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4.4 granulocyte colony-stimulating factor

A CBC will be obtained 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. Filgrastim will be discontinued as soon as the absolute neutrophil count recovers to 2000/microliter.
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4.5 avoidance of corticosteroids

Patients should not take corticosteroids including prednisone, dexamethasone or any other corticosteroid at a dose equivalent to 5 mg/day or more of prednisone for any purpose without approval of the Principal Investigator.
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4.6 excluded medications

Anticoagulation (e.g. warfarin) or anti-platelet therapy (e.g. aspirin > 325 mg/day or clopidogrel)
65 Version Date:May 27, 2020 4.7 TOXICITY **MANAGEMENT GUIDELINES**
See **Appendix C**. . 4.8 **MANAGEMENT OF PATIENTS WITH BURKITT AND OTHER HIGH-GRADE LYMPHOMAS**
Patients with Burkitt lymphoma and other high-grade lymphomas are at increased risk for tumor lysis syndrome. The following guidelines will apply for all patients with Burkitt or other highgrade lymphomas:
- All patients with high-grade lymphomas will have the following laboratories checked every 6 hours for the first 72 hours or longer if evidence of tumor lysis syndrome is present after receiving CAR T cells: sodium, potassium, magnesium, phosphorus, creatinine, BUN, uric acid, calcium. Electrolyte abnormalities will be promptly treated as indicated.  
- All patients with high-grade lymphomas will have a normal saline IV infusion maintained at a minimum of 100 mL/hr from the time of CAR T cell infusion until at least 24 hours after CAR T-cell infusion. If significant tumor lysis syndrome is observed, the rate should be increased as needed up to 250 cc/hour or other rates as appropriate.  
- All patients with high-grade lymphoma will start allopurinol 300 mg every 12 hours on the day before protocol conditioning chemotherapy starts
- Patients with an LDH ≥2X the upper limit of normal will receive rasburicase 0.2 mg/kg on the day of start of conditioning chemotherapy
- Patients with a uric acid of 8 mg/dL at any time after the start of protocol treatment
(including first day of chemotherapy) will receive rasburicase 0.2 mg/kg
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5 biospecimen collection

Biospecimen collection on this protocol will consist of blood draws and acquisition of bone marrow aspirates and possible biopsies of tumors for research purposes. The amount of blood that may be drawn from adult patients for research purposes shall not exceed 10.5 mL/kg or 550 mL, whichever is smaller, over any eight-week period.
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5.1 correlativestudies for research

Note regarding research Biospecimen **collection:** If any of the below time points fall on a federal holiday then, we may collect research blood on the next business day.  
| Test/assay     | Volume                | Type of Tube    | Collection Point   | Location of  Specimen  Processing/ Storage   |
|----------------|-----------------------|-----------------|--------------------|----------------------------------------------|
| (approx.)      | (+/- 48 hrs)          |                 |                    |                                              |
| Immunological  | Blood                 | CPT tube        | Within the 3 days  | Surgery Branch Cell                          |
| and RCR Assays | prior to the start of | Production Cell |                    |                                              |  
| Test/assay                                                    | Volume                                                       | Type of Tube                                                                                                                   | Collection Point                                                   | Location of  Specimen  Processing/ Storage   |
|---------------------------------------------------------------|--------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------|----------------------------------------------|
| (approx.)                                                     | (+/- 48 hrs)                                                 |                                                                                                                                |                                                                    |                                              |
| 96 mL                                                         | (12 tubes x 8                                                | conditioning                                                                                                                   |                                                                    |                                              |
| mL each)                                                      | chemotherapy                                                 | Production Facility  SB-CPF                                                                                                    |                                                                    |                                              |
| (can be collected on  different days within  the 3-day range) | Bldg. 10 3W3808. Phone: 240- 858-3755                                                              |                                                                                                                                |                                                                    |                                              |
| Immunological  Assays (Serum  cytokine levels)                | Blood                                                        | SST tubes                                                                                                                      | Within 3 days prior to  the start of the  chemotherapy             | Figg Lab                                     |
| 16 mL                                                         | (2 tubes x 8 mL  each)                                       |                                                                                                                                |                                                                    |                                              |
| Apheresis cells  to prepare the  CAR T cells                  | Apheresis                                                    | NA                                                                                                                             | Prior to the start of                                              |                                              |
| cells                                                         | conditioning  chemotherapy                                   | DTM CCE                                                                                                                        |                                                                    |                                              |
| Immunological                                                 | Apheresis                                                    |                                                                                                                                |                                                                    |                                              |
| Assays                                                        | cells left  over after  CCE has  used all  necessary  cells. | Cell culture bag                                                                                                               | Prior to the start of                                              |                                              |
| or tube.                                                      | conditioning  chemotherapy                                   | Cell Production  Facility SB-CPF Bldg. 10 3W3808. Phone: 240- 858-3755                                                                                                                                |                                                                    |                                              |
| Sample of CAR  T cells from  Culture                          | CAR T                                                        | NA                                                                                                                             | End of CAR T cells                                                 | Cell Production                              |
| cells                                                         | culture                                                      | Facility SB-CPF Bldg. 10 3W3888. Phone: 240- 858-3755                                                                                                                                |                                                                    |                                              |
| Immunological  Assays (Serum  cytokine levels)                | Blood                                                        | SST tube                                                                                                                       | Prior to CAR T cell                                                | Figg Lab                                     |
| infusion on Day 0                                             |                                                              |                                                                                                                                |                                                                    |                                              |
| 8 mL                                                          | (1 tube x 8 mL)                                              |                                                                                                                                |                                                                    |                                              |
| Immunological                                                 | Blood                                                        |                                                                                                                                |                                                                    |                                              |
| Assays                                                        | CPT tubes                                                    | Every Monday,  Wednesday, and  Friday during  hospitalization,  starting on the first  Monday, Wednesday,  or Friday after the | Surgery Branch Cell  Production Facility  SB-CPF (CPT tubes  only) |                                              |
| 48 mL                                                         | (6 tubes x 8 mL  each)                                       | Bldg. 10 3W3808. Phone: 240- 858-3755                                                                                                                                |                                                                    |                                              |  
| Test/assay                                               | Volume                                                                                                                   | Type of Tube   | Collection Point                                                                                                           | Location of  Specimen  Processing/ Storage                                                                                 |
|----------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------|----------------|----------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------|
| (approx.)                                                | (+/- 48 hrs) CAR T-cell infusion  and lasting up until  14 days after infusion  of Hu1928-Hu20BB CAR-transduced T  cells |                |                                                                                                                            |                                                                                                                            |
| Immunological  Assays (Serum  cytokine levels)           | Blood                                                                                                                    | SST tube       | Figg Lab (SST tubes  only)                                                                                                 |                                                                                                                            |
| 8 mL                                                     | (1 tube x 8 mL)                                                                                                          |                |                                                                                                                            |                                                                                                                            |
| Immunological  Assays (Serum  cytokine levels)           | Blood                                                                                                                    | SST tube       | On the first Sunday  after CAR T-cell  infusion (If the  Monday is a holiday,  Sunday research  blood will not be  drawn). | Figg Lab (tube may  be stored refrigerated  on the nursing unit  and processed first  thing Monday  morning at the latest) |
| 8 mL                                                     | (1 tube x 8 mL)                                                                                                          |                |                                                                                                                            |                                                                                                                            |
| Immunological  Assays (Used for  RCR on 3MO,  6MO, 12MO) | Blood                                                                                                                    | CPT tubes      | Outpatient follow-up  clinic visits 2 weeks,  1, 2, 3, 6, 9 and 12  months after CAR Tcell infusion                                                                                                                            | Surgery Branch Cell  Production Facility  (CPT tubes only)                                                                 |
| 48 mL                                                    | (6 tubes x 8 mL  each)                                                                                                   | Bldg. 10 3W3808. Phone: 240- 858-3755                |                                                                                                                            |                                                                                                                            |
| Immunological  Assays (Serum  cytokine levels)           | Blood                                                                                                                    | SST tube       | Figg Lab (SST tubes  only)                                                                                                 |                                                                                                                            |
| 8 mL                                                     | (1 tube x 8 mL)                                                                                                          |                |                                                                                                                            |                                                                                                                            |
| Immunological                                            | Bone                                                                                                                     |                |                                                                                                                            |                                                                                                                            |
| Assays                                                   | marrow  aspirate                                                                                                         | Heparinized    | Outpatient follow-up                                                                                                       |                                                                                                                            |
| syringe                                                  | clinic visits (2 weeks,  2 and 6 months after  CAR T-cell infusion)                                                      | Surgery Branch Cell  Production Facility Bldg. 10 3W3808. Phone: 240- 858-3755                |                                                                                                                            |                                                                                                                            |
| 2-2.5 mL                                                 |                                                                                                                          |                |                                                                                                                            |                                                                                                                            |
|                                                          |                                                                                                                          |                |                                                                                                                            |                                                                                                                            |  
5.1.1 Immunological Testing
- T-cell assays: Direct immunological monitoring will consist of quantifying CD3+ T cells that express the CAR by quantitative PCR, and/or by flow cytometry. These assays will be performed to measure the persistence and estimate the proliferation of the infused CAR+ T cells. A quantitative PCR assay or a flow cytometry assay will be used to quantitate CAR+ T cells at all post-infusion time-points up to at least 2 months after infusion, and CAR+ T cell analysis will continue until the CAR+ T cell level drops to undetectable levels unless a stable low level of CAR+ T cells is present at more than 3 years after infusion. The absolute number of CAR+ PBMC will be estimated by multiplying the percentage of CAR+ PBMC by the absolute number of lymphocytes plus monoctyes per microliter of blood. Ex vivo immunological assays might be used to measure the antigen-specific functional activity of the CAR+ T cells and will consist of assays such as enzyme-linked immunosorbent assays (ELISAs), intracellular cytokine staining, and anti-CD107a degranulation assays. Immunological assays will be standardized by the inclusion of pre-infusion recipient PBMC and in some cases an aliquot of the engineered T cells cryopreserved at the time of infusion.  
- Serum cytokine levels will also be measured by enzyme-linked immunosorbent assays
(ELISAs) or similar assays.  
- Gene expression studies will be performed on patient lymphoma cells and on the infusion CAR T cells of each patient. Methods used will be either Nanostring and/or RNAseq (RNA sequencing).  
- Patients' blood samples will be obtained for detection of replication competent lentiviruses (RCL) by PCR at 3 months, 6 months, and 12 months after cell administration. Infusion cells will be tested for RCL prior to infusion by PCR targeting the VSV-G gene. Monitoring for RCR will be discontinued if all patient samples have been negative for RCR at the 12 month time-point during this trial, efforts will be made to assay a biopsy sample for RCL. If any post-treatment samples are positive, further analysis of the RCL and more extensive patient follow-up will be undertaken, in consultation with the FDA. RCL PCR assays are performed by the National Gene Vector Laboratory at Indiana University The results of these tests are maintained by the National Gene Vector Laboratory at Indiana University and by the Surgery Branch research team.  
- Due to nature of these studies, it is expected that expansion of specific T-cell clones will be observed as T-cell proliferate in response to the targeted antigen. Therefore, care will be taken to track T-cell persistence, but presence of an oligoclonal T cell population does not indicate an insertional mutagenesis event. If any patient shows an increasing population of CAR gene transduced T cells at month 6 or later (by FACS staining or qPCR), the previously archived samples will be subjected to techniques that would allow the identification of predominant clonal populations of transduced cells. Such techniques may include T cell cloning or LAM-PCR. If a predominant or monoclonal T cell clone derived from CAR gene transduced cells is identified during the follow-up, the integration site and sequence will be identified and subsequently analyzed against human genome database to determine whether the sequences are associated with any known human cancers. If a predominant integration site is observed, the T cell cloning, or LAM-PCR test will be used at an interval of no more than three months after the first observation to see if the clone persists or is transient. In all instances where monoclonality is persistent and particularly in instances where there is expansion of the clone, regardless of whether or not the sequence is known to be associated with a known human cancer, the subject should be monitored closely for signs of malignancy, so that treatment, if available, may be initiated early.
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5.1.2 additional biopsies and additional

Patients might be asked to undergo biopsies or additional blood draws as as clinically indicated. Additional blood draws might be necessary to investigate T cell responses and serum cytokine levels in cases of clinical events such as rapid regressions of malignancy or toxicity. Remainder material from such biopsies including open surgical biopsies, fine needle aspirations, and core needle biopsies could be used to investigate CAR T-cell persistence or function at tumor sites. Open surgical, fine needle, or core needle biopsies might also be needed in some but not all patients to confirm continued antigen expression by tumor cells in order to meet protocol eligibility requirements for antigen expression on the tumor cells before any CAR T-cell infusion. Standard techniques will be used for biopsies which may include CT and/or ultrasound guided biopsy.  
These biopsies will only be performed if minimal morbidity is expected based on the procedure performed and the granulocyte and platelet count. Biopsy tissue will be processed in the NIH Department of Pathology. Studies will be performed to evaluate the antigen expression by the tumor and to evaluate the presence of transduced cells.
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5.1.3 future studies

Blood and tissue specimens collected in the course of this research project may be banked and used in the future to investigate new scientific questions related to this study. However, this research may only be done if prospective IRB approval is obtained or the project is determined to not be human subjects research. Patient PBMC not needed for future clinical use can be used for experiments aimed at developing new T-cell therapies not directly related to individual patients with permission of the PI. If new risks are associated with the research (e.g. analysis of germ line genetic mutations) a protocol amendment will be required, and informed consent will be obtained from all research subjects to whom these new studies and risks pertain. 5.1.4 Samples Sent to Figg Lab
- Venous blood samples will be collected in either a 4-mL or an 8-mL SST tube to be processed for serum and stored for future research.  
o Record the date and exact time of draw on the tube. Blood tubes may be kept in the refrigerator until pick-up.
o For sample pick-up, page 102-11964.  
o For immediate help, call 240-760-6180 (main Blood Processing Core number) or, if no answer, 240-760-6190 (main clinical pharmacology lab number).  
o For questions regarding sample processing, contact the Blood Processing Core
(BPC) at NCIBloodcore@mail.nih.gov or 240-760-6180.  
o The samples will be processed, barcoded, and stored in the Figg lab until requested by the investigator.
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70 version datemay 27 2020

After delivery to the SB-CPF, peripheral blood mononuclear cell samples will be sent to the Head, Clinical Support Laboratory Clinical Services Program, Applied/Developmental Directorate Frederick National Laboratory for Cancer Research for processing and cryopreservation. They will be stored long-term at the NCI Frederick Repository.
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5.2 sample storage tracking and

Samples will be ordered in CRIS and tracked through a Clinical Trial Data Management system. Should a CRIS screen not be available, the CRIS downtime procedures will be followed. All samples will be sent to Blood Processing Core (BPC) and/or SB-CPF for processing and/or and storage until they are distributed to the designated place of analysis as described in the protocol. Samples will not be sent outside NIH without appropriate approvals and/or agreements, if required.
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5.2.1 samples managed by dr.

Please e-mail NCIBloodcore@mail.nih.gov at least 24 hours before transporting samples (the Friday before is preferred). For sample pickup, page 102-11964. For immediate help, call 240-760-6180 (main blood processing core number) or, if no answer, 240-760-6190 (main clinical pharmacology lab number). For questions regarding sample processing, contact NCIBloodcore@mail.nih.gov.
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5.2.1.2 sample data collection

All samples sent to the Blood Processing Core (BPC) (Dr. Figg's lab) will be barcoded, with data entered and stored in Labmatrix utilized by the BPC. This is a secure program, with access to Labmatrix limited to defined Figg lab personnel, who are issued individual user accounts. Installation of Labmatrix is limited to computers specified by Dr. Figg. These computers all have a password restricted login screen. Labmatrix creates a unique barcode ID for every sample and sample box, which cannot be traced back to patients without Labmatrix access. The data recorded for each sample includes the patient ID, name, trial name/protocol number, time drawn, cycle time point, dose, material type, as well as box and freezer location. Patient demographics associated with the clinical center patient number are provided in the system. For each sample, there are notes associated with the processing method (delay in sample processing, storage conditions on the ward, etc.).
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5.2.1.3 sample storage and destruction

Barcoded samples are stored in barcoded boxes in a locked freezer at either -20 or -80°C
according to stability requirements. These freezers are located onsite in the BPC and offsite at NCI Frederick Central Repository Services in Frederick, MD. Visitors to the laboratory are required to be accompanied by laboratory staff at all times. 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 Labmatrix. 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 or returned to the patient, if so requested.. The PI will record any loss or unanticipated destruction of samples as a deviation. Reporting will be per the requirements of section 7.2.  
Sample bar-codes are linked to patient demographics and limited clinical information. This information will only be provided to investigators listed on this protocol, via registered use of the Labmatrix. It is critical that the sample remains linked to patient information such as race, age, dates of diagnosis and death, and histological information about the tumor, in order to correlate genotype with these variables.
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5.2.2 sample storage tracking and

Samples received by the Surgery Branch research lab will be tracked using password protected web-based NCI database Labmatrix. 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 Labmatrix with identification and storage location. Access to the stored specimens will be restricted. Access to Labmatrix 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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5.2.3 protocol completion/sample destruction

All specimens obtained in the protocol are used as defined in the protocol. The PI will report any loss or unanticipated destruction of samples per Section **7.2.1**.  
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. Freezer problems, lost samples, or other problems associated with samples that meet expedited reporting requirements (see Section **7.2.1**) will be reported.  
5.2.4 Samples for Genetic/Genomic Analysis Samples used for gene expression analysis will be RNAseq and/or NanostringTM. These studies will be used to determine gene expression in lymphoma cells and infusion CAR T cells. The purpose of these studies is to assess gene expression at the RNA level not to study germline mutations.
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5.2.4.1 description of the scope

RNAseq and/or NanostringTM will be used to determine gene expression in lymphoma cells and infusion CAR T cells. The purpose of these studies is to assess gene expression at the RNcrisA level not to study germline mutations. One purpose of these studies is to determine if different levels of gene expression in malignant cells are associated with response to CAR T-cell therapy. Another purpose of these studies is to determine if different levels of gene expression in infusion CAR T cells are associated with anti-malignancy responses caused by CAR T cells or persistence of CAR T cells.
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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.  
- If no CAR-T cells administered: Document AEs from the first day of study chemotherapy through 30 days after last dose of study chemotherapy or until off study, whichever comes first. Beyond 30 days after the last dose of chemotherapy, only adverse events which are serious and related to the study intervention need to be recorded.  
- If CAR-T cells given: Document AEs from the first infusion of CAR-T-cells through 60 days after the subject receives the last administration of CAR-T-cells. Beyond 60 days after the last CAR-T cell infusion, 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:
- 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.  
If any abnormal laboratory result is considered clinically significant, the investigator will provide details about the action taken with respect to the study drug and about the patient's outcome. All patients receiving a second treatment will be identified as patients receiving repeat treatments in any reports of results of this trial. Information on all concomitant medications, administered blood products, as well as interventions occurring during the study must be recorded on the patient's eCRF.  
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. 6.1.1 Adverse event recording:  
- Grade 2 adverse events that will be recorded:
a. Unexpected events that are possibly, probably, or definitely related to the research. b. Expected events that are possibly, probably or definitely related to the study interventions will be recorded only for the first year after the infusion.  
c. All Infections proven by culture, PCR, antigen detection or other laboratory methods will be recorded for the first year after infusion regardless of attribution.  
- All grade 3, 4, and 5 adverse events will be recorded regardless of attribution.  
- All serious events regardless of attribution
6.2 DATA SHARING PLANS
6.2.1 Human Data Sharing Plan
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what data will be shared?

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.
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6.3 genomic data sharing plan

Unlinked genomic data will be deposited in the database of genotypes and phenotypes (dbGaP) in compliance with the NIH Genomic Data Sharing Policy.
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6.4 response criteria response criteria

Revised Response Criteria for Malignant Lymphoma, Journal of Clinical Oncology 2007 178 and Recommendations for Initial Evaluation, Staging, andResponse Assessment of Hodgkin and NonHodgkin Lymphoma: The Lugano Classification Journal of Clinical Oncology, 2014179)
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6.4.1 response criteria

6.4.1.1 Complete Remission (CR):
- CR requires all of the following: Complete disappearance of all detectable clinical evidence of disease and disease-related symptoms if present before therapy. Regardless of FDG-avidity, if all extranodal masses and lymph nodes are less than or equal to 1.5 cm or less in longest diameter, the patient is considered to be in CR.  
- Typically FDG-avid lymphoma (large cell, mantle cell and follicular lymphomas are all typically FDG-avid): in patients with no pretreatment PET scan or when the PET scan was positive before therapy, a post-treatment residual mass of any size is permitted as long as it is PET negative.  
- Variably FDG-avid lymphomas/FDG avidity unknown: in patients without a pretreatment PET scan, or if a pretreatment PET scan was negative, all lymph nodes and nodal masses must have regressed to normal size (≤ 1.5 cm in greatest diameter if > 1.5 cm before therapy). Previously biopsy-proven involved nodes that were 1.1 to 1.5 cm in their long axis and more than 1 cm in their short axis before treatment must have decreased to ≤ 1.0 cm in their short axis after treatment.  
- The spleen and/or liver, if considered to be enlarged before therapy on basis of physical exam or CT scan, must be normal size on CT scan for FDG-negative lymphoma. If FDG-avid lesions were present in the spleen or liver before treatment, these FDG-avid lesions must have resolved.  
- A bone marrow aspirate and biopsy is performed only when the patient had bone marrow involvement with lymphoma prior to therapy (all patients must have a pretreatment bone marrow biopsy) or if new abnormalities in the peripheral blood counts or blood smear cause clinical suspicion of bone marrow involvement with lymphoma after treatment. The bone marrow aspirate and biopsy must show no evidence of disease by morphology or if indeterminate by morphology it must be negative by immunohistochemistry.
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6.4.1.2 partial remission (pr) pr

- ≥ 50% decrease in sum of the product of the diameters (SPD) of up to 6 of the largest dominant nodes or nodal masses. Dominant nodes or nodal masses should be clearly measurable in at least 2 perpendicular dimensions, should be from different regions of the body if possible and should include mediastinal and retroperitoneal nodes if possible.  
- No increase in size of nodes, liver or spleen and no new sites of disease.  
- If multiple splenic and hepatic nodules are present, they must regress by ≥ 50% in the SPD. There must be a > 50% decrease in the greatest transverse diameter for single nodules.  
- Bone marrow is irrelevant for determination of a PR. If patient has persistent bone marrow involvement and otherwise meets criteria for CR the patient will be considered a PR.  
- Typically FDG-avid lymphoma: for patients with no pretreatment PET scan or if the PET scan was positive before therapy, the post-treatment PET scan should be positive in at least one previously involved site. Note: in patients with follicular lymphoma or mantle-cell lymphoma, a PET scan is only indicated in patients with one or at most two residual masses that have regressed by 50% on CT scan.
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6.4.1.3 progressive disease (pd)

- Defined by at least one of the following:
- ≥ 50% increase from nadir in the sum of the products of at least two lymph nodes, or if a single node is involved at least a 50% increase in the product of the diameters of this one node.  
- Appearance of a new lesion greater than 1.5 cm in any axis even if other lesions are decreasing in size
- Greater than or equal to a 50% increase in size of splenic or hepatic nodules - At least a 50% increase in the longest diameter of any single previously identified node more than 1 cm in its short axis.  
- Lesions should be PET positive in typically FDG-avid lymphomas unless the lesion is too small to be detected by PET (<1.5 cm in its long axis by CT)
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6.4.1.4 stable disease (sd)

Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. PET should be positive in typically FDG-avid lymphomas.  
- Flow cytometric, molecular or cytogenetic studies will not be used to determine response.  
6.4.2 Response criteria for CLL: (Hallek et al. International workshop on chronic lymphocytic leukemia (iwCLL) guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL.  
Blood 2018 )180 6.4.2.1 Complete Remission:
The designation of a complete response of CLL for this protocol requires all of the following as assessed at least 2 months after Hu1928-Hu20BB CAR-transduced T cell infusion:
- No lymph nodes ≥ 1.5 cm (physical exam, relevant CT scans) - No hepatomegaly or splenomegaly (physical exam, relevant CT scans) - Absence of constitutional symptoms - Normal CBC as exhibited by platelets >100,000/ul and hemoglobin > 11.0 g/dl
(untransfused), and neutrophils ≥ 1500/ul,
- Blood B lymphocyte count<4,000/ul - Bone marrow aspirate and biopsy should be performed only after requirements \#1-
\#5 are first met. Bone marrow aspirate and biopsy that is normocellular for age with <30% of the nucleated cells being B cells (CD19 or CD 20) fits CR criteria. If lymphoid nodules are detected on marrow examination, IHC or flow cytometry should be performed to determine whether these are composed of CLL cells versus T cells or other B cell types. If the nodules are not composed of CLL cells, a CR can be documented. If the marrow is hypocellular, a repeat determination should be performed in one month.  
- Patients who fulfill all of the criteria for CR except for having bone marrow lymphoid nodules will be considered to be in a PR
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6.4.2.2 partial remission

The designation of partial response requires at least two of the following: a ≥ 50% decrease in peripheral Blymphocyte count from pre-treatment value, or a ≥50% reduction in lymphadenopathy, or a ≥ 50% reduction in splenomegaly/hepatomegaly for a period of at least 8 weeks based on physical exam and relevant CT scans. If the patient had only 1 of the abnormal parameters above prior to starting on study, then improvement of that parameter meets criteria for PR. No increase in any lymph node or appearance on newly enlarged nodes is allowed. Additionally, designation of PR requires at least one of the following:
- Platelets > 100,000/ul or 50% improvement from pre-treatment value
- Hemoglobin > 11.0 g/dl (untransfused) or 50% improvement from pre-treatment value 6.4.2.3 Progressive Disease:
The designation of progressive disease is characterized by any one of the following:
- A ≥ 50% increase in the greatest diameter of any lymph node that was enlarged pretreatment.  
- The appearance of new palpable lymph nodes
- A ≥ 50% increase in the absolute number of circulating B lymphocytes (value must exceed 5,000/ul)
- ≥50% increase in the size of the liver and/or spleen as determined by measurement below the respective costal margin or by CT scan; appearance of palpable hepatomegaly or splenomegaly, which was not previously present.  
- Transformation to a more aggressive histology - Patients not fulfilling the above criteria for progressive disease but demonstrating a decrease in hemoglobin value of > 2 gm/dl from baseline or a decrease of > 50% in platelet or granulocyte count will not be considered as evidence of progressive disease, because these changes may occur as both a consequence of many therapies or of underlying CLL/SLL; in such cases, a repeat bone marrow biopsy is recommended.
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6.4.2.4 stable disease

Patients who do not fulfill the criteria for complete or partial response and do not fulfill the criteria for progressive disease will be considered as having stable disease.
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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). Cytokine release syndrome will be graded based on the Lee 2019 ASTCT system of reporting CRS (**Appendix**
F)181 (A)
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7 nih reporting requirements /

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. 7.2.2 NIH Intramural IRB Requirements for PI Reporting at Continuing Review 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/IRB 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, deaths not reported to the OHSRP that occur within 30 days after receiving a research intervention regardless of attribution 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-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-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 the IBC in lieu of a separate report. Please include the IBC protocol number on the report.
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7.4.3 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.  
7.4.4 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 nihrequired data and safety

The clinical research team will meet approximately weekly when patients are being actively treated on the trial to discuss each patient. All data will be collected in a timely manner and reviewed by the principal investigator or a lead associate 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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7.5.1 safety monitoring committee (smc)

This protocol will be periodically reviewed by an intramural Safety Monitoring Committee. 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 based on the risks presented in the study. For initial and subsequent reviews, protocols will not be reviewed if there is no accrual within the review period. The SMC review will focus on unexpected protocol-specific safety issues that are identified during the conduct of the clinical trial. 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. Special addition to safety monitoring plan as requested by NIH IRBO: There will be a pause to enrollment only for Cohort 2 (Hodgkin Lymphoma) after 3 patients have been treated on this cohort. At this time, a report will be sent to the Safety Monitoring Committee to allow an assessment of the safety of this cohort before more patients are enrolled on Cohort 2. The SMC report will be forwarded to the IRB for the IRB to determine if enrollment can continue on this cohort.
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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)) 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.  
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) 8.1.4 Severity The severity of each Adverse Event will be assessed utilizing the CTCAE version 5.0. 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 reporting pregnancy 8.4.1 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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8.4.2 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 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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8.5 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. 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

10.1.1 Primary objectives The primary endpoint of this trial is to determine the safety and feasibility of administering CARexpressing T cells to patients with relapsed or persistent B-cell malignancies.  
10.1.2 Secondary objectives Secondary objectives of this trial are to measure persistence and peak blood levels of CARexpressing T cells, to assess anti-malignancy activity of the CAR T cells, and to assess the relationship between expression of CD19 and CD20 and response.
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10.2 sample size determination

Patients will be enrolled on 2 separate cohorts: **Cohort 1**: Patients who have B-cell malignancies including lymphoma and CLL and **Cohort 2** Patients who have Hodgkin lymphoma. Each cohort will have a separate but identical dose-escalation scheme. The dose escalation schemes are separate because of the possibility of greater toxicity in one cohort or the other due to the different characteristics of B-cell malignancies compared with Hodgkin lymphoma. DLTs occurring on one cohort's dose escalation will not affect dose escalation of the other cohort. Maximum tolerated, and maximum administered doses will be determined independently for each cohort. Both cohorts can undergo repeat treatments only after a maximum tolerated or maximum administered dose is determined for the cohort in question. For each cohort, a dose escalation scheme with up to 4 doses and up to 6 patients per dose level will be carried out (maximum 24 patients) In addition, up to 10 additional patients can be treated at the MTD/maximum administered dose for each cohort to establish additional safety and toxicity data at that level. Thus, with two cohorts, up to 2 x (24+10) =68 patients may be enrolled onto the trial. In addition, we will allow 20 additional patients to allow the trial to be completed as planned if some patients who enroll are not treated due to reasons such as rapid clinical deterioration requiring cancellation of protocol participation. The degree of persistence of Hu1928-Hu20BB CAR-transduced T cells will be evaluated by a quantitative measure (flow cytometry and/or quantitative PCR) in all patients. Anti-malignancy effects will be measured by clinical response and categorized according to Section 6.4. The clinical 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.
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10.3 populations for analyses

All treated patients receiving at least one dose of CAR T cells will be included in the safety and efficacy analysis 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. 10.4.2 Analysis of the Primary Endpoints 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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10.4.3 analysis of the secondary

Secondary objectives of this trial are to measure persistence and peak blood levels of CARexpressing T cells, to assess anti-malignancy activity of the CAR T cells, and to assess the relationship between expression of CD19 and CD20 and response. The persistence and peak blood levels of CAR-expressing T cells will be reported using descriptive statistics, at each dose level, as well as overall. The anti-malignancy activity of the CAR T cells will be assessed by response criteria as separately defined for each disease treated, with 95% confidence intervals provided about the rates of response. Comparison of peak blood CAR T-cell levels in patients obtaining an anti-malignancy response versus patients not obtaining an anti-malignancy response will be done by testing the peak levels between responders and non-responders using an exact Wilcoxon rank sum test, both at all dose levels individually and overall. 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. 10.4.5 Baseline Descriptive Statistics None will be provided in a formal manner; brief descriptions may be incorporated in a final report. 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 3.6.  
10.4.7 Sub-Group Analyses None 10.4.8 Tabulation of individual Participant Data None 10.4.9 Exploratory Analyses The following evaluations will be performed using exploratory techniques. Assessing for associations between blood cytokine levels and response and toxicity will be done by comparing cytokine levels between responders and non-responders, as well as between those with a DLT or not, both at all dose levels individually and overall, using exact Wilcoxon rank sum tests. A variety of clinical predictors of anti-lymphoma responses and toxicity may be evaluated, using non-parametric tests.  
The phenotypes of infused CAR T cells and CAR T cells from the blood of patients will be evaluated and will be reported descriptively.  
When any statistical tests are performed, no formal adjustment for multiple comparisons will be done since the evaluations are being done to generate hypotheses, but the results will be reported in the context of the number of tests performed. Since the evaluations are being done to generate hypotheses, and the results are expected to be based on very limited subjects, the results will be interpreted cautiously.
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11 collaborative agreements

There is a Collaborative Research and Development Agreement (CRADA\# 03019) in place between Kite Pharma, Inc. and the National Cancer Institute for this protocol.
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12 human subjects protections 12.1

The patients to be entered in this protocol have advanced B-cell malignancies that are almost always incurable diseases. These patients have limited life expectancies. Subjects from both genders 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.
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12.2 participation/selection rationale

- The eligibility criteria for this protocol only allow enrollment of patients with advanced Bcell malignancies that are usually incurable despite recent advances in standard therapies.  
- Patients with treatment options with proven efficacy and limited toxicity will not be enrolled.  
- Improving the treatment of advanced B-cell malignancies is an important area of clinical research.  
- In previous studies, anti-CD19 CAR T cells have demonstrated dramatic activity against B-cell lymphoma and B-cell leukemia. Many patients have obtained remissions lasting more than 2 years on multiple clinical trials of anti-CD19 CAR T cells. Some of these studies were clinical trials conducted by the Principal Investigator of this trial, and some patients treated on the Principal Investigator's prior trials have been in complete remission for over 3 years. Despite these impressive results, improvements in anti-CD19 CAR T cells to increase efficacy and to decrease toxicity are still needed. This trial aims to improve upon prior results by targeting CD20 in addition to CD19
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12.3 participation of children

Children (younger than 18 years) will not be enrolled on this study, 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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12.4 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 12.5 ), 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. 12.5 RISK/BENEFIT ASSESSMENT
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12.5.1 known potential benefits

The experimental treatment has a chance to provide clinical benefit although it is quite possible that patients will obtain no clinical benefit. 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, specifically CAR T cells. The risks of the study fall into 5 general categories.
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12.5.2 known potential risks

The primary risk to patients participating in this research study is from the toxicity of chemotherapy and CAR-T cells.  
First, chemotherapy that could cause cytopenias is part of the protocol. 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, hypotension, and fever. A third area of toxicity is neurological toxicity such as delirium, obtundation, myoclonus, seizures, headache, and transient focal neurological toxicities including aphasia and focal paresis. Cytokine-release-type toxicities and neurological toxicities have appeared in other clinical trials of CAR T cells during the first 2 weeks after CAR T cells were infused.70,141 The 4th main category of toxicity is direct damage to normal tissues by the CAR T cells. This could happen because of unexpected cross-reactivity of the Hu1928-Hu20BB
CAR with proteins other than CD19 or CD20 in vivo. A 5th possible toxicity is hypogammaglobulinemia. Hypogammaglobulinemia has been a complication of many patients on clinical trials of anti-CD19 CAR-expressing T cells.70,71 Hypogammaglobulinemia in these patients was routinely treated with infusions of intravenous immunoglobulins.70 The lentiviral vector used in this trial inserts into the T-cell DNA of patients, so in theory, insertional mutagenesis could occur, but insertional mutagenesis has not occurred in any of the hundreds of patients treated with mature T cells that were genetically modified by gammaretroviral or lentiviral vectors.73-75
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12.5.2.1 risk of biopsy

All care will be taken to minimize risks that may be incurred by tumor sampling. However, there are procedure-related risks (such as bleeding, infection and visceral injury) that will be explained fully during informed consent.
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12.5.2.2 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) CT-Guided biopsies and seven (7)18FDG-PET/CT in the first year of the study. The total additional radiation dose for research purposes will be approximately 19.1 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 PET scans will immediately cease as soon as CR is documented, and patients not obtaining CRs almost always go off-study in less than 6 months due to progressive lymphoma. In addition, CT imaging will be modified based on lymphoma locations. For example, many patients will not receive any post-CAR T-cell infusion neck CT on the study since many patients do not have baseline neck involvement with lymphoma.
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12.5.2.3 research blood collection risks

Risks of blood draws include pain and bruising in the area where the needle is placed, lightheadedness, and rarely, fainting. When large amounts of blood are collected, low red blood cell count (anemia) can develop.
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12.5.2.4 other risks

Risks include the possible occurrence of any of a range of side effects which are listed in the Consent Document or this protocol document. Frequent monitoring for adverse effects will help to minimize the risks associated with administration of the study agents.
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12.5.2.5 non-physical risks of genetic

Anxiety and stress may arise as a result of the anticipation that unwanted information regarding disease related RNA sequencing or disease tendencies, or misattributed paternity. Patients will be clearly informed that the data related to RNA sequencing and genetic analysis is coded, investigational and will not be shared with patients, family members or health care providers.
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risk related to possibility that

This includes the risk that data related to genotype, RNA sequencing or risk for disease tendency or trait can be released to members of the public, insurers, employers, or law enforcement agencies. Although there are no plans to release results to the patients, family members or health care providers, this risk will be included in the informed consent document 12.5.3 Assessment of Potential Risks and Benefits for Recipients The experimental treatment has a chance to provide clinical benefit although it is quite possible that patients will obtain no clinical benefit. 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, specifically CAR T cells. The risks of the study fall into 5 general categories. First, chemotherapy that could cause cytopenias is part of the protocol. 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, hypotension, and fever. A third area of toxicity is neurological toxicity such as delirium, obtundation, myoclonus, seizures, headache, and transient focal neurological toxicities including aphasia and focal paresis. Cytokine-release-type toxicities and neurological toxicities have appeared in other clinical trials of CAR T cells during the first 2 weeks after CAR T cells were infused.70,141 The 4th main category of toxicity is direct damage to normal tissues by the CAR T cells. This could happen because of unexpected cross-reactivity of the Hu1928-Hu20BB
CAR with proteins other than CD19 or CD20 in vivo. A 5th possible toxicity is hypogammaglobulinemia. Hypogammaglobulinemia has been a complication of many patients on clinical trials of anti-CD19 CAR-expressing T cells.70,71 Hypogammaglobulinemia in these patients was routinely treated with infusions of intravenous immunoglobulins.70 The lentiviral vector used in this trial inserts into the T-cell DNA of patients, so in theory, insertional mutagenesis could occur, but insertional mutagenesis has not occurred in any of the hundreds of patients treated with mature T cells that were genetically modified by gammaretroviral or lentiviral vectors.73-75 The success of this clinical trial cannot be predicted at this time. A number of clinically appropriate strategies to minimize risks to patients have been built into the protocol through the means of inclusion/exclusion criteria, monitoring strategies, and management guidelines. Because all patients in this protocol have advanced B-cell malignancies 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. Potential adverse reactions attributable to the administration of the study drugs utilized in this trial are discussed in the FDA packet insert. All care will be taken to minimize side effects, but they can be unpredictable in nature and severity.
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12.6 consent process and documentation

The informed consent document will be provided to the participant or consent designee(s) (e.g., 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. 13 The initial consent process as well as **re-consent, when required, may take place in**
person 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). Whether in person or remote, the privacy of the subject will be maintained. Consenting investigators (and participant/consent designee, when in person) will be located in a private area (e.g., clinic consult room). When consent is conducted remotely, the participant/consent designee will be informed of the private nature of the discussion and will be encouraged to relocate to a more private setting if needed. **REGULATORY AND OPERATIONAL CONSIDERATIONS**
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13.1 study discontinuation and closure

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

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

The independence of this study from any actual or perceived influence, such as by the pharmaceutical industry, is critical. Therefore, any actual conflict of interest of persons who have a role in the design, conduct, analysis, publication, or any aspect of this trial will be disclosed and managed. Furthermore, persons who have a perceived conflict of interest will be required to have such conflicts managed in a way that is appropriate to their participation in the design and conduct of this trial. The study leadership in conjunction with the NCI has established policies and procedures for all study group members to disclose all conflicts of interest and will establish a mechanism for the management of all reported dualities of interest.
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14 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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14.1 gamma-retroviral vector containing the

14.1.1 Source/Acquisition and Accountability After cells are obtained by apheresis, further cell processing to generate CAR-expressing T cells will occur in the Department of Transfusion Medicine according to standard operating procedures (SOPs). Individual single IV bags accordingly dose requirements of the dose-escalation plan described in Section **3.1.4** will be prepared for each study participant by DTM personnel. Each single IV bags will be delivered from the Department of Transfusion Medicine to patient care unit where drug will be infused to the patient.
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14.1.2 cells manufacturing

The retroviral vector supernatant (MSGV1-Hu1928-Hu20BB) encoding 2 CARs directed against CD19 and CD20 was prepared and preserved following cGMP conditions in the University of Cincinnati Medical Center Vector Production Facility. The retroviral vector utilizes the MSGV1 retroviral vector backbone and consists of 7007 bps including the 5' LTR from the murine stem cell virus (promoter), packaging signal including the splicing donor (SD) and splicing acceptor sites, the Hu1928-Hu20BB CAR construct encodes 2 separate proteins: (1.) The Hu19-CD828Z CAR containing a signal peptide from human CD8-alpha signal sequence, the human Hu19 scFv, CD8-alpha hinge and transmembrane domains, CD28 (cytoplasmic region), and TCR-zeta (cytoplasmic region), followed by an F2A ribosomal skip domain and (2.) A second CAR called Hu20-CD8BBZ that includes a signal peptide from human CD8-alpha signal sequence, the human Hu20 scFv, CD8-alpha hinge and transmembrane domains, CD28 (cytoplasmic region), and TCRzeta (cytoplasmic region) after this second CAR comes 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 NCI Frederick Biorepository, Frederick, MD. Both storage facilities are equipped with around-the-clock temperature monitoring. Upon request, supernatant will be delivered on dry ice to be used in *in vitro* transductions of T cells. 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 (BSL-2). The specific guidelines for Biosafety Level-2 (BSL-2) can be viewed at http://bmbl.od.nih.gov/sect3bsl2.htm 14.1.3 Toxicities Please refer to section **1.2.15**
14.1.4 Administration procedures Please see section 3.3.  
14.2 **COMMERCIAL AGENTS**
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 14.2.1 Cyclophosphamide 14.2.1.1 Source/Acquisition and Accountability Cyclophosphamide will be provided by the NIH Clinical Center Pharmacy according to standard pharmacy procedures. Individual IV bags will be prepared for each study participant according to assigned dose by NIH Pharmacy personnel. IV bags will be delivered from NIH Pharmacy to patient unit where drug will be infused to the patient.  
14.2.1.2 Administration procedures The cyclophosphamide used in this regimen will be given as Intravenous infusion over 30 minutes. 14.2.2 FLUDARABINE
14.2.2.1 Acquisition and Accountability Fludarabine monophosphate will be provided by the NIH Clinical Center Pharmacy according to standard pharmacy procedures. Individual IV bags will be prepared for each study participant according to assigned dose by NIH Pharmacy personnel. IV bags will be delivered from NIH
Pharmacy to patient unit where drug will be infused to the patient.  
14.2.2.2 Administration procedures Fludarabine is administered as an IV infusion in 100 mL 0.9% sodium chloride, USP over 30 minutes.
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134. Lenz G, Dreyling M, Hoster E, et al. Immunochemotherapy with rituximab and cyclophosphamide, doxorubicin, vincristine, and prednisone significantly improves response and time to treatment failure, but not long-term outcome in patients with previously untreated mantle cell lymphoma: results of a prospective randomized trial of the German Low Grade Lymphoma Study Group (GLSG). *J Clin Oncol.*
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141. Brentjens RJ, Davila ML, Riviere I, et al. CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. *Science* Translational Medicine. 2013;5(177).  
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159. Finlay WJJ, Coleman JE, Edwards JS, Johnson KS. Anti-PD1 'SHR-1210' aberrantly targets pro-angiogenic receptors and this polyspecificity can be ablated by paratope refinement. *mAbs.* 2019;11(1):26-44.  
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161. North RJ. Cyclophosphamide-facilitated adoptive immunotherapy of an established tumor depends on elimination of tumor-induced suppressor T cells. *Journal of* Experimental Medicine. 1982;155(4):1063-1074.  
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166. Dudley ME, Wunderlich JR, Robbins PF, et al. Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. *Science.* 2002;298(5594):850-854.  
167. Dudley ME, Yang JC, Sherry R, et al. Adoptive cell therapy for patients with metastatic melanoma: evaluation of intensive myeloablative chemoradiation preparative regimens. Journal of Clinical Oncology. 2008;26(32):5233-5239.  
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171. Li S, Yang J, Urban FA, et al. Genetically engineered T cells expressing a HER2-specific chimeric receptor mediate antigen-specific tumor regression. *Cancer Gene Therapy.* 2008;15(6):382-392.  
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175. Lee DW, Kochenderfer JN, Stetler-Stevenson M, et al. T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: A
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16 appendices 16.1 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, |                                                                                                                                                                                       |                                                |
| 1                                                                                                       | but ambulatory and able to carry out work of a light or sedentary nature  (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,       |                                                                                                                                                                                       |                                                |  
* 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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16.2 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 - Performance Status - Date of original diagnosis - Tumor Histology and date of confirmation - CD19/CD20 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
- Number of prior lines of therapy B. **Study Drug administration and response for each course of therapy given**
- Dates anti-CD19 and anti CD20 CAR-transduced T cells given - Dose level, actual dose, schedule and route given - Height, weight, and body surface area at start of each course (a course is defined as chemotherapy followed by a CAR T-cell infusion)
- 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-CMV, HSV, EBV, toxoplasmosis, adenovirus (patient and donor) TTV data 2. All staging studies including CT scan, PET scan results and bone marrow biopsy and peripheral blood flow cytometry results will be reported at the scheduled follow-up points at 1 months and 2 months after infusion; after 2 months only the overall malignancy status (CR, PR, stable disease, progression) will be reported.
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d. adverse events

Please see section **6.1.1** Adverse Event Reporting 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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16.3 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:
- Any history of syncope or near-syncope within 1 month before CAR T-cell infusion or any time after CAR T-cell infusion.  
- 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.  
- 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.
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- patients with a systolic

- 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 70% 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** infused IV over 1 hour (dose should not exceed 800 mg). If clinical improvement is not observed after the first dose, up to three additional doses of tocilizumab may be administered until clinical improvement is seen.  
- 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 more than 5 mcg/minute 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 3x upper limit of normal - AST or ALT of 400 U/L or higher
- Serum sodium of 127 mmol/L or lower Intermediate-dose methylprednisolone for toxicities not responsive to tocilizumab 1. Give methylprednisolone 50 mg every 6 hours for any of the toxicities under \#19 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 2 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 methylprednisolone, 1000 mg of methylprednisolone can be administered.  
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. 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
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114 version datemay 27 2020

neurological toxicity, so it should not be given when patients have isolated neurological toxicity.  
1. Inability of patient to follow simple commands such as "squeeze my fingers".  
2. Any generalized seizure 1. Somnolence that is different than normal sleep such as constant sleep or difficult to arouse or any difficulty with airway protection or Grade 3 somnolence (stupor).  
2. Ataxia severe enough to preclude ambulation 3. Disorientation to person or place that persists longer than 48 hours 4. Neurologic toxicity lasting more than 2 hours that is severe enough to interfere with self-care activities of daily living (ADLs)
5. Cerebral edema
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16.4 appendix dinfusion instructions 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.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          | RN will be informed of the approximate  time of cell arrival at the bedside by cell  processing. | a. 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 is 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. |                                                                                                  |                                                                         |  
116 Version Date:May 27, 2020  
| Version Date:May 27, 2020 8. Verify the patency of the patient's IV                                                                                                                                                                                                                                                                                                                                                                                                                                                                                | A central venous access device such as a                                                                                                                                                                                                                                                    |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| access.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            | non-valved 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 sign the tag on the cell bag. 13. Infuse the cells by INFUSION PUMP or syringe over 20-30 minutes. 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 | This prevents the cells from clumping in 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. |                                                                                                                                                                                                                                   |  
118 Version Date:May 27, 2020
untitled h1
16.5 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)
119 Version Date:May 27, 2020 16.6 APPENDIX F: CYTOKINE RELEASE SYNDROME GRADING ASSESSMENT (ADAPTED FROM
LEE ET AL, 2019). ASTCTCRS **CONSENSUS GRADING**  
| Table 2 ASTCT CRS Consensus Grading   |                                                           |                                                                                                                                                                               |                   |         |
|---------------------------------------|-----------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------|---------|
| CRS                                   |                                                           |                                                                                                                                                                               |                   |         |
| Parameter                             | Grade 1                                                   | Grade 2                                                                                                                                                                       | Grade 3           | Grade 4 |
| Fever⁎**                              | Temperature  Temperature  ≥38°C                           | Temperature ≥38°C                                                                                                                                                             | Temperature ≥38°C |         |
| ≥38°C                                 |                                                           |                                                                                                                                                                               |                   |         |
| With                                  | Requiring multiple  vasopressors  (excluding vasopressin) |                                                                                                                                                                               |                   |         |
| And/or††                              | Requiring a vasopressor  with or without  vasopressin     |                                                                                                                                                                               |                   |         |
| Hypotension None                      | Not requiring  vasopressors Requiring lowflow nasal  cannula‡‡ or  blow-by                                                           | Requiring high-flow  nasal cannula‡‡,  facemask, nonrebreather  mask, or Venturi mask Requiring positive  pressure (eg, CPAP,  BiPAP, intubation and  mechanical ventilation) |                   |         |
| Hypoxia                               | None                                                      |                                                                                                                                                                               |                   |         |  
Organ toxicities associated with CRS may be graded according to CTCAE v5.0 but they do not influence CRS grading.  
Fever is defined as temperature ≥38°C not attributable to any other cause. In patients who have CRS then receive antipyretic or anticytokine therapy such as tocilizumab or steroids, fever is no longer required to grade subsequent CRS severity. In this case, CRS grading is driven by hypotension and/or hypoxia. Hypotension is defined as a systolic blood pressure <90 mm Hg. †CRS grade is determined by the more severe event: hypotension or hypoxia not attributable to any other cause. For example, a patient with temperature of 39.5°C, hypotension requiring 1 vasopressor, and hypoxia requiring low-flow nasal cannula is classified as grade 3 CRS. ‡Low-flow nasal cannula is defined as oxygen delivered at ≤6L/minute. Low flow also includes blow-by oxygen delivery, sometimes used in pediatrics. High-flow nasal cannula is defined as oxygen delivered at >6L/minute.