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8.4.2 general toxicity management considerations

Replication-competent lentivirus (RCL): Information on the risks of RCL is contained in Section 1.5.3.9. Regulatory agencies and the gene therapy community have previously discussed measures to be taken should an RCL be confirmed in a subject. However, because the probability and characteristics of an RCL are unknown, no guidelines have been put in place. Nevertheless, all agree that the subject must be isolated until an understanding of how to manage the subject becomes clear. Some considerations are  
o Intensive follow-up of subject in consultation with gene therapy experts, study investigators, FDA and NIH.  
o Inform local public health officials and CDC. o Identify sexual partners and provide appropriate counseling and intervention.
RCL will be monitored by a suitable Q-PCR DNA assay for detection of the lentivirus (for example: HIV gag DNA or VSV-G DNA). If a positive RCL DNA assay result is obtained, the PI will be informed and the subject rescheduled for a retest for the DNA test. If the second DNA test is positive, then infusions of subsequent patients will be temporarily halted. The patient will undergo a blood draw for isolation of HIV from his/her cells. The virus will be sequenced and compared to sequences of the transfer vector and packaging constructs, as well as to available HIV sequences to determine the origin of the virus. Determination of the origin of the virus can be easily performed by evaluation for HIV accessory genes such as vif, vpr and vpu which are not present in the packaging constructs. If the sequence is derived from wt-HIV then infusions for all subjects can resume, and the patient will be referred to treatment for HIV. If an RCL is confirmed, or the virus cannot be isolated from the blood draw, the patient will be scheduled for apheresis and will undergo a full biological RCL testing for detection and/or characterization of the RCL.  
Clonality and insertional oncogenesis: Four of nine treated patients in a gene therapy trial for Xlinked Severe Combined Immunodeficiency (SCID) developed T cell leukemia 31-68 months posttreatment. The T cell leukemias were attributable to clonal expansion conferred by gammaretroviral vector integration sites in the CD34+ bone marrow stem cell modification (Hacein-Bey-Abina et al., 2008). This represents the most severe adverse event caused by vector integration. However, there is also evidence for retroviral vector integration site dominance in a gene therapy trial of -thalassaemia without malignancy (Cavazzana-Calvo et al., 2010). The lentiviral vector used for CART-19 manufacturing is part of a vector class that may have a lower risk for integration in or near oncogenic regions than oncoretroviral vectors (Montini et al., 2009). As of May 2015, none of the patients treated with CART-19 have developed a new malignancy, T cell or otherwise, related to lentiviral vector integration. Subjects will be monitored for evidence of unexpected CART-19 expansion by CART-19 transgene quantitation by qPCR and clinical monitoring for malignancy by complete blood count (CBC) as part of the study design. If an unexpected pattern of CART-19 cell expansion is observed (i.e. CART-19 cell expansion in the absence of CD19+ target), subjects will be closely monitored clinically for new malignancies, particularly T cell, and further studies, including insertion site analysis, will be considered to investigate the molecular basis of the expansion. Investigators should consult with the Regulatory Sponsor if an unexpected pattern of CART-19 expansion and/or a new malignancy arises. Subjects will continue to be similarly monitored for clonality and insertional oncogenesis when enrolled on the long term follow-up protocol.  
Uncontrolled T cell proliferation. CART-19 cells could proliferate without control of normal homeostatic mechanisms. It is expected that the T cells will proliferate in response to signals from the malignant tumor or normal B and plasma cells. This could be beneficial or harmful depending on the extent of proliferation. Clonal dominance of adoptively transferred T cells has been associated with tumor reduction in adoptive transfer trials25. If uncontrolled T cell proliferation occurs, subjects may be treated with corticosteroids. Subjects will be treated with pulse methylprednisolone (2 mg/kg i.v. divided q8 hr x 2 days), followed by a rapid taper.  
B cell depletion. It is possible that B cell depletion and hypogammaglobulinemia will occur. This is common with anti-CD20 directed therapies71. In the event of clinically significant hypogammaglobulinemia (i.e. systemic infections or prolonged periods with total serum IgG levels
<500 mg/dL), consideration will be given to intravenous immunoglobulin (IVIG) by established clinical dosing guidelines to restore normal levels of serum immunoglobulin levels, as has been done with Rituximab. Determination about IVIG therapy will be made on a case-by-case basis based on each patient's medical history, current condition, and risk of adverse reaction to IVIG.  
Infusion reaction. Acetaminophen and diphenhydramine hydrochloride may be repeated every 6 hours as needed. A course of non-steroidal anti-inflammatory medication may be prescribed if the patient continues to have fever not relieved by acetaminophen. It is recommended that patients not receive corticosteroids at any time, except in the case of a life threatening emergency, since this may have an adverse effect on CART-19 cells.
Febrile reaction. In the event of febrile reaction, an evaluation for infection should be initiated, and patients managed appropriately with antibiotics, fluids and other supportive care as medically indicated and determined by the treating physician. In the event that the patient develops sepsis or systemic bacteremia following CAR T cell infusion, appropriate cultures and medical management should be initiated. If a contaminated CART-19 T cell product is suspected, the product can be retested for sterility using archived samples that are stored in the . Consideration of a cytokine release syndrome (see below) should be given.  
Macrophage activation syndrome (MAS). Based on the observations of subjects treated on UPENN
protocol , there is some concern for macrophage activation syndrome (MAS).
Treatment and timing of treatment of this toxicity will be at the discretion of the patient's physician and the study investigator. Suggested management might include: if the subject has a fever greater than 101°F that lasts more than 2 consecutive days and there is no evidence of infection (negative blood cultures, CXR or other source), tocilizumab 8 mg/kg can be considered. The addition of corticosteroids and anti-TNF therapy can be considered at the physician's discretion.  
Cytokine Release Syndrome (CRS) / Macrophage Activation Syndrome (MAS)
Selective tocilizumab therapy has been utilized (described below) to manage CRS/MAS toxicity without precluding CAR T cell expansion in patients. Please note, steroids or other immunosuppressant drugs should NOT be used as pre-medication for CART-19 cell therapy but may be considered in the management of CRS. The moderate to severe cases of CRS observed required intervention with single dose tocilizumab with or without high dose corticosteroids, between 2 and 9 days after T cell infusion to date. This resulted in rapid reversal of the high persistent fevers and hemodynamic instability associated with CRS in most but not all patients.  
Given the dramatic clinical improvement of patients after treatment with anti-cytokine therapy, patients with moderate to severe cytokine toxicities should be managed with administration of tocilizumab.  
Tocilizumab should be used as a single, weight-based dose of 8 mg/kg at the time of hemodynamic instability. This management approach is designed to avoid life-threatening toxicities, while attempting to allow the CART-19 cells to establish a proliferative phase that appears to correlate with anti-tumor efficacy. Thus, the timing of the tocilizumab should be individualized, in close consultation with the Principal Investigator and/or expert consultants for the trial. Steroids have not always been effective in this setting and may not be necessary given the rapid response to tocilizumab. Because steroids will interfere with CART-19 cell function and efficacy, if used, they should be rapidly tapered. Upon developing the prodrome of high-persistent fevers following CART-19 cell infusion, patients should be followed closely. Infection and tumor lysis syndrome work-up should be immediately undertaken. The pharmacy should be notified of the potential need for tocilizumab. Patient management in an intensive care unit may be required and the timing is dependent upon local institutional practice. In addition to supportive care, tocilizumab may be administered in cases of moderate to severe CRS, especially if the patient exhibits any of the following:
o Hemodynamic instability despite intravenous fluid challenges and moderate stable vasopressor support o Worsening respiratory distress, including pulmonary infiltrates, increasing oxygen requirement including high-flow O2, and/or need for mechanical ventilation.  
o Any other signs or symptoms of rapid deterioration despite medical management The recommended dosing for tocilizumab is 8 mg/kg i.v. single dose. Not all Grade 4 CRS reactions following CAR T cell infusions have been immediately treated with tocilizumab and decisions are, in part, based upon the rapidity of the syndrome onset and the individual patient's physiologic reserve.  
Other anti-cytokine therapies, such as repeat administration of tocilizumab or use of siltuximab or etanercept, may also be considered if the patient does not respond to the initial dose of tocilizumab. If the patient experiences ongoing CRS despite administration of anti-cytokine directed therapies, anti T-cell therapies such as cyclophosphamide, ATG, or alemtuzumab may be considered.  
CRS has been associated with biochemical and physiologic abnormalities consistent with MAS.  
Moderate to extreme elevations in serum C-reactive protein (CRP) and ferritin have been seen with CART-19 associated CRS, however the magnitude and kinetics vary greatly between individual patients. CRS management decisions should be based upon clinical signs and symptoms and response to interventions, not these laboratory values *per se*. Refer to Figure 8-1 below for a CRS Management Algorithm.  
In all cases of CRS, we will perform serum cytokine analysis at baseline using a 30-plex Luminex assay. This analysis will be repeated at all time-points collected during the event until its clinical resolution. This analysis will be batched and not available in real time; thus, it will not be used for clinical decisions. We will report these results to FDA.
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figure 8-1 crs management algorithm

.  
Tumor Lysis Syndrome. TLS resulting in renal insufficiency, or rapidly rising uric acid, or evidence of organ dysfunction will be managed with intravenous fluids and rasburicase as needed and determined by the treating physicians. Appropriate clinical therapy will be administered should any significant tumor lysis occur. Prophylactic administration of allopurinol is at the discretion of the clinical investigator.
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8.5 protocol exceptions and deviations

A one time, intentional action or process that departs from the approved study protocol, intended for one occurrence. If the action disrupts the study progress, such that the study design or outcome (endpoints) may be compromised, or the action compromises the safety and welfare of study subjects, advance documented approval from the Regulatory Sponsor, IRB, ACC DSMC, and other local regulatory review committees per institutional guidelines is required. Approval from the Regulatory Sponsor must be received prior to submission to the IRB, ACC DSMC, and other applicable regulatory review committees for approval.  
CONFIDENTIAL
This document is confidential and the property of the University of Pennsylvania.  No part of it may be transmitted, reproduced, published, or used by other persons without prior written authorization from the 61 of 76 No exception would be granted if the action disrupts the study progress, such that the study design or outcome (endpoints) may be compromised, or the action compromises the safety and welfare of study subjects.  
Exceptions to eligibility will not be granted for this study.
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deviation

A one time, **unintentional** action or process that departs from the IRB and ACC CTSRMC approved study protocol, involving one incident and **identified retrospectively**, after the event occurred. If the impact on the protocol disrupts the study design, may affect the outcome (endpoints) or compromises the safety and welfare of the subjects, the deviation must be reported to the Regulatory Sponsor and ACC DSMC
within 5 business days, and the IRB within 10 business days of PI knowledge.  
Any departure from the protocol that meets the following criteria should be submitted:
Impacts subject safety Impacts the integrity of the study design or outcome Based on the PI's judgment is reportable Other deviations should be explained in a memo to file (such as a subject missing a visit is not an issue unless a critical/important treatment or procedure was missed and must have been done at that specific time).  
Include the following information on the Sponsor supplied exception/deviation form: protocol number, subject study number, description of the exception/deviation from the protocol, and rationale. Ensure all completed exception/deviation forms are signed by the Principal Investigator (or sub-investigator) and submitted to the Sponsor Project Manager for review.  
Attention: Sponsor Project Manager The Sponsor Project Manager will submit the exception and/or deviation request to the Regulatory  
 Sponsor or designee for review and approval/acknowledgement. Once approval of the exception request or acknowledgement of the deviation has been granted by the Regulatory Sponsor or designee, the exception or deviation will be submitted to the IRB, ACC DSMC and all other applicable committees for review and approval.
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8.6 medical monitoring

It is the responsibility of the Principal Investigator to oversee the safety of the study at his/her site. This safety monitoring will include careful assessment and appropriate reporting of adverse events as noted above. Medical monitoring will include a regular assessment of the number and type of serious adverse events.
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8.7 independent data and safety

A Data and Safety Monitoring Board (DSMB) comprised of four individuals including physicians with experience in oncology and/or gene transfer therapy will be assembled and will work under a charter 62 of 76 specifically developed for safety oversight of this study. The DSMB will provide guidance/advice to the Regulatory Sponsor. The DSMB will evaluate patient-subject safety as specified in the DSMB Charter.  
The DSMB will meet approximately every 6 months. If necessary, additional meeting of the DSMB may be held if safety issues arise in between scheduled meetings.  
It is envisioned that the DSMB may make four types of recommendations, namely:
- No safety or efficacy issues, ethical to continue the study as planned
- Serious safety concerns precluding further study treatment, regardless of efficacy
- Overwhelming evidence for futility, recommend stopping the study. - Recommendation to continue the study but proposing an amendment to the protocol (e.g.,
incorporate an additional safety assessments)
A sponsor representative will share the outcome of the DSMB meeting with the PI via email, for submission to local regulatory review committees as required per institutional policy.
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9. data handling and recordkeeping

Information about study subjects will be kept confidential and managed according to the requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA). Those regulations require a signed subject authorization informing the subject of the following:
What protected health information (PHI) will be collected from subjects in this study Who will have access to that information and why Who will use or disclose that information The rights of a research subject to revoke their authorization for use of their PHI.  
In the event that a subject revokes authorization to collect or use PHI, the investigator, by regulation, retains the ability to use all information collected prior to the revocation of subject authorization. For subjects that have revoked authorization to collect or use PHI, attempts should be made to obtain permission to collect at least vital status (i.e. that the subject is alive) at the end of their scheduled study period.
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9.2 source documents

Source data is all information, original records of clinical findings, observations, or other activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Source data are contained in source documents Examples of these original documents, and data records include: hospital records, clinical and office charts, laboratory notes, memoranda, subjects' diaries or evaluation checklists, pharmacy dispensing records, recorded data from automated instruments, copies or transcriptions certified after verification as being accurate and complete, microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject files, and records kept at the pharmacy, at the laboratories, and at medico-technical departments involved in the clinical trial. The investigator must maintain source documents for each subject in the study, consisting of case and visit notes (hospital or clinical medical records) containing demographic and medical information, laboratory data, electrocardiograms and the results of any other tests or assessments. All information recorded on the eCRFs must be traceable to source documents in the patient's file. The investigator must also keep the original signed informed consent form, and a signed copy must be given to the patient.
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9.3 case report forms

The study case report form (CRF) is the primary data collection instrument for the study. All data requested on the CRF must be recorded. All entries will be entered into an electronic data capture system (EDC) via VELOS. The Principal Investigator is responsible for assuring that the data entered into eCRF is complete, accurate, and that entry and updates are performed in a timely manner.
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9.4 records retention

It is the investigator's responsibility to retain study essential documents for at least 2 years after the last approval of a marketing application in their country and until there are no pending or contemplated marketing applications in their country or at least 2 years have elapsed since the formal discontinuation of clinical development of the investigational product. These documents should be retained for a longer period if required by an agreement with the sponsor. In such an instance, it is the responsibility of the sponsor to inform the investigator/institution as to when these documents no longer need to be retained.
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10. study monitoring auditing and

This study will be monitored according to the Sponsor Data and Safety Monitoring Plan.  
Interim Monitoring Visits will be conducted during the course of the study. The Monitors will assure that submitted data are accurate and in agreement with source documentation; verify that investigational products are properly stored and accounted for, verify that subjects' consent for study participation has been properly obtained and documented, confirm that research subjects entered into the study meet inclusion and exclusion criteria, and assure that all essential documentation required by Good Clinical Practices (GCP) guidelines are appropriately filed.  
At the end of the study, Monitors will conduct a close-out visit and will advise on storage of study records and disposition of unused investigational products. The investigator will allocate adequate time for such monitoring activities. The Investigator will also ensure that the monitor or other compliance or quality assurance reviewer is given access to all the above noted study-related documents and study related facilities (e.g. pharmacy, diagnostic laboratory, etc.),
and has adequate space to conduct the monitoring visit.
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10.2 auditing and inspecting

The investigator will permit study-related monitoring, audits, and inspections by the IRB, the sponsor, government regulatory bodies, and University compliance and quality assurance groups of all study related documents (e.g. source documents, regulatory documents, data collection instruments, study data etc.). The investigator will ensure the capability for inspections of applicable study-related facilities (e.g. pharmacy, diagnostic laboratory, etc.).  
64 of 76 Participation as an investigator in this study implies acceptance of potential inspection by government regulatory authorities and applicable University compliance and quality assurance offices.  
Please notify the Sponsor in real-time if an audit/inspection notice is received.
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11. ethical considerations

This study is to be conducted according to US and international standards of Good Clinical Practice (FDA Title 21 part 312 and International Conference on Harmonization guidelines), applicable government regulations and Institutional research policies and procedures. This protocol and any amendments will be submitted to a properly constituted independent Institutional Review Board (IRB), in agreement with local legal prescriptions, for formal approval of the study conduct.  
The decision of the IRB concerning the conduct of the study will be made in writing to the investigator and a copy of this decision will be provided to the sponsor before commencement of this study.  
All subjects for this study will be provided a consent form describing this study and providing sufficient information for subjects to make an informed decision about their participation in this study. The consent form will be submitted with the protocol for review and approval by the IRB for the study. The formal consent of a subject, using the IRB-approved consent form, must be obtained before that subject is submitted to any study procedure. This consent form must be signed by the subject and the investigatordesignated research professional obtaining the consent.  
The protocol is listed under clinicaltrials.gov.
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12. study finances 12.1 funding

This study will be funded by Novartis Pharmaceuticals and the National Institutes of Health (NIH).
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12.2 conflict of interest

All University of Pennsylvania Investigators will follow the University of Pennsylvania Policy on Conflicts of Interest Related to Research.
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12.3 subject stipends or payments

There is there is no subject stipend/payment for participation in this protocol.
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12.4 study discontinuation

The study may be discontinued at any time by the IRB, the Sponsor, the FDA, or other government agencies as part of their duties to ensure that research subjects are protected.
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13. publication plan

Publication of the results of this trial will be governed by University of Pennsylvania policies. Neither the complete nor any part of the results of the study carried out under this protocol, nor any of the information provided by the sponsor for the purposes of performing the study, will be published or passed on to any third party without the consent of the study sponsor. Any investigator involved with this study is obligated to provide the sponsor with complete test results and all data derived from the study.
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14. references

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39. Maus MV, Thomas AK, Leonard DGB, et al. *Ex vivo* expansion of polyclonal and antigen-specific cytotoxic T lymphocytes by artificial APCs expressing ligands for the T cell receptor, CD28 and 4-1BB. Nat Biotechnol 2002;20:143-8. 40. Levine BL, Bernstein W, Craighead N, Lindsten T, Thompson CB, June CH. Effects of CD28 Costimulation on Long Term Proliferation of CD4+ T cells in the Absence of Exogenous Feeder Cells. J Immunol 1997;159:5921-30. 41. Eshhar Z, Waks T, Bendavid A, Schindler DG. Functional expression of chimeric receptor genes in human T cells. Journal of Immunological Methods 2001;248:67-76. 42. Finney HM, Akbar AN, Lawson AD. Activation of resting human primary T cells with chimeric receptors: costimulation from CD28, inducible costimulator, CD134, and CD137 in series with signals from the TCR zeta chain. J Immunol 2004;172:104-13. 43. Sadelain M, Rivière I, Brentjens R. Targeting tumours with genetically enhanced T lymphocytes. Nature reviews Cancer 2003;3:35-45. 44. Cooper LJN, Topp MS, Serrano LM, et al. T-cell clones can be rendered specific for CD19: toward the selective augmentation of the graft-versus-B-lineage leukemia effect. Blood 2003;101:1637-44. 45. Willemsen RA, Weijtens ME, Ronteltap C, et al. Grafting primary human T lymphocytes with cancer-specific chimeric single chain and two chain TCR. Gene Therapy 2000;7:1369-77. 46. Finney HM, Lawson ADG, Bebbington CR, Weir ANC. Chimeric receptors providing both primary and costimulatory signaling in T cells from a single gene product. Journal of Immunology 1998;161:2791-7. 47. Krause A, Guo HF, Latouche JB, Tan C, Cheung NK, Sadelain M. Antigen-dependent CD28 signaling selectively enhances survival and proliferation in genetically modified activated human primary T lymphocytes. J Exp Med 1998;188:619-26. 48. Imai C, Mihara K, Andreansky M, et al. Chimeric receptors with 4-1BB signaling capacity provoke potent cytotoxicity against acute lymphoblastic leukemia. Leukemia 2004;18:676-84. 49. Friedmann-Morvinski D, Bendavid A, Waks T, Schindler D, Eshhar Z. Redirected primary T cells harboring a chimeric receptor require costimulation for their antigen-specific activation. Blood 2005;105:3087-93. 50. Maher J, Brentjens RJ, Gunset G, Riviere I, Sadelain M. Human T-lymphocyte cytotoxicity and proliferation directed by a single chimeric TCR zeta/CD28 receptor. Nature Biotechnology 2002;20:70-5. 51. Finney HM, Akbar AN, Lawson ADG. Activation of resting human primary T cells with chimeric receptors: Costimulation from CD28, inducible costimulator, CD134, and CD137 in series with signals from the TCR zeta chain. Journal of Immunology 2004;172:104-13.  
69 of 76 52. Carpenito C, Milone MC, Hassan R, et al. Control of large established tumor xenografts with genetically re-targeted human T cells containing CD28 and CD137 domains. Proc Natl Acad Sci U S A 2009;106:3360-5. 53. Milone MC, Fish JD, Carpenito C, et al. Chimeric Receptors Containing CD137 Signal Transduction Domains Mediate Enhanced Survival of T Cells and Increased Antileukemic Efficacy In Vivo. Mol Ther 2009;17:1453-64. 54. Garfall AL, Maus MV, Hwang W-T, et al. Chimeric Antigen Receptor T Cells against CD19 for Multiple Myeloma. The New England journal of medicine 2015;373:1040-7. 55. Rapoport AP, Levine BL, Badros A, et al. Molecular remission of CML after autotransplantation followed by adoptive transfer of costimulated autologous T cells. Bone marrow transplantation 2004;33:53-60. 56. Rapoport AP, Stadtmauer EA, Aqui N, et al. Restoration of immunity in lymphopenic individuals with cancer by vaccination and adoptive T-cell transfer. Nature medicine 2005;11:1230-7.  
57. Rapoport AP, Stadtmauer EA, Aqui N, et al. Rapid immune recovery and graft-versushost disease-like engraftment syndrome following adoptive transfer of Costimulated autologous T cells. Clinical cancer research : an official journal of the American Association for Cancer Research 2009;15:4499-507. 58. Lamers CHJ, Sleijfer S, Vulto AG, et al. Treatment of metastatic renal cell carcinoma with autologous T-lymphocytes genetically retargeted against carbonic anhydrase IX: first clinical experience. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2006;24:e20-2. 59. Scholler J, Brady TL, Binder-Scholl G, et al. Decade-long safety and function of retroviral-modified chimeric antigen receptor T cells. Science translational medicine 2012;4:132ra53.  
60. Henter JI, Horne A, Aricó M, et al. HLH‐2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatric blood & cancer 2007;48:124-31. 61. Watts MJ, Sullivan AM, Jamieson E, et al. Progenitor-cell mobilization after low-dose cyclophosphamide and granulocyte colony-stimulating factor: an analysis of progenitor-cell quantity and quality and factors predicting for these parameters in 101 pretreated patients with malignant lymphoma. J Clin Oncol 1997;15:535-46.  
62. Jantunen E, Putkonen M, Nousiainen T, Pelliniemi TT, Mahlamaki E, Remes K. Lowdose or intermediate-dose cyclophosphamide plus granulocyte colony-stimulating factor for progenitor cell mobilisation in patients with multiple myeloma. Bone Marrow Transplant 2003;31:347-51. 63. Hamadani M, Kochuparambil ST, Osman S, et al. Intermediate-dose versus low-dose cyclophosphamide and granulocyte colony-stimulating factor for peripheral blood stem cell mobilization in patients with multiple myeloma treated with novel induction therapies. Biol Blood Marrow Transplant 2012;18:1128-35. 64. Shimura Y, Kuroda J, Uchiyama H, et al. Hematopoietic progenitor cell mobilization using low-dose cyclophosphamide and granulocyte colony-stimulating factor for multiple myeloma. J Clin Apher 2013;28:368-73. 65. Durie BGM, Harousseau JL, Miguel JS, et al. International uniform response criteria for multiple myeloma. Leukemia 2006;20:1467-73. 66. Keats JJ, Speyer G, Christophe L, et al. Identification of Initiating Trunk Mutations and Distinct Molecular Subtypes: An Interim Analysis of the Mmrf Commpass Study. Blood 2015;126:722-. 67. Rajkumar SV, Dimopoulos MA, Palumbo A, et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. The lancet oncology 2014;15:e538-48. 68. Luyt CE, Eldon MA, Stass H, Gribben D, Corkery K, Chastre J. Pharmacokinetics and tolerability of amikacin administered as BAY41-6551 aerosol in mechanically ventilated patients with gram-negative pneumonia and acute renal failure. J Aerosol Med Pulm Drug Deliv 2011;24:183-90. 69. Davila ML, Riviere I, Wang X, et al. Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia. Sci Transl Med 2014;6:224ra25. 70. Russell JA, Walley KR, Singer J, et al. Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med 2008;358:877-87. 71. Shortt J, Spencer A. Adjuvant rituximab causes prolonged hypogammaglobulinaemia following autologous stem cell transplant for non-Hodgkin's lymphoma. Bone marrow transplantation 2006;38:433-6.  
CART-19 post-ASCT in Multiple Myeloma Version V3.04-11-2017
17 of 76
appendix 1 schedule of evaluations

| Days Post-CART-19             |            |         |          |        |        |         |         |        |        |       |
|-------------------------------|------------|---------|----------|--------|--------|---------|---------|--------|--------|-------|
| ASC                           | 4 (+/-7d)  | 9       |          |        |        |         |         |        |        |       |
| (+7d)                         |            |         |          |        |        |         |         |        |        |       |
| 0                             | 4d         |         |          |        |        |         |         |        |        |       |
| pre-                          | ~Day +55
(+/- 2d)¹⁴            | 17      |          |        |        |         |         |        |        |       |
| months
nitiation                               | temic mye  | 10      | ~Day +52
(+/-1d)¹³          | s      | (p     | T       | z       | r      |        |       |
| therapy                       | 28 (+/-3d) |         |          |        |        |         |         |        |        |       |
| Day -2                        | +60        | 10, 14, | (/- 1d)  | onths  | nth 8,
17 (+/-        | Month
(+/-14c         | Month
(+/- 14)         |        |        |       |
| (+/-7                         |            |         |          |        |        |         |         |        |        |       |
| weeks                         | Month      | onth    |          |        |        |         |         |        |        |       |
| Day                           |            |         |          |        |        |         |         |        |        |       |
| t                             |            |         |          |        |        |         |         |        |        |       |
| vi                            | b          |         |          |        |        |         |         |        |        |       |
| Pre-                          | End of     |         |          |        |        |         |         |        |        |       |
| Screening/                    | Pre-       | LD      | CART-19  | Follow | Follow | Follow- | Follow- | Follow | Safety |       |
| ASCT                          | ASCT       | Study   |          |        |        |         |         |        |        |       |
| Enrollment²                   | Infusion   | Chemo   | Infusion | -up    | -up    | up      | up      | up     | (RCL)  | Visit |
| Eval                          |            |         |          |        |        |         |         |        |        |       |
| CLINICAL ASSESSMENTS          |            |         |          |        |        |         |         |        |        |       |
| Consent                       | X          |         |          |        |        |         |         |        |        |       |
| Recent Med. History           |            |         |          |        |        |         |         |        |        |       |
| Physical Examination,         | X          | x       | x        | X      | X      | x       | X       | x      | X      | X     |
| Performance Status            |            |         |          |        |        |         |         |        |        |       |
| Concomitant Meds              | x          | x       | X        | x      | x      | x       | x       | x      | X      | x     |
| Adverse Events                | X          | X       |          |        |        |         |         |        |        |       |
| x                             | X          | X       | X        | X      | X      |         |         |        |        |       |
| Vital Sign Assessments7       | x          | x       | x        | x      | x      | x       | x       | x      | x      | x     |
| Leukapheresis screening       | X          |         |          |        |        |         |         |        |        |       |
| (pre-donor evaluation) 5      |            |         |          |        |        |         |         |        |        |       |
| Skeletal bone survey          | x 12       | x 12    | x12      | x 12   |        |         |         |        |        |       |
| Bone marrow biopsy and        | X²¹        |         |          |        |        |         |         |        |        |       |
| X                             | x          | X       |          |        |        |         |         |        |        |       |
| aspirate                      |            |         |          |        |        |         |         |        |        |       |
| EKG                           | X          |         |          |        |        |         |         |        |        |       |
| ECHO/MUGA                     | X          |         |          |        |        |         |         |        |        |       |
| PFTs                          | X          |         |          |        |        |         |         |        |        |       |
| Imaging Studies               | x12        | x12     | x12      | x12    |        |         |         |        |        |       |
| CLINICAL LAB TESTS            |            |         |          |        |        |         |         |        |        |       |
| SPEP with immunofixation,     |            |         |          |        |        |         |         |        |        |       |
| quantitative                  |            |         |          |        |        |         |         |        |        |       |
| immunoglobulins (IgG, IgA,    | x          | X       | X19      | x      | x      | x       | x       | X      |        |       |
| lgM), serum free light chains |            |         |          |        |        |         |         |        |        |       |
| (20 mL SST)                   |            |         |          |        |        |         |         |        |        |       |  
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This document is confidential and the property of the University of Pennsylvania.  No part of it may be transmitted, reproduced, published, or used by other persons without prior written authorization from the regulatory sponsor.
page 72 of 76
appendix 1 schedule of evaluations

| ASCT                           | Days Post-CART-19   | 4 (+/-7d)   | t          |         |        |         |         |         |        |    |    |
|--------------------------------|---------------------|-------------|------------|---------|--------|---------|---------|---------|--------|----|----|
| (+7d)                          | 9                   |             |            |         |        |         |         |         |        |    |    |
| 0                              | pti                 |             |            |         |        |         |         |         |        |    |    |
| temic myel                     | r                   | Month 20
(+/-14d)             | r)
17            |         |        |         |         |         |        |    |    |
| pre-                           | to                  | s           |            |         |        |         |         |         |        |    |    |
| months
nitiation                                | therapy             | °Day +5
(+/-1d)             | 28 (+/-3d) |         |        |         |         |         |        |    |    |
| ~Day +!
(+/- 2d)                                | , 10, 14,
(+/- 1d)                     | Month 2
(+/- 14)             |            |         |        |         |         |         |        |    |    |
| z-                             | +60                 | onths
(+/-7)             | ''         | 17 (+/- |        |         |         |         |        |    |    |
| SP                             | Month               |             |            |         |        |         |         |         |        |    |    |
| Day                            | Month               |             |            |         |        |         |         |         |        |    |    |
| wee                            | Day                 | Me          | +          |         |        |         |         |         |        |    |    |
| t                              | b                   |             |            |         |        |         |         |         |        |    |    |
| s                              |                     |             |            |         |        |         |         |         |        |    |    |
| Pre-                           | End of              |             |            |         |        |         |         |         |        |    |    |
| Screening/                     | Pre-                | LD          | CART-19    | Follow  | Follow | Follow- | Follow- | Follow- | Safety |    |    |
| ASCT                           | ASCT                | Study       |            |         |        |         |         |         |        |    |    |
| Enrollment²                    | Infusion            | Chemo       | Infusion   | -up     | -up    | up      | up      | up      | (RCL)  |    |    |
| Eval                           | Visit               |             |            |         |        |         |         |         |        |    |    |
| 24 hour urine for total        |                     |             |            |         |        |         |         |         |        |    |    |
| protein, UPEP and              | X                   | X           | X19        | x       | x      | X       | X       | X       |        |    |    |
| immunofixation                 |                     |             |            |         |        |         |         |         |        |    |    |
| C, differential (5 mL EDTA)    | X                   | x           | x          | x17     | x      | x       | x       | x       | x      | X  | x  |
| Chemistry (3 mL SST)³          | x                   |             |            |         |        |         |         |         |        |    |    |
| X                              | X                   | X           | X          | X       | x      | X       | X       | X       | X      |    |    |
| Pregnancy test®                | x                   | x           |            |         |        |         |         |         |        |    |    |
| CD3, CD4, CD8 count  (4mL      | X                   | X           | X          | X       |        |         |         |         |        |    |    |
| EDTA)                          |                     |             |            |         |        |         |         |         |        |    |    |
| Hepatitis serologies²  (5ml)   | x                   |             |            |         |        |         |         |         |        |    |    |
| HIV  test (1 mL SST)           | X                   |             |            |         |        |         |         |         |        |    |    |
| Coagulation Factors (PT, PTT,  |                     |             |            |         |        |         |         |         |        |    |    |
| INR, fibrinogen, D-dimer) (1   | X                   |             |            |         |        |         |         |         |        |    |    |
| blue top - 5mL)                |                     |             |            |         |        |         |         |         |        |    |    |
| HLH/MAS labs (serum            |                     |             |            |         |        |         |         |         |        |    |    |
| ferritin, triglycerides,       | X                   |             |            |         |        |         |         |         |        |    |    |
| haptoglobin, CRP) (4mL SST;    |                     |             |            |         |        |         |         |         |        |    |    |
| 3ml EDTA)                      |                     |             |            |         |        |         |         |         |        |    |    |
| Respiratory viral panel (nasal | x                   |             |            |         |        |         |         |         |        |    |    |
| swab)                          |                     |             |            |         |        |         |         |         |        |    |    |
| INTERVENTIONS                  |                     |             |            |         |        |         |         |         |        |    |    |
| High-dose Melphalan            | X13                 |             |            |         |        |         |         |         |        |    |    |
| Stem Cell Infusion             | x13                 |             |            |         |        |         |         |         |        |    |    |
| Cyclophosphamide               | X16                 | X16         |            |         |        |         |         |         |        |    |    |
| CART-19 cell infusion          |                     |             |            |         |        |         |         |         |        |    |    |
| Leukapheresis                  | X                   |             |            |         |        |         |         |         |        |    |    |
| Lenalidomide                   | χ²²                 |             |            |         |        |         |         |         |        |    |    |  
CONFIDENTIAL
This document is confidential and the property of the University of Pennsylvania.  No part of it may be transmitted, reproduced, published, or used by other persons without prior written authorization from the regulatory sponsor.  
| Days Post-CART-19          | (7d)                                                                                                                                      | 9          |          |        |        |         |         |         |        |    |    |    |    |
|----------------------------|-------------------------------------------------------------------------------------------------------------------------------------------|------------|----------|--------|--------|---------|---------|---------|--------|----|----|----|----|
| r                          | 4 (+/-)                                                                                                                                   |            |          |        |        |         |         |         |        |    |    |    |    |
| to                         | S                                                                                                                                         |            |          |        |        |         |         |         |        |    |    |    |    |
| mic my                     | d                                                                                                                                         | (Day +5)
(+/-1d)            |          |        |        |         |         |         |        |    |    |    |    |
| itiation                   | "Day +"
|+/- 2d                                                                                                                                           | 7, 10, 14, | (/-3d)   | Month
(+/-14)        | Month
(+/- 14        |         |         |         |        |    |    |    |    |
| thera                      | z-                                                                                                                                        | +60        | (/- 1d)  | onths  | ''     | 17 (+/  |         |         |        |    |    |    |    |
| SK                         | Day                                                                                                                                       | Month      | +/       |        |        |         |         |         |        |    |    |    |    |
| wee                        | Day                                                                                                                                       |            |          |        |        |         |         |         |        |    |    |    |    |
| t                          |                                                                                                                                           |            |          |        |        |         |         |         |        |    |    |    |    |
| s                          |                                                                                                                                           |            |          |        |        |         |         |         |        |    |    |    |    |
| Pre-                       | End of                                                                                                                                    |            |          |        |        |         |         |         |        |    |    |    |    |
| Screening/                 | Pre-                                                                                                                                      | LD         | CART-19  | Follow | Follow | Follow- | Follow- | Follow- | Safety |    |    |    |    |
| ASCT                       | ASCT                                                                                                                                      | Study      |          |        |        |         |         |         |        |    |    |    |    |
| Enrollment²                | Infusion                                                                                                                                  | Chemo      | Infusion | -up    | -up    | up      | up      | up      | (RCL)  |    |    |    |    |
| Eval                       | Visit                                                                                                                                     |            |          |        |        |         |         |         |        |    |    |    |    |
| RESEARCH SPECIMENS 10      |                                                                                                                                           |            |          |        |        |         |         |         |        |    |    |    |    |
| Marrow aspirate  ~ 20 mL   |                                                                                                                                           |            |          |        |        |         |         |         |        |    |    |    |    |
| (Purple top tubes) for     | X                                                                                                                                         | x          | X        | X      |        |         |         |         |        |    |    |    |    |
| mononuclear cells          |                                                                                                                                           |            |          |        |        |         |         |         |        |    |    |    |    |
| Marrow aspirate ~ 2mL (Red | X                                                                                                                                         | x          | X        | X      |        |         |         |         |        |    |    |    |    |
| top tube) for serum        |                                                                                                                                           |            |          |        |        |         |         |         |        |    |    |    |    |
| Total research             | 2mL                                                                                                                                       | 2mL        | 2mL      | 2mL    |        |         |         |         |        |    |    |    |    |
| marrow needs               |                                                                                                                                           |            |          |        |        |         |         |         |        |    |    |    |    |
| Peripheral blood           |                                                                                                                                           |            |          |        |        |         |         |         |        |    |    |    |    |
| mononuclear cells          | X11                                                                                                                                       | X          | X        | x18    | x      | χ²      | X       | X       | X      | X  | X  |    |    |
| ~25 mL (purple top tubes)  |                                                                                                                                           |            |          |        |        |         |         |         |        |    |    |    |    |
| DNA (Q-PCR persistence)    | x                                                                                                                                         | x          | x        | x      | x      | X       | x       |         |        |    |    |    |    |
| x                          |                                                                                                                                           |            |          |        |        |         |         |         |        |    |    |    |    |
| VVV-G (Q-PCR)              | X                                                                                                                                         | x'         | χ²³      | χ²³    | x      |         |         |         |        |    |    |    |    |
| x                          |                                                                                                                                           |            |          |        |        |         |         |         |        |    |    |    |    |
| Peripheral blood serum  ~5 | x                                                                                                                                         | x18        | X        | x      | X      | x       | x       | X       |        |    |    |    |    |
| mL (Red top tube)          |                                                                                                                                           |            |          |        |        |         |         |         |        |    |    |    |    |
| Immunogenicity             | x                                                                                                                                         | x          |          |        |        |         |         |         |        |    |    |    |    |
| (HAMA/HACA)                |                                                                                                                                           |            |          |        |        |         |         |         |        |    |    |    |    |
| Multiplex Cytokines        | x                                                                                                                                         | X          | x        |        |        |         |         |         |        |    |    |    |    |
| Total research blood needs | 25                                                                                                                                        | 25         | 0        | 30     | 0      | 41      | 30      | 65      | 30     | 30 | 30 | 25 | 30 |
| (mL)                       |                                                                                                                                           |            |          |        |        |         |         |         |        |    |    |    |    |
| TOTAL BLOOD DRAW  (mL)     | 44                                                                                                                                        | 53         | 0        | 71     | 8      | 49      | 38-58   | 93      | 62     | 58 | 58 | 25 | 62 |
| 1.                         | Screening procedures used to assess eligibility to participate must be completed within 4 weeks prior to enrollment.  For the purposes of |            |          |        |        |         |         |         |        |    |    |    |    |  
Version V3.04-11-2017 this study and in order to standardize the timing of study windows, enrollment will be defined as the date eligibility is confirmed by the Principal Investigator.  
Required Hepatitis Serologies: Hepatitis B surface antigen (HBsAG), Hepatitis B surface antibody, Hepatitis B core antibody, and HCV
antibody.  If the HCV antibody is positive, a screening HCV RNA by any RT-PCR or bDNA assay must be performed.  Eligibility will be CONFIDENTIAL
This document is confidential and the property of the University of Pennsylvania.  No part of it may be transmitted, reproduced, published, or used by other persons without prior written authorization from the regulatory sponsor.  
2.  
determined based on the screening value. The HCV RNA test is not required if documentation of a negative result of a HCV RNA test performed within 60 days prior to screening is provided.  
3. Chemistry Panel- Glucose, BUN, Creatinine, Sodium, Potassium, Chloride, Calcium, Total Protein, Albumin, Total Bilirubin, ALK PHos, AST,
ALT, MG, Phos, LDH, Uric Acid 4. Performed at the Month 5 visit only.  
5. Pre-donor evaluation of peripheral veins to determine whether apheresis can be performed without central venous access. If central venous access is felt to be necessary, catheter placement will be arranged.  
6. Enrollment and mononuclear cell apheresis to harvest T cells for CART-19 manufacturing will take place prior to standard-of-care hematopoietic stem cell mobilization and collection. Cryopreserved historical apheresis products collected from the patient prior to study entry are usable for CART-19 manufacturing if collected at an appropriately certified apheresis center and the product meets adequate mononuclear cell yields, these cells may be used as the source of cells for CART-19 cell manufacturing. If a historical apheresis product is not available, an apheresis procedure will be performed for cell procurement after study eligibility has been confirmed.  
Please see section 6.4 for additional information.  
7. Vital sign assessments include weight, temperature, pulse, blood pressure and oxygen saturation by pulse oximetry. Height will be collected at screening only. On the day of the CART-19 infusion, vital signs will be measured within 10 minutes prior, within 10 minutes after the infusion, and then every 15 minutes for the first hour, and then every hour for the next 2 hours until these signs are satisfactory and stable. If the subject's vital signs are not satisfactory and stable three hours post CART-19 infusion, vital signs will continue to be monitored at a minimum of every hour or as clinically indicated until stable. The subject will be discharged after the physician managing their care on the day of the infusion has determined that they are in satisfactory condition.  
8. Female of child-bearing potential only.  
9. Serum (1ml SST) or urine pregnancy test may be performed within 14 days prior to enrollment. A serum pregnancy test will be performed at the pre-infusion visit (~Day + 55 ± 2d).  
10. Research bone marrow aspirates and blood draws should be sent to Translational and Correlative Studies Laboratory. TCSL has requested labs be delivered to TCSL as soon as drawn. If required to keep research labs after hours, please keep red tops upright, purple tubes should be room temperature on rotating platforms. In the event that something unexpected occurs, research sample collection may be done as necessary, not to exceed 3 tablespoons of blood twice in one week time window, in addition to the protocol-specified time points. This would be done at the PI's discretion.  
11. Collected at the time of apheresis (if performed).  
12. If the treating investigator feels advanced imaging (PET-CT, CT or MRI) is necessary for adequate characterization of the subject's response, these modalities will be performed per routine care. If not, a standard skeletal survey will be performed.  
13. Melphalan will be administered as a single dose on day -2 or -1, or in two divided doses, according to standard institutional practice.  
Please see Section 5.3.1 for complete details regarding melphalan administration and ASCT.  
75 of 76 14. Pre-infusion visit to occur 3-7 days prior to the CART-19 infusion. If the CART-19 infusion is re-scheduled between the pre-infusion visit and CART-19 infusion, the pre-infusion evaluations, with the exception of the bone marrow biopsy, will be repeated within 3-7 days prior to the re-scheduled CART-19 infusion.  
15. Lymphodepleting chemotherapy will be administered 3 days +/- 1 day prior to CART-19 infusion. Please see Section 6.8 for additional information.  
16. Cyclophosphamide will be administered at a dose of 1.5 g/m2 intravenously as a single infusion. Administration of lymphodepleting chemotherapy and infusion of CART-19 cells may be delayed up to 4 weeks from the originally scheduled date to address any factors that make a subject ineligible for CART-19 infusion. Delay of lymphodepleting chemotherapy and CART-19 infusion beyond 4 weeks from the scheduled date is acceptable only with approval of the Sponsor. Please refer to Section 5.2 for complete details.  
17. If performed within 48 hours of the visit, these do not need to be repeated.  
18. To be performed prior to the CART-19 infusion and 1-2 hours post-infusion. Pre-infusion samples: ~25mL PBMC and ~5mL serum; Postinfusion Samples: ~5mL PBMC and ~2mL serum.  
19. To be performed at the D14 post-CART19 visit only.  
20. A 60 ml blood draw (collected in purple top tubes) will be performed.  
21. Optional; performed if clinically appropriate as determined by the treating investigator.  
22. Lenalidomide will be initiated at the standard-of-care dose and schedule of 10 mg daily beginning at approximately day 90 post-ASCT
and at least 4 weeks post-CART19. Before maintenance lenalidomide is initiated, toxicities of CART-19 and lymphodepleting chemotherapy must be resolved to Grade < 2 and stabilized in the judgment of the treating investigator. Maintenance lenalidomide may be withheld, delayed or dose-reduced at the discretion of the treating investigator if there are clinical contraindications to beginning maintenance therapy on the usual dose and schedule.  
23. RCL testing - VSV-g PCR will be performed at Months 5, 8 and 14 visits (Months 3, 6 and 12 post-CART19 infusion). Blood will be collected at Month 20 (Month 18 post-CART19 infusion) and will be archived if all tests in the first year post-CART19 infusion are negative.
appendix 2 new york heart
classification

| Functional Capacity: How a patient with cardiac disease feels during     |                                                                               |
|--------------------------------------------------------------------------|-------------------------------------------------------------------------------|
| Class                                                                    | physical activity                                                             |
| Patients with cardiac disease but resulting in no limitation of physical |                                                                               |
| l                                                                        | activity. Ordinary physical activity does not cause undue fatigue,            |
| palpitation, dyspnea or anginal pain.                                    |                                                                               |
| Patients with cardiac disease resulting in slight limitation of physical |                                                                               |
| l                                                                        | activity. They are comfortable at rest. Ordinary physical activity results in |
| fatigue, palpitation, dyspnea or anginal pain.                           |                                                                               |
| Patients with cardiac disease resulting in marked limitation of physical |                                                                               |
| =                                                                        | activity. They are comfortable at rest. Less than ordinary activity causes    |
| fatigue, palpitation, dyspnea or anginal pain.                           |                                                                               |
| Patients with cardiac disease resulting in inability to carry on any     |                                                                               |
| physical activity without discomfort. Symptoms of heart failure or the   |                                                                               |
| IV                                                                       | anginal syndrome may be present even at rest.  If any physical activity is    |
| undertaken, discomfort increases.                                        |                                                                               |