                                                                                                                                                                                                                                        |                                                                                                                                                                                                                                  |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
|                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       | c. Note: in some cases cells will arrive  from DTM in a syringe. In this case  infuse the cells via syringe over 20-30  minutes in the dedicated NS line  proximal port, see nursing cellular  infusion SOP for further details. |
| 14. Measure and record VS before and after  the cell infusion, q1h x 4, and then q4h after  completion of the infusion.  a.Assess and document the patient's  respiratory and circulatory status  post cell infusion.  15. Documentation: a. After the cells have infused, remove  the adhesive backed "cell therapy  product" tag from the cell bag and  place it on a progress note in the  patient's chart.  b. Document the cell infusion in  CRIS using the appropriate screens. |                                                                                                                                                                                                                                  |
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15.5 appendix e cartox (adapted

- One point is assigned for each task. Normal function defined by overall score of 10.
- TASKS:  
Orientation to year, month, city, hospital and President of country
(maximum 5 points)
Name three objects (ex: point to clock, pen, button) (maximum of 3 points)
Write a standard sentence (1 point) Count backwards from 100 in tens (1 point)
15.6 **APPENDIX F: CYTOKINE RELEASE SYNDROME GRADING ASSESSMENT (ADAPTED FROM**
LEE ET AL, **2019).**
Grade 1 CRS:
- Fever and: - Constitutional symptoms Grade 2 CRS:
- Fever and: - Hypotension; responds to fluids. - Hypoxia requiring low flow nasal cannula or blow-by.  
Grade 3 CRS:
- Fever and; - Hypotension: requires pressor +/- vasopressin)
Hypoxia: requiring high-flow nasal cannula, facemask, nonrebreather mask or venturi mask. Grade 4 CRS:
- Fever and; - Positive pressure - - Multiple Pressors