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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:_clinical trials.gov. _X_ BTRIS (automatic for activities in the Clinical Center) _X_ Publication and/or public presentations. When will the data be shared? _X_ Before publication. _X_ At the time of publication or shortly thereafter.
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6.3 response criteria 6.3.1 response

(Cheson et al. Revised Response Criteria for Malignant Lymphoma, Journal of Clinical Oncology 2007 182 and Recommendations for Initial Evaluation, Staging, and Response Assessment of NonHodgkin Lymphoma: The Lugano Classification Journal of Clinical Oncology, 2014183)
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6.3.1.1 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 1.0 cm or less in longest diameter, the patient is considered to be in CR.  
1. In typically FDG-avid lymphoma (diffuse large B cell lymphoma, and T cell lymphomas):
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.  
2. 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 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.  
3. The spleen and/or liver, if considered to be enlarged before therapy on basis of Physical exam or CT scan mustbe 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.  
4. A bone marrow aspirate and biopsy is performed only when the patient had bone marrow involvement with lymphoma prior to therapy 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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6.3.1.2 partial remission (pr) pr

1. ≥ 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.  
2. No increase in size of nodes, liver or spleen and no new sites of disease. 3. 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.  
4. 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.  
5. 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.  
6.3.1.3 Progressive Disease (PD): Defined by at least one of the following:
1. ≥ 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.  
2. Appearance of a new lesion greater than 1.5 cm in any axis even if other lesions are decreasing in size 3. Greater than or equal to a 50% increase in size of splenic or hepatic nodules 4. At least a 50% increase in the longest diameter of any single previously identified node more than 1 cm in its short axis.  
5. 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)
- 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.  
1. Flow cytometric, molecular or cytogenetic studies will not be used to determine response.
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6.4 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 with the exception of cytokine release syndrome (CRS), which will be graded according to the CRS grading scale of Lee et al.184. 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 (https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm\#ctc_50).
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7 nih reporting requirements/data and

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

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

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

Problems expeditiously reported to the OHSRP in iRIS will also be reported to the NCI Clinical Director. A separate submission is not necessary as reports in iRIS will be available to the Clinical Director. In addition to those reports, all deaths that occur within 30 days after receiving a research intervention should be reported via email to the Clinical Director unless they are due to progressive disease. To report these deaths, please send an email describing the circumstances of the death to 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 the study agent 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 study agent, but are not fatal or life-threatening, must be reported to the NIH IBC as soon as possible, but not later than 15 calendar days after the investigator's initial receipt of the information. Adverse events may be reported by using the FDA Form 3500a.
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7.4.2 annual reports to ibc

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

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

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

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

An adverse event or suspected adverse reaction is considered serious if in the view of the investigator or the sponsor, it results in any of the following:
- Death, - A life-threatening adverse event (see section 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)
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8.1.4 severity

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

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

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

Any AE that meets a protocol-defined serious criterion or meets the definition of Adverse Event of Special Interest that require expedited reporting must be submitted immediately (within 24 hours of awareness) to OSRO Safety using the CCR SAE report form. All SAE reporting must include the elements described in section 8.2. SAE reports will be submitted to the Center for Cancer Research (CCR) at: OSROSafety@mail.nih.gov and to the CCR PI and study coordinator. CCR SAE report form and  
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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 receiving protocol treatment. Pregnancy of the patient's partner is not considered to be an AE. However, the outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, or congenital abnormality) occurring from the date of the first dose until (*120 days)* after the last dose should, if possible, be followed up and documented.
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8.5 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

The primary endpoint of this trial is to determine the safety of administering CAR-expressing T
cells to patients with malignancies. Secondary objectives of this trial are to measure any antimalignancy effect that might occur, to assess the feasibility of administering CAR-expressing T
cells, and to measure persistence and function of CAR-expressing T cells. The study will be conducted using a standard 3+3 approach as defined in section 3.1. Patients will be enrolled on a 2 different cohorts: **Cohort 1**: Patients who have not had an allogeneic hematopoietic stem cell transplant (allo HSCT) and **Cohort 2**: Patients who have had a 9/10 or 10/10 HLA-matched sibling or an 9/10 or 10/10-matched unrelated donor transplant. 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 the patients who have undergone prior alloHSCT. DLTs occurring on one cohort's dose escalation will not affect dose escalation of the other cohort.  
The trial will be conducted as 2 different dose escalation schemes, one for Cohort 1 (nonalloHSCT) and Cohort 2 (alloHSCT recipients). For each cohort, a dose escalation scheme with up to 5 dose levels and up to 6 patients per dose level will be carried out. (There will be an additional 3 patients in Cohort 1 Dose Level 3 who received the lower chemotherapy dose before Amendment E, Protocol version: 08/03/2018) In addition, up to 8 additional patients can be treated at the MTD for each cohort to establish additional safety and toxicity data at that level. Thus, up to 79 patients may be enrolled onto the trial. The fraction of post-allogeneic transplant patients experiencing Grade 3 or 4 toxicities will be compared to the fraction of patients who never had an allogeneic transplant experiencing Grade 3 or 4 toxicities by using a Fisher's exact test. The degree of persistence of CAR-transduced T cells will be evaluated by a quantitative measure (flow cytometry or quantitative PCR) in all patients. Anti-malignancy effects will be measured by clinical response and categorized according to Section 6.3. 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. All other evaluations of secondary objectives will be performed using exploratory techniques. No formal adjustment for multiple comparisons will be used since the evaluations are being done to generate hypotheses.  
It is anticipated that 5 years will be required to enroll up to a maximum of 79 patients onto this trial.
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11 human subjects protections 11.1

The patients to be entered in this protocol have advanced hematologic malignanciesthat 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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11.2 participation/selection rationale

- The eligibility criteria for this protocol only allow enrollment of patients with advanced 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 hematologic 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. The success of anti-CD19 CAR T cells against B-cell lymphomas provides a rationale for developing an anti-CD30 CAR for treating CD30+ lymphomas.  
- Because patients on previous trials of CAR T cells have experienced hypotension, tachycardia, prolonged fevers, neurological toxicities, and depressed myocardial function, participation in this trial clearly carries significant risk. In many patients on prior CAR trials, toxicities were severe enough to require intensive care unit admission. We will limit enrollment to patients 73 years of age or less because based on our admittedly limited experience with prior CAR-T cell clinical trials, younger patients tolerate and recover from these toxicities better than elderly patients.
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11.3 participation of children

Children 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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11.4 participation ofsubjects unable togiveconsent

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 **11.5**), all patients subjects ≥ age 18 will be offered the opportunity to fill in their wishes for research and care, and assign a substitute decision maker on the "NIH Advance Directive for Health Care and Medical Research Participation" form so that another person can make decisions about their medical care in the event that they become incapacitated or cognitively impaired during the course of the study. Note: The PI or AI will contact the NIH Ability to Consent Assessment Team (ACAT) for evaluation as needed for the following: an independent assessment of whether an individual has the capacity to provide consent; assistance in identifying and assessing an appropriate surrogate when indicated; and/or an assessment of the capacity to appoint a surrogate. For those subjects that become incapacitated and do not have pre-determined substitute decision maker, the procedures described in NIH HRPP SOP 14E for appointing a surrogate decision maker for adult subjects who are (a) decisionally impaired, and (b) who do not have a legal guardian or durable power of attorney, will be followed.
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11.5 evaluation of benefits and

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 6 general categories (see section 12 for details). 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.122,158 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 antiCD30 CAR with proteins other than CD30 in vivo. A 5th category of toxicity caused by anti-CD30 CAR T cells is impairment of normal immunity because CD30 is expressed on activated T cells and activated B cells. A 6th possible toxicity is gene-therapy-related toxicity caused by the lentiviral vector. 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.125-127 The risks associated with biopsies are pain and bleeding at the biopsy site. In order to minimize pain, local anesthesia will be used. Rarely, there is a risk of infection at the sampling site. The success of this clinical trial cannot be predicted at this time. Because all patients in this protocol have advanced hematologic 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.
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11.5.1 risks of exposure to

The procedures for performing the CT scans will follow clinical policies, no special procedures apply to these additional assessments for research purposes. In summary, subjects may receive additional radiation exposure from up to eight (8) CT neck +CAP , three (3) CT-Guided biopsies and eight (8)18FDG-PET/CT scans in the first year of the study. The total additional radiation dose for research purposes will be approximately 22.4 rem in the first year of the study. This amount is more than would be expected from everyday background radiation. Being exposed to too much radiation can cause harmful side effects such as an increase in the risk of cancer. The risk of getting cancer from the radiation exposure in this study is 2.2 out of 100 (2.2%) and of getting a fatal cancer is 1.1 out of 100 (1.1%).
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11.5.2 risks of scans and

If contrast dye is used, there is a small chance of developing an allergic reaction from the contrast material, which may cause symptoms ranging from mild itching or a rash to severe difficulty breathing, shock or rarely, death. The contrast material may also cause kidney problems. Common reactions include pain in the vein where the contrast was given, a metallic or bitter taste in the mouth , headache, nausea and a warm or flushing feeling that lasts from 1-3 minutes. An IV line may need to be inserted for administration of the contrast agent or anesthetic, which may cause pain at the site where the IV is placed and there is a small risk of bruising or infection
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11.5.3 risks of blood sampling

Side effects of blood draws include pain and bruising, lightheadedness, and rarely, fainting.
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11.5.4 risks of bone marrow

Side effect of bone marrow aspiration and biopsy may feel a pressure sensation when the needle is being inserted and a pulling sensation and brief pain as the marrow is withdrawn. Potential complications of this procedure are local bleeding, pain at the site, and infection. Both of these are very rare. Bleeding can be stopped by applying local pressure and an infection can be treated with antibiotics.
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11.5.5 risks of intravenous catheter

Side effect of placing some catheters include pain, bleeding, infection and rarely, collapsed lung. The long- term risks of the catheter rarely include infection and clotting of veins.
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11.5.6 risks of lumbar puncture

Side effect of lumbar puncture may cause pain at the site where the needle goes in and the spinal fluid is taken. There is a small risk of infection or bleeding. A third or fewer patients may experience some headache while the body replaces the fluid that is removed.
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11.5.7 risks of apheresis

The risks of apheresis are similar to whole blood donation and include pain and bruising at the needle insertion site in the arms, lightheadedness, dizziness, nausea, and rarely fainting due to a rare reflex reaction to needle placement and to the temporary decrease in blood volume during apheresis. It may also feel tingling around your mouth or in your fingers caused by a blood thinner given during the procedure. The tingling may reduce by giving calcium containing chewable antacid. All the symptoms usually go away within a few minutes of stopping the procedure.
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11.6 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. 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. Consent for the optional biopsies performed on this study will be obtained at the time of the procedure. If the patient refuses the optional biopsy at that time, the refusal will be documented in the medical record and in the research record
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12 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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12.1 lentiviralvector containing the anti-cd30cargene

The lentiviral vector (LSIN-5F11-28Z) encoding a chimeric antigen receptor (CAR) directed against CD30 was prepared and preserved following cGMP conditions in the Indiana University Vector Production Facility. This self-inactivating 3rd generation lentiviral vector includes the murine stem cell virus promoter, and a truncated version of the woodchuck post-transcriptional regulatory element (WPRE) designated oPRE.  
185 The anti-CD30 CAR protein encoded by this vector contains a signal peptide from human CD8-alpha, 5F11 fully-human antibody light chain variable region (5F11 VL), linker peptide, 5F11 fully-human antibodyheavy chain variable region (5F11 VH), human CD28 hinge, transmembrane, and cytoplasmic regions and the CD3-zeta (cytoplasmic region) T-cell activation domain. The vector will be stored at –80° C in the Dept. of Transfusion Medicine, Clinical Center NIH. Both storage facilities are equipped with around-the-clock temperature monitoring. Vector will be used in *in vitro* transductions of T cells. There will be no re-use of the same unit of supernatant for different patients. Handling of the vector should follow the guidelines of Biosafety Level-2 (BSL2). The specific guidelines for Biosafety Level-2 (BSL-2) can be viewed at http://bmbl.od.nih.gov/sect3bsl2.htm
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12.2 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
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12.2.1 cyclophosphamide

12.2.1.1 Source Cyclophosphamide will be purchased by the NIH Clinical Center Pharmacy Department from commercial sources. 12.2.1.2 Administration procedures The cyclophosphamide used in this regimen will be given as Intravenous infusion over 60 minutes.
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12.2.2 fludarabine

12.2.2.1 Source Fludarabine monophosphate will be purchased by the NIH Clinical Center Pharmacy Department from commercial sources. 12.2.2.2 Administration procedures Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Fludarabine is administered as an IV infusion in 100 ml 0.9% sodium chloride, USP over 15 to 30 minutes. The doses will be based on body surface area (BSA).
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13 references

1. Gattinoni L, Finkelstein SE, Klebanoff CA, et al. Removal of homeostatic cytokine sinks by lymphodepletion enhances the efficacy of adoptively transferred tumor-specific CD8+
T cells. *Journal of Experimental Medicine.* 2005;202(7):907-912.  
2. 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.  
3. Klebanoff CA, Khong HT, Antony PA, Palmer DC, Restifo NP. Sinks, suppressors and antigen presenters: How lymphodepletion enhances T cell-mediated tumor immunotherapy. *Trends in Immunology.* 2005;26(2):111-117.  
4. Stein H, Mason DY, Gerdes J, et al. The expression of the Hodgkin's disease associated antigen Ki-1 in reactive and neoplastic lymphoid tissue: Evidence that Reed-Sternberg cells and histiocytic malignancies are derived from activated lymphoid cells. *Blood.*
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100 Version Date:October 19, 2020
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14 appendices 14.1 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. 14.2 APPENDIX B: **DATA COLLECTION ELEMENTS REQUIRED BY PROTOCOL** 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 - Stage at diagnosis - Tumor Histology and date of confirmation
- CD30 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 - Findings of consultations done at screening
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b. study drug administration and

- Dates anti-CD30-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

- 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
- 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.  
D. **Adverse Events**
Please see section **6.1.1** Adverse Event Reporting
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e. tumor response and measurements

- Restaging studies performed at protocol specified time points and as clinically indicated.  
- Any physical exam finding before 1 month after the infusion will not be collected in C3D, only labs and Adverse Events.  
- Years 5-15 follow-up is only for survival.  
F. Off study
- Date and reason for off study
- Date and cause of death - Autopsy findings
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14.3 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.122 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 at all possible to avoid killing or impairing the function of the CAR T cells.
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general supportive care guidelines

1. All patients with significant malignancy burdens and without a contradiction such as allergy should be started on allopurinol at the time of the start of the chemotherapy conditioning regimen or 1 day before the CAR T cell infusion. The suggested allopurinol dose is 200 to 300 mg/day with a possible loading dose of 300 to 400 mg.  
2. Vital signs should be checked a minimum of every 4 hours during hospitalization.  
Increasing the time interval between vital sign checks for patient convenience or other reasons should be avoided.  
3. Strict ins and outs should be recorded on all patients. 4. As a minimum, keep hemoglobin greater than 8.0 g/dL and platelets greater than 20K/microliter.  
5. Administer fresh frozen plasma (FFP) for a PTT 1.5-fold or more above the upper limit of normal.  
6. For patients with an increased PTT, check the fibrinogen level and keep the fibrinogen level above 100 mg/dL with cryoprecipitate.  
7. Fevers should be treated with acetaminophen and comfort measures. NSAIDs and corticosteroids should be avoided.  
8. Patients with a heart rate persistently higher than 115/minute and fever should have vital signs checked every 2 hours.  
9. Patients who are neutropenic and febrile should be receiving broad-spectrum antibiotics. 10. Avoid meperidine due to seizure risk. 11. Minimize benzodiazepine use to avoid aggravating delirium. 12. Patients on this protocol will be placed on strict fall precautions including instructions to get out of bed only with assistance under the following conditions:
1) Any history of syncope or near-syncope within 1 month before CAR T-cell infusion or any time after CAR T-cell infusion.  
2) Any blood pressure reading of less than 100 mm Hg systolic blood pressure after anti-CD19 CAR T-cell infusion if 100 mm Hg is lower than the patients baseline systolic blood pressure.  
3) Heart rate greater than 100 beats per minute.  
13. Any patient with syncope, near-syncope, or light-headedness will have orthostatic blood pressure and heart rate checked and receive intravenous fluids as appropriate. These patients will also receive an ECG.  
14. A CBC will be obtained twice daily while the patient is inpatient. If the absolute neutrophil count becomes less than 500/microliter, Filgrastim will be initiated at a dose of 300 micrograms daily for patients under 70 kg in weight and a dose of 480 micrograms daily for patients over 70 kg in weight only in patients with absolute neutrophil counts less than 500/microliter. Filgrastim will be discontinued as soon as the absolute neutrophil count recovers to 2000/microliter.  
15. Hypotension is a common toxicity requiring intensive care unit (ICU) admission. In general patients should be kept well-hydrated. Maintenance I.V. fluids (normal saline (NS) should be started on most patients with high fevers especially if oral intake is poor or the patient has tachycardia. I.V. fluids are not necessary for patients with good oral intake and mild fevers. For patients who are not having hypotension or tumor lysis syndrome, a generally even fluid balance should be strived for after allowing for insensible fluid losses in patients with high fevers. The baseline systolic blood pressure is defined for this protocol as the average of all systolic blood pressure readings obtained during the 24 hours prior to the CAR T-cell infusion. The first treatment for hypotension is administration of IV NS boluses.  
- Patients with a systolic blood pressure that is less than 80% of their baseline blood pressure and **less than 100 mm Hg should receive a 1 L NS bolus.**
- Patients with a systolic blood pressure less than 90 mm **Hg should receive a 1 L**
NS bolus regardless of baseline blood pressure.  
These I.V. fluid management suggestions may need to be modified based on the clinical characteristics of individual patients such as pulmonary status, cardiac function, edema and other factors.  
16. Patients receiving more than 1 fluid bolus for hypotension should have a stat EKG and troponin, and a cardiac echocardiogram as soon as possible.
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icu transfer

Patients should be transferred to the ICU under these circumstances. Patients not meeting these criteria could also require ICU admission at the discretion of the clinical team caring for the patient.  
- Systolic blood pressure less than 75% the patient's baseline blood pressure and less than 100 mm Hg after administration of a 1L NS bolus.  
- Anytime the systolic blood pressure is less than 90 mm Hg after a 1L NS bolus if 90 mm Hg is less than the patient's baseline systolic blood pressure.  
- 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).  
- 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 micrograms/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 40% or greater fraction of inspired oxygen (FIO2) for maintain oxygen saturation of >92%.  
- Subjective significant dyspnea and respiratory rate greater than 25 for 2 hours or more.  
- PTT or INR>2x upper limit of normal - Bleeding possibly related to cytokine-release syndrome - Creatine kinase greater than 5x upper limit of normal
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intermediate-dose methylprednisolone for toxicities not

1. Give methylprednisolone 50 mg every 6 hours for any of the toxicities under \#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 8 hours or more. If the patient has not already had tocilizumab, administer 8 mg/kg tocilizumab in addition to methylprednisolone.  
3. Give methylprednisolone 200 mg every 6 hours for any left ventricular ejection fraction 30%
or less. If the patient has not already had tocilizumab, administer 8 mg/kg tocilizumab in addition to methylprednisolone.  
4. Give methylprednisolone 200 mg every 6 hours for any situation in which pulmonary toxicity makes mechanical ventilation likely to be required within 4 hours. If the patient has not had tocilizumab, administer 8 mg/kg tocilizumab in addition to methylprednisolone.  
5. In life-threating toxicity not improving after 200 mg of 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 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 3. Somnolence severe enough to potentially limit airway protection  
4. Ataxia severe enough to preclude ambulation 5. Disorientation to person or place that persists longer than 48 hours 6. Neurologic toxicity lasting more than 2 hours that is severe enough to interfere with activities of daily living (ADLs)  
| Stage   | Skin                                     | Liver                    | Gut               |
|---------|------------------------------------------|--------------------------|-------------------|
| 1       | Rash < 25% BSAa                          | Total bilirubin 2.0-2.9  | Diarrhea >500-    |
| mg/dlb  | 1000ml/day, or  upper GI symptoms        |                          |                   |
| 2       | Rash 25-50% BSA                          | Total bilirubin 3.0-6.0  | Diarrhea 1001-    |
| mg/dl   | 1500ml/day                               |                          |                   |
| 3       | Rash >50% BSA                            | Total bilirubin 6.1-15.0 | Diarrhea 1501 to  |
| mg/dl   | 2000 ml/d                                |                          |                   |
| 4       | Bullae                                   | Total bilirubin > 15.0   | Diarrhea >2000 mL |
| mg/dl   | /day or severe  abdominal pain or  ileus |                          |                   |  
14.4 APPENDIX D:CLINICAL STAGING AND TREATMENT OF ACUTE GVHD **108,109**
aBSA = body surface area; use "rule of nines" or burn chart to determine extent of rash.  
bRange given as total bilirubin.  
Note: Elevation of transaminase without elevation of bilirubin is not recognized as acute GVHD (A note should say "GVHD transaminitis" and mention if biopsy proven or not.)
c Persistent nausea with histologic evidence of GVHD in the stomach or duodenum.  
The nominal stage is reduced by one if the organ is simultaneously and unequivocally affected by a complication other than GVHD.  
Gradee Skin Liver Gut  
0 (none) None None None I Stage 1-2 None None II Stage 3 Stage 1 Stage 1 III Stage 2-3 Stage 2-4  
IVd Stage 4e Stage 4 Stage 4  
eCriteria for grading given as minimum degree of organ involvement required to confer that grade.  
The highest single organ stage determines the overall grade.  
dPatients with Stage 4 gut GVHD are usually Grade IV. Stage 4 gut GVHD can only be a part of Grade III when it is not severe enough to cause a substantially impaired performance status. A substantially impaired performance status would be an ECOG performance status of 3 or 4.  
eDesignation of Grade III is appropriate for only scattered bullae.  
The NIH Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versushost Disease defines classic acute GVHD as maculopapular rash, nausea, vomiting, anorexia, profuse diarrhea, ileus, or cholestatic hepatitis occurring within 100 days after transplantation or DLI 107. We will define acute GVHD in the same manner for this trial.  
This schema is intended to serve as a guideline and to promote consistency in our clinical practice; it may be modified for individual patients as clinical circumstances warrant. Failure to follow these guidelines is not a protocol deviation.
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grade i gvhd

1) Topical corticosteroids (usually 0.1% triamcinolone; 1% hydrocortisone to face) applied to rash BID.  
Grade II-IV GVHD: 1) Methylprednisolone (MP) 1 mg/kg per dose IV, BID for 4 consecutive days. 2) If no response after 4 days, continue until response (7-day maximum trial); the dose may be doubled (4 mg/kg/day).  
3) If response within 7 days, taper as follows:
a) 0.75 mg/kg per dose IV BID for 2 days. b) 0.5 mg/kg per dose IV BID for 2 days. c) 0.375 mg/kg per dose IV BID for 2 days. d) If clinically appropriate, change MP to oral prednisone to equivalent of IV dose) daily for 2 days. MP may be converted to prednisone later in the taper at the investigators' discretion.  
e) After this, steroids will be reduced by 10% of starting oral dose each week until a dose of 10 mg/day is reached. Subsequent reductions will be made at the investigators' discretion.  
f) If GVHD worsens during taper, steroids should be increased to previous dose.  
g) During steroid taper, maintain cyclosporine at therapeutic levels.  
4) If no response is observed within 7 days of MP treatment:
a) Increase Methylprednisolone to 10 mg/kg per dose IV, BID for 2 days. b) If there is no improvement, consideration will be given to using second-line immunosuppressive therapy, e.g., tacrolimus, mycophenolic acid, monoclonal antibodies, or studies of investigational agents for acute GVHD, if they are available.  
5) Antifungal prophylaxis with agents effective against mould will be started when it is anticipated that the patient will be receiving steroids at > 1 mg/kg/day of methylprednisolone (or equivalent) for > 2 weeks. Voriconazole, caspofungin, liposomal amphotericin B (Ambisome), posaconazole or amphotericin B lipid complex (Abelcet) are valid alternatives. During prophylaxis with any of the above agents, fluconazole should be discontinued. In patients with therapeutic cyclosporine levels at the initiation of voriconazole therapy, the cyclosporine or Tacrolimus dose should be decreased by approximately 50%. In patients with therapeutic Sirolimus levels at the initiation of voriconazole therapy, the Sirolimus dose should be decreased by approximately 90%.  
6) Determination of GVHD treatment response should be made within 96 hours of starting the treatment. The following are criteria to determine definitions of response to GVHD treatment:  
a) Complete response: Complete resolution of all clinical signs and symptoms of acute GVHD.  
b) Partial Response: 50% reduction in skin rash, stool volume or frequency, and/or total bilirubin. Maintenance of adequate performance status (Karnofsky Score > 70%).  
c) Non-responder: < 50% reduction in skin rash, stool volume or frequency, and/or total bilirubin. Failure to maintain adequate performance status (Karnofsky Score ≤ 70%).
Progressive disease: Further progression of signs and symptoms of acute GVHD, and/or decline in performance status after the initiation of therapy.  
111 Version Date:October 19, 2020
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14.5 appendix e infusion instructions

Primary IV tubing (2) Secondary IV tubing (1) NS (sodium chloride 0.9%) 250cc bags (2) IV infusion pump Gloves  
| Steps:                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          | Key Points:                                                                       |    |                                                                      |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------|----|----------------------------------------------------------------------|
| 1.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              | The RN will be informed of the  approximate time of cell arrival at  the bedside. | 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 and DPA  are signed. 4. Ensure that emergency and monitoring  equipment are available in the patient's  room: - oxygen - suction - vital sign monitor with pulse oximeter  and thermometer  5. Provide patient education covering  infusion procedure, potential complications  and associated symptoms to report. |                                                                                   |    |                                                                      |  
| 7. Measure and record baseline vital signs,  respiratory and circulatory assessments. 8. Verify the patency of the patient's IV                                                                                                                                                                                                                                                                                                                                                                              | A central venous access device such as a                                                                                                                                                                                                                                                    |                  |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------|
| 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  and infuse this at the same rate as the  cells; rinse bag until NS runs clear.                                                                                                                                                                                                                                                                                                                                                                  | This prevents the cells from clumping in the  bag.                                                                                                                                                                              |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
|                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       | 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. |                                                                                                                                                                                                                                 |