Pilot Study of Anakinra to Mitigate CAR-T Toxicity in Subjects With Relapsed or Refractory Large B-Cell Lymphoma
Phase: PHASE2
Conditions: Hematopoietic and Lymphoid Cell Neoplasm, Recurrent Diffuse Large B-Cell Lymphoma, Recurrent High Grade B-Cell Lymphoma, Recurrent Primary Mediastinal (Thymic) Large B-Cell Lymphoma, Recurrent Transformed Follicular Lymphoma to Diffuse Large B-Cell Lymphoma, Refractory Diffuse Large B-Cell Lymphoma, Refractory High Grade B-Cell Lymphoma, Refractory Primary Mediastinal (Thymic) Large B-Cell Lymphoma, Refractory Transformed Follicular Lymphoma to Diffuse Large B-Cell Lymphoma
Sponsor: M.D. Anderson Cancer Center

MD Anderson IND Sponsor Cover Sheet 
Protocol ID 
2019-1051 
Protocol Title 
Pilot study of anakinra to mitigate CAR-T toxicity in subjects with 
relapsed or refractory large B-cell lymphoma 
Protocol Version 
7.0 
Version Date 
9/25/2023 
Protocol PI 
Paolo Strati, MD 
Department 
Lymphoma/Myeloma 
IND Sponsor 
MD Anderson Cancer Center 
IND # 
150059 
Proprietary Information of MD Anderson

Protocol: 2019-1051                                             Phase II study of anakinra and axi-cel 
 
2
Pilot study of anakinra to mitigate CAR-T toxicity in subjects with relapsed 
or refractory large B-cell lymphoma 
 
 
 
 
Principal Investigator: 
Paolo Strati, M.D., Assistant Professor 
Department of Lymphoma and Myeloma 
The University of Texas M.D. Anderson Cancer Center 
1515 Holcombe Blvd, Unit 903 
Houston, TX – 77030 (USA) 
Tel: (713) 792 2860 
Fax: (713) 794 5656 
 
Co-Principal Investigators: 
Sattva S. Neelapu, M.D., Professor 
Department of Lymphoma and Myeloma 
 
Jason Westin, M.D., Associate Professor 
Department of Lymphoma and Myeloma 
 
David S Hong, M.D., Professor 
Department of Investigational Cancer Therapeutics 
 
Michael Green, PhD, Associate Professor 
Department of Lymphoma and Myeloma 
 
Collaborator: 
Lei Feng MS, Biostatistician 
Department of Biostatistics 
 
Bilal Mujtaba, MD 
Musculoskeletal Imaging Department 
 
 
Investigational Drug: Anakinra 
 
 
Source of Investigational Drug: Sobi 
 
IND NUMBER: 150059 
 
 
Revised: 09/25/2023 
Proprietary Information of MD Anderson

Protocol: 2019-1051                                             Phase II study of anakinra and axi-cel 
 
3
 
 
 
 
 
 
Proprietary Information of MD Anderson

Protocol: 2019-1051                                             Phase II study of anakinra and axi-cel 
 
4
TABLE OF CONTENTS 
 
1.0 
TRIAL SUMMARY.................................................................................................... 5 
2.0 
TRIAL DESIGN.......................................................................................................... 6 
3.0 
OBJECTIVE(S) & HYPOTHESIS(ES) .................................................................... 7 
4.0 
BACKGROUND & RATIONALE ............................................................................ 8 
5.0 
METHODOLOGY ................................................................................................... 13 
6.0 
TRIAL FLOW CHART ........................................................................................... 22 
7.0 
TRIAL PROCEDURES ........................................................................................... 24 
8.0 
STATISTICAL CONSIDERATIONS .................................................................... 33 
9.0 
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ................................................................................................................. 37 
10.0 
ADMINISTRATIVE AND REGULATORY DETAILS ....................................... 38 
11.0 
REFERENCES .......................................................................................................... 41 
12.0 
APPENDICES ........................................................................................................... 44 
 
 
 
Proprietary Information of MD Anderson

Protocol: 2019-1051                                             Phase II study of anakinra and axi-cel 
 
5
1.0 TRIAL SUMMARY 
Abbreviated Title 
Pilot study of anakinra to mitigate CAR-T toxicity in relapsed or 
refractory large B-cell lymphoma 
Clinical Indication 
The treatment of adult subjects with relapsed or refractory large B-
cell lymphoma who receive axicabtagene ciloleucel (axi-cel) CAR T-
cell therapy 
Trial Type 
Interventional 
Route of administration 
Subcutaneous 
Trial Blinding 
Unblinded, open-label 
Treatment Groups  
Subjects will receive anakinra by subcutaneous injection for 7 days 
starting on day 0 of axi-cel treatment. Anakinra will be tested at a dose 
level of 100 mg daily and 100 mg BID. A 3+3 design will be used for 
a safety run-in phase within each dose level of Anakinra 
Number of trial subjects 
Maximum of 20 with 10 subjects per dose level cohort. 
Estimated duration of trial It is estimated that the trial will require approximately 12 months from 
the time the first subject signs the informed consent until the last 
subject’s last visit. 
Duration of Participation 
This is a single institution, open-label pilot study. Each subject will 
participate in the trial from the time the subject signs the Informed 
Consent through the final protocol-specified time period. Subjects 
with r/r diffuse large B-cell lymphoma (DLBCL), high-grade B-cell 
lymphoma (HGBCL), primary mediastinal B-cell lymphoma 
(PMBCL), or transformed follicular lymphoma (tFL) after at least 2 
systemic therapies and who are otherwise eligible to receive standard 
of care axi-cel therapy will be enrolled. Anakinra will be administered 
by subcutaneous injection daily for 7 days starting on day 0 of axi-cel 
treatment.  
The primary objective is to assess the safety and tolerability of 
anakinra when used as a prophylactic strategy to mitigate toxicity 
associated with use of CAR T cells. 
Secondary objectives include the incidence of different grades and 
duration of both CRS and ICANS, overall and complete response 
rates, progression-free survival (PFS), and overall survival (OS).  
Exploratory objectives include determining CAR T cell levels in the 
blood, serum cytokine and chemokine levels, and effect on the 
phenotype and/or function of monocytes. 
 
 
 
Proprietary Information of MD Anderson

Protocol: 2019-1051                                             Phase II study of anakinra and axi-cel 
 
6
2.0 TRIAL DESIGN 
2.1 
Trial Design 
This is a single center, open label, pilot study of anakinra in combination with axi-cel in 
subjects with relapsed or refractory large B-cell lymphoma. A maximum of 20 subjects will 
be enrolled in this trial to examine the safety, tolerability and efficacy of anakinra 
administered subcutaneously at a dose of 100 mg daily (N=10) or 100 mg BID (N=10), 
starting on day 0 of axi-cel infusion, for 7 days. A 3+ 3 design will be used for a safety run-
in phase within each dose level cohort. Adverse events (AEs) will be monitored throughout 
the trial and graded in severity according to the guidelines outlined in the NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 5.0. ASTCT consensus 
guidelines will be applied to grade CRS and ICANS. Response will be determined according 
to the Recommendations for Initial Evaluation, Staging, and Response Assessment of 
Hodgkin and Non-Hodgkin Lymphoma: The Lugano Classification.1 
Patients will be followed until documented progression of disease (PD), unacceptable AE(s), 
intercurrent illness that prevents further administration of treatment, investigator’s decision 
to withdraw the subject, subject withdraws consent, pregnancy of the subject, noncompliance 
with trial treatment or procedure requirements, administrative reasons, or the subject has 
completed 2 years of follow-up. After the end of treatment, each subject will be followed for 
30 days for AE monitoring (serious adverse events (SAEs) will be collected for 30 days after 
the end of treatment). Subjects who discontinue treatment for reasons other than disease 
progression will have post-treatment follow-up for disease status until disease progression, 
initiating a non-study cancer treatment, withdrawing consent, or becoming lost to follow-up. 
The primary objective of the trial is to assess safety and tolerability of anakinra in reducing 
incidence of CRS within 30 days after infusion of CAR T cells. Secondary objectives include 
incidence of different grades and duration of both CRS and ICANS, overall response rate 
(ORR) complete response rate (CRR), progression-free survival (PFS), and overall survival 
(OS). Exploratory objectives include evaluation of pharmacodynamics effects of anakinra, 
and biomarkers of toxicity, response and resistance.  
This study will be conducted in conformance with Good Clinical Practices. 
Specific procedures to be performed during the trial, as well as their prescribed times and 
associated visit windows, are outlined in the Trial Flow Chart - Section 6.0. Details of each 
procedure are provided in Section 7.0 – Trial Procedures. 
 
2.2 
Trial Diagram 
The trial design is depicted in Figure 1. 
 
 
 
 
Proprietary Information of MD Anderson

Protocol: 2019-1051                                             Phase II study of anakinra and axi-cel 
 
7
 
 
3.0 OBJECTIVE(S) & HYPOTHESIS(ES) 
3.1 
Primary Objective(s) & Hypothesis(es) 
(1) Objective: The primary objective of the study is to assess safety and tolerability of anakinra 
in reducing incidence of CRS within 30 days after infusion of CAR T cells in subjects with 
relapsed or refractory large B-cell lymphoma. 
Hypothesis: Anakinra will be safe, well-tolerated and effective in decreasing the incidence of 
axi-cel-related CRS in patients with r/r large B-cell lymphoma. 
3.2 Secondary Objective(s) & Hypothesis(es) 
(1) Objective: To determine incidence of all grades and duration of both CRS and ICANS.  
(2) Objective: To determine the CRR, ORR, PFS and OS. 
Hypothesis:  Administration of anakinra in the setting of axi-cel therapy will decrease 
incidence of all grades and duration of both CRS and ICANS in patients with r/r large B-cell 
lymphoma. Response rates and survival with anakinra and axi-cel therapy will be comparable 
to those observed with axi-cel alone in patients with r/r large B-cell lymphoma. 
3.3 Exploratory Objective 
(1) 
Objective: To determine the effects of anakinra on the cytokine and chemokine profile in 
peripheral blood after CAR-T therapy. 
(2) 
Objective: To determine the effects of anakinra on the expansion and persistence of CAR T 
cells. 
(3) 
Objective: To correlate baseline characteristics with toxicity, response and survival after 
anakinra combined with CAR-T therapy. 
Proprietary Information of MD Anderson

Protocol: 2019-1051                                             Phase II study of anakinra and axi-cel 
 
8
4.0 BACKGROUND & RATIONALE 
4.1 Background 
4.1.1 Axicabtagene ciloleucel for relapsed or refractory large B-cell lymphoma 
Outcomes with first- and second-line therapies in large B-cell lymphoma. Approximately 
60% of patients affected by aggressive B-cell lymphoma are cured with the use of frontline 
chemoimmunotherapy.2-4 Salvage high-dose chemotherapy followed by autologous stem cell 
transplant is potentially curative after failure of frontline therapy.5 However, only 50% of 
patients who relapse after frontline chemoimmunotherapy are transplant-eligible, because of 
age, performance status or comorbidities. Of these, only half will respond to salvage 
chemotherapy, and of those who will respond and will be able to proceed to transplant, less 
than half will be cured.6,7 As a consequence, novel effective and safe therapies are 
desperately needed for patients with relapsed or refractory aggressive B-cell lymphoma.   
 
CAR T cell biology. Chimeric antigen receptor (CAR) modified T cells are a form of adoptive 
cellular therapy, employing genetically engineered T lymphocytes, created in the laboratory 
in 1989, but refined and brought to the clinic only in the last few years.8 Autologous T cells 
are collected from the patient usually through leukapheresis, engineered with CAR and 
expanded ex vivo, and subsequently reinfused (ideally after conditioning). Unlike donor T 
lymphocytes employed in allogeneic stem cell transplant or endogenous T cells that 
recognize unique antigens expressed on tumor cells through a HLA-restricted manner via 
their naturally expressed T-cell receptor, CAR T cells recognize antigens on tumor cells in 
an HLA-independent mechanism via their artificially expressed receptor. This allows broad 
therapeutic use of CAR T cells generated from either autologous or allogeneic source and 
also likely overcomes tumor escape mediated by low HLA expression.9 
 
First generation CAR T cells. CARs are formed of 3 parts: an extracellular, a transmembrane 
and an intracellular domain. The extracellular domain is usually a single-chain variable 
fragment (scFv) derived from the variable heavy and light chains of an antibody targeting a 
specific tumor antigen (e.g. CD19 in B-cell lymphomas). Upon engagement with its cognate 
antigen, the extracellular domain initiates the activation signal to the CAR T cell via the 
intracellular domain.10 The first generation of CAR T cells was composed of an extracellular 
domain recognizing a target tumor antigen, and an intracellular signaling domain, CD3ζ, 
which mediates signal 1 to the T-lymphocyte. However, limited efficacy was observed with 
this structure.11  
Second generation CAR T cells. In the second generation CARs, the intracellular domain is 
typically composed of two signaling domains: CD3ζ to provide signal 1 and a co-stimulatory 
domain, which mediates signal 2 and promotes the proliferation, cytotoxic activity, and 
persistence of CAR T cells. The 2 most commonly used co-stimulatory domains are CD28 
and CD137 (4-1BB).12 Investigators at Baylor College of Medicine treated 6 patients affected 
by relapsed refractory B-cell lymphoma (including DLBCL, t-FL and chronic lymphocytic 
leukemia [CLL]) with an anti-CD19 CAR T cell product, engineered to express CD28 as co-
stimulatory domain. No conditioning regimen was used. As opposed to first-generation CAR 
T cells, persistence of the product was observed up to 6 months, with stable disease obtained 
in 2 patients.13 A similar construct was used at the same time by investigators at the National 
Cancer Institute (NCI), first in a patient with relapsed FL, and subsequently in 15 patients 
Proprietary Information of MD Anderson

Protocol: 2019-1051                                             Phase II study of anakinra and axi-cel 
 
9
with either relapsed or refractory DLBCL, CLL or indolent lymphomas. Conditioning with 
fludarabine and cyclophosphamide was used, to decrease the risk of rejection of the CAR T 
cells. This approach resulted in prolonged product persistence and significant clinical activity 
with 8 complete responses [CR] and 4 partial responses [PR] in the 13 evaluable patients. 
However, grade 3 or greater toxicity was observed in all patients, including cytokine release 
syndrome (CRS) and neurotoxicity, but all resolving within 3 weeks.14,15 Of interest, in a 
subsequent trial conducted by the same group, the use of a less intense conditioning therapy 
resulted in a significantly lower rate of severe toxicity (55%), despite comparable product 
persistence and clinical activity.16  
 
Multicenter axi-cel trial and FDA approval. The encouraging results observed with 
axicabtagene ciloleucel or axi-cel (the 2nd generation CAR developed at the NCI) led to its 
evaluation further in a multicenter single-arm phase II clinical trial in relapsed or refractory 
aggressive B-cell lymphomas, the ZUMA-1 study. Seven patients with relapsed or refractory 
DLBCL were enrolled in the phase I component of the ZUMA-1 trial, and conditioning 
consisted of both cyclophosphamide and fludarabine.17 In the subsequent phase II component 
of the study, 101 patients with relapsed or refractory DLBCL, t-FL and primary mediastinal 
B-cell lymphoma (PMBCL) were treated using the same conditioning regimen. In the 
combined phase I plus phase II study of 108 patients, ORR was 83%, CR rate 58%, and grade 
3 or higher cytokine release syndrome (CRS) and immune-cell associated neurotoxicity 
syndrome (ICANS) were reported in 11% and 32% of patients, respectively.18,19 These 
results led to FDA approval of this product, marketed as Yescarta, in October 2017 for 
patients with relapsed or refractory DLBCL, PMBCL, t-FL, and high-grade B-cell 
lymphoma after at least 2 lines of systemic therapy. Recently, the long term activity of axi-
cel has been reported: at a median follow-up of 27.1 months, the median progression-free 
survival was 5.9 months, median overall survival has not been reached, and 39% of the 
patients were in ongoing remission.19 Improved therapeutic and preventive treatments 
require a better understanding of CRS and ICANS physiopathology, which has so far 
remained elusive. 
 
4.1.2 Physiopathology of CRS and ICANS 
Cytokine release syndrome (CRS). CRS results from rapid activation and proliferation of 
CAR T cells, with subsequent supraphysiologic release of pro-inflammatory cytokines from 
the CAR T cells themselves as well as bystander immune cells.20 It can manifest with fever, 
hypotension, hypoxia, and signs/symptoms of organ dysfunction. CRS typically peaks at 
time of maximal in vivo CAR T cell expansion, and resolves within 3 weeks from the 
infusion.21,22 Most patients experience grade 1-2 CRS, however, severe toxicity may occur 
in patients with bulky disease. Severe CRS has been associated with serum IL-6 levels and 
tocilizumab, an anti-IL-6 receptor antibody, has been used successfully for CRS 
management. Severe CRS, refractory to tocilizumab, may require use of corticosteroids, 
which can suppress multiple immune cells and downregulate production of multiple 
cytokines.23 Rarely, patients may develop fulminant macrophage activating syndrome or 
hemophagocytic lymphohistiocytosis following CAR T therapy.18,23 Such patients are also 
initially managed with anti-IL6 and corticosteroid therapy, before considering other therapies 
such as etoposide.24   
Proprietary Information of MD Anderson

Protocol: 2019-1051                                             Phase II study of anakinra and axi-cel 
 
10 
Immune cell-associated neurotoxicity syndrome (ICANS). The pathophysiology of 
neurotoxicity, also referred to as CAR-related encephalopathy syndrome (CRES) or immune 
effector cell-associated neurotoxicity syndrome (ICANS), remains largely unknown.20,23 
Possible mechanisms include diffusion of cytokines and transmigration of CAR T cells into 
the central nervous system, activation of endothelial cells and disruption of the blood-brain 
barrier, and activations of myeloid cells by IL-1, GM-CSF, and possibly other cytokines.25-
30 It typically presents as toxic encephalopathy, with word-finding difficulty, aphasia, altered 
level of consciousness, and impairment of cognitive skills, and in more severe cases, motor 
weakness, seizures, and cerebral edema. Like CRS, most patients experience grade 1-2 
neurotoxicity and it is usually self-limiting and completely reversible. Neurotoxicity 
occurring concurrently with CRS can be successfully treated with CRS-directed therapy. 
However, severe neurotoxicity occurring in the absence of CRS may require use of 
corticosteroids and intensive monitoring and supportive care through a multidisciplinary 
team.23 
 
4.1.3 Preclinical and Clinical Trial Data with Anakinra 
Role of IL-1 in CRS and ICANS. To study CRS in the absence of GVHD, Norelli et al used 
human T cells that had matured in humanized mice and hence were tolerant to mouse 
antigens (xenotolerant).28 When infused into humanized mice, CD19- and CD44v6-modified 
CAR-Ts expanded in response to human CD19+ B cells and CD44v6+ monocytes eliminated 
these normal cells and induced severe CRS-like toxicity that was enhanced in the presence 
of tumor. As greater monocyte numbers in humanized mice were associated with more severe 
CRS, the authors investigated the role of monocytes in CRS. Monocyte depletion in tumor-
bearing, humanized mice before CAR-T infusion completely eliminated CRS without 
preventing leukemic remission. However, tumor elimination was delayed, and CAR-T 
expansion was reduced. Further, CD44v6 CAR-Ts used to eliminate human monocytes in 
mice before leukemia engraftment responded poorly to leukemic cells, and tumor responses 
were reduced. These results suggest that myeloid cells may be important for CAR-T efficacy 
in addition to having a role in CRS. In addition, to study the role of cytokines in the induction 
of CRS, Norelli et al evaluated the kinetics of cytokine production by monocytes in co-
cultures with CD19.CAR T cells and leukemic cells. IL-1 preceded IL-6 by 24 h. Giavridis 
et al produced a CRS-like syndrome in immunodeficient beige mice after infusion of 
CD19.28z CAR-Ts, but only if the CAR-Ts were infused intraperitoneally and only in mice 
with a high tumor burden.29 Notably, CRS was not induced in more immunodeficient NSG 
mice using the same conditions, likely because unlike beige mice, NSG mice harbor defects 
in (IL-6- and IL-1-producing) monocytes and macrophages. CRS in beige mice was 
accompanied by an increase in both human and mouse cytokines and chemokines and by 
massive infiltration of mouse myeloid cells, mostly macrophages, into the tumor site and the 
spleen. Intratumoral murine macrophages were the major source of lL-6, and a murine IL-6-
receptor antibody infused at the time of CAR T cell infusion prevented CRS-induced 
mortality, showing that human CAR-Ts are able to activate murine macrophages. CRS was 
enhanced by expression of murine CD40 ligand on the human CAR-Ts, highlighting the 
importance of cell-to-cell contact between macrophages and CAR-Ts. This interaction 
induced inducible nitric oxide synthase (iNOS) from tumor-infiltrating macrophages. 
Pre-clinical activity of anakinra for CRS and ICANS. In their mouse model, Norelli et al 
Proprietary Information of MD Anderson

Protocol: 2019-1051                                             Phase II study of anakinra and axi-cel 
 
11 
blocked the receptor for both IL-1 (with anakinra) and IL-6 at the time of CAR-T infusion 
prevented CRS without affecting CAR-T expansion or leukemic clearance.28 Unexpectedly, 
about 30 days post-infusion, mice that had received prophylactic IL-6-receptor blockade 
developed lethal neurotoxicity. Importantly, mice that received prophylactic anakinra 
remained free of neurotoxicity, and only anakinra could prevent both CRS and neurotoxicity. 
In the mouse model developed by Giavridis et al, severe CRS toxicity could also be alleviated 
by iNOS inhibitors.29 As iNOS is induced by both IL-1 and IL-6, the authors also blocked 
IL-1 receptor signaling with Anakinra, which, as in the study of Norelli et al, prevented CRS. 
The authors went on to show that CAR-Ts expressing a recombinant IL-1-receptor antagonist 
could also inhibit CRS without loss of tumor control. This CAR-T intrinsic strategy could 
eliminate the requirement for administration of expensive recombinant proteins after CAR-
T infusion. 
Current clinical use of anakinra. Anakinra is currently approved for the treatment of patients 
with rheumatoid arthritis (RA) who have failed 1 or more lines of disease modifying anti-
rheumatic drugs, and for the treatment of patients with Neonatal-Onset Multisystem 
Inflammatory Disease (NOMID), a form of Cryopyrin-Associated Periodic Syndromes 
(CAPS).31-34 Anakinra is used at the dose of 100 mg subcutaneously daily in RA, and 1-2 
mg/Kg (up to 8 mg/Kg) subcutaneously daily for patients with NOMID/CAPS. Every other 
day dosing is recommended in case of creatinine clearance < 30 mL/min. In patients with 
RA, the most common adverse reactions (incidence ≥ 5%) are injection site reaction, 
worsening of RA, upper respiratory tract infection, headache, nausea, diarrhea, sinusitis, 
arthralgia, flu like-symptoms, and abdominal pain; in patients with NOMID/CAPS, the most 
common AEs during the first 6 months of treatment (incidence >10%) are injection site 
reaction, headache, vomiting, arthralgia, pyrexia, and nasopharyngitis. For study details 
please refer to the Investigator’s Brochure. 
 
4.2 Rationale 
4.2.1 Rationale for the Trial and Selected Subject Population 
As described above, IL-1 blockade can associate with reduction of CRS and ICANS, without 
affecting axi-cel efficacy. Therefore, administration of anakinra without affecting efficacy 
may increase the safety and potentially the efficacy of axi-cel in patients with relapsed or 
refractory large B-cell lymphoma. Based on the known mechanisms of action of anakinra 
and axi-cel and their established safety profile, the combination is not expected to increase 
the toxicity of either agent. No other clinical trials are currently investigating this 
combination, this being a pilot study. Given that the many patients with relapsed or refractory 
B-cell lymphoma in need of CAR T cell therapy are older or with significant comorbidities, 
development of such therapeutic strategies that without affecting efficacy increase safety and 
potentially the efficacy of axi-cel is highly desirable. 
4.2.2 Rationale for Dose Selection/Regimen/Modification  
The absolute bioavailability of anakinra after a 70 mg subcutaneous bolus injection was 
evaluated in 11 healthy subjects and was 95%. In 18 subjects with RA, maximum plasma 
concentrations occurred 3 to 7 hours after administration at clinically relevant doses (1 to 2 
Proprietary Information of MD Anderson

Protocol: 2019-1051                                             Phase II study of anakinra and axi-cel 
 
12 
mg/kg): the terminal half-life ranged from 4 to 6 hours and no unexpected accumulation of 
was observed after daily subcutaneous doses for up to 24 weeks.35 
The safety and efficacy of anakinra have been evaluated in 3 randomized, double-blind, 
placebo-controlled trials of 1392 patients > 18 years of age with active RA. An additional 
fourth study was conducted to assess safety.35 In the efficacy trials, anakinra was studied in 
combination with other disease-modifying antirheumatic drugs (studies 1 and 2) or as a 
monotherapy (study 3). The highest investigated dose was 100 mg daily. The most serious 
adverse reactions were neutropenia (any grade, 8% of patients) and infections (grade 3-4 in 
2% of patients), and more common in patients receiving other immunosuppressive agents. 
The safety and efficacy of anakinra have also been investigated in an open label study 
including 43 patients with NOMID/CAPS, using doses up to 8 mg/Kg daily, for up to 15 
months.35 The most serious adverse reaction was represented by infections, reported in 7 
patients (grade 3-4), and more common in patients < 12 years. 
The dose of anakinra typically used for the treatment of RA (100 mg daily) may or may not 
be biologically effective for the purpose of IL-1 blockade in patients with relapsed or 
refractory large B-cell lymphoma receiving axi-cel therapy. The 2 dose levels selected for 
this study (100 mg daily and 100 mg BID), corresponding to a dose ranging between 1 mg/Kg 
and 6 mg/Kg, are based on safety established in clinical trials with doses as high as 8 mg/Kg, 
used for prolonged time. In addition, as the dosage form is a pre-filled syringe of 100 mg for 
subcutaneous use, selected dose levels will limit the treatment to no more than 2 
subcutaneous injection a day for treated patients. The duration of treatment of 7 days, starting 
on day 0 of axi-cel infusion, is based on the kinetics of IL-1RA observed in patients with 
large B-cell lymphoma treated with axi-cel,36 showing the highest concentrations in the 
peripheral blood of treated patients during the first week after axi-cel infusion. 
 
4.2.3 Rationale for Endpoints 
4.2.3.1 Safety and Efficacy Endpoints 
The primary endpoint is the safety and tolerability of anakinra in decreasing CAR T cell-
related toxicity measured as incidence of any grade CR within 30 days after infusion of CAR 
T cells in patients with relapsed or refractory large B-cell lymphoma. Secondary efficacy 
endpoints will include incidence of different grades and duration of both CRS and ICANS, 
ORR, CR rate, PFS, and OS. Cheson 2014 Lugano Classification response criteria for 
malignant lymphoma will be used to assess clinical responses.1 After prolonged follow-up, 
use of axi-cel in patients with relapsed or refractory large B-cell lymphoma was associated 
with an ORR of 83%, a CR rate of 58%, and a rate of grade 3 or higher CRS and ICANS of 
11% and 32%, respectively.18,19 Given the mechanism of action of anakinra and the absence 
of significant overlapping toxicity, we expect to observe a reduction in CRS and ICANS, 
without any additional AEs. We may also observe an improvement in ORR, CR rate, PFS 
and OS as compared with axi-cel monotherapy. 
Proprietary Information of MD Anderson

Protocol: 2019-1051                                             Phase II study of anakinra and axi-cel 
 
13 
4.2.3.2 Biomarker Research 
Blood samples and tumor biopsies will be obtained from consenting patients at baseline 
and/or on treatment from subjects enrolled on the study at the indicated time points shown 
in the Trial Flow Chart under Section 6.0. The overall goal of the biomarker studies is to 
identify pharmacodynamic effects of anakinra combined with axi-cel therapy. Peripheral 
blood mononuclear cells (PBMC) and plasma will be isolated from blood samples and 
cryopreserved for batched analysis. Both blood sample and tumor biopsy collection are 
optional. 
PBMC samples will be analyzed by up to 14-color multiparametric flow cytometry to 
determine the expansion, phenotype, and persistence of CAR T cells as well as alteration in 
the phenotype and number of multiple cellular components, including normal B and T 
lymphocytes, monocytes, and natural killer cells. Plasma samples will be analyzed for 
alteration in various cytokines and chemokines. CAR T cell levels will also be monitored by 
qPCR.  
 
5.0 METHODOLOGY 
5.1 Entry Criteria 
5.1.1 Diagnosis/Condition for Entry into the Trial 
Male or female subjects with relapsed or refractory diffuse large B-cell lymphoma, primary 
mediastinal B-cell lymphoma, transformed follicular lymphoma or high-grade B-cell 
lymphoma receiving standard of care therapy with axicabtagene ciloleucel. 
5.1.2 Subject Inclusion Criteria 
In order to be eligible for participation in this trial, the subject must: 
1. Relapsed or refractory DLBCL, PMBCL, tFL, or HGBCL, at least 2 prior lines of 
systemic therapy  
2. Planned to receive standard of care therapy with axicabtagene ciloleucel 
3. ≥ 18 years of age 
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (Appendix 
1) 
5. Measurable disease of ≥ 1.5 cm 
6. At least two weeks or 5 half-lives, whichever is shorter, must have elapsed since any 
prior systemic therapy at the time the subject is planned for axi-cel therapy, except for 
systemic immune checkpoint inhibitory / immune stimulatory therapy. At least 3 half-
lives must have elapsed from any prior systemic immune checkpoint inhibitory / 
immune stimulatory therapy at the time the subject is planned for leukapheresis (e.g. 
ipilimumab, nivolumab, pembrolizumab, atezolizumab, OX40 agonists, 4-1BB 
agonists, etc) 
7. Toxicities due to prior therapy must be stable and recovered to ≤ Grade 1 (except for 
clinically non-significant toxicities such as alopecia) 
Proprietary Information of MD Anderson

Protocol: 2019-1051                                             Phase II study of anakinra and axi-cel 
 
14 
8. Absolute neutrophil count of ≥ 1.0×109/L 
9. Platelet count of ≥ 60×109/L 
10. Creatinine clearance (as estimated by Cockcroft Gault) ≥ 45 mL/min  
11. Serum alanine transaminase (ALT) / aspartate transaminase (AST) ≤ 2.5 upper limit of 
normal (ULN)  
12. Total bilirubin ≤1.5 mg/dL, except in subjects with Gilbert’s syndrome.  
13. Cardiac ejection fraction ≥ 50% with no evidence of pericardial effusion 
14. Baseline oxygen saturation > 92% on room air  
15. No evidence, suspicion, and/or history of lymphoma involving the central nervous 
system (CNS) 
16. Females of childbearing potential must have a negative serum or urine pregnancy test 
(females who have undergone surgical sterilization or who have been postmenopausal 
for at least 2 years are not considered to be of childbearing potential)  
 
5.1.3 Subject Exclusion Criteria 
The subject must be excluded from participating in the trial if the subject: 
1. History of malignancy other than nonmelanoma skin cancer or carcinoma in situ (e.g. 
cervix, bladder, breast) unless disease free for at least 3 years  
2. History of Richter’s transformation of chronic lymphocytic leukemia (CLL)  
3. Autologous stem cell transplantation within 6 weeks of planned axi-cel infusion  
4. History of allogeneic stem cell transplantation  
5. Prior CD19 targeted therapy 
6. Prior chimeric antigen receptor therapy or other genetically modified T cell therapy  
7. Presence of fungal, bacterial, viral, or other infection that is uncontrolled or requiring 
IV antimicrobials for management. Simple UTI and uncomplicated bacterial 
pharyngitis are permitted if responding to active treatment and after consultation with 
the Principal investigator 
8. Known history of infection with HIV or hepatitis B (HBsAg positive) or hepatitis C 
virus (anti-HCV positive). A history of hepatitis B or hepatitis C is permitted if the viral 
load is undetectable per quantitative PCR and/or nucleic acid testing.  
9. Known history of tuberculosis. A negative Quantiferon or PPD up to 2 months before 
start of anakinra is enough if no specific risk factors 
10. Presence of any indwelling line or drain (e.g., percutaneous nephrostomy tube, 
indwelling foley catheter, biliary drain, or pleural/peritoneal/pericardial catheter). 
Dedicated central venous access catheters such as a Port-a-Cath or Hickman catheter 
are permitted  
Proprietary Information of MD Anderson

Protocol: 2019-1051                                             Phase II study of anakinra and axi-cel 
 
15 
11. Subjects with detectable cerebrospinal fluid malignant cells, or brain metastases, or 
with a history of CNS lymphoma, cerebrospinal fluid malignant cells or brain 
metastases  
12. History or presence of CNS disorder such as seizure disorder, cerebrovascular 
ischemia/hemorrhage, dementia, cerebellar disease, or any autoimmune disease with 
CNS involvement  
13. Subjects with cardiac atrial or cardiac ventricular lymphoma involvement  
14. History of myocardial infarction, cardiac angioplasty or stenting, unstable angina, or 
other clinically significant cardiac disease within 12 months of enrollment 
15. Requirement for urgent therapy due to tumor mass effects such as bowel obstruction or 
blood vessel compression  
16. Primary immunodeficiency  
17. History of autoimmune disease (e.g. Crohns, rheumatoid arthritis, systemic lupus) 
resulting in end organ injury or requiring systemic immunosuppression/systemic 
disease modifying agents within the last 2 years  
18. History of symptomatic deep vein thrombosis or pulmonary embolism within 6 months 
of enrolment  
19. Any medical condition likely to interfere with assessment of safety or efficacy of study 
treatment  
20. History of severe immediate hypersensitivity reaction to any of the agents used in this 
study, including E coli-derived proteins  
21. Live vaccine ≤ 6 weeks prior to planned start of conditioning regimen  
22. Women of child-bearing potential who are pregnant or breastfeeding because of the 
potentially dangerous effects of the preparative chemotherapy on the fetus or infant.  
23. Subjects of both genders who are not willing to practice birth control from the time of 
consent through 6 months after the completion of anakinra injections 
24. In the investigator’s judgment, the subject is unlikely to complete all protocol-required 
study visits or procedures, including follow-up visits, or comply with the study 
requirements for participationTrial Treatments 
 
5.1.4 Dose Selection/Modification 
5.1.4.1 Dose Selection 
The rationale for selection of doses to be used in this trial is provided in Section 4.0 – 
Background and Rationale. The 2 dose levels of Anakinra to be used in this trial are 
outlined below in Table 1. A 3+3 design will be used for a safety run-in phase within each 
dose level cohort. 
Table 1.  Dose levels (DL) 
Proprietary Information of MD Anderson

Protocol: 2019-1051                                             Phase II study of anakinra and axi-cel 
 
16 
 
5.1.4.2 Guidelines for Dose Modification  
Dose modifications of anakinra are not permitted within each subject. Any subject who 
experiences toxicity from anakinra may be discontinued from further injections of anakinra 
at the discretion of the Principal Investigator.  
5.1.5 Timing of Dose Administration 
Administration of conditioning chemotherapy. Subjects will receive cyclophosphamide 
(500 mg/m2/day) and fludarabine (30 mg/m2/day) for 3 days on days -5, -4, and -3. Weight 
of the subject measured at any time between days -14 and -5 may be used for calculation 
of chemotherapy doses. Antiemetic prophylaxis, mesna, and intravenous hydration will be 
included as per standard guidelines. The administration start/stop time of 
cyclophosphamide, fludarabine, and mesna will all be noted in the subject medical record. 
Administration of axi-cel. Subjects will be hospitalized for axi-cel infusion. Axi-cel 
treatment consists of a single infusion of CAR transduced autologous T cells administered 
on day 0 in under 30 minutes. Axi-cel will be infused intravenously via a central venous 
catheter at a dose of 2×106 anti-CD19 CAR+ T cells/kg with a maximum of 2×108 CAR+ 
T cells for patients weighing >100 kg. Body weight on the day of leukapheresis will be 
used for calculation of axi-cel dose. Subjects will remain in the hospital through at least 
day 7 post-axi-cel infusion. Subjects should not be discharged from the hospital until all 
axi-cel-related non-hematological toxicities return to ≤ grade 1 or baseline. Subjects may 
be discharged with non-critical and clinically stable or slowly improving toxicities (e.g., 
renal insufficiency) even if > grade 1, if deemed appropriate by the Principal Investigator. 
Administration of anakinra. The study drug, anakinra will be administered daily by 
subcutaneous injection for 7 days. The initial dose will be administered on day 0, at least 
6 hours prior to axi-cel infusion. Two dose levels will be investigated: 100 mg daily and 
100 mg BID. A 3+3 design will be used for a safety run-in phase within each dose level 
cohort. 
5.2 Concomitant Medications/Vaccinations (allowed & prohibited) 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  If there is a clinical indication for one of these or other medications 
or vaccinations specifically prohibited during the trial, discontinuation from trial therapy or 
vaccination may be required. The final decision on any supportive therapy or vaccination 
rests with the investigator and/or the subject's primary physician. However, the decision to 
continue the subject on trial therapy or vaccination schedule requires the mutual agreement 
of the Investigator and the subject.  
Drug 
Potency 
Frequency 
Route of Administration 
Treatment Period 
DL1: Anakinra 
100 mg 
daily 
subcutaneous 
7 days, starting on day 0 of 
axi-cel infusion 
DL2: Anakinra 
100 mg 
Twice a day 
subcutaneous 
7 days, starting on day 0 of 
axi-cel infusion 
Proprietary Information of MD Anderson

Protocol: 2019-1051                                             Phase II study of anakinra and axi-cel 
 
17 
5.2.1 Acceptable Concomitant Medications 
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards 
of medical care.  All concomitant medication will be recorded on the case report form 
(CRF) including all prescription, over-the-counter (OTC), herbal supplements, and IV 
medications and fluids.  If changes occur during the trial period, documentation of drug 
dosage, frequency, route, and date may also be included on the CRF. Subjects may remain 
on anti-coagulation therapy as long as the PT or PTT is within therapeutic range of the 
intended use of anticoagulants. 
All concomitant medications received within 28 days before the first dose of trial treatment 
and 30 days after the last dose of trial treatment should be recorded. Concomitant 
medications administered after 30 days after the last dose of trial treatment should be 
recorded for SAEs as defined in Section 7.2. 
5.2.2 Prohibited Concomitant Medications 
Subjects are prohibited from receiving the following therapies during the Treatment Phase 
of this trial: 
• Antineoplastic systemic chemotherapy or biological therapy  
• Immunotherapy not specified in this protocol 
• Chemotherapy not specified in this protocol 
• Investigational agents other than anakinra 
• Radiation therapy  
• Live vaccines within 6 weeks prior to the first dose of trial treatment and while 
participating in the trial.  Examples of live vaccines include, but are not limited to, 
the following: measles, mumps, rubella, chicken pox, yellow fever, rabies, BCG, 
and typhoid (oral) vaccine. Seasonal influenza vaccines for injection are generally 
killed virus vaccines and are allowed; however intranasal influenza vaccines (e.g. 
Flu-Mist®) are live attenuated vaccines, and are not allowed.  
• Systemic use of glucocorticoids for any purpose other than for management of 
CAR-T associated toxicities during the first 30 days after axi-cel infusion. The use 
of physiologic doses of corticosteroids may be allowed (</= 5 mg/day of prednisone 
or equivalent doses of other corticosteroids).  
Subjects who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the trial. 
Subjects may receive other medications that the investigator deems to be medically 
necessary. 
5.3 Rescue Medications & Supportive Care 
5.3.1 Supportive Care Guidelines 
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator including but not limited to the items outlined below: 
Proprietary Information of MD Anderson

Protocol: 2019-1051                                             Phase II study of anakinra and axi-cel 
 
18 
• Infection Prophylaxis: Subjects should receive prophylaxis for pneumocystis pneumonia, 
herpes simplex/zoster, and fungal infections according to standard institutional practice.  
• Tumor Lysis Syndrome: all subjects with significant malignancy burden and without a 
contradiction such as allergy should be started on prophylaxis (e.g. allopurinol) as per 
institutional guidelines prior to axi-cel infusion. Prophylaxis may be discontinued when 
the risk of tumor lysis has passed.  
• B Cell Depletion: it is possible that B cell depletion and hypogammaglobulinemia will 
occur due to the effects of axi-cel on normal B cells. Gammaglobulin will be administered 
for hypogammaglobulinemia according to institutional guidelines. 
• Fever and Neutropenia: evaluation for source of infection, antipyretics, initiation of 
antibiotics, and comfort measures including IV hydration should be performed per 
institutional guidelines.  
• Blood Product Support: all blood products should be irradiated. Subjects should receive 
platelets and packed red blood cells as needed. Attempts should be made to keep 
hemoglobin >8.0 gm/dL and platelets >10,000/mm3. Leukocyte filters should be utilized 
for all blood and platelet transfusions to decrease sensitization to transfused WBC’s and 
decrease the risk of CMV infection.   
5.3.1.1 Supportive Care Guidelines for CRS and ICANS 
Acute toxicities associated with axi-cel infusion include cytokine release syndrome (CRS) 
and immune effector cell-associated neurotoxicity syndrome (ICANS). Efforts should be 
made to rule out neoplastic, infectious, metabolic, or other causes prior to labeling an AE 
as CRS or ICANS.     
Cytokine release syndrome (CRS). CRS is a symptom complex associated with the use of 
monoclonal antibodies and adoptive cell therapies that activate lymphocytes. The condition 
results from the release of cytokines from cells targeted by antibodies, immune effector 
cells recruited to the tumor area and subject’s immune cells activated during this process. 
When cytokines are released, a variety of clinical signs and symptoms associated with CRS 
present themselves including cardiac, gastrointestinal, laboratory (coagulation, renal and 
hepatic), neurological, respiratory, skin, vascular (hypotension) and constitutional (fever, 
rigors, headaches malaise, fatigue arthralgia, nausea and vomiting). 
The goal of CRS management after CAR T cell therapy is to prevent life-threatening 
conditions while preserving the benefits of antitumor effects. The ASTCT (American 
Society for Transplantation and Cellular Therapy) CRS Consensus Grading system will be 
used to assess the severity of CRS (Appendix 2; Lee et al 2018) as well as guide 
management. However, we will also capture the individual data elements to be able to 
assess the CRS according to the grading described by Lee et al 2014 (Appendix 3) in order 
to compare the toxicities to historical data. The diagnostic work-up and management of 
CRS will be performed as per CARTOX Guidelines (Appendix 5). 
Hemophagocytic lymphohistiocytosis/ macrophage activation syndrome (HLH/MAS). 
CRS and classic acquired HLH/MAS have many shared features, and the 2 entities likely 
are not distinct, reflecting the activation of the reticuloendothelial system initiated by T 
cell-mediated inflammation. Most patients with moderate to severe CRS have laboratory 
Proprietary Information of MD Anderson

Protocol: 2019-1051                                             Phase II study of anakinra and axi-cel 
 
19 
results that meet the classic criteria for HLH/MAS such as elevation of ferritin, 
triglycerides, and soluble CD25 but may or may not have hepatosplenomegaly, 
lymphadenopathy, or overt evidence of hemophagocytosis. The symptoms and signs 
suggestive of HLH/MAS subside with CRS resolution in most patients. However, 
refractory and fulminant HLH/MAS has been described in rare cases after CAR T-cell 
therapy and may be treated as previously described using tocilizumab and corticosteroids 
with or without etoposide.23 
Immune effector cell-associated neurotoxicity syndrome (ICANS). Neurotoxicity (e.g. 
encephalopathy, somnolence, aphasia) have been observed with anti-CD19 CAR T cell 
therapies. The ASTCT Consensus Grading will be used for to assess the severity of ICANS 
(Appendix 4; Lee et al 2018) as well as guide the management. However, we will also 
grade and capture the symptoms and signs of neurotoxicity as per CTCAE v 5.0 in order 
to be able to compare the toxicities to historical data. The diagnostic work-up and 
management of ICANS will be performed as per CARTOX Guidelines (Appendix 6). 
Endotracheal intubation may be needed for airway protection in severe cases. 
Corticosteroids may be considered for any severe or life-threatening neurotoxicity and anti-
seizure and sedatives may be considered as clinically indicated. If there is no 
contraindication, subjects will receive levetiracetam (750 mg PO or IV BID) for seizure 
prophylaxis starting on Day 0. Levetiracetam may be tapered and discontinued after day 
30. 
5.4 Other Considerations 
5.4.1 Contraception 
Chemotherapy agents used for conditioning before axi-cel infusion and anakinra  may have 
adverse effects on a fetus in utero. Furthermore, it is not known if anakinra has transient 
adverse effects on the composition of sperm. Non-pregnant, non-breast-feeding women 
may be enrolled if they are willing to use 2 methods of birth control or are considered 
highly unlikely to conceive. Highly unlikely to conceive is defined as 1) surgically 
sterilized, or 2) postmenopausal (a woman who is ≥45 years of age and has not had menses 
for greater than 1 year will be considered postmenopausal), or 3) not heterosexually active 
for the duration of the study. The two birth control methods can be either two barrier 
methods or a barrier method plus a hormonal method to prevent pregnancy. Subjects should 
start using birth control from study visit 1 and throughout the study period up to 6 months 
after the last dose of study therapy.  
The following are considered adequate barrier methods of contraception: diaphragm, 
condom (by the partner), copper intrauterine device, sponge, or spermicide. Appropriate 
hormonal contraceptives will include any registered and marketed contraceptive agent that 
contains an estrogen and/or a progestational agent (including oral, subcutaneous, 
intrauterine, or intramuscular agents). 
Subjects should be informed that taking the study medication may involve unknown risks 
to the fetus (unborn baby) if pregnancy were to occur during the study. In order to 
participate in the study they must adhere to the contraception requirement (described 
above) for the duration of the study and during the follow-up period defined in section 
7.2.2-Reporting of Pregnancy and Lactation to Sobi. If there is any question that a subject 
Proprietary Information of MD Anderson

Protocol: 2019-1051                                             Phase II study of anakinra and axi-cel 
 
20 
will not reliably comply with the requirements for contraception, that subject should not 
be entered into the study. 
5.4.2 Use in Pregnancy 
If a subject inadvertently becomes pregnant while on treatment with anakinra, the subject 
will immediately be removed from the study. The site will contact the subject at least 
monthly and document the subject’s status until the pregnancy has been completed or 
terminated. The outcome of the pregnancy will be reported to Sobi without delay and 
within 24 hours if the outcome is a serious adverse experience (e.g., death, abortion, 
congenital anomaly, or other disabling or life-threatening complication to the mother or 
newborn). The study investigator will make every effort to obtain permission to follow the 
outcome of the pregnancy and report the condition of the fetus or newborn to Sobi. If a 
male subject impregnates his female partner the study personnel at the site must be 
informed immediately and the pregnancy reported to Sobi and followed as described above 
and in Section 7.2.2. 
5.4.3 Use in Nursing Women 
It is unknown whether anakinra is excreted in human milk. Since many drugs are excreted 
in human milk, and because of the potential for serious adverse reactions in the nursing 
infant, subjects who are breast-feeding are not eligible for enrollment. 
5.5 Subject Withdrawal/Discontinuation Criteria 
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the 
discretion of the investigator should any untoward effect occur. In addition, a subject may be 
withdrawn by the investigator if enrollment into the trial is inappropriate, the trial plan is 
violated, or for administrative and/or other safety reasons. Specific details regarding 
discontinuation or withdrawal are provided in Section 7.1.4. 
A subject must be discontinued from the trial for any of the following reasons: 
• The subject or legal representative (such as a parent or legal guardian) withdraws 
consent. 
• Confirmed radiographic disease progression 
• Unacceptable AEs (grade > 3 AE lasting > 2 weeks) 
• Intercurrent illness that prevents further administration of treatment 
• Investigator’s decision to withdraw the subject 
• The subject has a confirmed positive serum pregnancy test 
• Noncompliance with trial treatment or procedure requirements 
• The subject is lost to follow-up 
• Administrative reasons 
5.6 Subject Replacement Strategy 
Additional subjects may be enrolled to ensure that the required number of evaluable subjects 
is achieved in the applicable analysis population. 
Proprietary Information of MD Anderson

Protocol: 2019-1051                                             Phase II study of anakinra and axi-cel 
 
21 
5.7 Clinical Criteria for Early Trial Termination 
Early trial termination will be the result of the criteria specified below: 
1. Quality or quantity of data recording is inaccurate or incomplete 
2. Poor adherence to protocol and regulatory requirements 
3. Incidence or severity of adverse drug reaction in this or other studies with anakinra 
indicates a potential health hazard to subjects 
4. Plans to modify or discontinue the development of the study drug 
5. Evidence of significant Dose-limiting toxicity (DLT) at dose level 1 as defined in Section 
8.1. 
In the event of Sobi decision to no longer supply study drug, ample notification will be 
provided so that appropriate adjustments to subject treatment can be made. 
Proprietary Information of MD Anderson

Protocol: 2019-1051                                            Phase II study of anakinra and axi-cel 
 
  
 
 
 
22 
6.0 TRIAL FLOW CHART 
6.1 
Schedule of Assessments – Table 2. 
Procedures 
Screening (Days 
before 
enrollment) 
Enrollment 
Conditioning 
Chemotherapy 
Period 
CAR-T cell 
Administration 
Period 
Post Treatment Follow-
up (each visit calculated 
from Day 0) 
Day 
Within 28 days of 
enrollment 
-5 
-4 
-3 
-2 
-1 
0 
1 - 7 
Week 2 
Week 4 
(± 3 days) 
Month 2 
(± 1 week) 
Months 3, 6, 9, 
12, 18, 24 
(± 2 weeks) 
Medical history 
X 
 
 
 
 
Physical examk 
 
X 
Daily 
X 
X 
X 
X 
Neurological assessmentk 
 
X 
Daily 
 
X 
 
X (month 3) 
ECOG Performance Statusk 
 
 
ECG 
X 
 
LVEF assessment by ECHOa 
X 
 
Leukapheresis 
X 
 
Fludarabine/Cyclophosphamide 
X 
X 
X 
 
Axi-cel infusion IV 
X 
 
Anakinrai 
X 
Daily (days 1-
6) 
Brain MRI 
X 
 
PET-CT/ CT CAP for disease 
Xb 
 
X 
X 
ICE Scorek 
 
X 
X 
X 
X 
 
 
Vital signsc  
X 
X 
X 
X 
X 
Daily 
X 
X 
X 
X 
Weight and heightd 
X 
X 
X 
X 
 
 
X 
 
Pregnancy test (serum or urine)e 
X 
X 
 
 
Urinalysis 
X 
 
Chemistry panel 
X 
X 
 
 
X 
Daily 
X 
X 
X 
X 
CBC w/differential 
X 
X 
 
 
X 
Daily 
X 
X 
X 
X 
PT, PTT 
X 
X 
 
 
X 
Weekly 
X 
X 
X 
X 
CRP and ferritin levels 
X 
X 
Daily 
 
 

Protocol: 2019-1051                                            Phase II study of anakinra and axi-cel 
 
  
 
 
 
23 
 
 
aECHO is acceptable if it is performed within 6 weeks of enrollment. 
bPET-CT (Neck-Chest-Abdomen-Pelvis)/disease assessment PET-CT performed following last line of therapy (>28 days from enrollment) may be used for confirmation of eligibility.  
If PET-CT performed > 28 days prior to the initiation of conditioning chemotherapy or if subject receives any anti-cancer therapy between screening and conditioning chemotherapy, 
baseline scans must be repeated. Screening PET-CT should be completed as close to enrollment as possible. As applicable, bone marrow aspirate/biopsy will be performed to confirm 
response (i.e., for subjects presenting with bone marrow involvement 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). Disease assessments or scans performed as part of routine clinical management are acceptable for use as the screening 
scan if they are of diagnostic quality and performed within 42 days prior to the first dose of trial treatment 
cVital signs should include temperature, pulse, respiratory rate blood pressure and oxygen saturation 
dWeight will be measured at any time between days -14 and -5may be used for calculation of chemotherapy doses. Body weight will be collected on the day of leukaphersis. Height 
will be measured at screening only. 
e For women of reproductive potential, a urine pregnancy test will be performed within 72 hours prior to the first dose of trial treatment. If urine pregnancy results cannot be confirmed 
as negative, a serum pregnancy test will be required (performed by the local study site laboratory). 
fTest for HIV, hepatitis B and C serology to be performed within 60 days of enrollment; PCR will be performed only in case of positive serology, for confirmation 
gThis will be repeated at time of first response assessment if initially positive and patient has achieved CR by PET-CT 
hIf possible, the 30 day Safety Follow-up visit must occur before the first dose of the new therapy. Once new anti-cancer therapy has been initiated the subject will move into survival 
follow-up. 
i The initial dose will be administered on Day 0 approximately 6 hours prior to Axi-cel infusion 
j  Screening bone marrow biopsy and aspirate can be waived if PET-CT and/or blood counts, at the discretion of the treating physician, are not concerning for lymphoma 
involvement 
k Within 28 days of starting treatment. 
IgG, IgM, IgA 
 
X 
 
 
X 
X 
HIV and Hepatitis serology 
Xf 
 
 
 
 
 
ELISpot for tuberculosis 
X 
 
 
 
 
 
Bone marrow biopsy/aspirate 
Xj 
 
 
 
Xg 
Xg 
Blood draw for biomarkers 
X 
X 
Days 1, 3, 7 
X 
X 
X 
Adverse events/ Concomitant 
medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xh 
 
 

Protocol: 2019-1051                                            Phase II study of anakinra and axi-cel 
 
  
 
 
24 
7.0 TRIAL PROCEDURES 
7.1 Trial Procedures 
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each 
visit. Individual trial procedures are described in detail below. It may be necessary to 
perform these procedures at unscheduled time points if deemed clinically necessary by the 
investigator. 
7.1.1 Administrative Procedures 
7.1.1.1 Informed Consent 
The informed consent will adhere to IRB requirements, applicable laws and regulations 
and Sponsor requirements. 
7.1.1.2 Inclusion/Exclusion Criteria 
All inclusion and exclusion criteria will be reviewed by the investigator or qualified 
designee to ensure that the subject qualifies for the trial.  
7.1.1.3 Medical History 
A medical history will be obtained by the investigator or qualified designee. Medical 
history will include all active conditions, and any condition diagnosed within the prior 10 
years that are considered to be clinically significant by the Investigator. Details regarding 
the disease for which the subject has enrolled in this study will be recorded separately and 
not listed as medical history.   
7.1.1.4 Prior and Concomitant Medications Review 
7.1.1.4.1 Prior Medications 
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the subject 
within 28 days before starting the trial. Treatment for the disease for which the subject has 
enrolled in this study will be recorded separately and not listed as a prior medication.  
7.1.1.4.2 Concomitant Medications 
The investigator or qualified designee will record medication, if any, taken by the subject 
during the trial. All medications related to reportable SAEs should be recorded as defined 
in Section 7.2. 
7.1.1.5 Disease Details and Treatments 
7.1.1.5.1 Disease Details 
The investigator or qualified designee will obtain prior and current details regarding 
disease status.  
7.1.1.5.2 Prior Treatment Details 
The investigator or qualified designee will review all prior cancer treatments including 
systemic treatments, radiation and surgeries. 
Proprietary Information of MD Anderson

Protocol: 2019-1051                                            Phase II study of anakinra and axi-cel 
 
  
 
 
25 
7.1.1.5.3 Subsequent Anti-Cancer Therapy Status 
The investigator or qualified designee will review all new anti-neoplastic therapy initiated 
after the last dose of trial treatment. If possible, the 30 day Safety Follow-up visit must 
occur before the first dose of the new therapy. Once new anti-cancer therapy has been 
initiated the subject will move into survival follow-up.  
7.1.2 Clinical Procedures/Assessments 
7.1.2.1 Adverse Event Monitoring 
The investigator or a physician designee will assess each subject to evaluate for potential 
new or worsening AEs as specified in the Trial Flow Chart and more frequently if clinically 
indicated. Adverse experiences will be graded and recorded throughout the study and 
during the follow-up period according to NCI CTCAE Version 5.0. CRS and ICANS will 
be graded according to the ASTCT consensus guidelines and Lee et al 2014. Toxicities will 
be characterized in terms of seriousness, causality, toxicity grading, and action taken with 
regard to trial treatment.  
Please refer to section 7.2 for detailed information regarding the assessment and recording 
of AEs. 
7.1.2.2 Full Physical Exam and Vital Signs 
The investigator or qualified designee will perform a full physical exam during the 
screening period. After the first dose of trial treatment new clinically significant abnormal 
findings should be recorded as AEs. The investigator or qualified designee will also take 
vital signs at screening, prior to the administration of each dose of trial treatment and at 
treatment discontinuation as specified in the Trial Flow Chart (Section 6.0). Vital signs 
should include temperature, pulse, respiratory rate, weight and blood pressure, oxygen 
saturation. Height will be measured at screening only. 
7.1.2.3 Neurocognitive Assessment and Magnetic Resonance Imaging 
Neurocognitive assessments will be standardized by using the Immune-Effector Cell-
Associated Encephalopathy (ICE) Score as per ASTCT consensus grading (Appendix 4). 
A full neurological assessment will be completed during screening to establish a baseline. 
Subsequent assessments will be performed before axi-cel administration on Day 0 and on 
day 1-7 as well as week 4 and month 3. If CNS symptoms develop, ICE score will be 
performed daily until resolution of symptoms or discharged from the hospital. Each subject 
will undergo a screening Brain MRI to rule out CNS metastasis during the screening period 
of the study.   
7.1.2.4 Cardiac Function 
Each subject’s cardiac function as measured by Left Ventricular Ejection Fraction (LVEF) 
will be assessed during the screening period to confirm study eligibility. No evidence of 
pericardial effusion as required by eligibility will also be confirmed. Both LVEF and 
pericardial effusion will be assessed prior to study entrance by ECHO. To establish a 
baseline, a 12-lead ECG will also be performed prior to initiating study treatment. 
Proprietary Information of MD Anderson

Protocol: 2019-1051                                            Phase II study of anakinra and axi-cel 
 
  
 
 
26 
7.1.2.5 Eastern Cooperative Oncology Group (ECOG) Performance Scale 
The investigator or qualified designee will assess ECOG status (see Section 12.1) at 
screening as specified in the Trial Flow Chart. 
7.1.2.6 Tumor Imaging and Assessment of Disease 
7.1.2.6.1 Criteria for Assessment of Disease 
The Recommendations for Initial Evaluation, Staging, and Response Assessment of 
Hodgkin and Non-Hodgkin Lymphoma: The Lugano Classification1 criteria will be applied 
as the primary measure for assessment of disease response and as a basis for all protocol 
guidelines related to disease status (e.g. discontinuation of study therapy) (Appendix 7). 
7.1.2.6.2 Initial Disease Assessment 
Initial disease assessment or tumor imaging must be performed within 28 days prior to the 
first dose of trial treatment. PET-CT fusion imaging scans with oral contrast/water and IV 
contrast will be used for initial disease assessment unless there is a contraindication. 
Disease assessments or scans performed as part of routine clinical management are 
acceptable for use as the screening scan if they are of diagnostic quality and performed 
within 42 days prior to the first dose of trial treatment. 
7.1.2.6.3 Disease Assessment During Trial 
Disease response assessments will occur 4 weeks after initiation of therapy, then at months 
3, 6, 9, 12, 18, and 24. There is a ±14-day window for all imaging assessments. Disease 
response assessments will be performed by CT scans or PET-CT scan at the indicated time 
points (see Trial Flow Chart - Section 6.0).  
In subjects achieving a complete remission by CT scan criteria, PET-CT scan will be 
repeated once to confirm response. In addition, unilateral bone marrow aspiration and 
biopsy will be repeated once in such patients if the bone marrow was involved with 
lymphoma at baseline. 
Disease assessments and imaging should continue to be performed until documented 
disease progression, the start of new anti-cancer treatment, withdrawal of consent, death, 
or the end of the study, whichever occurs first. 
7.1.2.7 Blood Sampling and Tumor Tissue Collection for Correlative Studies 
Biomarker analysis will be performed on blood and tumor samples to evaluate the effects 
of anakinra on mechanisms of CRS, ICANS and on the function of infused CAR T cells. 
Prognostic markers in large B-cell NHL may also be evaluated. 
The expansion, persistence, and immunophenotype of transduced anti-CD19 CAR+ T cells 
will be monitored in the blood primarily by PCR analysis, complemented by flow 
cytometry. 
Levels of serum cytokines will also be evaluated in the blood. The following cytokines 
may be included in the panel: pro-inflammatory and immune modulating cytokines IL-6, 
TNFα, IL-8, IL-1, IL-2, GM-CSF, IL 15, IL-17a, IFNγ, IL-12p40/p70; immune effector 
Proprietary Information of MD Anderson

Protocol: 2019-1051                                            Phase II study of anakinra and axi-cel 
 
  
 
 
27 
molecules Granzyme A, B, Perforin, sFasL; correlates of acute phase response CRP, SAA 
and chemokines MIP-1α, MIP-3α, IP-10, Eotaxin, MCP-4. 
These samples and any other components from these samples may be stored up to 15 years 
to address exploratory research scientific questions related to the treatment or disease under 
study. Each subject will have the right to have the sample material destroyed at any time 
by contacting the investigator who in turn can contact the central laboratory. The 
investigator should provide the sponsor the study and subject number so that the sample 
can be located and destroyed. 
For subjects who withdraw consent, any samples that were not requested to be returned or 
destroyed will remain with the investigator and any data that may be generated will be 
entered in the study database. 
7.1.3 Laboratory Procedures/Assessments 
Details regarding specific laboratory procedures/assessments to be performed in this trial 
are provided below. The schedule for laboratory assessments is provided under the Trial 
Flow Chart. 
Laboratory tests for screening or entry into the trial should be performed within 28 days 
prior to the first dose of treatment. Pre-dose laboratory procedures will be conducted daily 
prior to dosing. Results must be reviewed by the investigator or qualified designee and 
found to be acceptable prior to each dose of trial treatment. 
The schedule for laboratory assessments is provided under the Trial Flow Chart. CBC with 
differential should include total white count, absolute neutrophil count, absolute 
lymphocyte count, hemoglobin, and platelet count. Comprehensive serum chemistry panel 
should include sodium (Na), potassium (K), chloride (Cl), glucose, bicarbonate (CO2), 
blood urea nitrogen (BUN), creatinine (Cr), calcium (Ca), magnesium (Mg), phosphorus, 
total protein, albumin, alkaline phosphatase, aspartate transaminase (AST), alanine 
transaminase (ALT), total bilirubin, uric acid, and lactate dehydrogenase (LDH). Direct 
bilirubin should be obtained if total bilirubin is above the upper limit of normal. 
Coagulation indexed will include PT and PTT. Urinalysis should include blood, glucose, 
protein, and specific gravity. HIV and Hepatitis serology (including PCR in case of positive 
serology, for confirmation). ELISpot for tuberculosis.  
7.1.4 Withdrawal/Discontinuation 
When a subject discontinues/withdraws prior to trial completion, all applicable activities 
scheduled for the final trial visit should be performed at the time of discontinuation, if the 
patient consents. Any AEs which are present at the time of discontinuation/withdrawal 
should be followed in accordance with the safety requirements outlined in Section 7.2 - 
Assessing and Recording AEs, if the patient consents. After discontinuing treatment, these 
subjects should return to the site for a Safety Follow-up Visit (described in Section 7.1.5.2) 
and then proceed to the Follow-Up Period of the study (described in Section 7.1.5.3). 
However, the follow-ups do not apply when consent and/ or authorization are withdrawn 
by the subject. 
Proprietary Information of MD Anderson

Protocol: 2019-1051                                            Phase II study of anakinra and axi-cel 
 
  
 
 
28 
7.1.5 Visit Requirements 
Visit requirements are outlined in Section 6.0 - Trial Flow Chart. Specific procedure-
related details are provided above in Section 7.1 - Trial Procedures. 
7.1.5.1 Screening Period 
Approximately 28 days prior to enrollment, potential subjects will be evaluated to 
determine that they fulfill the entry requirements as set forth in Section 5.1. Visit 
requirements are outlined in Section 6.0 – Trial Flow Chart. 
Written consent for the main study must be obtained prior to performing any protocol 
specific procedure. Results of a test performed prior to the subject signing consent as part 
of routine clinical management are acceptable in lieu of a screening test if performed within 
the specified time frame. Screening procedures are to be completed within 28 days prior to 
the first dose of trial treatment except for the following: 
• Laboratory tests are to be performed within 7 days prior to the first dose of trial 
treatment. 
• For women of reproductive potential, a urine pregnancy test will be performed 
within 72 hours prior to the first dose of trial treatment. If urine pregnancy results 
cannot be confirmed as negative, a serum pregnancy test will be required 
(performed by the local study site laboratory). 
Subjects may be rescreened after initially failing to meet the inclusion/exclusion criteria. 
Results from assessments performed during the initial screening period are acceptable in 
lieu of a repeat screening test if performed within the specified time frame and the 
inclusion/exclusion criteria is met. 
7.1.5.2 Post-Treatment Safety Follow-Up Visit 
If possible, the Safety Follow-Up Visit should be conducted approximately 30 days after 
the last dose of trial treatment or before the initiation of a new anti-cancer treatment, 
whichever comes first. All AEs that occur prior to the Safety Follow-Up Visit should be 
recorded. SAEs that occur within 30 days of the end of treatment or before initiation of a 
new anti-cancer treatment should be followed and recorded.   
7.1.5.3 Follow-up Visits 
Subjects who discontinue trial treatment for a reason other than disease progression will 
move into the Follow-Up Phase and should be assessed by radiologic imaging to monitor 
disease status. Imaging assessments will be performed every 3 months during the first year 
and every 6 months during the second year. Every effort should be made to collect 
information regarding disease status until the start of new anti-neoplastic therapy, disease 
progression, death, or end of the study. 
7.2 Assessing and Recording AEs 
Data will be recorded in RedCap. CORe database will be used along with RedCap for 
subject registration. 
Proprietary Information of MD Anderson

Protocol: 2019-1051                                            Phase II study of anakinra and axi-cel 
 
  
 
 
29 
An AE is defined as any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product and which does not necessarily have to have 
a causal relationship with this treatment. An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding, for example), symptom, or 
disease temporally associated with the use of a medicinal product or protocol-specified 
procedure, whether or not considered related to the medicinal product or protocol-specified 
procedure.  Any worsening (i.e., any clinically significant adverse change in frequency 
and/or intensity) of a preexisting condition that is temporally associated with the use of the 
anakinra, is also an AE. 
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered AEs. Examples of this 
may include, but are not limited to, onset of menopause occurring at a physiologically 
appropriate time. 
Adverse events may occur during the course of the use of anakinra in clinical trials or 
within the follow-up period specified by the protocol, or prescribed in clinical practice, 
from overdose (whether accidental or intentional), from abuse and from withdrawal. 
Adverse events may also occur in screened subjects during any pre-allocation baseline 
period as a result of a protocol-specified intervention, including washout or discontinuation 
of usual therapy, diet, placebo treatment or a procedure. 
All AEs will be recorded from the time the consent form is signed through 30 days 
following cessation of treatment and at each examination on the AE CRFs/worksheets. The 
reporting timeframe for AEs meeting any serious criteria is described in Section 7.2.3.1.  
Adverse events will not be collected for subjects during the pre-screening period (for 
determination of archival tissue status) as long as that subject has not undergone any 
protocol-specified procedure or intervention.  If the subject requires a blood draw, fresh 
tumor biopsy etc., the subject is first required to provide consent to the main study and AEs 
will be captured according to guidelines for standard AE reporting. The AE reporting 
guidelines are detailed in Table 3 below: 
 
 
 
 
 
 
 
 
 
 
Proprietary Information of MD Anderson

Protocol: 2019-1051                                            Phase II study of anakinra and axi-cel 
 
  
 
 
30 
 
Table 3: AE Reporting Guidelines 
 
Attribution - the determination of whether an adverse event is related to a medical 
treatment or procedure.  
• Definite - the adverse event is clearly related to the investigational agent(s). 
• Probable - the adverse event is likely related to the investigational agent(s). 
• Possible - the adverse event may be related to the investigational agent(s). 
• Unlikely - The adverse event is doubtfully related to the investigational agent(s). 
• Unrelated - The adverse event is clearly NOT related to the investigational 
agent(s).  
 
The investigator (or physician designee) is responsible for verifying and providing source 
documentation for all adverse events and assigning the attribution for all adverse events 
for subjects enrolled. 
7.2.1 Definition of an Overdose for This Protocol and Reporting of Overdose  
For purposes of this trial, an overdose will be defined as any dose exceeding the prescribed 
dose for anakinra by 20% over the prescribed dose. No specific information is available on 
the treatment of overdose of anakinra. In the event of overdose, anakinra should be 
discontinued and the subject should be observed closely for signs of toxicity. Appropriate 
supportive treatment should be provided if clinically indicated. 
If an AE(s) is associated with (“results from”) the overdose of anakinra, the AE(s) is 
reported as a serious AE, even if no other seriousness criteria are met. 
If a dose of anakinra meeting the protocol definition of overdose is taken without any 
associated clinical symptoms or abnormal laboratory results, the overdose is reported as a 
Phase I         
Phase II  
Phase III
Phase I         
Phase II  
Phase III
Definitive Phase I          
Phase II
Phase I         
Phase II  
Phase III
Phase I         
Phase II  
Phase III
Phase I         
Phase II  
Phase III
Phase I         
Phase II  
Phase III
Phase I         
Phase II  
Phase III
Phase I         
Phase II  
Phase III
Phase I          
Phase II
Phase I         
Phase II  
Phase III
Phase I         
Phase II  
Phase III
Phase I         
Phase II  
Phase I         
Phase II  
Phase III
Phase I         
Phase II  
Phase III
Phase I         
Phase II  
Phase III
Phase I         
Phase II  
Phase III
Phase I         
Phase II  
Phase III
Unlikely
Possible
Phase I          
Phase II
Probable
Grade 4
Phase I
Phase I
Phase I
Phase I
Phase I         
Phase II  
Grade 5
Recommended Adverse Event Recording Guidelines 
Unrelated
Phase I         
Phase II  
Phase III
Attribution
Grade 1
Grade 2
Grade 3
Proprietary Information of MD Anderson

Protocol: 2019-1051                                            Phase II study of anakinra and axi-cel 
 
  
 
 
31 
non-serious AE, using the terminology “accidental or intentional overdose without adverse 
effect.” 
Overdoses must be reported within 2 working days to MD Anderson Cancer Center IND 
Office (IND Sponsor) and Swedish Orphan Biovitrum AB, unless they are life threatening 
or result in an SAE in which case they will be reported within 24 hours to MD Anderson 
Cancer Center IND Office (IND Sponsor). 
7.2.2 Reporting of Pregnancy and Lactation to the Sponsor and to Sobi 
Although pregnancy and lactation are not considered AEs, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject 
(spontaneously reported to them), including the pregnancy of a male subject's female 
partner that occurs during the trial or within 120 days of completing the trial, or 30 days 
following cessation of treatment if the subject initiates new anticancer therapy, whichever 
is earlier.  All subjects and female partners of male subjects who become pregnant must be 
followed to the completion/termination of the pregnancy. Pregnancy outcomes of 
spontaneous abortion, missed abortion, benign hydatidiform mole, blighted ovum, fetal 
death, intrauterine death, miscarriage and stillbirth must be reported as serious events 
(Important Medical Events). If the pregnancy continues to term, the outcome (health of 
infant) must also be reported. 
Such events must be reported within 2 working days to MD Anderson Cancer Center IND 
Office (IND Sponsor) and Swedish Orphan Biovitrum AB, unless they are life threatening 
or result in an SAE in which case they will be reported within 24 hours to MD Anderson 
Cancer Center IND Office (IND Sponsor).  
7.2.3 Immediate Reporting of AEs to the Sponsor and to Sobi 
7.2.3.1 Serious Adverse Events (SAEs) 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of 
either the investigator or the sponsor, it results in any of the following outcomes: 
• Death 
• A life-threatening adverse drug experience – any adverse experience that places the 
patient, in the view of the initial reporter, at immediate risk of death from the 
adverse experience as it occurred. It does not include an adverse experience that 
had it occurred in a more severe form, might have caused death. 
• Inpatient hospitalization or prolongation of existing hospitalization 
• A 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 
Proprietary Information of MD Anderson

Protocol: 2019-1051                                            Phase II study of anakinra and axi-cel 
 
  
 
 
32 
definition. Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or convulsions 
that do not result in inpatient hospitalization, or the development of drug dependency 
or drug abuse (21 CFR 312.32). 
• Important medical events as defined above, may also be considered serious 
adverse events. Any important medical event can and should be reported as 
an SAE if deemed appropriate by the Principal Investigator or the  Sponsor, 
IND Office. 
 
• All events occurring during the conduct of a protocol and meeting the definition of 
a SAE must be reported to the IRB in accordance with the timeframes and 
procedures outlined in “The University of Texas M. D. Anderson Cancer Center 
Institutional Review Board Policy for Investigators on Reporting Unanticipated 
Adverse Events for Drugs and Devices”.  Unless stated otherwise in the protocol, 
all SAEs, expected or unexpected, must be reported to the IND Office, regardless 
of attribution (within 5 working days of knowledge of the event). 
 
• All life-threatening or fatal events, that are unexpected, and related to the study 
drug, must have a written report submitted within 24 hours (next working day) of 
knowledge of the event to the Safety Project Manager in the IND Office and within 
2 working days to Swedish Orphan Biovitrum AB.   
 
• Unless otherwise noted, the electronic SAE application (eSAE) will be utilized 
for safety reporting to the IND Office and MDACC IRB.  
 
• Serious adverse events will be captured from the time of the first protocol-
specific intervention, until 30 days after the last dose of drug, or the initiation 
of new anti-cancer therapy, whichever is earlier, whether or not related to 
anakinra, unless the participant withdraws consent. Serious adverse events 
must be followed until clinical recovery is complete and laboratory tests have 
returned to baseline, progression of the event has stabilized, or there has been 
acceptable resolution of the event. 
 
• Additionally, any serious adverse events that occur after the 30 day time 
period that are related to the study treatment must be reported to the IND 
Office. This may include the development of a secondary malignancy. 
 
Reporting to FDA: 
• Serious adverse events will be forwarded to FDA by the IND Sponsor (Safety 
Project Manager IND Office) according to 21 CFR 312.32. 
 
Proprietary Information of MD Anderson

Protocol: 2019-1051                                            Phase II study of anakinra and axi-cel 
 
  
 
 
33 
It is the responsibility of the PI and the research team to ensure serious adverse events 
are reported according to the Code of Federal Regulations, Good Clinical Practices, 
the protocol guidelines, the sponsor’s guidelines, and Institutional Review Board 
policy. 
Investigator Communication with Supporting Companies: 
All SAEs will be reported within 2 working days to Swedish Orphan Biovitrum AB.  
A copy of all 15-Day Reports and Annual Progress Reports is submitted as required by 
FDA. Investigators will cross-reference this submission according to local regulations to 
Swedish Orphan Biovitrum AB at the time of submission. Additionally investigators will 
submit a copy of these reports to Swedish Orphan Biovitrum AB  at the time of submission 
to FDA. 
7.2.4 Evaluating AEs 
Severity of the adverse events (AEs) -The severity of the adverse events (AEs) will be 
graded according to the National Cancer Institute Common Terminology Criteria for 
Adverse Events (NCI CTCAE) V.5.0.  Events not included in the NCI CTCAE will be 
scored as follows: 
General grading: 
• Grade 1: Mild: discomfort present with no disruption of daily activity, no treatment 
required beyond prophylaxis. 
• Grade 2: Moderate: discomfort present with some disruption of daily activity, 
require treatment. 
• Grade 3: Severe: discomfort that interrupts normal daily activity, not responding 
to first line treatment.  
• Grade 4: Life Threatening: discomfort that represents immediate risk of death  
 
Any AE which changes CTCAE grade over the course of a given episode will have each 
change of grade recorded on the AE CRFs/worksheets. CRS and ICANS will be assessed 
according to the ASTCT consensus guidelines and Lee et al 2014. All AEs regardless of 
CTCAE grade must also be evaluated for seriousness. 
 
8.0 STATISTICAL CONSIDERATIONS 
This is an open label, pilot designed to evaluate the safety, tolerability and early efficacy 
of anakinra by subcutaneous injection for 7 days starting on day 0 of axicabtagene 
ciloleucel (axi-cel) treatment in patients with relapsed or refractory DLBCL, PMBCL, 
transformed FL, and high-grade BCL.  Anakinra will be tested at a dose level of 100 mg 
daily and 100 mg BID. A 3+3 design will be used for a safety run-in phase within each 
dose level of Anakinra. 
Proprietary Information of MD Anderson

Protocol: 2019-1051                                            Phase II study of anakinra and axi-cel 
 
  
 
 
34 
The study consists of two phases within each dose level cohort: 1) safety run-in phase, and 
2) expansion phase.  The maximum number of patients that will be recruited for the study 
is 20: for each dose level cohort, according to 3+3 design, a maximum of 6 patients will be 
enrolled, and 4-7 additional patients will be enrolled during the escalation phase, for a 
maximum of 10 patients per dose level cohort. 
8.1 Part 1: Safety Run-in Phase 
The objective of the safety run-in phase is to investigate the safety and tolerability of 
anakinra in combination with axi-cel in patients with relapsed or refractory large B-cell 
lymphoma.  
A standard 3+3 design will be employed within each dose level cohort.  Patients will be 
treated in cohorts of size 3 to 6 and the dosage will be claimed safe if the clinical toxicity 
is acceptable.   
Dose-limiting toxicity (DLT) is defined as the following sequenced therapy-related events 
(Sequenced therapy refers to the addition of anakinra to the approved axi-cel treatment 
regimen.) with onset within the first 28 days following the start of anakinra and 
axicabtagene ciloleucel infusion: 
• Grade 4 neutropenia lasting longer than 21 days from the day of cell transfer 
• Grade 4 thrombocytopenia lasting longer than 28 days from the day of cell transfer 
• Any sequenced therapy-related AE requiring intubation, including Grade 4 
encephalopathy requiring intubation for airway protection, is considered to be a 
DLT 
• Any sequenced therapy-related Grade 5 event  
• All other clinically significant Grade 3 toxicities lasting more than 3 days and all 
Grade 4 toxicities, with the exception of the following conditions which are not 
considered DLT’s: 
 Encephalopathy that resolves to at worst Grade 1 within 2 weeks and to 
baseline within 4 weeks 
 Grade 3 fever 
 Myelosuppression (includes bleeding in the setting of platelet count < 50 x 
109/L and documented bacterial infections in the setting of neutropenia), 
defined as lymphopenia, decreased hemoglobin, neutropenia, and 
thrombocytopenia unless neutropenia and thrombocytopenia meet the DLT 
definition described above 
 Immediate hypersensitivity reactions occurring within 2 hours of cell 
infusion or anakinra injection that are reversible to Grade 2 or less within 
24 hours of administration with standard therapy 
 Renal toxicity which requires dialysis for ≤ 7 days 
 Tumor lysis syndrome including associated manifestations attributable to 
tumor lysis syndrome (eg, electrolyte abnormalities, renal function, 
hyperuricemia 
 Grade 3 transaminase, alkaline phosphatase, bilirubin or other liver function 
test elevation that resolve to ≤ Grade 2 within 14 days 
Proprietary Information of MD Anderson

Protocol: 2019-1051                                            Phase II study of anakinra and axi-cel 
 
  
 
 
35 
 Grade 4 transient serum hepatic enzyme abnormalities that resolve to ≤ 
Grade 3 within < 72 hours 
 Grade 3 or 4 hypogammaglobulinemia 
 Grade 3 nausea or anorexia 
If grade 3 or 4 changes in vital signs and/or neurological status are not due to CRS or 
ICANS but to one of the exceptions above, the event will not be considered a DLT. 
 
The dose can be claimed safe if at most one out of six patients treated had DLT. The design 
scheme is as follows: 
 
         Table 4.  Decision Rules for 3+3 Design Schema  
Number of Patients with 
DLT at a Dose Level 
Decision 
0 of 3 
Claim the dose is safe and proceed to the expansion phase. 
1 of 3 
Enroll 3 additional subjects at this dose level. 
>/=2 of 3  
Claim the dose level is too toxic. An alternative dose or schedule 
may be explored. 
1 of 6 
Claim the dose is safe and proceed to the expansion phase. 
>/=2 of 6 
Claim the dose level is too toxic. An alternative dose or schedule 
may be explored. 
 
Frequencies of toxicities will be tabulated according to the NCI Common Toxicity Criteria 
for Adverse Events (CTCAE) v5.0.  CRS will be assessed by both Lee 2014 criteria as well 
as ASTCT Consensus Grading system. ICANS will be assessed by both CTCAE v5.0 as 
well as ASTCT Consensus Grading system.  Patients will be continued to be followed for 
one year for evidence of late toxicity.  
 
Data from all subjects who receive the study drug will be included in the safety analyses. 
Subjects who entered the study and did not take the study drug and had this confirmed, will 
not be evaluated for safety. Safety and efficacy data will be reviewed after each 3-6 patient 
cohort will complete 30 days of treatment during the safety run-in phase, and accrual will 
be placed on hold while this analysis is pending.  If there is unacceptable study drug-related 
toxicity, the study will be placed on hold and no further treatment of any patient will occur 
until further review and discussion with the FDA. The study may proceed after appropriate 
amendments have been made to address the observed study drug-related toxicity. 
8.2 Part 2: Expansion phase 
Additional 4-7 patients will be treated, for a total of 10 patients per dose level cohort, to 
further investigate safety and tolerability of the combination and in order to explore 
preliminary evidence of efficacy. Once each dose level cohort is completed, a Safety 
Proprietary Information of MD Anderson

Protocol: 2019-1051                                            Phase II study of anakinra and axi-cel 
 
  
 
 
36 
Review Team (SRT), consisting of the PI, Co-PI, and Biostatistician, will review the data 
and make recommendations based on overall safety profile of the combined treatment 
regimen. Rate and grade of CRS and ICANS during the first 30 days after the first injection 
of anakinra will be considered efficacy endpoints. Quality of response to axi-cel, as 
determined by Lugano criteria, and progression-free survival will also be considered an 
efficacy endpoint.  
Data from all subjects who receive any study drug will be included in the safety analyses. 
Subjects who entered the study and did not take any of the study drug and had this 
confirmed, will not be evaluated for safety. 
Safety and efficacy data will be reviewed after 3-6, and 10 patients have completed 30 days 
of treatment for each dose level, and accrual will be placed on hold while this analysis is 
pending.  If there is unacceptable study drug-related toxicity, the study will be placed on 
hold and no further treatment of any patient will occur until further review and discussion 
with the FDA. The study may proceed after appropriate amendments have been made to 
address the observed study drug-related toxicity. 
The Investigator is responsible for completing safety/efficacy summary reports and 
submitting them to the IND Office Medical Affairs and Safety Group for review and 
approval. These should be submitted as follows: 
• Run-In Phase: 
After the first 3 evaluable patients per dose level, complete 30 days post CAR-T cell 
infusion, and after the first 6 evaluable patients per dose level, complete 30 days post CAR-
T cell infusion. IND Office approval must be obtained before advancing/changing dose 
levels. 
• Expansion Phase 
After a total of 10 evaluable subjects per dose level, complete 30 days of study treatment. 
A copy of the safety summary report should be placed in the Investigator’s Regulatory 
Binder under “Sponsor correspondence”. 
 
 
8.3 Power and population size calculation for efficacy endpoint 
In this pilot study, 10 patients will be enrolled and treated at the lower dose level of 
anakinra (100 mg daily).  Assuming a ICANS rate of 70% at 30 days without the treatment 
of anakinra,18,37  a sample size of 10 will ensure the study with 84% power to detect the 
reduction to 30% in ICANS rate for the patients treated with anakinra with a one-sided type 
I error rate of 0.05 using an exact binomial test (nQuery Advisor 7.0).  We will estimate 
the ICANS rate after the evaluation of the 10th patient at 30 days. If deemed safe during the 
safety run-in phase, we will enroll and treat a maximum of 10 patients at the higher dose 
level (100 mg BID).  If we achieve ICANS rate of 30% or lower) with at least one of the 2 
dose levels, the one producing the highest reduction will be selected for future randomized 
Proprietary Information of MD Anderson

Protocol: 2019-1051                                            Phase II study of anakinra and axi-cel 
 
  
 
 
37 
studies.  Otherwise, we will reevaluate whether a higher dose level needs to be investigated 
for anakinra. Even if a 30% ICANS rate is observed with the lower dose level, if deemed 
safe, the higher dose level will also be tested to explore the possibility to further reduce 
ICANS without any increase in toxicity. When the true ICANS rate is 70% for both doses,  
the probability of observing ICANS rate of 30% or lower for at least one dose is 
0.021.When the true ICANS rate is 30% for both doses, the probability of observing 
ICANS rate of 30% or lower for at least one dose is 0.877.  If a 30% or lower ICANS 
incidence rate is observed during the pilot portion by one of the anakinra doses, the study 
will be amended to include a subsequent portion, where the efficacy of anakinra will be 
compared to placebo in mitigating CAR-T toxicity in a randomized setting.  If none of the 
anakinra doses produces a 30% or lower ICANS incidence rate during the pilot portion, 
then we will reevaluate whether a higher dose level needs to be investigated for anakinra. 
8.4 Analysis plan 
Patient demographic information, clinical characteristics, and outcomes will be 
summarized.  CAR T cell levels in the blood, serum cytokine and chemokine levels will be 
reported. ICANS rate, CRS rate, response rate, and their exact 95% confidence intervals 
(CIs) will be estimated.  Logistic regression may be utilized to assess the effect of patient 
prognostic factors on the response rate, the ICANS rate, and CRS rate.  The distribution of 
time-to-event endpoints including progression free survival (PFS) and overall survival 
(OS) will be estimated using the method of Kaplan and Meier.  Time for PFS is the time 
interval from the start of treatment to disease progression or death due to any cause 
whichever happened first.  Patients would be censored at the last follow-up date if neither 
progression nor death occurred.  Time for OS is the time interval from the start of treatment 
to death due to any cause.  Patients would be censored at the last follow-up date if death 
did not occur.  Comparison of time-to-event endpoints by important subgroups will be 
made using the log-rank test. 
 
9.0 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL SUPPLIES 
9.1 Investigational Product  
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of 
investigational product in accordance with the protocol and any applicable laws and 
regulations. 
Clinical Supplies of anakinra will be provided by Sobi as summarized in Table 6. 
Rituximab will be obtained through standard commercial sources. 
             Table 6.  Investigational Product Descriptions 
 
Product Name & Potency 
Dosage Form 
Anakinra 100 mg/0.67 mL  
Solution Prefilled Syringe, Subcutaneous 
 
Proprietary Information of MD Anderson

Protocol: 2019-1051                                            Phase II study of anakinra and axi-cel 
 
  
 
 
38 
9.2 Packaging and Labeling Information 
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements. 
9.3 Clinical Supplies Disclosure 
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor and/or 
designee are not blinded to treatment. Drug identity (name, strength) is included in the label 
text; random code/disclosure envelopes or lists are not provided. 
9.4 Storage and Handling Requirements 
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.   
Receipt and dispensing of trial medication will be recorded by an authorized person at the 
trial site. 
Clinical supplies may not be used for any purpose other than that stated in the protocol. 
9.5 Returns and Reconciliation 
The investigator is responsible for keeping accurate records of the clinical supplies 
received from Sobi or designee, the amount dispensed to and returned by the subjects and 
the amount remaining at the conclusion of the trial.  
Upon completion or termination of the study, all unused and/or partially used 
investigational product will be destroyed at the site per institutional policy. It is the 
Investigator’s responsibility to arrange for disposal of all empty containers, provided 
that procedures for proper disposal have been established according to applicable federal, 
state, local and institutional guidelines and procedures, and provided that appropriate 
records of disposal are kept. 
 
10.0 ADMINISTRATIVE AND REGULATORY DETAILS 
10.1 IND Annual Reports 
If the FDA has granted an IND number, it is a requirement of 21 CFR 312.33, that an 
annual report is provided to the FDA within 60-days of the IND anniversary date.  21 CRF 
312.33 provides the data elements that are to be submitted in the report. The Annual Report 
should be filed with MD Anderson Cancer Center IND Office (IND Sponsor), who will 
then forward to FDA. An additional copy should be placed in the study's Regulatory Binder 
and a copy must be sent to Sobi as a supporter of this study. 
10.2 IND Safety Reports 
Sobi shall notify the Investigator via an IND Safety Report of the following information: 
• 
Any AE associated with the use of study drug in this study or in other studies that is 
both serious and unexpected. 
Proprietary Information of MD Anderson

Protocol: 2019-1051                                            Phase II study of anakinra and axi-cel 
 
  
 
 
39 
• 
Any finding from tests in laboratory animals that suggests a significant risk for human 
subjects including reports of mutagenicity, teratogenicity, or carcinogenicity. 
The Investigator shall notify his IRB promptly of these new serious and unexpected AE(s) 
or significant risks to subjects. 
The Investigator must keep copies of all AE information, including correspondence with 
Sobi and the IRB on file. 
10.3 Compliance with Trial Registration and Results Posting Requirements 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and 
the Food and Drug Administration Amendments Act (FDAAA), the Sponsor of the trial is 
solely responsible for determining whether the trial and its results are subject to the 
requirements 
for 
submission 
to 
the 
Clinical 
Trials 
Data 
Bank, 
http://www.clinicaltrials.gov. Information posted will allow subjects to identify potentially 
appropriate trials for their disease conditions and pursue participation by calling a central 
contact number for further information on appropriate trial locations and trial site contact 
information.     
10.4 Data Security/Confidentiality 
Participant confidentiality and privacy is strictly held in trust by the participating 
investigator, their staff, the safety and oversight monitor(s), and the sponsor(s) and funding 
agency. This confidentiality is extended to the data being collected as part of this study. 
Data that could be used to identify a specific study participant will be held in strict 
confidence within the research team. No personally identifiable information from the study 
will be released to any unauthorized third party without prior written approval of the 
sponsor/funding agency, as applicable. 
 
All research activities will be conducted in as private a setting as possible. 
 
Access to Study Records 
Study records may be accessed by IRB approved study personnel, or authorized inspectors. 
The study monitor, other authorized representatives of the sponsor or funding agency, 
representatives of the Institutional Review Board (IRB), regulatory agencies or 
representatives from companies or organizations supplying the product, may inspect all 
documents and records required to be maintained by the investigator, including but not 
limited to, medical records (office, clinic, or hospital) and pharmacy records for the 
participants in this study. The clinical study site will permit access to such records. 
 
Methods of Storage of Study Records 
All data collected from MD Anderson Cancer Center (MDACC) sources will be 
maintained on a password protected server compliant with HIPAA. Study staff will have 
role based restricted access to directories and files on the server, according to project 
Proprietary Information of MD Anderson

Protocol: 2019-1051                                            Phase II study of anakinra and axi-cel 
 
  
 
 
40 
responsibilities. Only those with data entry permissions can add records. The PI or a 
delegate will review the conditions under which data will be released to recipient- 
investigators. Each application for use will need IRB approval and consents, if appropriate. 
The level of identifiability will determine the process for review and approval as well as 
the way information is shared. 
 
Any study data or records maintained in paper documents will be stored in the offices of 
the PI or other delegated study staff, in a locked cabinet or other comparable controlled 
environment, and will be accessible only to authorized study team members or authorized 
inspectors.   
 
Duration of Study Record Storage 
The study participant’s contact information will be securely stored at each clinical site for 
internal use during the study. At the end of the study, all records will continue to be kept 
in a secure location for as long a period as dictated by the reviewing IRB, Institutional 
policies, or sponsor/funding agency requirements. 
 
Sharing of Study Records 
There are no plans to share study data with entities external to MD Anderson Cancer 
Center, aside from authorized inspectors as applicable (i.e. authorized representatives of 
the sponsor or funding agency, representatives of the Institutional Review Board (IRB), 
regulatory agencies or representatives from companies or organizations supplying the 
product).  If data will be shared, IRB approval will be sought, and applicable inter-
institutional agreements executed, prior to data sharing.   
Proprietary Information of MD Anderson

Protocol: 2019-1051                                            Phase II study of anakinra and axi-cel 
 
  
 
 
41 
11.0 REFERENCES 
1. 
Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for Initial Evaluation, 
Staging, and Response Assessment of Hodgkin and Non-Hodgkin Lymphoma: The Lugano 
Classification. J Clin Oncol 2014. 
2. 
Pfreundschuh M, Trumper L, Osterborg A, et al. CHOP-like chemotherapy plus rituximab 
versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell 
lymphoma: a randomised controlled trial by the MabThera International Trial (MInT) Group. 
Lancet Oncol 2006;7:379-91. 
3. 
Habermann TM, Weller EA, Morrison VA, et al. Rituximab-CHOP versus CHOP alone or 
with maintenance rituximab in older patients with diffuse large B-cell lymphoma. J Clin Oncol 
2006;24:3121-7. 
4. 
Coiffier B, Thieblemont C, Van Den Neste E, et al. Long-term outcome of patients in the 
LNH-98.5 trial, the first randomized study comparing rituximab-CHOP to standard CHOP 
chemotherapy in DLBCL patients: a study by the Groupe d'Etudes des Lymphomes de l'Adulte. 
Blood 2010;116:2040-5. 
5. 
Philip T, Guglielmi C, Hagenbeek A, et al. Autologous bone marrow transplantation as 
compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin's 
lymphoma. N Engl J Med 1995;333:1540-5. 
6. 
Sehn LH, Gascoyne RD. Diffuse large B-cell lymphoma: optimizing outcome in the 
context of clinical and biologic heterogeneity. Blood 2015;125:22-32. 
7. 
Crump M, Neelapu SS, Farooq U, et al. Outcomes in refractory diffuse large B-cell 
lymphoma: results from the international SCHOLAR-1 study. Blood 2017;130:1800-8. 
8. 
Gross G, Waks T, Eshhar Z. Expression of immunoglobulin-T-cell receptor chimeric 
molecules as functional receptors with antibody-type specificity. Proc Natl Acad Sci U S A 
1989;86:10024-8. 
9. 
Nair R, Neelapu SS. The promise of CAR T-cell therapy in aggressive B-cell lymphoma. 
Best Pract Res Clin Haematol 2018;31:293-8. 
10. 
Dotti G, Gottschalk S, Savoldo B, Brenner MK. Design and development of therapies using 
chimeric antigen receptor-expressing T cells. Immunol Rev 2014;257:107-26. 
11. 
Jensen MC, Popplewell L, Cooper LJ, et al. Antitransgene rejection responses contribute 
to attenuated persistence of adoptively transferred CD20/CD19-specific chimeric antigen receptor 
redirected T cells in humans. Biol Blood Marrow Transplant 2010;16:1245-56. 
12. 
Strati P, Patel S, Nastoupil L, et al. Beyond Chemotherapy: Checkpoint Inhibition and Cell-
Based Therapy in Non-Hodgkin Lymphoma. Am Soc Clin Oncol Educ Book 2018:592-603. 
13. 
Savoldo B, Ramos CA, Liu E, et al. CD28 costimulation improves expansion and 
persistence of chimeric antigen receptor-modified T cells in lymphoma patients. J Clin Invest 
2011;121:1822-6. 
14. 
Kochenderfer JN, Wilson WH, Janik JE, et al. Eradication of B-lineage cells and regression 
of lymphoma in a patient treated with autologous T cells genetically engineered to recognize 
CD19. Blood 2010;116:4099-102. 
15. 
Kochenderfer JN, Dudley ME, Kassim SH, et al. Chemotherapy-refractory diffuse large 
B-cell lymphoma and indolent B-cell malignancies can be effectively treated with autologous T 
cells expressing an anti-CD19 chimeric antigen receptor. J Clin Oncol 2015;33:540-9. 
Proprietary Information of MD Anderson

Protocol: 2019-1051                                            Phase II study of anakinra and axi-cel 
 
  
 
 
42 
16. 
Kochenderfer JN, Somerville RPT, Lu T, et al. Lymphoma Remissions Caused by Anti-
CD19 Chimeric Antigen Receptor T Cells Are Associated With High Serum Interleukin-15 Levels. 
J Clin Oncol 2017;35:1803-13. 
17. 
Locke FL, Neelapu SS, Bartlett NL, et al. Phase 1 Results of ZUMA-1: A Multicenter 
Study of KTE-C19 Anti-CD19 CAR T Cell Therapy in Refractory Aggressive Lymphoma. Mol 
Ther 2017;25:285-95. 
18. 
Neelapu SS, Locke FL, Bartlett NL, et al. Axicabtagene Ciloleucel CAR T-Cell Therapy 
in Refractory Large B-Cell Lymphoma. N Engl J Med 2017;377:2531-44. 
19. 
Locke FL, Ghobadi A, Jacobson CA, et al. Long-term safety and activity of axicabtagene 
ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1-2 
trial. Lancet Oncol 2018. 
20. 
Lee DW, Santomasso BD, Locke FL, et al. ASBMT Consensus Grading for Cytokine 
Release Syndrome and Neurological Toxicity Associated with Immune Effector Cells. Biol Blood 
Marrow Transplant 2018. 
21. 
Lee DW, Gardner R, Porter DL, et al. Current concepts in the diagnosis and management 
of cytokine release syndrome. Blood 2014;124:188-95. 
22. 
McGuirk J, Waller EK, Qayed M, et al. Building blocks for institutional preparation of 
CTL019 delivery. Cytotherapy 2017;19:1015-24. 
23. 
Neelapu SS, Tummala S, Kebriaei P, et al. Chimeric antigen receptor T-cell therapy - 
assessment and management of toxicities. Nat Rev Clin Oncol 2018;15:47-62. 
24. 
Jordan MB, Allen CE, Weitzman S, Filipovich AH, McClain KL. How I treat 
hemophagocytic lymphohistiocytosis. Blood 2011;118:4041-52. 
25. 
Lee DW, Kochenderfer JN, Stetler-Stevenson M, et al. T cells expressing CD19 chimeric 
antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-
escalation trial. Lancet 2015;385:517-28. 
26. 
Gust J, Hay KA, Hanafi LA, et al. Endothelial Activation and Blood-Brain Barrier 
Disruption in Neurotoxicity after Adoptive Immunotherapy with CD19 CAR-T Cells. Cancer 
Discov 2017;7:1404-19. 
27. 
Santomasso BD, Park JH, Salloum D, et al. Clinical and Biological Correlates of 
Neurotoxicity Associated with CAR T-cell Therapy in Patients with B-cell Acute Lymphoblastic 
Leukemia. Cancer Discov 2018;8:958-71. 
28. 
Norelli M, Camisa B, Barbiera G, et al. Monocyte-derived IL-1 and IL-6 are differentially 
required for cytokine-release syndrome and neurotoxicity due to CAR T cells. Nat Med 
2018;24:739-48. 
29. 
Giavridis T, van der Stegen SJC, Eyquem J, Hamieh M, Piersigilli A, Sadelain M. CAR T 
cell-induced cytokine release syndrome is mediated by macrophages and abated by IL-1 blockade. 
Nat Med 2018;24:731-8. 
30. 
Sterner RM, Sakemura R, Cox MJ, et al. GM-CSF inhibition reduces cytokine release 
syndrome and neuroinflammation but enhances CAR-T cell function in xenografts. Blood 2018. 
31. 
Bresnihan B, Alvaro-Gracia JM, Cobby M, et al. Treatment of rheumatoid arthritis with 
recombinant human interleukin-1 receptor antagonist. Arthritis Rheum 1998;41:2196-204. 
32. 
Cohen S, Hurd E, Cush J, et al. Treatment of rheumatoid arthritis with anakinra, a 
recombinant human interleukin-1 receptor antagonist, in combination with methotrexate: results 
of a twenty-four-week, multicenter, randomized, double-blind, placebo-controlled trial. Arthritis 
Rheum 2002;46:614-24. 
Proprietary Information of MD Anderson

Protocol: 2019-1051                                            Phase II study of anakinra and axi-cel 
 
  
 
 
43 
33. 
Genovese MC, Cohen S, Moreland L, et al. Combination therapy with etanercept and 
anakinra in the treatment of patients with rheumatoid arthritis who have been treated 
unsuccessfully with methotrexate. Arthritis Rheum 2004;50:1412-9. 
34. 
Goldbach-Mansky R, Dailey NJ, Canna SW, et al. Neonatal-onset multisystem 
inflammatory disease responsive to interleukin-1beta inhibition. N Engl J Med 2006;355:581-92. 
35. 
Ramirez J, Canete JD. Anakinra for the treatment of rheumatoid arthritis: a safety 
evaluation. Expert Opin Drug Saf 2018;17:727-32. 
36. 
Locke FL, Rossi J, Xue XD, et al. Immune signatures of cytokine release syndrome and 
neurologic events in a multicenter registrational trial (ZUMA-1) in subjects with refractory diffuse 
large B cell lymphoma treated with axicabtagene ciloleucel (KTE-C19). Cancer Res 2017;77. 
37. 
Locke FL, Ghobadi A, Jacobson CA, et al. Long-term safety and activity of axicabtagene 
ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1-2 
trial. Lancet Oncol 2019;20:31-42. 
Proprietary Information of MD Anderson

Protocol: 2019-1051                                            Phase II study of anakinra and axi-cel 
 
  
 
 
44 
12.0  APPENDICES 
Appendix 1: ECOG Performance Status 
Grade 
Description 
0 
Normal activity. Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time. Ambulatory and capable of all self-care, but 
unable to carry out any work activities. Up and about more than 50% 
of waking hours. 
3 
In bed >50% of the time. Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-care. 
Totally confined to bed or chair. 
5 
Dead. 
* As published in Am. J. Clin. Oncol.:  Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., 
McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology 
Group. Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative Oncology Group, Robert Comis 
M.D., Group Chair. 
 
Proprietary Information of MD Anderson

Protocol: 2019-1051                                            Phase II study of anakinra and axi-cel 
 
  
 
 
45 
Appendix 2: ASTCT Consensus Grading for CRS 
 
 
Proprietary Information of MD Anderson

Protocol: 2019-1051                                            Phase II study of anakinra and axi-cel 
 
  
 
 
46 
Appendix3: CRS Grading as per Lee et al 2014 
 
Definition of high-dose vasopressors 
 
 
 
Proprietary Information of MD Anderson

Protocol: 2019-1051                                            Phase II study of anakinra and axi-cel 
 
  
 
 
47 
Appendix 4: ASTCT Consensus Grading for ICANS 
ICE Score 
 
 
ICANS Grading 
 
Proprietary Information of MD Anderson

Protocol: 2019-1051                                            Phase II study of anakinra and axi-cel 
 
  
 
 
48 
Appendix 5: Management of CRS 
ASTCT CRS Grade 
Management 
Grade 1 
• 
Anti-pyretics and IV hydration 
• 
Diagnostic work-up to rule out infection 
• 
Consider growth factors and antibiotics if neutropenic 
Grade 2 
• 
Supportive care as in grade 1 
• 
IV fluid boluses and/or supplemental oxygen 
• 
Tocilizumab +/- dexamethasone or its equivalent of methylprednisolone 
Grade 3 
• 
Supportive care as in grade 1 
• 
Consider monitoring in intensive care unit 
• 
Vasopressor 
support 
and/or 
supplemental 
oxygen 
Tocilizumab 
+ 
dexamethasone 10-20 mg IV q 6hrs or its equivalent of methylprednisolone 
Grade 4 
• 
Supportive care as in grade 1 
• 
Monitoring in intensive care unit 
• 
Vasopressor support and/or supplemental oxygen via positive pressure 
ventilation 
• 
Tocilizumab + methylprednisolone 1000 mg/day 
 
Proprietary Information of MD Anderson

Protocol: 2019-1051                                            Phase II study of anakinra and axi-cel 
 
  
 
 
49 
Appendix 6: Management of ICANS 
ASTCT ICANS Grade 
Management 
Grade 1 
• 
Aspiration precautions and IV hydration 
• 
Seizure prophylaxis with levetiracetam 
• 
Electroencephalogram (EEG)  
• 
Imaging of brain 
• 
Consider tocilizumab if there is concurrent CRS 
Grade 2 
• 
Supportive care as in grade 1 
• 
Consider dexamethasone or its equivalent of methylprednisolone 
Grade 3 
• 
Supportive care as in grade 1 
• 
Dexamethasone 10-20 mg IV q 6hrs or its equivalent of methylprednisolone 
• 
Control any seizures with benzodiazepines (for short-term control) and 
levetiracetam +/- phenobarbital and/or lacosamide 
• 
For focal cerebral edema, high-dose methylprednisolone 1000 mg/day 
Grade 4 
• 
Supportive care as in grade 1 
• 
High-dose methylprednisolone 1000 mg/day  
• 
Control seizures with benzodiazepines (for short-term control) and 
levetiracetam +/- phenobarbital and/or lacosamide 
• 
For motor weakness, imaging of spine 
• 
For diffuse cerebral edema, lower intracranial pressure by hyperventilation, 
hyperosmolar therapy with mannitol/hypertonic saline, and/or neurosurgery 
consultation for ventriculoperitoneal shunt 
 
Proprietary Information of MD Anderson

Protocol: 2019-1051                                            Phase II study of anakinra and axi-cel 
 
  
 
 
50 
Appendix 7: Response Evaluation Criteria 
Response will be determined by the Principal Investigator according to the 
Recommendations for Initial Evaluation, Staging, and Response Assessment of Hodgkin 
and Non-Hodgkin Lymphoma: The Lugano Classification1 and documented in the CRFs. 
The response criteria are summarized below: 
   
 
Proprietary Information of MD Anderson

Protocol: 2019-1051                                            Phase II study of anakinra and axi-cel 
 
  
 
 
51 
 
 
Proprietary Information of MD Anderson