Clinical trial NCT03121534
Conditions: Hematopoietic/Lymphoid Cancer Richter's Transformation
Keywords: Hematopoietic/Lymphoid Cancer Richter's transformation RT Blinatumomab Dexamethasone Decadron
Sponsor: M.D. Anderson Cancer Center
Start date: 2017-06-22; Completion date: 2022-02-11
Enrollment: 9 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The goal of this clinical research study is to learn if blinatumomab can help to control Richter Transformation (RT, a type of blood cancer). The safety of this drug will also be studied.

This is an investigational study. Blinatumomab is FDA approved and commercially available for the treatment of acute lymphoblastic leukemia (ALL). It is investigational to use blinatumomab to treat patients with RT. The study doctor can explain how the study drug is designed to work.

Up to 21 participants will be enrolled in this study. All will take part at MD Anderson.

Detailed description:
Study Drug Administration:

The study has 2 study cycles. Cycle 1 is 8 weeks, followed by a 4-8 week break, and then Cycle 2 is 4 weeks.

If you are found to be eligible to take part in this study, you will receive blinatumomab by a central venous catheter (CVC) continuously (non-stop) for 1-2 cycles, depending on how you are responding to the study drug. A CVC is a sterile flexible tube that will be placed into a large vein while you are under local anesthesia. Your doctor will explain this to you in more detail, and you will be required to sign a separate consent form for this procedure.

During Cycle 1, the blinatumomab infusion will be started in the hospital. You will be in the hospital for up to at least 16 nights/17 days so that you can be checked for side effects. During Cycle 2, the blinatumomab infusion will also be started in the hospital. You will be in the hospital for at least 2 nights/3 days. Your doctor will decide when you can leave the hospital. Also, if treatment is interrupted for more than 4 hours, for any reason, you will need to be admitted to the hospital to restart the treatment.

Blinatumomab will be delivered by a small pump, which you will carry with you for the whole time you receive the drug. You will be given a shoulder or belt bag to hold the pump and infusion bag. You will be able to wear regular clothes, walk around, and perform daily living activities. You will be given instructions for taking a shower and other activities. There will be some things that you should not do, such as go swimming. The study staff will give you more information on activities you should not do while receiving the drug.

You will need to come to MD Anderson to have the infusion bags changed every 48 hours. The study staff will let you know when you need to return to the clinic.

You will be given standard drugs, such as dexamethasone, to help decrease the risk of side effects. You may ask the study staff for information about how the drugs are given and their risks.

If you have severe side effects, your study doctor may decide to stop treatment permanently or temporarily. If you recover or if the symptoms have improved, the treatment may be continued. If the doctor thinks it is needed, you will have an MRI and possibly also a spinal tap (lumbar puncture) to test the fluid around the brain, before you restart treatment.

Length of Study:

You may receive blinatumomab for up to 2 cycles. You will no longer be able to take the study drug if the disease gets worse, if serious side effects occur, or if you are unable to follow study directions. Additionally, if your doctor feels it is in your best interests to receive an alternative treatment for your Richter Transformation, such as allogeneic stem cell transplantation, you will no longer be able to receive blinatumomab.

Your participation on this study will be over after you have completed follow-up.

Study Visits:

At any time the doctor thinks it is needed, you may have a neurological exam.

Based on the results of the below tests after Cycle 1, the study doctor will decide if you will continue to receive the study drug during Cycle 2. If you do not receive the drug during Cycle 2, you will have an end-of-study visit (described below).

On Days 1-17 of Cycle 1 (the time you are in the hospital), every week during Cycle 1, Days 1-3 of Cycle 2, and every week of Cycle 2:

* You will have a physical exam.
* Blood (about 2-3 teaspoons) will be drawn for routine tests.

About 2-4 weeks after Cycles 1 and 2:

* You will have a physical exam.
* Blood (about 2-3 teaspoons) will be drawn for routine tests.
* You will have a bone marrow biopsy/aspiration to check the status of the disease.
* You will have a PET/CT or CT scan.

About 24 weeks after the first dose of study drug and then every 12 weeks after that for up to 96 weeks:

* You will have a physical exam.
* Blood (about 2-3 teaspoons) will be drawn for routine tests.
* You will have a PET/CT or CT scan to check the status of the disease.

End-of-Study Visit:

After the last dose of study drug, you will continue to receive routine medical care as part of your standard care. However, if the disease comes back or worsens while you are receiving the study drug:

* You will have a physical exam.
* Blood (about 2-3 teaspoons) will be drawn for routine tests.
* You will have a bone marrow biopsy/aspiration
* You will have a PET/CT scan to check the status of the disease.
* If the doctor thinks it is needed, you may have a lymph node biopsy to confirm that the disease has come back.
* If you can become pregnant, blood (about 1 teaspoon) or urine will be collected for a pregnancy test.

Long-Term Follow-up:

After you have completed your participation in this study, you will be asked to participate in a separate leukemia department protocol (DR09-0223). The purpose of this protocol is to determine how long patients live after receiving leukemia treatment. On this study, if you are not having follow-up at MD Anderson, study staff will contact you via phone, email, or MyMDAnderson every 6-12 months, to see how you are doing. Phone calls will take approximately 5-10 minutes. If you agree, you will sign a separate consent form for this study.

Arms: arm 1: 2 (8week) cycles of ibrutinib, nivolumab and blinatumomab. 9 (4week) cycles ibrutinib and nivolumab. Maintenance with ibrutinib monotherapy until disease progression following completion of nivolumab.

Ibrutinib treatment will begin cycle 1, day 1 at 420mg/d. Nivolumab for up to a total of 52 weeks. Dosing will be 240mg IV every 2 weeks, commencing on day 1 until 2nd response assessment, then 480mg IV every 4 weeks.

blinatumomab continuous IV infusion, starting day 15 of cycle 1 and day 1 of cycle 2, for 2 courses of 4 weeks each separated by a 2 week blinatumomab treatment-free interval. Hospitalization in cycle 1 on day 15-31 (first 17 days of blinatumomab therapy). Blinatumomab will be initiated at 9mcg/day from day 15-21, followed by 28 mcg/day from day 22-28, followed by 112 mcg/day from day 29-42. In cycle 2, patients will be admitted for the first 3 days. Blinatumomab in cycle 2 will be administered at a dose of 112 mcg/day from day 1-28.
Interventions: intervention 1: Blinatumomab intervention 2: Dexamethasone intervention 3: Ibrutinib intervention 4: Nivolumab
Intervention descriptions: intervention 1: Patients will receive blinatumomab as a continuous IV infusion, commencing on day 15 of cycle 1 and day 1 of cycle 2, for 2 courses of 4 weeks each separated by a 2 week .

blinatumomab will be initiated at 9mcg/day from day 15-21, followed by 28 mcg/day from day 22-28. This will be followed by 112 mcg/day from day 29-42. In cycle 2, patients will be admitted for the first 3 days.blinatumomab treatment-free interval. intervention 2: Dexamethasone 20 mg by mouth or vein 24 hours prior to and within 1 hour before start of treatment in each treatment cycle. If treatment is interrupted for \>4 hours at any point, Dexamethasone treatment given before re-initiation of therapy. Dexamethasone 8 mg by mouth or vein every 8 hours given for 48 hours at the commencement of the infusion and after each dose increment. intervention 3: Ibrutinib treatment will commence on cycle 1, day 1 at 420mg/d. Dose reductions to 280mg/d or 140mg/d are allowed per treating physician discretion, but the reason must be documented in the medical record. Ibrutinib will be given continuously until disease progression or toxicity. intervention 4: Patients will receive nivolumab for up to a total of 52 weeks. Dosing will be 240mg IV every 2 weeks, commencing on day 1 until 2nd response assessment, then 480mg IV every 4 weeks.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
MD Anderson IND Sponsor Cover Sheet 
 
Protocol ID 
2016-0765 
Protocol Title 
A phase II study of ibrutinib, nivolumab and blinatumomab in 
Richter Transformation. 
Protocol Version 08 
Version Date 
03/08/2020 
 
Protocol PI 
Philip Thompson, MB BS 
Department 
Leukemia 
 
IND Sponsor 
MD Anderson Cancer Center 
IND # 
134551 
 
 


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2016-0765. A phase II study of ibrutinib, nivolumab and blinatumomab in Richter 
Transformation. 
 
Contents 
1.0 OBJECTIVES AND STUDY ENDPOINTS................................................................................................................. 6 
Primary endpoint ................................................................................................................................................................ 6 
Secondary endpoints .......................................................................................................................................................... 6 
Exploratory objectives ........................................................................................................................................................ 6 
2.0 BACKGROUND AND RATIONALE ............................................................................................................................ 6 
2.1 Richter Transformation ................................................................................................................................................. 6 
2.2 Blinatumomab ............................................................................................................................................................... 7 
2.2.1 Blinatumomab in Precursor B-cell Acute Lymphoblastic Leukemia ...................................................................... 8 
2.2.2 Blinatumomab in Diffuse Large B-cell Lymphoma (DLBCL).................................................................................... 8 
2.2.3 Blinatumomab in Richter Transformation. ............................................................................................................ 9 
2.3 Ibrutinib + nivolumab in RT: ........................................................................................................................................ 13 
3.0 STUDY POPULATION................................................................................................................................................ 14 
3.1 Inclusion Criteria ......................................................................................................................................................... 14 
3.2 Exclusion Criteria ......................................................................................................................................................... 14 
4.0 TREATMENT PLAN  ................................................................................................................................................... 15 
Figure 4. Schematic of treatment plan ............................................................................................................................. 16 
Patients will receive treatment as follows: ....................................................................................................................... 16 
4.1 Ibrutinib therapy. ........................................................................................................................................................ 16 
4.2 Nivolumab therapy. .................................................................................................................................................... 16 
4.3 Blinatumomab therapy ............................................................................................................................................... 17 
4.4 Response assessment ............................................................................................................................................. 18 
4.5 ..................................................................................................................................................................................... 19 
Allogeneic stem cell transplantation. ............................................................................................................................... 19 
4.6 Surveillance after completion of blinatumomab. ....................................................................................................... 19 
5.0 STUDY MEDICATIONS .............................................................................................................................................. 19 
5.1 Blinatumomab ............................................................................................................................................................. 19 
5.1.1. Blinatumomab formulation, reconstitution and administration ........................................................................ 19 
5.1.2 Adverse events associated with blinatumomab ...................................................................................................... 20 
5.1.2.1 General Infusion Reactions ............................................................................................................................... 20 
5.1.2.2 Hepatic/Biliary/Pancreatic ................................................................................................................................ 21 
5.1.2.3 Immune Cytokine Release Syndrome Cytokine Release Syndrome (CRS) ........................................................ 21 


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5.1.2.4 Tumor Lysis Syndrome ...................................................................................................................................... 21 
5.1.2.5 Infections........................................................................................................................................................... 21 
5.1.2.6 Hematologic abnormalities ............................................................................................................................... 21 
5.1.2.7 Neurologic abnormalities .................................................................................................................................. 22 
5.1.2.8 Leukoencephalopathy ....................................................................................................................................... 22 
5.1.3 Inpatient admission.................................................................................................................................................. 22 
5.1.4 Dexamethasone during pre-phase and as pre-medication before blinatumomab ................................................. 23 
5.1 ..................................................................................................................................................................................... 23 
5.1.5 Blinatumomab dosage, administration, and schedule ............................................................................................ 23 
5.1 ..................................................................................................................................................................................... 23 
5.1.6 Blinatumomab inpatient dosing .............................................................................................................................. 23 
5.1.7 Blinatumomab outpatient dosing ............................................................................................................................ 23 
5.2 Nivolumab. .................................................................................................................................................................. 23 
5.2.1 Preparation and Dispensing of Nivolumab .......................................................................................................... 23 
5.2.2 Administration of Nivolumab ............................................................................................................................... 24 
5.2.3 Patient Monitoring During Infusion ..................................................................................................................... 24 
5.2.4 Treatment of Nivolumab Related Infusion Reactions .......................................................................................... 25 
5.2.5. AEs associated with nivolumab: .......................................................................................................................... 26 
5.2.5.1 Pulmonary Adverse Events: .............................................................................................................................. 26 
5.2.5.2 Gastrointestinal adverse events. ...................................................................................................................... 27 
5.2.5.3 Diverticular Perforation .................................................................................................................................... 28 
5.2.5.4 Hepatic Adverse Events ..................................................................................................................................... 28 
5.2.5.5. Endocrinopathies ............................................................................................................................................. 29 
5.2.5.6. Skin Adverse Events ......................................................................................................................................... 30 
5.2.5.7 Renal Adverse events ........................................................................................................................................ 30 
5.2.5.8 Neurologic Adverse events ............................................................................................................................... 31 
5.2.5.9 Infusion Reactions ............................................................................................................................................. 32 
5.2.5.10 Lipase/Amylase Elevations .............................................................................................................................. 32 
5.2.5.11 Uveitis and visual complaints. ......................................................................................................................... 33 
5.2.5.12 Other Immune-mediated Adverse Events ...................................................................................................... 33 
5.2.5.13 Overdose, Warnings, and Precautions ............................................................................................................ 34 
5.3 Ibrutinib. ...................................................................................................................................................................... 35 
5.3.1 Ibrutinib - How Supplied ...................................................................................................................................... 35 
5.3.2 Stability ................................................................................................................................................................ 36 


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5.3.3 Pharmacology....................................................................................................................................................... 36 
5.3.4 Pharmacokinetics and Product Metabolism ........................................................................................................ 36 
5.3.5 Summary of Clinical Safety ................................................................................................................................... 37 
5.3.5.6 Non-Melanoma Skin Cancer ............................................................................................................................. 39 
6.0 DOSE DELAYS, MODIFICATIONS AND MANAGEMENT OF TOXICITY ........................................................ 42 
6.1 Blinatumomab Infusion interruption/dose modification due to adverse events ....................................................... 42 
Table 2. Dose interruptions, modifications and criteria for discontinuation and recommencement of therapy ............ 42 
6.1.1 Infusion interruption/dose modification due to CNS events ............................................................................... 44 
6.1.2 Dose interruption and modification for cytokine release syndrome (CRS) and/or DIC/coagulopathy ............... 46 
6.1.3 Dose interruption and modification for all other events ..................................................................................... 46 
6.1.4 Resumption of dosing and dose escalation after dose interruption ................................................................... 47 
6.2 Recommendations for management of nivolumab-associated toxicity. .................................................................... 48 
6.3 - management of ibrutinib-associated toxicity and dose modifications .................................................................... 48 
6.3.1 Recommended dose modifications: .................................................................................................................... 48 
6.3.2 Hematologic toxicity: ........................................................................................................................................... 48 
6.3.3 Non-hematologic toxicity: .................................................................................................................................... 49 
6.3.4 Leukocytosis/Leukostasis: .................................................................................................................................... 49 
6.3.5 Dose Modification for Hepatic Impaired Subjects ............................................................................................... 49 
6.3.6 Dose Modification of Ibrutinib in patients receiving CYP3A4 enzyme inhibitors and inducers: ......................... 49 
7.0 CONCOMITANT THERAPY ...................................................................................................................................... 50 
7.1 Allowed concomitant therapy..................................................................................................................................... 50 
7.2 Excluded concomitant therapy ................................................................................................................................... 50 
7.3 Recommended anti-infective prophylaxis .................................................................................................................. 50 
7.4 Tumor lysis syndrome prophylaxis.............................................................................................................................. 51 
8.0 PRE-TREATMENT EVALUATION ............................................................................................................................ 52 
Table 3. Pre-treatment evaluation .................................................................................................................................... 52 
9.0 EVALUATION DURING TREATMENT .................................................................................................................... 53 
Table 4: evaluation which will take place pre-treatment and during the study ............................................................... 53 
10.0 CRITERIA FOR RESPONSE .................................................................................................................................. 57 
10.1 Richter’s Transformation .......................................................................................................................................... 57 
10.2 Response Criteria in Chronic Lymphocytic Leukemia ............................................................................................... 57 
11.0 ADVERSE EVENT REPORTING ........................................................................................................................... 58 
11.1 Leukemia-specific Adverse Event Recording and Reporting Guidelines ................................................................... 58 
11.1.1 Electronic case report (eCRF) ............................................................................................................................. 58 


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11.1.2 Guidelines for recording and reporting of adverse and serious adverse events ............................................... 58 
11.1.3 Abnormal hematologic and chemical values ..................................................................................................... 59 
11.1.4 Attribution of AEs ............................................................................................................................................... 59 
11.1.5 Documentation of grade 3 and greater non-hematologic adverse events ....................................................... 60 
11.1.6 Serious Adverse Event Reporting (SAE) ............................................................................................................. 60 
11.1.7 Serious adverse reaction (SAR) .......................................................................................................................... 60 
11.1.8 Suspected Unexpected Serious Adverse Reaction (SUSAR) ............................................................................... 60 
11.2 "Serious Adverse Event Reporting (SAE) for M. D. Anderson-Sponsored IND Protocols" ........................................ 61 
11.3 Reporting to FDA ....................................................................................................................................................... 61 
11.4 Investigator Communication with Amgen ................................................................................................................ 62 
11.5 Investigator Communication with BMS .................................................................................................................... 62 
12.0 CRITERIA FOR REMOVAL FROM STUDY. ........................................................................................................ 66 
13.0 CORRELATIVE STUDIES ....................................................................................................................................... 67 
13.1 Immunologic analyses ............................................................................................................................................... 67 
13.1.1 Studies on tumor tissue ..................................................................................................................................... 67 
13.1.2 Studies on peripheral blood T-cell population ................................................................................................... 67 
13.2 Tumor banking. ......................................................................................................................................................... 67 
13.3 Evaluation of plasma circulating tumor DNA (ctDNA) .............................................................................................. 68 
14.0. STATISTICAL CONSIDERATIONS ...................................................................................................................... 68 
Response Stopping Boundaries ...................................................................................................................................... 70 
Stopping boundaries for toxicity ....................................................................................................................................... 70 
15.0 REFERENCES .......................................................................................................................................................... 72 
Appendix C. Grading of Cytokine Release Syndrome (CRS) ..................................................................................... 74 
Appendix D: Definition of high-dose vasopressors ....................................................................................................... 75 
Appendix E: ASTCT INCANS Consensus Grading for Adults .............................................................................................. 76 
Appendix F. CTCAE v5.0 grading of common adverse events ................................................................................... 77 
Appendix G. Simplified 10-point neurologic examination............................................................................................. 78 
Appendix I – response criteria in CLL. ............................................................................................................................... 81 
Appendix J – Grading of hematologic toxicity in CLL trials. .............................................................................................. 82 
Appendix K – Management Algorithms. ........................................................................................................................... 83 
 


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1.0 OBJECTIVES AND STUDY ENDPOINTS 
 
Primary endpoint 
1. Determine the overall response rate (complete remission plus partial remission) in Richter 
transformation (RT) after 2 courses of blinatumomab, ibrutinib and nivolumab treatment. 
 
Secondary endpoints 
1. Assess the safety and feasibility of administering blinatumomab combined with ibrutinib and 
nivolumab to patients with RT. 
2. Determine the complete remission rate for RT after 1 and 2 courses of therapy. 
3. Determine the progression-free survival rate for RT at 1 year. 
4. Determine the overall survival rate for RT at 1 year. 
5. Determine the proportion of patients who proceed to allogeneic stem cell transplantation as next 
treatment. 
 
Exploratory objectives 
1. Pre- and post-treatment (progression) tumor biopsies for immunologic analysis, including immune 
checkpoint expression by tumor and by infiltrating T cells, flow cytometry and RNA-sequencing 
analysis (including the potential to perform single cell RNA-seq) or array-based analysis of 
immune cell subsets. 
 
 
1. 
Immune checkpoint expression by circulating T cells and T cell subset analysis. 
2. 
“Liquid biopsy” using circulating tumor DNA analysis and comparison with mutational profile 
identified in concurrent CLL specimen and tumor biopsy. This will also be used as an MRD 
analysis tool.  
Correlation of RT microRNA profile with response to treatment and outcomes. 
 
2.0 BACKGROUND AND RATIONALE 
 
2.1 Richter Transformation 
RT is defined as the transformation of CLL into a more aggressive lymphoma; while this is most 
commonly diffuse large B cell lymphoma (DLBCL) histology, rare cases of transformation to Hodgkin 
Lymphoma (HL)1 histology are recognized. A large series, comprising all newly diagnosed CLL 
patients seen at the Mayo Clinic over 12 years, demonstrated that 2.3% of patients subsequently 


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developed biopsy-proven RT, at a rate of 0.5% per year; almost half had never required treatment for 
CLL prior to the diagnosis of RT.2 Clinicopathologic features suggestive of the diagnosis include high 
fever, weight loss, rapidly enlarging lymph nodes, hypercalcemia and elevated LDH.3 There is an 
ongoing incidence of RT seen in patients treated with highly effective, novel, targeted therapies for 
CLL, such as ibrutinib4 and venetoclax.5 
 
Prognosis is determined by both genetic and clinical features. Approximately 80% of DLBCL 
transformations are clonally related to the underlying CLL; the 20% with clonally unrelated DLBCL 
have a significantly better prognosis. Clonal relationship can be determined by comparing the 
sequences of the IGHV gene of the lymphoma to that of untransformed CLL cells. Two clinical 
prognostic models have been developed,6, 7 the latter of which also demonstrated the importance of 
TP53 disruption as a negative prognostic feature.  
 
Treatment is generally unsatisfactory. Moderate to high-intensity chemoimmunotherapy regimens 
have produced CR rates of 5-38%, with median survival in most series of <1 year.8-12 TP53 disruption 
likely plays a major role in chemotherapy resistance. A minority of patients achieved long-term 
survival after allogeneic stem cell transplantation (alloSCT),6 but most patients are not eligible for this 
treatment due to age, co-morbidities, lack of appropriate donor, and/or failure to achieve a response 
to initial treatment. Nonetheless, long-term survival after alloSCT in a subgroup of patients suggests 
that immunologic control is possible. More effective therapy is urgently needed in order to increase 
the proportion of patients able to undergo alloSCT and to achieve more durable disease control in 
those patients who are not candidates for alloSCT. 
 
2.2 Blinatumomab 
Blinatumomab (BLINCYTO®) is a murine recombinant single-chain antibody construct combining 
both the binding specificity for the pan B cell antigen CD19 and the epsilon chain of the T cell 
receptor/CD3 complex on one polypeptide chain. It is monomeric, non-glycosylated, with a molecular 
weight of 55 kilo-Daltons (kDa). It belongs to a new class of bispecific antibody constructs called 
bispecific T cell engagers (BITE). Bispecific T cell engagers were designed to direct T-effector 
memory cells against target cells. The proximity induced by the BITE triggers target cell-specific 
cytotoxicity, which resembles typical cytotoxic T lymphocyte (CTL) activation. This T cell–mediated 
target-specific killing is the therapeutic mechanism of action of blinatumomab.13, 14  


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Blinatumomab specifically targets cells that express CD19, a B cell-restricted surface antigen. 
Blinatumomab recruits and activates T cells via a lower affinity interaction with CD3 (8.7 x 10-8 M). 
The activated T cells then induce a half-maximal target cell lysis ranging in vitro between 10 to 100 
pg/mL showing blinatumomab to be an extremely potent molecule.15 
 
During the course of tumor cell elimination, activated T cells synthesize and secrete 
pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α), interferon-gamma (IFN-γ), 
interleukin (IL)-6, and IL-2, which can induce symptoms such as fever or decreases of blood 
pressure. In vitro data demonstrate cytokine release as a result of blinatumomab-mediated activation, 
which can be attenuated by corticosteroids without impairing the cytotoxic activity. In vivo data 
indicate cytokine release to be most prominent following the first dose of blinatumomab. 
 
2.2.1 Blinatumomab in Precursor B-cell Acute Lymphoblastic Leukemia 
A large, 189 patient phase II study in precursor B cell acute lymphoblastic leukemia (B-ALL), 
confirmed the safety and efficacy of blinatumomab and was the basis for FDA approval in that 
disease. Blinatumomab was given as a continuous IV infusion (4 weeks on followed by 2 weeks off) 
for up to 5 cycles (cycle 1 only: 9 μg/d days 1-7; then 28 μg/d). Regardless of causality, the most 
common adverse events (AEs) were pyrexia (59%), headache (35%) and febrile neutropenia (29%). 
The most common grade ≥3 AEs were febrile neutropenia (26%), anemia (15%) and neutropenia 
(15%); 2% had grade ≥3 cytokine release syndrome. The most common grade ≥3 nervous system 
disorders were headache (4%), encephalopathy (3%) and ataxia (2%). Three (2%) pts had grade 5 
AEs considered treatment-related (sepsis, n=2; candida infection, n=1).16  
 
2.2.2 Blinatumomab in Diffuse Large B-cell Lymphoma (DLBCL) 
An ongoing phase 2 study in patients with heavily pre-treated relapsed/refractory diffuse large B cell 
lymphoma (DLBCL) showed that blinatumomab, delivered by continuous infusion for 8 weeks, has an 
acceptable safety profile.17 After closure of one cohort, where blinatumomab was dosed at 
112mcg/day from day 1, a stepwise dose escalation (9mcg/day for 1 week, 28mcg/day for 1 week 
then 112mcg/day for the remaining 6 weeks) was used for the remaining 23 patients. Serious AEs 
occurred in 22 (95%) of the patients, regardless of causality; the most common were pneumonia 
(13%), device-related infection (13%), and cytopenias (34%). Six of 23 (26%) had grade ≥3 
neurologic AEs; there were no grade 4 or 5 neurologic events thought to relate to the study drug.18 


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The drug demonstrated considerable efficacy in this high-risk population, with an overall response 
rate of 43% (4 CRs and 5 PRs in 21 evaluable patients). The study permitted a 4 week consolidation 
period after a 4 week treatment-free period in patients achieving an objective response after the 8 
week induction period. All patients who responded did so within the first 8 weeks. All patients 
received prophylactic dexamethasone (2 × 20 mg before infusion start and at infusion start; 3 × 8 
mg/day for the first 2 days after infusion start and at each dose increase).  
 
Given the importance of TP53 mutation in the pathogenesis of RT, the use of a treatment that acts in 
a TP53-independent manner, such as blinatumomab, is attractive. 
 
2.2.3 Blinatumomab in Richter Transformation. 
9 patients have been treated at MD Anderson with blinatumomab in an ongoing phase II study, using 
a high-dose regimen (112mcg/d) that was used in DLBCL.7 One patient, who was refractory to 3 prior 
therapies, had a durable CR lasting >1y. Of note, this patient had received ibrutinib and nivolumab as 
his most recent prior therapy, without response. Several notable, but transient, responses were also 
seen:  
 
1. One patient had a 40% nodal reduction during C1 before progressing after C2. 
2. One patient had complete resolution of all nodal disease, but progressed in bone marrow. 
3. One patient had a packed bone marrow, with 40% circulating DLBCL cells, and initially cleared 
her circulating DLBCL, before developing disease progression. 
 
Our impression, from in this patient cohort, is that there was less toxicity than was seen in the study 
by Viardot et al. in DLBCL, where the same high-dose blinatumomab regimen was used. We saw 
only 1 case of significant neurotoxicity (grade 3). This occurred in a patient who had escalated to full 
dose blinatumomab (patient #3, above), but had a fall in the hospital, resulting in a fractured neck of 
femur that required surgical repair. As a result, blinatumomab was interrupted and, despite 
appropriate pre-medication, neurotoxicity developed on re-initiation of therapy. Otherwise there were 
no cases of ≥grade 1 CRS or neurotoxicity. None of the other 7 patients required dose interruption or 
reduction of blinatumomab due to toxicity). 
 


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During the study, patients had blood samples taken pre-treatment and at day 1, 7, 14, 28 and 84 
during blinatumomab therapy for analysis of T cell subsets and immune checkpoint molecule 
expression. All patients were lymphopenic and there was a skewing of T cell subsets toward effector 
and effector-memory subtypes, with very few naïve and central memory T cells present. Additionally, 
most patients expressed high levels of multiple immune checkpoint molecules, particularly TIGIT, 
PD1 and, to a lesser extent, TIM3. (see Figure 1). 
 
Immune checkpoint molecule expression and individual patient-level data suggests a complementary 
and potentially synergistic role for ibrutinib + nivolumab and blinatumomab in RT. 
 
There was significant inter-patient variability in immune checkpoint molecule expression in patients 
analyzed in the blinatumomab trial, both in terms of the expression levels and specific immune 
checkpoint molecules expressed. However, the most highly expressed molecules were TIGIT, PD1 
and TIM3, which were all expressed at much higher levels than in normal controls in most patients.  
The consistent expression of PD1, which often increased during therapy, suggests that PD1 inhibition 
may be synergistic with blinatumomab in RT. Eventually, the heterogeneity of immune checkpoint 
expression may lead to a personalized approach to targeting specific immune checkpoint molecules. 
However, currently, the most practical path to drug development would be to combine approaches 
that have demonstrated safety and response in the clinic in RT. 
 
At the individual patient level, two patients received sequential therapy with ibrutinib + nivolumab and 
blinatumomab on separate clinical trials and are therefore very informative when developing potential 
combination approaches: 
1. Patient #1 (T cell immune checkpoint profile shown in Figure 1 and PETCT shown in Figure 2) 
received ibrutinib + nivolumab, without response. He had multi-focal, bulky, extra-nodal disease 
and achieved CR lasting >1 year with blinatumomab therapy. This patient had the lowest level of 
immune checkpoint molecule expression (particularly of PD1) of all patients tested. The fact that 
his was the most favorable response to blinatumomab is suggestive of the importance of immune 
checkpoint molecule expression on T cells in mediating blinatumomab resistance. 
2. Patient #2 (T cell immune checkpoint profile shown in figure 3) received blinatumomab, with 
transient response (clearance of circulating DLBCL cells from the blood) followed by an MRD-


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negative CR lasting >1y with ibrutinib + nivolumab. This patient had very high levels of PD1 on her 
T cells, which increased during blinatumomab therapy.  
 
 
 
Figure 1. Sequential Immune checkpoint expression profiling pre-treatment and during 
therapy on patient #1 treated with blinatumomab. This patient had recently received ibrutinib and 
nivolumab, without response. His CD4 and CD8 T cells showed the lowest PD1 expression of all the 
patients profiled in the study. He achieved CR with blinatumomab (PETCT shown in Figure 2) 


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Figure 2. PETCT prior to blinatumomab (left) and post-cycle 2 of blinatumomab (right) in a 
patient who achieved CR with treatment. 
 
 
 


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Figure 3. Sequential Immune checkpoint expression profiling pre-treatment and during 
therapy on two patients treated with blinatumomab. In each panel, the control specimen from a 
healthy donor is left-most, followed by baseline specimen from the patient and then serial on-
treatment specimens for the same patient. The top panel shows patientprofiling showed high levels of 
expression of PD1, TIM3 and TIGIT on CD4 and CD8 cells pre-treatment, with a notable increased 
expression during therapy on CD4+ and CD8+ T cells of both PD1 and TIGIT. This patient had a 
transient response to blinatumomab, with clearance of circulating DLBCL cells, before progressing. 
She subsequently had a durable MRD-negative CR (lasting ~1y) with ibrutinib + nivolumab, before 
progressing with CNS disease. 
 
2.3 Ibrutinib + nivolumab in RT: 
• This regimen is a major advance in RT treatment. In a phase II, single center study at M.D. 
Anderson, there was an overall response rate of 43% and a complete remission rate of 35% in 
23 heavily pre-treated patients.6 
• In addition to the high CR rate achieved in this difficult-to-treat population patients with RT 
(median 3 prior therapies), this regimen was delivered entirely as an outpatient and was very 
well tolerated, even by older patients (median age was 65, with patients as old as 88 


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successfully enrolled). There were only two grade 3-4 immune-related toxicities: 1 patient had 
grade 3 transaminitis and one patient had grade 4 lipase/amylase elevation. One patient 
developed grade 2 pneumonitis, and one patient had grade 2 uveitis. These toxicities were 
manageable with corticosteroids and continued therapy was possible in all patients. Only one 
patient eventually stopped treatment due to toxicity, which was the development of psoriasis 
after 20 cycles of therapy. 
• Although encouraging, responses are seen in <50% of patients and there are relapses after 
initial response, suggesting that the addition of other potentially synergistic agents to this 
treatment backbone is needed. 
 
3.0 STUDY POPULATION 
30 patients will be enrolled in this phase II study, 9 in the blinatumomab monotherapy phase and 21 
in the combination phase. 
 
3.1 Inclusion Criteria 
1. Patients with previously treated CLL and biopsy-proven Richter’s transformation with DLBCL 
histology according to IWCLL criteria (Richter Transformation – RT) AND CD19 positive by 
flow cytometry OR immunohistochemistry. 
2. Eastern Co-operative Oncology Group (ECOG) performance status ≤2. 
3. Age ≥18 years at the time of informed consent. 
4. Able to provide informed consent and be willing to participate in study schedule and events. 
 
3.2 Exclusion Criteria 
1. Other active malignancy receiving systemic therapy. 
2. History or presence of clinically relevant disorder affecting the CNS such as epilepsy, 
childhood or adult seizure, paresis, aphasia, stroke, severe brain injuries, dementia, 
Parkinson’s disease, cerebellar disease, organic brain syndrome, or psychosis, with the 
exception of a history of CNS lymphoma that is controlled with intrathecal therapy. 
3. Known active DLBCL in the CNS (confirmed by CSF analysis). 
4. Current autoimmune disease requiring >/= 20mg/day of prednisone or systemic 
immunosuppressive therapy (eg. With cyclosporine or azathioprine). 
5. Allogeneic HSCT within 24 weeks before the start of protocol-specified therapy. 


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6. Active Graft-versus-Host Disease (GvHD), grade 2-4 according to the Glucksberg criteria,  
active chronic GvHD requiring systemic treatment or requirement for systemic GvHD 
prophylaxis with cyclosporine or tacrolimus. 
7. Cancer chemotherapy within 2 weeks before start of protocol-specified therapy, with the 
exception of intrathecal chemotherapy, dexamethasone, and oral small molecule inhibitors 
such as BTK-inhibitor, PI3K-inhibitor, or Bcl-2-inhibitor, which are allowed until the start of 
protocol-specified therapy). In addition, any subject whose organ toxicity (excluding 
hematologic) from prior treatment has not resolved to no more than CTCAE grade 1 
8. Radiotherapy within 2 weeks before the start of protocol-specified therapy 
9. Abnormal screening laboratory values as defined below: 
- 
ALT (SGOT) and/or ALT (SGPT) and/or ALP ≥5 x upper limit of normal (ULN) 
- 
Total bilirubin ≥ 1.5 x ULN, unless due to Gilbert’s disease 
- 
Creatinine ≥ 2.0 x ULN or creatinine clearance <50 mL/min (calculated) 
10. Known infection with human immunodeficiency virus (HIV) or chronic infection with hepatitis B 
virus (HBsAg positive) or hepatitis C virus (anti-HCV positive) 
11. Patient is pregnant or breast feeding 
12. Woman of childbearing potential and is not willing to use 2 highly effective methods of 
contraception while receiving protocol-specified therapy and for an additional 5 months after 
the last dose of protocol-specified therapy 
13. Male who has a female partner of childbearing potential or a pregnant partner, and is not 
willing to use a condom during sexual activity while receiving protocol-specified therapy and for 
7 months after the last dose of protocol-specified therapy 
14. Currently receiving treatment in another investigational device or drug study  
15. Subject previously treated with blinatumomab 
16. History or evidence of any other clinically significant disorder, condition or disease (with the 
exception of those outlined above) that, in the opinion of the Principal Investigator would pose 
a risk to subject safety or interfere with the study evaluation, procedures or completion. 
17. Previously received nivolumab or other PD1 inhibitor. 
 
4.0 TREATMENT PLAN  
This is a single arm, open label, phase II study of ibrutinib, nivolumab and blinatumomab in patients 
with RT.  


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Figure 4. Schematic of treatment plan 
Patients will receive treatment as follows: 
1. 2 cycles of 3 drug combination (ibrutinib, nivolumab and blinatumomab). These cycles will be 8 
weeks each. 
2. 9 cycles of 2 drug combination (ibrutinib and nivolumab). These cycles will be 4 weeks each. 
3. Maintenance treatment with ibrutinib monotherapy until disease progression following 
completion of nivolumab. 
 
4.1 Ibrutinib therapy. 
Ibrutinib treatment will commence on cycle 1, day 1 at 420mg/d. Dose reductions to 280mg/d or 
140mg/d are allowed per treating physician discretion, but the reason must be documented in the 
medical record. Ibrutinib will be given continuously until disease progression or toxicity. 
 
4.2 Nivolumab therapy. 


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Patients will receive nivolumab for up to a total of 52 weeks. Dosing will be 240mg IV every 2 weeks, 
commencing on day 1 until 2nd response assessment, then 480mg IV every 4 weeks. 
 
4.3 Blinatumomab therapy 
Patients will receive blinatumomab as a continuous IV infusion, commencing on day 15 of cycle 1 and 
day 1 of cycle 2, for 2 courses of 4 weeks each separated by a 2 week blinatumomab treatment-free 
interval. 
In cycle 1 and cycle 2 of blinatumomab, dexamethasone pre-medication will be given as outlined in 
table 1, below. 
 
Table 1. Dexamethasone treatment during the study 
Treatment phase 
Target patient 
Dexamethasone dose 
Screening 
Patients with bulky 
or 
rapidly-
progressive disease 
Dose and duration at the discretion of the 
investigator 
Pre-dose dexamethasone 
before 
cycle 
1 
and 
2 
of 
blinatumomab and before dose-
escalation 
All patients (before 
each blinatumomab 
cycle 
and 
dose 
increase) 
Dexamethasone 20 mg IV/PO 12-24 hours 
prior to and within 1 hour before start of 
blinatumomab treatment in each treatment 
cycle, and before dose increase 
During cycle 1 and 2 for the first 
48 hours of blinatumomab and 
after each dose escalation 
All patients, for the 
first 48 hours of 
each 
treatment 
cycle 
Dexamethasone 8mg IV/PO Q8 hours for 48 
hours. 
Infusion interruption/dose 
modification due to adverse 
event 
Patients 
who 
interrupt treatment 
> 4 hours 
Dexamethasone 20 mg IV/PO 12-24 hours 
prior to and within 1 hour before re-start of 
blinatumomab treatment 
In case of signs of cytokine 
release (CRS) of grade ≥2 (see 
Appendix C for grading of CRS 
and Appendix D for definition of 
high dose vasopressors)* 
Patients with signs 
of CRS 
Principal Investigator must be notified. 
Dexamethasone IV/PO at a dose of at least 
24mg per day. The dose should then be 
reduced step-wise over approximately 4 
days, 
provided 
signs 
of 
CRS 
have 


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improved/resolved. 
In case of CNS event grade ≥2 
(See Appendix E for grading)* 
Patients with CNS-
related AE 
Principal Investigator must be notified. 
Dexamethasone should be administered at a 
dose of at least 24mg/day. Dexamethasone 
should 
be 
reduced 
step-wise 
over 
approximately 4 days, provided neurological 
toxicity has improved/resolved. 
 
*Please note that when dexamethasone is given for the management of toxicity, the above 
dexamethasone doses are a guideline. Management of dexamethasone dosing should be 
individualized according to the severity of toxicity and the patient’s response. This management 
should be at the investigator’s discretion. 
 
In cycle 1 of blinatumomab, patients will be hospitalized on day 15-31 (for the first 17 days of 
blinatumomab therapy). To mitigate for potential CRS and CNS events associated with introduction of 
blinatumomab, in cycle 1, blinatumomab will be initiated at 9mcg/day from day 15-21, followed by 28 
mcg/day from day 22-28. This will be followed by 112 mcg/day from day 29-42. In cycle 2, patients 
will be admitted for the first 3 days. Blinatumomab in cycle 2 will be administered at a dose of 112 
mcg/day from day 1-28. 
 
4.4 Response assessment 
Formal response assessment will take place 2weeks (+/- 1 week) following completion of the first 
course of blinatumomab.. Response assessment will comprise laboratory evaluation (CBC), bone 
marrow examination and PETCT scan. Responses in RT for the primary study endpoint will be 
assessed according to the Lugano criteria19 and, as an exploratory endpoint, in co-existing CLL, 
according to 2018 IWCLL response criteria. Responses in RT will be assessed separately from 
responses in CLL. Any nodal or extranodal lesion with SUV ≥5.0 on PETCT will be considered 
indicative of RT, for the purposes of response assessment. Lesions with SUV <5.0 pre-treatment will 
be considered to be due to CLL, rather than RT; residual PET avidity in such lesions post-treatment 
will not be considered evidence of failure of control of RT, provided SUV remains <5.0. In order for 
CR to be attained, all lesions with SUV ≥5.0 pre-treatment must be PET negative post-treatment and 
there must be no new PET avid lesions, unless these are proven by biopsy not to be due to Richter 


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Transformation. PET characterization of target lesions as due to CLL or RT pre-treatment will allow 
separate response assessment for RT (the primary end point) and CLL (an exploratory endpoint), 
without discrepancies arising due to the differences in response criteria. When possible, biopsy of 
residual RT sites will be requested to evaluate for residual disease. 
 
Please note that there may be instances where PETCT is not able to be performed. In these 
instances, CT scan will be performed instead (see section 8.0 and 9.0) 
 
A second response assessment will be undertaken 4 weeks (+/-1 week) after completion of the 
consolidation cycle. 
 
4.5 Allogeneic stem cell transplantation.  
In patients where a suitable donor is identified and who are considered eligible, allogeneic stem cell 
transplantation may be offered any time after completion of the first cycle of blinatumomab and initial 
response assessment. Patients will be considered “off study” on the date they commence pre-
transplant conditioning chemotherapy. If the patient agrees, they will be enrolled on a departmental 
umbrella protocol (DR09-0223) to continue to follow them for overall survival. 
 
4.6 Surveillance after completion of blinatumomab. 
After completing blinatumomab, patients will have PETCT every 3 months until completion of 
nivolumab therapy. If PETCT cannot be performed, for whatever reason, CT with oral and IV contrast 
(unless contraindicated) will be performed instead. 
 
5.0 STUDY MEDICATIONS  
 
5.1 Blinatumomab 
 
5.1.1. Blinatumomab formulation, reconstitution and administration 
 
Blinatumomab will be supplied as 4 mL single-use glass injection vials containing a sterile, 
preservative-free, white to off-white, lyophilized powder for intravenous (IV) administration following 
reconstitution with sterile water for injection (sWFI). Each vial contains a target of 38.5 μg 


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blinatumomab (nominal) formulated with 3.68 mg citric acid monohydrate, 105.0 mg trehalose 
dihydrate, 25.55 mg lysine hydrochloride, and 0.70 mg polysorbate 80, pH of 7. Following 
reconstitution with 3 mL sterile water for injection the final concentration of blinatumomab will be 12.5 
μg/mL. 
 
Since blinatumomab will be administered via continuous intravenous route, it needs to be stabilized at 
low concentrations to prevent absorption to surfaces. Therefore, the IV bag must be conditioned by 
prior addition of a product-specific diluent (IV solution stabilizer - IVSS), resulting in a final diluent 
concentration of 0.5 mM citrate, 25 mM lysine hydrochloride and 0.002% (w/v) polysorbate 80. IVSS 
is supplied in 10 mL single-use glass injection vials as a sterile, preservative-free, clear, colorless-to-
slightly-yellow liquid concentrate. It consists of 25 mM citric acid monohydrate, 1.25 M L-lysine 
hydrochloride, and 0.1% (w/v) polysorbate 80, pH of 7. Following dilution in 0.9% NaCl, the ingredient 
concentrations are 25 mM L-lysine hydrochloride, 0.002% (w/v) polysorbate 80, and 0.5 mM citric 
acid monohydrate. Sterile water for injection and supplies required for reconstitution and injection of 
blinatumomab will not be provided to clinical sites. 
 
The drug administration should not be interrupted, if possible. In case of infusion interruption, due to 
any technical or logistic reason, the interruption should be as short as possible and the infusion 
continued at the earliest time possible. Every interruption longer than 1 hour should be documented. 
If the interruption is longer than 4 hours, re-start of the infusion should be performed in the hospital. 
The subject should be observed overnight for possible side effects after the re-start. Administration of 
dexamethasone premedication as described in Table 1 is required. If possible, the infusion duration 
before and after an interruption should total 28 days per treatment cycle (i.e. if interruptions occur, the 
missed days should be “made up” after re-commencement so a total of 28 days is given). This will not 
be considered a protocol violation if interruptions occurred for documented medical reasons. 
 
5.1.2 Adverse events associated with blinatumomab 
 
5.1.2.1 General Infusion Reactions 
Infusion reactions may be clinically indistinguishable from manifestations of cytokine release 
syndrome (CRS). Patients should be observed closely for infusion reactions, especially during the 


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first infusion of the first and second cycles. Management of infusion reactions may require either 
temporary interruption or discontinuation of blinatumomab. 
 
5.1.2.2 Hepatic/Biliary/Pancreatic  
Treatment with blinatumomab was associated with transient elevations in liver enzymes. The majority 
of these events were observed within the first week of blinatumomab initiation and did not require 
blinatumomab interruption or discontinuation. 
 
Pancreatitis, life threatening or fatal, has been reported in patients receiving blinatumomab in clinical 
trials and the post-marketing setting. High-dose steroid therapy may have contributed, in some cases, 
to the pancreatitis.  
 
5.1.2.3 Immune Cytokine Release Syndrome Cytokine Release Syndrome (CRS) 
This may be severe, life-threatening or fatal and was reported in patients receiving blinatumomab. 
Serious adverse events that may be associated with CRS included pyrexia, asthenia, headache, 
hypotension, total bilirubin increased, elevation of liver enzymes (AST and ALT). The median time to 
onset was 2 days. Disseminated intravascular coagulation (DIC) and Capillary leak syndrome (CLS) 
have been commonly associated with CRS. Hemophagocytic lymphohistiocytosis/macrophage 
activation syndrome (HLH/MAS) has been uncommonly reported in the setting of CRS.  
 
5.1.2.4 Tumor Lysis Syndrome 
Tumor lysis syndrome (TLS), which may be severe, life-threatening or fatal, has been observed in 
patients receiving blinatumomab. Appropriate prophylactic measures include aggressive hydration 
and antihyperuricemic therapies (such as allopurinol or rasburicase). 
 
5.1.2.5 Infections 
Pneumonia, bacteremia, opportunistic infections, and catheter site infections have been observed, 
some of which were life-threatening or fatal.  
 
5.1.2.6 Hematologic abnormalities 
Neutropenia and febrile neutropenia, including life threatening cases, have been observed in patients 
receiving blinatumomab.  


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5.1.2.7 Neurologic abnormalities 
General Neurologic events (any grade) were observed in approximately half of patients receiving 
blinatumomab. Grade 3 or higher (severe, life-threatening and fatal) neurologic events that occurred 
following the initiation of blinatumomab included: encephalopathy, convulsions, speech disorders, 
disturbances in consciousness, confusion and disorientation, coordination and balance disorders. 
Encephalopathy was the most frequently reported serious neurological event in the pivotal study and 
two cases resulted in death. Neurologic events, that may be associated with encephalopathy, include 
tremor, muscular weakness, confusion, stupor, coma, seizures, altered consciousness and 
personality changes. The median time to onset of a neurologic event was 9 days, and the majority of 
events resolved and infrequently led to blinatumomab treatment discontinuation. There is limited 
experience with blinatumomab in patients with active malignant involvement of the central nervous 
system (CNS) or a history of neurologic events. Patients with a history or presence of clinically 
relevant CNS pathology were excluded from clinical trials.  
 
5.1.2.8 Leukoencephalopathy 
Cranial magnetic resonance imaging (MRI) changes showing leukoencephalopathy have been 
observed in patients receiving blinatumomab, especially in patients with prior treatment with cranial 
irradiation and anti-leukemic chemotherapy (including systemic high dose methotrexate or intrathecal 
cytarabine). The clinical significance of these imaging changes is unknown.  
 
5.1.3 Inpatient admission 
As described above, patients receiving blinatumomab may experience a spectrum of neurologic and 
psychiatric events, such as seizure, encephalopathy, tremor, apraxia, speech disorders (dysarthria, 
aphasia) and disorientation. The incidence of patients experiencing neurologic and psychiatric events 
is greatest within the first few days of initiating blinatumomab therapy and on dose escalation. 
Reversible, grade 3 neurotoxicity was seen in 6 of 21 patients (26%) receiving blinatumomab for 
DLBCL, given at the same dose and schedule as will be used in this study. As such, patients will be 
hospitalized for the first 17 days of cycle 1 and 3 days of cycle 2 as outlined in section 5.1.6 and if 
dose interruption of >4 hours occurs during outpatient therapy. In addition, cytokine release syndrome 
(CRS) and/or tumor lysis syndrome (TLS) may occur on initiation of therapy, particularly in patients 
with high tumor load. Patients will receive IV hydration and allopurinol for tumor lysis syndrome 


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prophylaxis. Rasburicase will be given if indicated, according to institutional guidelines. Allopurinol (or 
equivalent, in the case of allergy) will be continued for the duration of hospitalization. Patients will be 
discharged after 17 days, provided no significant AEs requiring blinatumomab interruption and/or 
dose reduction have occurred. 
 
5.1.4 Dexamethasone during pre-phase and as pre-medication before blinatumomab 
Dexamethasone will be given during the study as outlined in table 1. 
5.15.1.5 Blinatumomab dosage, administration, and schedule 
Blinatumomab will be administered as a continuous intravenous infusion (CIVI), through a 
peripherally inserted central catheter (PICC) line or tunneled central venous catheter (CVC). 
Preparation and administration of blinatumomab will comply with the instructions in the US 
Prescribing Information or with institutional standards (outlined in the pharmacy manual). Schedule of 
administration is outlined in section 4.3. 
 
5.15.1.6 Blinatumomab inpatient dosing 
Patients will be hospitalized for the first 17 days of the cycle 1 and first 3 days of cycle 2. Patients will 
be re-admitted after dose interruptions of >4 hours as described in section 5.3.  
 
5.1.7 Blinatumomab outpatient dosing 
After a subject meets the minimum criteria for outpatient administration, as described in section 5.1.3, 
and if a subject is deemed stable by the investigator, continuation of blinatumomab infusion may 
continue as an outpatient. 24-hour emergency on-call service must be ensured in the outpatient 
setting. 
 
In the outpatient setting, the subject will return to the study site for changes of infusion bags. 
 
5.2 Nivolumab. 
Nivolumab is a fully human, IgG4 (kappa) isotype, monoclonal antibody that binds PD-1. Nivolumab 
will be supplied in vials of 100 mg (10 mg/mL), 5 vials per container, and packaged in an open-label 
fashion. See Pharmacy Reference Material. 
 
5.2.1 Preparation and Dispensing of Nivolumab 


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The product storage manager should ensure that the study drug is stored in accordance with the 
environmental conditions (temperature, light, and humidity) as determined by the Investigator 
Brochure. If concerns regarding the quality or appearance of the study drug arise, do not dispense 
the study drug and contact the sponsor immediately. 
 
Investigational product documentation must be maintained that includes all processes required to 
ensure drug is accurately administered. This includes documentation of drug storage, administration 
and, as applicable, storage temperatures, reconstitution, and use of required processes (e.g. required 
diluents, administration sets). 
 
Nivolumab vials must be stored at a temperature of 2°C to 8°C and should be protected from light. If 
stored in a glass front refrigerator, vials should be stored in the carton. Recommended safety 
measures for preparation and handling of nivolumab include laboratory coats and gloves. For details 
on prepared drug storage and use time of nivolumab under room temperature/light and refrigeration, 
please refer to the Investigator Brochure section for “Recommended Storage and Use Conditions”. 
Care must be taken to assure sterility of the prepared solution as the product does not contain any 
anti-microbial preservative or bacteriostatic agent. No incompatibilities between nivolumab and 
polyolefin bags have been observed. 
 
Nivolumab is to be administered as an IV infusion over approximately 30 minutes, using a volumetric 
pump with a 0.2/0.22 micron in-line filter at the protocol-specified dose. The drug can be diluted with 
0.9% normal saline for delivery but the total drug concentration of the solution cannot be below 1 
mg/ml. It is not to be administered as an IV push or bolus injection. At the end of the infusion, flush 
the line with a sufficient quantity of normal saline. 
 
Unused or expired nivolumab vials will be disposed per MDACC guidelines. 
 
5.2.2 Administration of Nivolumab 
Patients will receive nivolumab as an IV infusion over approximately 30 minutes. No doses 
of nivolumab may be given within 11 days of another. 
 
5.2.3 Patient Monitoring During Infusion 


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For first dose, patient vital signs should be monitored prior to dosing, about 15 minutes after initiation 
of the infusion (then every 15-20 minutes as indicated) and at 30 minutes after completion of the 
infusion, or longer if indicated, until the vital signs normalize or return to baseline. For subsequent 
infusions, vital signs should be collected prior to dosing and every 30 minutes during dosing. 
 
5.2.4 Treatment of Nivolumab Related Infusion Reactions 
Since nivolumab contains only human immunoglobulin protein sequences, it is unlikely to be 
immunogenic and induce infusion or hypersensitivity reactions. However, if such a reaction were to 
occur, it might manifest with fever, chills, rigors, headache, rash, pruritus, arthralgias, hypo- or 
hypertension, bronchospasm, or other symptoms. Infusion reactions should be graded according to 
NCI CTCAE (version 5.0) guidelines. 
 
Treatment recommendations for nivolumab related infusion reactions are provided below and may be 
modified based on MD Anderson treatment standards and guidelines, as appropriate: 
 
For Grade 1 symptoms (Mild reaction; infusion interruption not indicated; intervention not indicated): 
Remain at bedside and monitor subject until recovery from symptoms. The following prophylactic 
premedications are recommended for future infusions: diphenhydramine 50 mg (or equivalent) and/or 
acetaminophen 325 to 1000 mg at least 30 minutes before additional nivolumab administrations. 
 
For Grade 2 symptoms (Moderate reaction requires therapy or infusion interruption but responds 
promptly to symptomatic treatment [e.g. antihistamines, non-steroidal anti-inflammatory drugs, 
narcotics, corticosteroids, bronchodilators, IV fluids]; prophylactic medications indicated for ≤ 24 
hours): Stop the nivolumab infusion, begin an IV infusion of normal saline, and treat The subject with 
diphenhydramine 50 mg IV (or equivalent) and/or acetaminophen 325 to 1000 mg; remain at bedside 
and monitor subject until resolution of symptoms. Corticosteroid or bronchodilator therapy may also 
be administered as appropriate. If the infusion is interrupted, then restart the infusion at 50% of the 
original infusion rate when symptoms resolve; if no further complications ensue after 30 minutes, the 
rate may be increased to 100% of the original infusion rate. Monitor subject closely. If symptoms 
recur then no further nivolumab will be administered at that visit. Administer diphenhydramine 50 mg 
IV, and remain at bedside and monitor the subject until resolution of symptoms. The amount of study 
drug infused must be recorded on the case report form (CRF). The following prophylactic 


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premedications are recommended for future infusions: diphenhydramine 50 mg (or equivalent) and/or 
acetaminophen 325 to 1000 mg should be administered at least 30 minutes before additional 
nivolumab administrations. If necessary, corticosteroids (recommended dose: up to 25 mg of IV 
hydrocortisone or equivalent) may be used. 
 
For Grade 3 or Grade 4 symptoms [Severe reaction, Grade 3: prolonged (i.e. not rapidly responsive 
to symptomatic medication and/or brief interruption of infusion); recurrence of symptoms 
followinginitial improvement; hospitalization indicated for other clinical sequelae (e.g. renal 
impairment, pulmonary infiltrates), Grade 4: life- threatening; pressor or ventilatory support indicated]: 
Immediately discontinue infusion of nivolumab. Begin an IV infusion of normal saline, and treat the 
subject as follows: Recommend bronchodilators, epinephrine 0.2 to 1 mg of a 1:1,000 solution for 
subcutaneous administration or 0.1 to 0.25 mg of a 1:10,000 solution injected slowly for IV 
administration, and/or diphenhydramine 50 mg IV with methylprednisolone 100 mg IV (or equivalent), 
as needed. Subject should be monitored until the investigator is comfortable that the symptoms will 
not recur. Nivolumab will be permanently discontinued. Institutional guidelines will be followed for the 
treatment of anaphylaxis. Remain at bedside and monitor subject until recovery from symptoms. In 
the case of late-occurring hypersensitivity symptoms (e.g. appearance of a localized or generalized 
pruritus within 1 week after treatment), symptomatic treatment may be given (e.g. oral antihistamine 
or corticosteroids). 
 
5.2.5. AEs associated with nivolumab: 
 
5.2.5.1 Pulmonary Adverse Events: 
Pulmonary AEs have been observed following treatment with nivolumab. The frequency of 
pulmonary AEs may be greater with nivolumab combination therapies than with nivolumab 
monotherapy. The majority of cases reported were Grade 1 or 2, and subjects presented with either 
asymptomatic radiographic changes (eg, focal ground glass opacities and patchy infiltrates) or with 
symptoms of dyspnea, cough, or fever. Subjects with reported Grade 3 or 4 pulmonary AEs were 
noted  to  have  more severe symptoms, more extensive radiographic findings,  and hypoxia. 
 
Pulmonary AEs have been reported in subjects with a variety of tumor types; however, there have 
been numerically more cases in subjects with NSCLC. It is not clear whether the underlying NSCLC 


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is a distinct risk factor, or if subjects with NSCLC are more likely to develop radiographic changes and 
symptoms for which it is difficult to distinguish between nivolumab-related and unrelated causes. At 
this time, no other underlying risk factor, including prior radiotherapy, presence of lung metastases, 
or underlying pulmonary medical history, has yet to be identified. 
 
Asymptomatic subjects were typically managed with dose delay. Subjects with Grade 2 pneumonitis 
were managed with dose delay, treated with corticosteroids, and had resolution of pneumonitis 
within days to weeks. In cases where nivolumab treatment was restarted, recurrence of pneumonitis 
was infrequently reported across the nivolumab program. Subjects with more severe cases of 
pneumonitis can be difficult to treat. In a few cases, subjects who did not initially respond to 
corticosteroids were administered anti-tumor necrosis factor therapy (infliximab) and/or 
cyclophosphamide. In some of these cases, pneumonitis began to resolve following the use of these 
additional therapies. 
 
Guidelines on the recommended management of pneumonitis and other pulmonary AEs are found in 
Appendix K. Early recognition and treatment of pneumonitis is critical to its management. Subjects 
should be advised to seek medical evaluation promptly if they develop new-onset dyspnea, cough, 
or fever or if they have worsening of these baseline symptoms. As respiratory symptoms are 
common in subjects with cancer (eg, NSCLC), it is important that an evaluation/work-up 
distinguishes between non-drug-related causes (eg, infection or progression of disease) and a 
possible drug-related pulmonary toxicity as the management of these events can be quite different. 
For symptomatic nivolumab-related pneumonitis, the principal treatment is corticosteroids (Appendix 
K). All subjects with Grade 3-4 pneumonitis should discontinue nivolumab and initiate treatment with 
high doses of corticosteroids. Consultation with the PI or designee should be sought for all 
suspected cases of pneumonitis. 
 
5.2.5.2 Gastrointestinal adverse events. 
Gastrointestinal AEs have been observed following treatment with nivolumab (Section 5.5). Most 
cases of diarrhea were of low grade (Grade 1-2). Colitis occurred less frequently than diarrhea. 
High-grade cases of diarrhea and colitis were managed with corticosteroids and, in all cases, the 
events resolved. 
 


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The recommended management of GI AEs is provided in Appendix K. Early recognition and 
treatment of diarrhea and colitis are critical to their management. Subjects should be advised to 
seek medical evaluation if they develop new-onset diarrhea, blood in stool, or severe abdominal pain 
or if they have worsening of baseline diarrhea. As GI symptoms are common in subjects with cancer, 
it is important that an evaluation/work-up distinguishes between non-drug-related causes (eg, 
infection or progression of disease) and a possible drug-related AE as the management can be quite 
different. The principal treatment for high-grade GI AEs is corticosteroids (Appendix K). Caution 
should be taken in the use of narcotics in subjects with diarrhea, colitis, or abdominal pain as pain 
medicines may mask the signs of colonic perforation. Consultation with the PI or designee should be 
sought for all moderate- and high-grade cases of GI AEs. 
 
5.2.5.3 Diverticular Perforation 
The prevalence of diverticulosis in the general population is common and increases with age from 
10% under 40 years of age to approximately 50% over 60 years of age. Approximately 10% to 25% 
of subjects with diverticulosis develop diverticulitis. Perforation occurs in 50% to 70% of instances of 
complicated diverticulitis. Corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs), and opioid 
analgesics are known risk factors for diverticular perforation. Given the high prevalence of 
diverticulosis and diverticulitis in the general population, it is expected that some nivolumab-treated 
subjects will have these conditions concurrently with their malignancy. Cases of diverticular 
perforation while on concomitant corticosteroids (6 cases) or NSAID (1 case) were observed in 
nivolumab program. While there is insufficient evidence to suggest that diverticulosis or diverticulitis 
is a predisposing factor for GI perforation following nivolumab administration, clinical caution should 
be exercised, as appropriate, for subjects on concomitant medications of corticosteroids, NSAID, or 
opioid analgesics. In addition, be vigilant for signs and symptoms of potential perforation, especially 
in subjects with known diverticular disease. 
 
5.2.5.4 Hepatic Adverse Events 
Hepatic AEs, including elevated liver function tests (LFTs) and, infrequently, DILI, have been 
observed following treatment with nivolumab and nivolumab in combination with ipilimumab. Most 
cases were of low or moderate grade. Higher-grade hepatic AEs, including DILI, were managed with 
corticosteroids (with or without mycophenolate mofetil) and, in almost all cases, the events resolved. 
The recommended management of hepatic AEs is provided in Appendix K. Early recognition and 


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treatment of elevated LFTs and DILI are critical to their management. Subjects should be advised to 
seek medical evaluation if they notice jaundice (yellow appearance of skin or sclera) or if they 
develop bruising, bleeding, or right-sided abdominal pain. Physicians should monitor LFTs prior to 
each nivolumab treatment. As LFT abnormalities are common in subjects with cancer, it is important 
that an evaluation/work-up distinguishes between non-drug-related causes (eg, infection, 
progression of disease, concomitant medications, or alcohol) and a possible drug-related AE as the 
management can be quite different. The principal treatment for high-grade hepatic AEs is 
corticosteroids (Appendix K). Consultation with the PI or designee should be sought for all 
moderate- and high-grade hepatic AEs. 
 
5.2.5.5. Endocrinopathies 
Endocrinopathies have been observed following treatment with nivolumab (Section 5.5). Most cases 
were of low or moderate grade. The events have typically been identified through either routine 
periodic monitoring of specific laboratories (eg, TSH) or as part of a work-up for associated symptoms 
(eg, fatigue). Events may occur within weeks of beginning treatment, but also have been noted to occur 
after many months (while still on treatment). More than 1 endocrine organ may be involved (eg, 
hypophysitis [pituitary inflammation] may need to be evaluated at the time adrenal insufficiency or 
thyroid disorder is suspected). Moderate- to high-grade cases were managed with hormone 
replacement therapy and, in some cases, with the addition of corticosteroids. In some cases, 
nivolumab treatment was held until adequate hormone replacement was provided. 
 
Guidelines on the recommended management of endocrinopathies are provided in Appendix K. 
Early recognition and treatment of endocrinopathies are critical to its management. Subjects should be 
advised to seek medical evaluation if they notice new-onset fatigue, lightheadedness, or difficulty 
with vision or if baseline fatigue worsens. As fatigue is common in subjects with cancer, it is important 
that an evaluation/work-up distinguishes between non-drug-related causes (eg, progression of 
disease, anemia, concomitant medications, or depression) and a possible drug-related AE as the 
management can be quite different. The principal management of endocrinopathies is hormone 
replacement therapy. For subjects with moderate- or high-grade events, corticosteroids may also be 
used (Appendix K). Consultation with the PI or designee should be sought for all moderate- and 
high-grade cases of endocrinopathies. 
 


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5.2.5.6. Skin Adverse Events 
Rash and pruritus were the most common skin AEs observed following treatment with nivolumab 
(Section 5.5). The rash was typically focal with a maculopapular appearance occurring on the trunk, 
back, or extremities. Most cases have been of low or moderate grade. In some cases, rash and 
pruritus resolved without intervention. Topical corticosteroids have been used for some cases of 
rash. Anti-histamines have been used for some cases of pruritus. More severe cases responded to 
systemic corticosteroids. 
 
Subjects should be advised to seek medical evaluation if they notice new-onset rash. Early 
consultation with a dermatology specialist and a biopsy should be considered if there is uncertainty as 
to the cause of the rash, or if there is any unusual appearance or clinical feature associated with it. 
Other drugs that may cause rash should be considered in the differential and, if possible, 
discontinued. In addition, careful evaluation of potential benefit-risk is necessary when considering 
the use of nivolumab or ipilimumab in a patient who has previously experienced a severe or life-
threatening skin adverse reaction on a prior immune-stimulating therapy. 
 
Guidelines on the recommended management of skin AEs are provided in Appendix K. The principal 
treatment for skin AEs, such as rash and pruritus, consists of symptomatic management. Topical 
corticosteroids can be used for low- to moderate-grade focal rash. Systemic corticosteroids should be 
used for diffuse and high-grade rash. Consultation with the PI or designee should be sought for all 
moderate- and high-grade cases of skin AEs. 
 
Rare cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), some with 
fatal outcome, have been observed. If symptoms or signs of SJS or TEN appear, nivolumab or 
nivolumab in combination with ipilimumab should be withheld and the patient referred for specialized 
care for assessment and treatment. If the patient has confirmed SJS or TEN, permanent 
discontinuation of nivolumab or nivolumab in combination with ipilimumab is recommended. 
 
5.2.5.7 Renal Adverse events 
Elevated creatinine and biopsy-confirmed tubulointerstitial nephritis and allergic nephritis have been 
infrequently observed following treatment with nivolumab. The frequency of renal AEs may be 
greater with nivolumab combination therapies than with nivolumab monotherapy. Most cases were 


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Grade 2 or 3 and based on creatinine elevation. Subjects with a history of RCC or prior 
nephrectomy did not appear to be at higher risk. Events were managed with corticosteroids and, in all 
cases, renal function partially or fully improved. 
 
The recommended management of renal AEs is provided in Appendix K. Physicians should monitor 
creatinine regularly. As creatinine abnormalities are common in subjects with cancer and other 
comorbidities, it is important that an evaluation/work-up distinguishes between non-drug-related 
causes (eg, dehydration, concomitant medications, hypotension, or progression of disease) and a 
possible drug-related AE as the management can be quite different. The principal treatment for renal 
AEs is corticosteroids (Appendix K). Consultation with the PI or designee should be sought for all 
moderate- and high-grade cases of renal AEs. 
 
5.2.5.8 Neurologic Adverse events 
Neurologic AEs have been uncommonly observed following  treatment  with  nivolumab  (Section 
5.5). The frequency of neurologic AEs may be greater with nivolumab + ipilimumab combination 
therapies than with nivolumab monotherapy or other nivolumab combinations. Neurologic AEs can 
manifest as central abnormalities (eg, aseptic meningitis, encephalopathy, or encephalitis) or 
peripheral sensory/motor neuropathies (eg, Guillain-Barre Syndrome, myasthenia gravis complicated 
with sepsis and fatality). The onset has been observed as early as after a single treatment with the 
nivolumab + ipilimumab combination. 
 
The recommended management of neurologic AEs is provided in Appendix K. Early recognition and 
treatment of neurologic AEs is critical to its management. Subjects should be advised to seek 
medical evaluation if they notice impairment in motor function (eg, weakness), changes in sensation 
(eg, numbness), or symptoms suggestive of possible central nervous system abnormalities such as 
new headache or mental status changes. As neurologic symptoms can be common in subjects with 
cancer, it is important that an evaluation/work-up distinguishes between non-drug-related causes 
(eg, progression of disease, concomitant medications, or infection) and a possible drug-related AE 
as the management can be quite different. The principal treatments for neurologic toxicity are dose 
delay, corticosteroids, and IV immunoglobulin as outlined in the safety algorithm (Appendix K). For 
high-grade related neurological AEs, nivolumab should be discontinued. Consultation with the PI or 
designee should be sought for all moderate- and high-grade cases of neurologic AEs. 


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5.2.5.9 Infusion Reactions 
Infusion reactions, including high-grade hypersensitivity reactions, following administration of 
nivolumab are uncommon. Investigators are advised to monitor for fever, chills, shakes, itching, 
rash, hypertension or hypotension, or difficulty in breathing during and immediately after 
administration of nivolumab. Study protocols provide explicit guidance on the management of 
infusion-related reactions. 
 
5.2.5.10 Lipase/Amylase Elevations 
Asymptomatic elevations in lipase and amylase have been reported. In monotherapy studies, lipase 
and amylase levels were not systematically monitored, so an estimate of the frequency of 
asymptomatic lipase/amylase elevations is  unknown.  In studies evaluating the  safety  of the 
nivolumab + ipilimumab combination in multiple tumor types, lipase and amylase levels were 
systematically monitored, and elevations in any grade of lipase/amylase were consistently noted in  
approximately 10% to 30% of subjects. Very few subjects reported associated symptoms (eg, 
abdominal pain) or radiographic findings (eg, stranding) consistent with pancreatitis. Thus, there 
does not seem to be clinical significance to the elevated laboratory values. 
 
As lipase/amylase abnormalities are not uncommon in subjects with cancer, it is important that an 
evaluation/work-up distinguishes between non-drug-related causes (eg, progression of disease, 
concomitant medications, or alcohol) and a possible drug-related cause as the management can be 
quite different. The recommended management of nivolumab-related elevated lipase/amylase 
values centers around close observation. Physicians should ensure that subjects have no associated 
symptoms consistent with pancreatitis, such as abdominal pain. Corticosteroids do not seem to alter 
the natural history of lipase/amylase elevations. Laboratory values tend to fluctuate on a day-to-day 
basis and eventually return to baseline or low grade over the course of weeks, whether or not 
subjects receive corticosteroids. Asymptomatic elevations should be monitored approximately on a 
weekly basis, and nivolumab should be held per protocol instructions. For subjects with elevated 
lipase/amylase and symptoms consistent with possible pancreatitis, nivolumab should be 
discontinued, and consultation with a gastroenterologist should be considered. Consultation with the 
PI or designee should be sought for all high-grade cases of elevated lipase/amylase. 
 


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5.2.5.11 Uveitis and visual complaints. 
Immune therapies have been uncommonly associated with visual complaints. Inflammation of 
components within the eye (eg, uveitis) is an uncommon, but clinically important, event. Uveitis may 
occur more frequently with nivolumab + ipilimumab combination therapy than with nivolumab 
monotherapy or nivolumab in combination with other therapies. An ophthalmologist should evaluate 
visual complaints with examination of the conjunctiva, anterior and posterior chambers, and retina. 
Topical corticosteroids may be used to manage low-grade events. Low-grade events that do not 
resolve and high-grade events should be managed with systemic corticosteroids. Consultation with 
the PI or designee for all cases of ocular inflammatory events. Complaints of double vision should 
also prompt medical evaluation. In addition to ocular inflammatory events, a work-up should also 
consider pituitary inflammation as a cause (Section 5.2.2.4). 
 
Vogt-Koyanagi-Harada syndrome (VKH) is a T-cell mediated autoimmune attack on melanocytes. 
VKH manifests as a multi-system disorder characterized by granulomatous panuveitis with 
exudative retinal detachments, often associated with neurologic and cutaneous manifestations. Rare 
cases have been observed in post-marketing use of nivolumab. Based on the severity of the 
adverse reaction, nivolumab or nivolumab in combination with ipilimumab should be withheld or 
discontinued, and corticosteroids administered accordingly. 
 
5.2.5.12 Other Immune-mediated Adverse Events 
For suspected immune-related adverse reactions, adequate evaluation should be performed to 
confirm etiology or exclude other causes. Based on the severity of the adverse reaction, nivolumab 
should be withheld or discontinued, and corticosteroids administered accordingly. Upon 
improvement, nivolumab may be resumed after corticosteroid taper. If there is recurrence of any 
Grade 3 or 4 immune-related adverse reactions or life-threatening immune-related adverse 
reactions, nivolumab or nivolumab must be permanently discontinued. 
 
Cases of myotoxicity (myositis, myocarditis, and rhabdomyolysis), some with fatal outcome, have 
been reported with nivolumab. Diagnosis of myocarditis requires a high index of suspicion and in 
some cases can be asymptomatic. Therefore, any cases with cardiac or cardio-pulmonary symptoms 
should undergo prompt diagnostic work- up to evaluate for myocarditis with close monitoring. 
Troponin is a sensitive but not diagnostic marker of myocarditis. If suspected, prompt initiation of 


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high dose of steroids (prednisone 1 to 2 mg/kg/d or methylprednisolone 1 to 2 mg/kg/d) and 
cardiology consultation with diagnostic workup with ECG, troponin and echocardiogram. Additional 
testing as guided by the cardiologist and may include cardiac MRI. Once a diagnosis is confirmed, 
nivolumab should be withheld. For grade 3 myocarditis, nivolumab should be permanently 
discontinued. The recommended management of myocarditis is provided in Appendix K. 
 
The following events have been identified during post approval use of nivolumab. Because reports 
are voluntary from a population of unknown size, an estimate of frequency cannot be made. 
 
- 
Solid organ and tissue transplant rejection has been reported in patients who have previously 
undergone transplantation and who  were  subsequently  treated  with  programmed  cell  
death 1/programmed cell death ligand 1 (PD-1/PD-L1) inhibitors, including nivolumab. 
Treatment with nivolumab may increase the risk of rejection in solid organ or tissue transplant 
recipients. 
- 
Rapid-onset and severe GVHD, some with fatal outcome, has been reported in patients who 
had undergone prior allogeneic HSCT and subsequently received PD-1/PD-L1 inhibitors. 
Subjects should be screened to determine whether they have undergone a prior allogeneic 
HSCT prior to participating in nivolumab clinical trials. 
- 
Complications of allogeneic HSCT after treatment with PD-1/PD-L1 inhibitors including 
nivolumab, administered before allogeneic HSCT, may be associated with an increased risk of 
transplant-related complications, including GVHD. Fatal cases have been reported in clinical 
studies. Patients should be monitored closely for early evidence of transplant-related 
complications 
 
5.2.5.13 Overdose, Warnings, and Precautions 
There is no available information concerning overdose with nivolumab. Depending on the symptoms 
and/or signs leading to the suspicion of overdose, supportive medical management should be 
provided. There is no specific antidote. 
 
The nonclinical findings of increased late-stage pregnancy loss and early infant deaths/euthanasia in 
nivolumab-exposed pregnant monkeys (additional details in Section 4.3.8) suggest a potential risk to 
human pregnancy if there is continued treatment with nivolumab during pregnancy. However, cases 


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of human in-utero exposure to nivolumab (involving the fetuses of female subjects receiving 
nivolumab and female partners of male subjects receiving nivolumab) were reported. Given the 
potential risk suggested by preliminary data from nonclinical and clinical data, dosing during 
pregnancy will continue to be prohibited. In addition, women of childbearing potential (WOCBP) 
receiving nivolumab will be instructed to adhere to  contraception  for  a period  of  5 months after 
the last dose of nivolumab. Men receiving nivolumab and who are sexually active with WOCBP will 
be instructed to adhere to contraception for a period of 7 months after the last dose of nivolumab. 
 
These durations have been calculated using the upper limit  of  the  half-life  for  nivolumab (~25 
days) and are based on the recommendation that WOCBP use contraception for 5 half-lives plus 30 
days, and men who are sexually active with WOCBP use contraception for 5 half-lives plus 90 days 
after the last dose of nivolumab. Females should not breastfeed while receiving nivolumab and for 
any subsequent protocol-specified period. 
 
5.3 Ibrutinib. 
Ibrutinib is a small-molecule inhibitor of BTK. Ibrutinib forms a covalent bond with a cysteine residue 
in the BTK active site, leading to inhibition of BTK enzymatic activity. Ibrutinib 420 mg will be 
administered orally once daily. Ibrutinib should be administered at the same time each day with 8 
ounces (approximately 240 mL) of water. The capsules should be swallowed intact and patients 
should not attempt to open capsules or dissolve them in water. If a dose of ibrutinib is not taken at the 
scheduled time, it can be taken as soon as possible on the same day with a return to the normal 
schedule the following day. Extra capsules of ibrutinib should not be taken to make up for the missed 
dose.  
 
Concomitant use of strong CYP3A inhibitors which would be taken chronically (e.g. ritonavir, 
indinavir, nelfinavir, saquinavir, boceprevir, telaprevir, nefazodone) is prohibited. Concomitant use of 
strong CYP3A inducers (e.g. rifampin, rifabutin, phenytoin, carbamazepine, and St. John’s Wort) is 
prohibited. Avoid grapefruit and Seville oranges during ibrutinib treatment, as these contain moderate 
inhibitors of CYP3A.  
 
5.3.1 Ibrutinib - How Supplied  


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Supplied as 140mg capsules or as tablets of 3 different strengths: 140mg, 280mg and 420mg. 
Ibrutinib will be obtained commercially through the patient’s insurance. 
 
5.3.2 Stability  
Store bottles at room temperature 20°C to 25°C. 
 
5.3.3 Pharmacology  
Ibrutinib was designed as a selective and covalent inhibitor of the Btk. In vitro, ibrutinib is a potent 
inhibitor of Btk activity (IC50 = 0.39 nM). The irreversible binding of ibrutinib to cysteine-481 in the 
active site of Btk results in sustained inhibition of Btk catalytic activity and enhanced selectivity over 
other kinases that do not contain a cysteine at this position. When added directly to human whole 
blood, ibrutinib inhibits signal transduction from the B-cell receptor and blocks primary B-cell 
activation (IC50 = 80 nM) as assayed by anti-IgM stimulation followed by CD69 expression.  
 
5.3.4 Pharmacokinetics and Product Metabolism  
Following oral administration of ibrutinib at doses ranging of 420, 560, and 840 mg/day, exposure to 
ibrutinib increased as doses increased with substantial intersubject variability.  The mean half life (t1/2) 
of ibrutinib across 3 clinical studies ranged from 4 to 6 hours, with a median time to maximum plasma 
concentration (Tmax) of 1 to 2 hours.  Taking into account the approximate doubling in mean systemic 
exposure when dosed with food and the favorable safety profile, ibrutinib can be dosed with or 
without food. Ibrutinib is extensively metabolized primarily by CYP 3A4-mediated metabolic pathways. 
The on-target effects of metabolite PCI-45227 are not considered clinically relevant. Steady-state 
exposure of ibrutinib and PCI-45227 was less than 2-fold of first dose exposure. About 8% of ibrutinib 
is excreted renally. Ibrutinib exposure is not altered in patients with creatinine clearance (CrCl) 
>30 mL/min. Patients with severe renal impairment or patients on dialysis have not been studied. 
Following single dose administration, the AUC of ibrutinib increased 2.7-, 8.2- and 9.8-fold in subjects 
with mild (Child-Pugh class A), moderate (Child-Pugh class B), and severe (Child-Pugh class C) 
hepatic impairment compared to subjects with normal liver function.  A higher proportion of Grade 3 
or higher adverse reactions were reported in patients with B-cell malignancies (CLL, MCL and WM) 
with mild hepatic impairment based on NCI organ dysfunction working group (NCI-ODWG) criteria for 
hepatic dysfunction compared to patients with normal hepatic function.  
 


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5.3.5 Summary of Clinical Safety  
For monotherapy studies:  
Integrated safety data for a total of 1,523 subjects treated with ibrutinib monotherapy from 17 studies 
in B-cell malignancies, which includes subjects from 2 randomized-control studies who crossed over 
from comparator treatment or placebo to receive ibrutinib monotherapy, are summarized below.  
Most frequently reported treatment-emergent adverse events (TEAEs) in subjects receiving ibrutinib 
as monotherapy (N=1,523): 
 
Most frequently reported TEAEs 
>10%   
Most frequently reported Grade 
3 or 4 TEAEs >2%  
Most 
frequently 
reported 
Serious TEAEs >1%  
Diarrhea 
Neutropenia 
Pneumonia 
Fatigue 
 
Atrial fibrillation 
Nausea 
Thrombocytopenia 
Febrile neutropenia 
Cough 
Anemia 
 
Anemia 
 
Diarrhea 
Pyrexia 
 
Fatigue 
Neutropenia  
Upper respiratory tract infection 
Oedema peripheral 
Thrombocytopenia 
Muscle spasms 
Constipation 
Arthralgia 
Vomiting 
Decreased Appetite 
Dyspnoea 
Headache 
Pneumonia 
Rash 
Hypertension 
Abdominal Pain 
Back Pain 
Contusion 
Dizziness 
Diarrhea 
Fatigue 
Nausea 
Cough 
Pyrexia 
Muscle spasms 
Arthralgia 
Vomiting 
Decreased Appetite 
Rash 
 
Anemia 
Neutropenia 
Thrombocytopenia 
Pneumonia 
Hypertension 
Hypokalaemia 
Hyponatraemia 
 
 
For more detailed information refer to the current version of the IB. 
 
5.3.5.1 Bleeding-related events  
There have been reports of hemorrhagic events in subjects treated with ibrutinib both with and 
without thrombocytopenia. These include minor hemorrhagic events such as contusion, epistaxis, and 


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petechiae; and major hemorrhagic events, some fatal, including gastrointestinal bleeding, intracranial 
hemorrhage, and hematuria.   
 
In an in vitro platelet function study, inhibitory effects of ibrutinib on collagen-induced platelet 
aggregation were observed. Use of either anticoagulant or antiplatelet agents comcomitantly with 
ibrutinib increases the risk of major bleeding. A higher risk for major bleeding was observed with 
anticoagulant than with antiplatelet agents. Consider the risks and benefits of anticoagulant or 
antiplatelet therapy when co-administered with ibrutinib. Monitor for signs or symptoms of bleeding. 
 
Supplements such as fish oil and vitamin E preparations should be avoided. 
 
Ibrutinib should be held at least 3 to 7 days pre- and post-surgery depending upon the type of 
surgery and the risk of bleeding. 
 
Subjects with congenital bleeding diathesis have not been studied. 
 
5.3.5.2 Cardiac arrhythmias 
Atrial fibrillation, atrial flutter and cases of ventricular tachyarrhythmia, including some fatal events, 
have been reported in subjects treated with ibrutinib, particularly in subjects with cardiac risk factors, 
hypertension, acute infections, and a previous history of atrial fibrillation. Periodically monitor subjects 
clinically for atrial fibrillation. Subjects who develop arrhythmic symptoms (e.g., palpitations, 
lightheadedness, sycope, new onset of dyspnea or chest pain) should be evaluated clinically, and if 
indicated, have an ECG performed. For cardiac arrhythmias which persist, consider the risks and 
benefits of ibrutinib treatment and follow the protocol dose modification guidelines.  
 
5.3.5.3 Cytopenias  
Treatment-emergent Grade 3 or 4 cytopenias (neutropenia, thrombocytopenia, and anemia) were 
reported in subjects treated with ibrutinib. Subjects should be monitored for fever, weakness, or easy 
bruising and/or bleeding, and blood counts should be monitored as outlined in the protocol. 
 
5.3.5.4 Diarrhea  


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Diarrhea is the most frequently reported non-hematologic AE with ibrutinib monotherapy and 
combination therapy. Other frequently reported gastrointestinal events include nausea, vomiting, and 
constipation. These events are rarely severe and are generally managed with supportive therapies 
including antidiarrheals and antiemetics. Subjects should be monitored carefully for gastrointestinal 
AEs and cautioned to maintain fluid intake to avoid dehydration. Medical evaluation should be made 
to rule out other etiologies such as Clostridium difficile or other infectious agents. Should symptoms 
be severe or prolonged follow the protocol dose modification guidelines.  
 
5.3.5.5 Infections  
Fatal and non-fatal infections have occurred with ibrutinib therapy. At least 25% of subjects with 
mantle cell lymphoma (MCL) and 35% of subjects with CLL had Grade 3 or greater infections per NCI 
Common Terminology Criteria for Adverse Events (CTCAE). The most commonly reported infections 
include pneumonia, cellulitis, urinary tract infection and sepsis. Although causality has not been 
established, cases of progressive multifocal leukoencephalopathy (PML) have occurred in patients 
treated with ibrutinib. 
 
5.3.5.6 Non-Melanoma Skin Cancer 
Non-melanoma skin cancers have occurred in patients treated with ibrutinib.  Monitor patients for the 
appearance of non-melanoma skin cancer. 
 
5.3.5.7 Rash  
Rash has been commonly reported in subjects treated with either single agent ibrutinib or in 
combination with chemotherapy. In a randomized Phase 3 study (PCYC-1112-CA), rash occurred at 
a higher rate in the ibrutinib arm than in the control arm. Most rashes were mild to moderate in 
severity. One case of Stevens-Johnson Syndrome (SJS), with a fatal outcome, was reported in a 
subject with CLL. The subject received ibrutinib (420 mg/day) and was also receiving various 
antibiotics and anti-gout medication (allopurinol) known to be associated with SJS. 
 
5.3.5.8 Lymphocytosis and Leukostasis  
 
Leukostasis  


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There were isolated cases of leukostasis reported in subjects treated with ibrutinib. A high number of 
circulating lymphocytes (>400,000/µL) may confer increased risk.  
 
Lymphocytosis 
Upon initiation of treatment, a reversible increase in lymphocyte counts (ie, ≥50% increase from 
baseline and an absolute count >5000/µL), often associated with reduction of lymphadenopathy, has 
been observed in most subjects with CLL/ small lymphocytic lymphoma (SLL) treated with ibrutinib as 
single agent. This effect has also been observed in some subjects with MCL treated with ibrutinib. 
This observed lymphocytosis is a pharmacodynamic effect and should not be considered progressive 
disease in the absence of other clinical findings. In both disease types, lymphocytosis typically occurs 
during the first month of ibrutinib therapy (median time 1.1 weeks) and typically resolves within a 
median of 8.0 weeks in subjects with MCL and 18.7 weeks in subjects with CLL/SLL.  
A large increase in the number of circulating lymphocytes (eg, >400,000/µL) has been 
observed in some subjects. Lymphocytosis appeared to occur in lower incidence and at 
lesser magnitude in subjects with CLL/SLL receiving ibrutinib in combination with 
chemoimmunotherapy. 
 
5.3.9 Tumor Lysis Syndrome 
There have been reports of tumor lysis syndrome (TLS) events in subjects treated with single-agent 
ibrutinib or in combination with chemotherapy. Subjects at risk of tumor lysis syndrome are those with 
comorbidities and/or risk factors such as high tumor burden prior to treatment, increased uric acid 
(hyperuricemia), elevated lactate dehydrogenase (LDH), bulky disease at baseline, and pre‐existing 
kidney abnormalities. 
 
5.3.10 Interstitial Lung Disease (ILD) 
Cases of interstitial lung disease (ILD) have been reported in patients treated with ibrutinib. Monitor 
patients for pulmonary symptoms indicative of ILD. Should symptoms develop follow the protocol 
dose modification guidelines. 
 
5.3.11 Aspergillosis 
Preliminary information from a Phase 1b, single US-center CTEP study (ClinicalTrials.gov Identifier 
NCT02203526) of primary central nervous system lymphoma (PCNSL) using a novel immune-


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chemotherapy regimen of dose-adjusted temozolomide, etoposide, DOXIL®, dexamethasone, 
ibrutinib, and rituximab (DA-TEDDI-R) confirmed 4 cases of invasive aspergillosis in the first 18 
patients that initiated treated. Three of the 4 confirmed cases had a fatal outcome. Additionally, 3 
clinically suspected cases were reported in the same study, in which all 3 patients experienced Grade 
3 lung infections; however, aspergillosis could not be diagnostically confirmed (bronchoalvelolar 
lavage and blood cultures in 2 patients were negative for fungi). Two additional ISTs in subjects with 
relapsed/refractory CNS lymphoma are currently ongoing with single agent ibrutinib, and both allow 
the concomitant use of systemic steroids to control symptomatic disease. One case of invasive 
aspergillosis was reported for each of these studies, with incidences of 5.0% and 2.6%, respectively, 
for an overall incidence of 7.8% across all three IST/CTEP studies.  
 
There are currently no company sponsored clinical trials ongoing in PCNSL or CNS lymphoma. In a 
recent analysis of completed and ongoing sponsored ibrutinib clinical trials (N=3038), the reported 
incidence of aspergillosis was 0.49%, which was similar to the reported pooled incidence in 4 active 
comparator studies (0.5%) across the ibrutinib clinical development. Based on the existing clinical 
experience with ibrutinib in subjects with B-cell malignancies under approved indications, an 
association between ibrutinib and invasive aspergillosis could not be established at this time. 
 
5.3.12 Febrile Neutropenia / Infections  
Infections (including sepsis, bacterial, viral, or fungal infections) were observed in subjects treated 
with ibrutinib therapy. Some of these infections have been associated with hospitalization and death. 
Consider prophylaxis according to standard of care in subjects who are at increased risk for 
opportunistic infections. Although causality has not been established, cases of progressive 
multifocal leukoencephalopathy and hepatitis B reactivation have occurred in subjects treated with 
ibrutinib. Subjects should be monitored for signs and symptoms (fever, chills, weakness, confusion, 
vomiting and jaundice) and appropriate therapy should be instituted as indicated. 
 
5.3.13 Hypertension 
Hypertension has been commonly reported in subjects treated with ibrutinib. Monitor subjects for new 
onset of hypertension or hypertension that is not adequately controlled after starting ibrutinib. Adjust 
existing anti-hypertensive medications and/or initiate anti-hypertensive treatment as appropriate. 
 


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5.3.14 Overdose 
There is no specific experience in the management of ibrutinib overdose in patients. No maximum 
tolerated dose (MTD) was reached in the Phase 1 study in which subjects received up to 12.5 
mg/kg/day (1400 mg/day). Healthy subjects were exposed up to single dose of 1680 mg. One healthy 
subject experienced reversible Grade 4 hepatic enzyme increases (AST and ALT) after a dose of 
1680 mg. Subjects who ingested more than the recommended dosage should be closely monitored 
and given appropriate supportive treatment. 
 
6.0 DOSE DELAYS, MODIFICATIONS AND MANAGEMENT OF TOXICITY 
Adverse events that are clearly attributable to one medication (eg. atrial fibrillation due to ibrutinib or 
hypophysitis due to nivolumab) may be managed by dose interruption, reduction or permanent 
cessation of the offending medication, depending on the severity of the adverse event (see specific 
information for each drug, below). Provided the patient is clinically stable, in the opinion of the 
investigator, the other medication(s) may be continued per protocol. Where a severe adverse event 
occurs that is thought to be therapy-related, but it is unclear which of the study medications is 
responsible (eg. abnormal liver function tests), all study drugs should be held until severity has 
reduced to grade ≤1. If a severe adverse event occurs that leads to permanent cessation of either 
nivolumab or blinatumomab, but the patient continues to derive benefit from receiving the remaining 
study medications, the patient may remain on study. However, if both nivolumab and blinatumomab 
are ceased due to AEs, the patient will come off study. Ibrutinib discontinuation for AEs will not 
mandate that the patient be removed from the study 
 
If a decision is made to permanently discontinue a study medication due to an adverse event, this 
must be discussed with the PI or designee. 
 
6.1 Blinatumomab Infusion interruption/dose modification due to adverse events 
Dose modifications (interruptions, withholdings, and criteria for restarting treatment) are summarized 
in table 2. 
 
Table 
2. 
Dose 
interruptions, 
modifications 
and 
criteria 
for 
discontinuation 
and 
recommencement of therapy 


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Toxicity 
Grade 
Action 
Cytokine 
Release 
Syndrome 
(CRS) 
+/- 
DIC/coagulopathy 
Grade 
2 
Continue blinatumomab. Give IV fluid bolus (500-1000mL 
normal saline); repeat as necessary to keep systolic BP 
>90mmHg. If systolic BP ≤90mmHg after 2L IV normal 
saline, withhold blinatumomab and consider ICU transfer and 
inotropic support. Manage blinatumomab re-commencement 
as per grade 3 AE, below. 
Grade 
3 
Withhold blinatumomab until resolved to < or = grade 1, then 
restart blinatumomab at the next lowest dose* after 
dexamethasone pre-medication (see table 1). Re-escalate to 
the next highest dose level after 7 days and to the highest 
dose level after a further 7 days if toxicity does not recur. 
Grade 
4 
Discontinue blinatumomab permanently. 
Neurological Toxicity 
Seizure Discontinue blinatumomab permanently if more than one 
seizure occurs. 
 
Grade 
3* 
Withhold blinatumomab for at least 3 days and until no more 
than Grade 1 (mild) and, then restart blinatumomab at the 
next 
lowest 
dose 
level†, 
after 
dexamethasone 
pre-
medication. Re-escalate to the next highest level after 7 days 
and to the highest dose level after a further 7 days if the 
toxicity does not recur. If the toxicity occurred at 9 mcg/day, 
or if the toxicity takes more than 7 days to resolve, 
discontinue blinatumomab permanently. 
 
Grade 
4 
Discontinue blinatumomab permanently. 
Other 
Clinically 
Relevant 
Adverse Reactions at least 
possibly 
related 
to 
blinatumomab 
Grade 
3 
Withhold blinatumomab until no more than Grade 1 (mild) 
toxicity, then restart blinatumomab at the next lowest dose 
level†, after dexamethasone pre-medication. Re-escalate to 
the next highest level after 7 days and to the highest dose 
level after a further 7 days if the toxicity does not recur. If the 


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toxicity occurred at 9 mcg/day If the toxicity takes more than 
14 days to resolve, discontinue blinatumomab permanently. 
 
Grade 
4 
Discontinue blinatumomab permanently. 
Unrelated AEs 
All 
grades 
If blinatumomab was interrupted due to an AE that was 
ultimately deemed by the investigator to be unrelated to 
blinatumomab (eg. Infection resulting in febrile neutropenia), 
blinatumomab can be resumed at the same dose as prior to 
dose interruption, when the patient is deemed by the 
investigator to be clinically stable. Pre-medication with 
dexamethasone as per Table 1 should be given prior-to and 
after recommencement of blinatumomab. 
 
* NB. Grade 3 neurotoxicity due to >1 generalized seizure will mandate permanent cessation of 
blinatumomab. †The next lowest dose is 28mcg/day if the toxicity occurred at 112mcg/day or 
9mcg/day if the toxicity occurred at 28mcg/day. If the toxicity occurred at 9mcg/day, re-challenge after 
resolution to grade 1 or less may be attempted after appropriate pre-medication. Dose modifications 
other than those described in the table may be made, if deemed, after discussion with the PI, to be in 
the patient’s best interests. 
 
Common Terminology Criteria for Adverse Events (CTCAE) clinical grade 4 adverse events (AEs) 
that are characteristic of blinatumomab (i.e. CNS events and cytokine release syndrome (CRS), 
described in more detail below), will require permanent discontinuation of blinatumomab. For all other 
grade 4 AEs, the Principal Investigator or designee should be notified; an assessment should be 
made to determine causality and the risk:benefit for each individual patient to continue or discontinue 
blinatumomab treatment. CTCAE version 5.0 will be used for grading of AEs, with the exception of 
CRS (graded according to appendix C) and neurotoxicity (graded according to appendix E). Please 
see Appendix F for the CTCAE grading of common organ-associated AEs.  
 
6.1.1 Infusion interruption/dose modification due to CNS events 
Please see Appendix E for the grading of CNS-related AEs. In case of CNS-related AEs, 
dexamethasone should be administered at a dose of at least 24 mg/day. The dexamethasone dose 


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will then be reduced step-wise over approximately 4 days. The following investigations should be 
performed: 
 
If the CNS-related adverse event is CTCAE grade 3 or higher, blinatumomab will be stopped 
immediately and a physical exam, vital signs and safety laboratory tests will be performed. Additional 
measures can be taken at the discretion of the investigator, depending on the nature of the adverse 
event. The following diagnostic investigations are recommended: 
 
1. A non-contrast CT scan of the head to exclude CNS hemorrhage. 
2. Assessment of cerebrospinal fluid should be performed for cytology, cell count, B- and T-cell 
measurement (by flow cytometry), and viral studies (HSV 1/2, HSV6, JC virus and adenovirus).  
3. Additional investigations of the CSF should be performed as clinically appropriate. 
4. A contrast-enhanced magnetic resonance imaging (MRI) of the head should be performed for 
subjects who had to interrupt treatment because of a CNS event grade 3, before treatment is 
resumed.  
Please note that there may be circumstances in which some of the above investigations will not be 
able to be performed (for example, CSF assessment may not be possible in patients with low 
platelet counts or abnormal coagulation parameters, for safety reasons, and MRI may not be 
possible if patients are unable to lie still for the duration required to perform this examination). 
Therefore, not performing these tests will not be considered protocol deviations. 
 
For subjects who experience a CTCAE grade 3 CNS adverse event or serious adverse event leading 
to treatment interruption, if the event has decreased to at least CTCAE grade 1 within 1 week, 
treatment may be restarted within 2 weeks, but not earlier than 72 hours (3 days) after the infusion 
was stopped. When recommenced, treatment will begin at the next lowest dose.  
 
However, a grade 3 CNS event leading to treatment interruption at the dose of 9 μg/day or a CNS 
event needing more than 1 week to resolve to grade less than or equal to 1 will result in permanent 
treatment discontinuation. 
 


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In case of CNS-related events CTCAE grade 4, or in case of occurrence of more than one 
generalized seizure (considered grade 3 CNS toxicity), the infusion of blinatumomab will be stopped 
immediately and treatment will be permanently discontinued.  
 
For patients in whom the criteria for recommencement of blinatumomab, as described above, are 
met, blinatumomab can be recommenced, following dexamethasone premedication as described in 
Table 1, at the next lowest dose. Blinatumomab will be escalated to the next highest dose after 7 
days, if the toxicity does not recur. The subject should remain hospitalized until at least 2 days after 
re-escalation to the dose at which the toxicity first occurred.  
 
If the CNS event was a generalized seizure (CTCAE grade 2 or above), appropriate prophylactic 
anticonvulsant treatment will be administered prior to recommencing therapy. 
 
6.1.2 Dose interruption and modification for cytokine release syndrome (CRS) and/or 
DIC/coagulopathy 
For CTCAE grade 2 CRS which requires inotropes, grade 3 CRS and CTCAE grade 3 
DIC/coagulopathy, blinatumomab can then be restarted at the next lowest dose (see table 2), once 
the event has returned to grade ≤1 severity. If the event occurred at a dose of 9 mcg/day and no 
neurological toxicity of greater than or equal to grade 3 occurred, treatment with blinatumomab will be 
interrupted until the event resolves to less than or equal to grade 1 and then resumed at 9 mcg/d, 
after dexamethasone pre-medication as described in Table 1. However, if the AE lasts for ≥2 weeks, 
then blinatumomab will be permanently discontinued.  
 
In CRS of ≥grade 2, dexamethasone should be administered orally or IV at an initial dose of at least 3 
x 8 mg/day. The dose can then be reduced step-wise over approximately 4 days according to clinical 
response.  
 
6.1.3 Dose interruption and modification for all other events 
For all other CTCAE grade 3 events and clinically significant laboratory value changes, investigator 
assessment should be used to determine causation. If considered to be at least possibly related to 
blinatumomab, the blinatumomab must be interrupted. Blinatumomab can be recommenced after 
resolution of the AE to grade 1 or less, after dexamethasone pre-medication as described in Table 1. 


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6.1.4 Resumption of dosing and dose escalation after dose interruption 
Patients who have had their dose interrupted, who meet the safety criteria outlined above, will have 
an option to resume dosing, once the event has resolved to grade ≤1, after the time periods outlined 
for the specific AEs above and in table 2. Please note that, in the event of grade 3 neurological 
toxicity, the blinatumomab must not be resumed for at least 72 hours after interruption, in addition to 
waiting for the event to resolve to grade ≤1. After all other reasons for interruption, blinatumomab may 
be resumed when the toxicity has resolved to grade ≤1. 
 
Pre-medication will be given with 20mg of PO/IV dexamethasone 12-24 hours prior and 20mg 
dexamethasone 1 hour prior to recommencement of the infusion, as per table 1.  
 
Dosing should be resumed at the next lowest dose level (i.e. 9 μg/day if the AE occurred at 28 μg/day 
or 28 μg/day if the AE occurred at 112 μg/day). After 7 days of dosing, provided the patient is 
clinically stable, dose escalation may resume per protocol, with appropriate dexamethasone pre-
medication (as outlined in table 1). Alternatively, treatment may be continued at the reduced dose 
after discussion with the principal investigator, if it is felt that the risks of further dose escalation 
outweigh the benefits. Re-start of the infusion and all subsequent dose escalations should be 
performed in the hospital.  
 
The patient should be observed in hospital for the remainder of the dose re-escalation period and for 
3 days after reaching the highest dose that will be administered in that cycle.   
 
The total duration of blinatumomab in cycle 1 and 2 should total 28 days If dose interruptions occur, 
the missed days should be added to the end of the cycle. The total number of days of blinatumomab 
administration will not exceed 28 days, even if dose reductions occurred. An infusion interruption of 
more than 2 weeks due to an adverse event related to blinatumomab will lead to permanent 
discontinuation of treatment. In case of logistical difficulties, restart of treatment can be postponed for 
up to 7 additional days without resulting in permanent treatment discontinuation. Treatment may be 
also interrupted or permanently discontinued at the discretion of the investigator if any 
clinical/laboratory adverse event is considered to be medically relevant. 
 


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If there is recurrence of grade ≥3 toxicity, determined as at least possibly related to blinatumomab, 
after reinstitution of blinatumomab, blinatumomab will be permanently discontinued. 
 
For the sake of clarity, if blinatumomab is interrupted and subsequently recommenced, the days when 
blinatumomab was not given will not be counted as treatment days. e.g. If treatment was interrupted 
on day 7 for 3 days and then recommenced, the day that blinatumomab was recommenced will be 
numbered as day 8, not day 11. 
 
Nivolumab (in the absence of nivolumab-related adverse events requiring treatment interruption) will 
always be given on day 1 and day 15 of blinatumomab treatment. For this reason, if there are delays 
in blinatumomab administration due to adverse events, there will be an identical delay in 
administration of the next nivolumab dose. This is important both for reasons of clarity and also 
because nivolumab could potentiate blinatumomab-related adverse events. 
 
6.2 Recommendations for management of nivolumab-associated toxicity. 
Please see appendix K. 
 
6.3 - management of ibrutinib-associated toxicity and dose modifications  
Section 6.3 outlines recommendations for management of ibrutinib-associated toxicity. However, dose 
adjustments outside these guidelines can be made by the investigator if considered to be in the 
patient’s best interests. 
 
6.3.1 Recommended dose modifications: 
Recommended dose modifications of ibrutinib are described below: 
 
 
 
6.3.2 Hematologic toxicity: 
Interrupt ibrutinib for any Grade 3 or greater neutropenia with infection or fever, or Grade 4 
hematological toxicities. Once the toxicity has resolved to Grade ≤1 or baseline, reinitiate ibrutinib as 
Toxicity Occurrence 
Dose modification 
Starting Dose = 420 mg daily 
First 
Restart at 420 mg daily 
Second 
Restart at 280 mg daily 
Third 
Restart at 140 mg daily 
Fourth 
Discontinue ibrutinib 


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per the table above. 
 
6.3.3 Non-hematologic toxicity:  
Interrupt treatment for any grade 3 or greater non-hematological toxicity. Once the toxicity has 
resolved to grade ≤1 or baseline, restart the study drugs as per the guidelines for the hematologic 
toxicity as above. 
 
If the dose of ibrutinib is reduced, at the investigator’s discretion, the dose of ibrutinib may be re-
escalated after 2 cycles of a dose reduction if the toxicity that led to the reduction has resolved to 
Grade ≤1 or baseline. Dose changes will be recorded in the medical record.  
 
6.3.4 Leukocytosis/Leukostasis: 
A high number of circulating malignant cells (>400000/mcL) may confer increased risk of leukostasis; 
these subjects should be closely monitored. Administer supportive care such as hydration and/or 
leukophoresis as indicated. Ibrutinib may be temporarily held, and investigator should be contacted. 
 
6.3.5 Dose Modification for Hepatic Impaired Subjects 
Ibrutinib is metabolized in the liver and therefore subjects with clinically significant hepatic impairment 
at the time of screening (Child- Pugh class B or C) are excluded from study participation. For patients 
with mild liver impairment (Child-Pugh class A), recommended dose is 140mg per day. See Appendix 
L for Child-Pugh grading system. 
 
6.3.6 Dose Modification of Ibrutinib in patients receiving CYP3A4 enzyme inhibitors and 
inducers: 
Co-administration with strong or moderate CYP3A inhibitors should be avoided, where possible and 
alternative agents with less CYP3A inhibition considered. 
 
Concomitant use of strong CYP3A inhibitors which would be taken chronically (e.g., ritonavir, 
indinavir, nelfinavir, saquinavir, boceprevir, telaprevir, nefazodone) is not recommended. For short-
term use (treatment for 7 days or less) of strong CYP3A inhibitors (e.g., antifungals and antibiotics) 
consider interrupting ibrutinib therapy until the CYP3A inhibitor is no longer needed. 
 


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Reduce ibrutinib dose to 140 mg if a moderate CYP3A inhibitor must be used (e.g., fluconazole, 
darunavir, erythromycin, diltiazem, atazanavir, aprepitant, amprenavir, fosamprevir, crizotinib, 
imatinib, verapamil, and ciprofloxacin). 
  
Patients taking concomitant strong or moderate CYP3A inhibitors should be monitored more closely 
for signs of ibrutinib toxicity. 
 
Use of strong CYP3A4 enzyme inducers (eg. rifampicin) should be avoided. 
 
7.0 CONCOMITANT THERAPY 
7.1 Allowed concomitant therapy 
Patients should receive full supportive care during study participation, including hematopoietic growth 
factors, transfusion of blood products, fluid and electrolyte replacement, and antibiotics when 
appropriate. 
 
7.2 Excluded concomitant therapy 
Use of the following therapies is prohibited during the study: 
• 
Cytotoxic chemotherapy 
• 
Immunotherapy (outside of this study) 
• 
Radiotherapy (Note: Localized radiotherapy to an area not compromising bone marrow function 
is allowed), provided this is being performed for treatment of another malignancy. If radiotherapy 
is performed for progressive Richter Transformation, the patient should be removed from the 
study. 
• 
Any therapies intended for the treatment of lymphoma/leukemia whether FDA-approved or 
experimental (outside of this study) 
• 
Steroid therapy for anti-neoplastic intent, after initiation of blinatumomab. Inhaled steroids for 
asthma, topical steroids, steroids as part of premedication for blinatumomab or management of 
blinatumomab toxicity, or replacement/stress corticosteroids are permitted. 
 
7.3 Recommended anti-infective prophylaxis 


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• 
Pneumocystis pneumonia prophylaxis with co-trimoxazole 160/800mg twice daily on Mondays, 
Wednesdays and Fridays. Patients with hypersensitivity to co-trimoxazole may receive alternative 
prophylaxis, per investigator discretion. 
• 
Varicella Zoster prophylaxis with valacyclovir 500mg daily, or equivalent. 
• 
Anti-fungal prophylaxis may be given, per investigator discretion. 
 
7.4 Tumor lysis syndrome prophylaxis 
• 
All patients will receive allopurinol 300mg per day for the first 16 days of cycle 1, unless 
contraindicated. If the patient has a contraindication to allopurinol, a suitable alternative will be 
chosen. 
• 
Rasburicase may be given in high risk patients, per institutional guidelines.


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8.0 PRE-TREATMENT EVALUATION 
Pre-treatment evaluation is outlined in table 3. 
Table 3. Pre-treatment evaluation 
Pre-treatment evaluation is outlined in table 3, below. Further explanation for the specific tests 
ordered is provided in table 4, contained within section 9. 
 
Procedure 
Schedule 
Informed consent 
Within 30 days of therapy 
Medical history 
Within 14 days of therapy 
Complete physical examination including vital signs 
Within 14 days of therapy 
Complete neurologic exam 
Within 14 days of therapy 
Document concomitant medications 
Within 14 days of therapy 
Hematology 
Within 14 days of therapy 
Biochemistry 
Within 14 days of therapy 
Bone marrow aspirate and biopsy 
Within 60 days of therapy 
CLL prognostic marker evaluation on bone marrow (FISH, using    
probes for ATM (11q22.3), D12Z3 (12cen), D13S319 (13q14.3), 
LAMP1 (13q34), p53 (17p13.1); stimulated metaphase cytogenetics; 
next generation sequencing (NGS) panel for CLL-associated 
mutations, including TP53 (see below for details); IGHV mutational 
status and VH utilization (this does not need to be repeated if 
previously performed at M.D. Anderson); flow cytometry, including 
CD38. Please note tests can be done on peripheral blood if a bone 
marrow sample is not available. Additionally, some patients with 
Richter Transformation may not have sufficient CLL cells in bone 
marrow or blood to perform this testing. Not performing these tests 
will therefore not be considered as deviations. 
Within 60 days of therapy 
PETCT scan. If PETCT cannot be done for logistic reasons, CT scan 
of the neck, chest, abdomen and pelvis will be performed instead. 
Within 28 days of therapy 
Lymph node biopsy (or pathology review of recent biopsy material). If 
a lymph node biopsy consistent with Richter Transformation was 
performed outside this window and PETCT shows changes consistent 
with Richter Transformation, biopsy does not need to be repeated. 
Pathology review for out-of-window biopsies does not need to be 
performed if the diagnosis was made originally at M.D. Anderson.  
Within 28 days of therapy 
Prognostic marker evaluation on lymph node biopsy material. Where 
possible, this will include CLL FISH panel or array cGH, unstimulated 
and stimulated metaphase cytogenetics, IGHV mutational status and 
VH utilization and NGS panel  
 
Pregnancy test 
Within 7 days of therapy 
Immunologic evaluation, if patient consents to correlative studies 
Within 14 days of therapy 


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Tissue banking 
Within 28 days of therapy 
 
 
9.0 EVALUATION DURING TREATMENT 
Table 4: evaluation which will take place pre-treatment and during the study 
 
1Baseline/screening testing. This must be performed within the timeframes outlined in table 3. 
2Surveillance. Patients will have routine history and physical examination, CBC, routine biochemistry 
approximately every 12 weeks and a PETCT scan or CT scan with and without IV contrast 
approximately every 24 weeks (+/- 4 weeks) after completing ibrutinib + nivolumab consolidation, until 
2 years after initiation of therapy, until relapse,allogeneic stem cell transplantation, or initiation of 
salvage therapy, whichever occurs first. Patients who have not proceeded to allogeneic 
Assessment 
Base-
line(1) Cycle 1 
Response 
assess 
Cycle 2 
Response 
assess 
Ibrutinib 
+ 
nivolumab 
consolidation 
(q4w for 36 
weeks 
from 
2nd response 
assessment 
Survei-
llance 
(2) 
At 
progress-
sion/ 
End-of-
study 
Day 
within 
cycle(3) 
-28 to 
1 
1 
15-
31 
36 
43 
57 (+/- 1 
week) 
1-3 
8 
15 
22 
29 
43 
57 (+/- 1 
week) 
 
 
 
Informed 
consent(4) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical 
history(5) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
q12w 
X 
Physical 
examination(6) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
q12w 
X 
Neurological 
examination(7) 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
 
 
 
 
Concomitant 
medications(8) 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
q12w 
X 
CBC 
with 
differential(9) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
q12w 
X 
Bio-
chemistry(10) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
q12w 
X 
Thyroid 
function(11) 
X 
q4
w 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bone 
marrow(12) 
X 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
X 
PETCT 
scan(13) 
X 
 
 
 
 
X 
 
 
 
 
 
 
X 
q12 weeks 
q24w 
X 
Lymph 
node 
biopsy(14) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Pregnancy 
test(15) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
NGS 
panel(16) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Immunologic 
evaluation(17) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Tissue 
banking(18) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
ctDNA(19) 
X 
 
 
 
 
X 
 
 
 
 
 
 
X 
At 
completion of 
nivolumab 
 
X 
Saliva (20) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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transplantation and who remain in remission at the end of the study, and those who proceed to 
transplant, will be enrolled on a departmental umbrella protocol (DR09-0223) to follow them for 
overall survival. 
 
3Evaluations during the inpatient stay (planned for day 15-31) must take place on the scheduled day. 
Please note that many patients will have treatment delays, as a result of toxicity. This is expected. 
After hospital discharge, evaluations during cycle 1 occur weekly and can occur within +/- 4 days of 
the scheduled time. Response assessment must take place between 2 and 4 weeks after the 
completion of cycle 1 of therapy. Cycle 2 should commence 4-8 weeks after completion of cycle 1. 
Evaluation during cycle 2 days 1-3 (given as an inpatient) should occur on the scheduled day. 
Subsequent evaluations during cycle 2 can occur within +/- 4 days of the scheduled time. Subsequent 
response assessment must take place between 2 and 4 weeks after the completion of cycle 2 of 
therapy. Please note that response assessments should take place on day 57 of cycle 1 and cycle 2 
(+/- 1 week). Cycle 2 will not commence, until after completion of the first response assessment. 
 
4Informed consent. All patients must take part in the informed consent process. During the consent 
process, the person obtaining consent must inform the patient of all elements of informed consent. 
Adequate time must be allowed for questions and for the patient to make a voluntary decision. No 
protocol-specific procedures are to be performed until the patient has signed and dated an 
Institutional Review Board (IRB)/Ethics Committee (EC)-approved informed consent form. Each 
patient's participation in the trial begins with the signing and dating of the informed consent form. 
 
5Medical history. Medical and surgical history and demographic information will be recorded at 
baseline. Medical and surgical history includes diagnoses, therapies, and medical and surgical 
treatments. Particular attention should be paid to any pre-existing neurological symptoms. At 
subsequent assessments, focused history/AE assessment will be performed. 
 
6Physical examination, including vital signs. Vital signs are temperature, pulse, respiratory rate, and 
blood pressure. A complete physical examination, including measurement of weight, must be 
performed at screening; at Cycle 1, Day 1 prior to the first administration of study drug and at the end-
of-treatment Visit. Height need only be recorded at the initial visit. Following the physical examination 
for Cycle 1, Day 1 — with the exception of the end-of-treatment Visit, where a full physical 


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examination must also be performed — all subsequent physical examinations, can be focused to the 
individual needs of the individual patient. 
 
7A neurological examination must be performed during the screening period. Neurological 
examination at the screening assessment should include examination of the peripheral nervous 
system, cranial nerves and cognitive function. The latter must be determined using The M.D. 
Anderson simplified 10 point neurologic examination. Subsequent to the screening exam, the 
neurological assessment can be tailored, according to the patient’s symptoms. Whenever there is a 
change in neurological status suggestive of blinatumomab-related neurotoxicity, the M.D. Anderson 
10 point neurological examination score will be documented, to assist toxicity grading (see Appendix 
E and G).  
 
8Concomitant medications. These will be captured in the medical record. 
 
9Complete blood count with differential.  
 
10Biochemistry. At screening, at a minimum this should include the following: sodium, potassium, 
chloride, bicarbonate (or total carbon dioxide [CO2]), blood urea nitrogen (BUN, or urea), random 
glucose, albumin, creatinine, total bilirubin (direct and indirect), ALT +/- AST, alkaline phosphatase,  
phosphorous, calcium, uric acid and LDH. At subsequent timepoints, this should include, at a 
minimum, creatinine, potassium and ALT. On the day of and for two days after dose initiation or dose 
escalation, uric acid, calcium and phosphorous should be measured at least daily. 
 
11Thyroid function (at least TSH and T4) is required at baseline and approximately every 4 weeks 
during the study to monitor for nivolumab-induced hypothyroidism, until the completion of nivolumab 
therapy. 
 
12Bone marrow examination Bone marrow aspiration and trephine biopsy will be performed pre-
treatment for cytological and histological assessment during the screening period. The following 
additional studies will be performed on the pre-treatment bone marrow and on bone marrow 
evaluation performed at disease progression: CLL prognostic marker evaluation on bone marrow (or 
blood if bone marrow not available):  FISH, using  probes for ATM (11q22.3), D12Z3 (12cen), 
D13S319 (13q14.3), LAMP1 (13q34), p53 (17p13.1); stimulated metaphase cytogenetics; next 


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generation sequencing (NGS) panel for CLL-associated mutations, including TP53 (see below for 
details); IGHV mutational status and VH utilization (this does not need to be repeated if previously 
performed at M.D. Anderson); flow cytometry. Some patients with Richter Transformation may not 
have sufficient CLL cells in bone marrow or blood to perform this testing. Not performing the CLL 
prognostic factor evaluations outlined above will therefore not be considered as protocol deviations, 
Bone marrow evaluation for response assessment will include aspirate and biopsy for cytological and 
histological assessment and a standard 4-color flow cytometry panel for evaluation of minimal 
residual disease (MRD) in the co-existing CLL.  
 
1318-FDG PETCT scan, from the head to mid-thigh, will be performed during the screening period, for 
response assessment, during surveillance and at disease progression. Target lesions will be 
evaluated by a trained radiologist: bi-directional lymph node measurements will be performed and 
quantitation of 18-FDG uptake in target lesions, using standardized uptake values (SUV). If PETCT 
cannot be done for any reason, CT will be performed instead. If CT scan was done for initial staging 
purposes rather than PETCT, CT scan will also be performed for restaging and surveillance. 
 
14Lymph node biopsy may be performed. This is at treating physician discretion. The site for biopsy 
will be chosen according to the PETCT. The target lymph node for biopsy should have a maximal 
diameter of ≥1.5cm and a SUV of at least 5. An SUV of ≥10 is preferred for the biopsy. The 
investigator, in consultation with the proceduralist, who will perform the biopsy, will determine the 
optimal lymph node for biopsy. A surgical excisional biopsy is preferred, but if not feasible for 
technical or logistic reasons, a core biopsy, performed in interventional radiology, will be performed 
instead. If a diagnosis of RT has already been made from lymph node or bone marrow biopsy, 
patients need not have a repeat biopsy – however, the pathology will be reviewed at MD Anderson for 
diagnostic accuracy prior to the patient being considered eligible for the study. Patients will be asked 
for consent to store lymph node tissue for research purposes, on a separate protocol, prior to a 
diagnostic biopsy being performed. Lymph node biopsy will be performed during the pre-treatment 
screening period and at relapse. 
 
15Pregnancy test. The pregnancy test must be a beta-human chorionic gonadotropin (β-HCG) test, 
using either urine or serum. Women who are not of childbearing potential (status post-hysterectomy, 
status post-bilateral oophorectomy, or postmenopausal [defined as amenorrhea for at least 12 


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months]) do not need to have the test performed. If the test is deemed necessary, it must be 
performed within 7 days of treatment initiation and known to be negative prior to treatment initiation. 
Women of childbearing potential at study commencement must also complete the pregnancy test at 
the End-of-Treatment Visit. 
 
16A targeted next generation sequencing panel will be performed to identify important driver mutations 
in CLL and RT.  The panel will be performed during the pre-treatment screening period and at 
relapse. 
 
17Exploratory immunologic investigation will be performed. This will be optional and patients 
consented separately on protocol PA16-0360. 
 
18Patients will be asked to have tumor tissue stored in a sample bank for later exploratory genomic 
analyses, on a separate IRB protocol (PA15-0965). This is optional and a separate informed consent 
process will be undertaken for these studies. These will be performed on the diagnostic specimen 
and relapse specimen. 
 
19Blood samples will be taken pre-treatment, at each response assessment, at 1 year, 2 years and at 
disease progression for plasma and cell banking. These samples will be used to perform serial NGS 
(including potentially NGS and WGS), to identify gene mutations and copy number alterations in 
ctDNA and circulating mononuclear cells, if the patient agrees to participate in protocol PA16-0919. 
 
20Saliva collection will be done at baseline if the patient is participating in protocol PA16-0919. 
 
10.0 CRITERIA FOR RESPONSE 
10.1 Richter’s Transformation 
Response assessment in RT will be performed according to the Lugano criteria for diffuse large B-cell 
lymphoma, as outlined in Appendix H. 
 
10.2 Response Criteria in Chronic Lymphocytic Leukemia 
The response of the co-existing CLL will be assessed according to the 2018 IWCLL criteria, which are 
re-produced in appendix I Overall response is defined as a CR or PR. Patients with missing or no 
response assessment will be classified as non-responders. The full criteria are re-produced below. 
The co-existence of RT may result in difficulty determining whether residual nodal, splenic or hepatic 
enlargement is due to persistent RT or CLL. For the purposes of response assessment, PET criteria 


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will be used to distinguish the two. However, if diagnostic difficulty exists, biopsy may be required.  
 
11.0 ADVERSE EVENT REPORTING 
Toxicities will be graded according to the NCI Expanded Common Toxicity Criteria.21 
 
11.1 Leukemia-specific Adverse Event Recording and Reporting Guidelines 
These guidelines serve to bring the Department of Leukemia in compliance with the institutional 
policy on Reporting of Serious Adverse Events.  
 
An adverse event is any untoward medical occurrence that may present during treatment with a 
pharmaceutical product but which does not necessarily have a causal relationship with this treatment. 
An adverse drug reaction is a response to a drug which is noxious and unintended and which occurs 
at doses normally used in man for prophylaxis, diagnosis, or therapy of disease or for the modification 
of physiologic function.  
 
Assessing causal connections between agents and disease is fundamental to the understanding of 
adverse drug reactions. In general, a drug may be considered a contributory cause of an adverse 
event if, had the drug not been administered, 1) the event would not have happened at all, 2) the 
event would have occurred later than it actually did, or 3) the event would have been less severe. 
The Investigator or physician designee is responsible for verifying and providing source 
documentation for all adverse events and assigning the attribution for each event for all patients 
enrolled on the trial. 
 
11.1.1 Electronic case report (eCRF) 
PDMS/CORe will be used as the electronic case report form for this protocol. Adverse events 
will be documented in the medical record and entered into PDMS/CORe. 
 
11.1.2 Guidelines for recording and reporting of adverse and serious adverse events 
These guidelines will be followed for the recording and reporting of adverse (AEs) and serious 
adverse events (SAEs). 
1. Baseline events will be recorded in the medical history section of the case report form and will 
include the terminology event name, grade, and start date of the event.  The medical history 


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section of the case report form will serve as the source document for baseline events once 
signed and dated by the principal investigator. 
a. Baseline events are any medical condition, symptom, or clinically significant lab 
abnormality present before initiation of treatment: 
i. Hematologic laboratory abnormalities will not be recorded as baseline events for 
patients with acute leukemia, myelodysplastic syndrome, chronic lymphocytic 
leukemia, or chronic myeloid leukemia in blast phase. 
ii. If exact start date is unknown, month and year or year may be used as the start date of 
the baseline event. 
2. The maximum grade of the adverse event will be captured per course or protocol defined visit 
date. 
3. These adverse events will be recorded in the case report form: 
a. 
Any grade adverse event that is possibly, probably, or definitely related to the 
study drug(s). 
b. 
All serious adverse events regardless of attribution to the study drug(s). 
c. 
Any grade adverse event regardless of attribution to the study drug(s) that results 
in any dose modification. 
a. Hematologic adverse events will be recorded and reported according to IWCLL 
guidelines, as outlined in Appendix J.  
4. Serious adverse events will be reported according to institutional policy. 
5. Protocol specific language regarding the recording and reporting of adverse and serious 
adverse events will be followed in the event of discordance between the protocol and 
Leukemia-specific adverse event recording and reporting guidelines. 
 
11.1.3 Abnormal hematologic and chemical values 
Abnormal hematologic and chemical values, the apogee or nadir (whichever is appropriate) will be 
reported per course on the case report form. 
 
11.1.4 Attribution of AEs 
All events will be collected for the purpose of 
grading, and determining attribution to study drugs by the PI using the following scale: 
 


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• Unrelated: The AE is clearly NOT related to the intervention. 
• Unlikely: The AE is doubtfully related to the intervention. 
• Possible: The AE may be related to the intervention. 
• Probable: The AE is likely related to the intervention. 
• Definite: The AE is clearly related to the intervention. 
 
11.1.5 Documentation of grade 3 and greater non-hematologic adverse events 
All grade 3 and greater non-hematological events that are felt to be related to protocol treatment 
drugs will be documented on the toxicity log and entered into the case report form. The toxicity log 
and case report form data must reflect the relationship to the drug the event is felt to be related to. 
 
11.1.6 Serious Adverse Event Reporting (SAE) 
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; this is defined as any adverse experience that 
places the patient, in 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. 
 
11.1.7 Serious adverse reaction (SAR) 
An SAE where a causal relationship between a medicinal product and the SAE is at least a 
reasonable possibility, i.e., the relationship cannot be ruled out. 
 
11.1.8 Suspected Unexpected Serious Adverse Reaction (SUSAR) 
An SAR, the nature or severity of which is not consistent with the applicable product information i.e. 
Investigator’s Brochure for an unauthorized medicinal product or summary of product characteristics 
for an authorized product). 
 


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11.2 "Serious Adverse Event Reporting (SAE) for M. D. Anderson-Sponsored IND Protocols" 
• 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. 
• 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 100 days after the last dose of drug, 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 100 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. 
 
11.3 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.  
 
Important medical events that may not result in death, be life-threatening, or require hospitalization 
may be considered a serious adverse drug experience when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject and may require medical or surgical intervention 
to prevent one of the outcomes listed in this definition. 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). Pregnancy, drug overdose, and secondary malignancy 
will be handled as SAE. 
• 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 IND 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 


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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). 
 
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. 
 
11.4 Investigator Communication with Amgen 
• Suspected unexpected serious adverse reactions (SUSARs). When PI/Research staff receives 
a SUSAR, it shall transmit the final report of that event to Amgen within twenty four (24) 
hours of submitting that report to the applicable regulatory authority.   
• Any pregnancy occurring during the study must be reported to Amgen within 10 days. 
• SAEs will be reported to Amgen as a cumulative report, every 6 months. 
• All adverse events recorded during the study will be forwarded to Amgen at the completion of 
the study for reconciliation. However, expedited reporting is not required for AEs not classified 
as serious. 
• Investigational pharmacy will communicate with Amgen regarding how expired on unused drug 
will be handled. 
 
All SAEs and SUSARs should be reported via confirmed facsimile (fax) transmission, or scanned and 
reported via electronic mail to:  
Fax:  
888-814-8653 (toll-free, US) 
805-480-9205 (toll) OR 
E-mail: 
svc-ags-in-us@amgen.com.  
 
11.5 Investigator Communication with BMS 
 
• All Serious Adverse Events (SAEs) that occur following the subject’s written consent to 
participate in the study through 100 days of discontinuation of dosing must be reported to BMS 


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Worldwide Safety, whether related or not related to study drug. If applicable, SAEs must be 
collected that relate to any later protocol-specified procedure (eg, a follow-up skin biopsy). 
• Following the subject’s written consent to participate in the study, all SAEs, whether related or 
not related to study drug, are collected, including those thought to be associated with protocol-
specified procedures. The investigator should report any SAE occurring after these 
aforementioned time periods, which is believed to be related to study drug or protocol-specified 
procedure. 
• An SAE report should be completed for any event where doubt exists regarding its seriousness;  
• If the investigator believes that an SAE is not related to study drug, but is potentially related to 
the conditions of the study (such as withdrawal of previous therapy or a complication of a study 
procedure), the relationship should be specified in the narrative section of the SAE Report Form. 
• Institutional eSAE form will be used to submit SAE data to BMS. Note:  Please include the BMS 
Protocol number on the SAE form or on the  cover sheet with the SAE form transmission.   
• The Sponsor will reconcile the clinical database AE cases (case level only) transmitted to BMS 
Global Pharmacovigilance (Worldwide.Safety@bms.com).  
▪ The Investigator will request from BMS GPV&E, aepbusinessprocess@bms.com 
the SAE reconciliation report and include the BMS protocol number every 3 
months and prior to data base lock or final data summary 
▪ GPV&E will send the investigator the report to verify and confirm all SAEs have 
been transmitted to BMS GPV&E. 
▪ The data elements listed on the GPV&E reconciliation report will be used for 
case identification purposes. If the Investigator determines a case was not 
transmitted to BMS GPV&E, the case should be sent immediately to BMS 
(Worldwide.Safety@bms.com). 
• In addition to the Sponsor Investigator’s responsibility to report events to their local HA, 
suspected serious adverse reactions (whether expected or unexpected) shall be reported by 
BMS to the relevant competent health authorities in all concerned countries according to local 
regulations (either as expedited and/or in aggregate reports). 
• In accordance with local regulations, BMS will notify sponsor investigators of all reported SAEs 
that are suspected (related to the investigational product) and unexpected (ie, not previously 
described in the IB). An event meeting these criteria is termed a Suspected, Unexpected Serious 


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Adverse Reaction (SUSAR). Sponsor investigator notification of these events will be in the form 
of either a SUSAR Report or a Semi-Annual SUSAR Report.  
✓ Other important findings which may be reported by BMS as an Expedited Safety Report 
(ESR) include: increased frequency of a clinically significant expected SAE, an SAE 
considered associated with study procedures that could modify the conduct of the study, 
lack of efficacy that poses significant hazard to study subjects, clinically significant safety 
finding from a nonclinical (eg, animal) study, important safety recommendations from a 
study data monitoring committee, or sponsor or BMS decision to end or temporarily halt a 
clinical study for safety reasons. 
✓ Upon receiving an ESR from BMS, the investigator must review and retain the ESR with the 
IB. Where required by local regulations or when there is a central IRB/IEC for the study, the 
sponsor will submit the ESR to the appropriate IRB/IEC. The investigator and IRB/IEC will 
determine if the informed consent requires revision. The investigator should also comply 
with the IRB/IEC procedures for reporting any other safety information.  
 
SAEs, whether related or not related to study drug, and pregnancies must be reported to BMS within 
24 hours \ 1 Business Day of becoming aware of the event. SAEs must be recorded on either 
CIOMS, MedWatch, or approved site SAE form.   
 
Pregnancies must be reported and submitted to BMS.  BMS will perform due diligence follow-up 
using the BMS Pregnancy Form which the investigator must complete.  
 
SAE Email Address:  Worldwide.Safety@BMS.com 
 
SAE Facsimile Number:  +1 609-818-3804 
If only limited information is initially available, follow-up reports are required. (Note: Follow-up SAE 
reports should include the same investigator term(s) initially reported.)  
 
If an ongoing SAE changes in its intensity or relationship to study drug or if new information becomes 
available, a follow-up SAE report should be sent within 24 hours \ 1 Business Day to BMS using the 
same procedure used for transmitting the initial SAE report.  
 


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All SAEs should be followed to resolution or stabilization. 
 
The causal relationship to study drug is determined by a physician and should be used to assess all 
adverse events (AE). The casual relationship can be one of the following: 
Related: There is a reasonable causal relationship between study drug administration and the AE. 
Not related: There is not a reasonable causal relationship between study drug administration and the 
AE.  
 
The term "reasonable causal relationship" means there is evidence to suggest a causal relationship.  
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a subject. (In order to prevent reporting bias, subjects should not be 
questioned regarding the specific occurrence of one or more AEs.) 
 
NONSERIOUS ADVERSE EVENT 
• Non-serious Adverse Events (AE) are to be provided to BMS in aggregate via interim or final 
study reports as specified in the agreement or, if a regulatory requirement [eg, IND US trial] as 
part of an annual reporting requirement.  
• Non-serious AE information should also be collected from following the subject’s written 
consent to participate in the study.  
 
Non-serious Adverse Event Collection and Reporting 
The collection of non-serious AE information should begin following the subject’s written consent to 
participate in the study. All non-serious adverse events (not only those deemed to be treatment-
related) should be collected continuously during the treatment period and for a minimum of 100 days 
following the last dose of study treatment.  
 
Non-serious AEs should be followed to resolution or stabilization, or reported as SAEs if they become 
serious. Follow-up is also required for non-serious AEs that cause interruption or discontinuation of 
study drug and for those present at the end of study treatment as appropriate.  


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Laboratory Test Abnormalities 
All laboratory test results captured as part of the study should be recorded following institutional 
procedures. Test results that constitute SAEs should be documented and reported to BMS as such. 
The following laboratory abnormalities should be documented and reported appropriately: 
• 
any laboratory test result that is clinically significant or meets the definition of an SAE 
• 
any laboratory abnormality that required the participant to have study drug discontinued or 
interrupted 
• 
any laboratory abnormality that required the subject to receive specific corrective therapy.  
 
It is expected that wherever possible, the clinical rather than laboratory term would be used by the 
reporting investigator (eg, anemia versus low hemoglobin value). 
 
12.0 CRITERIA FOR REMOVAL FROM STUDY. 
Criteria for removal from study include, but are not restricted to, the following: 
• Clinically significant progressive disease. 
• Recurrent non-compliance by the patient with protocol requirements. 
• Patient's request to be removed from the study. 
• Investigator’s decision that a subject does not benefit from treatment anymore, e.g., non-
response or development of progressive disease 
• Transition to an alternative therapy, including allogeneic stem cell transplantation. 
• Permanent cessation of nivolumab and blinatumomab: if a patient permanently discontinues 
either nivolumab or blinatumomab (but not both) due to adverse events, they may remain on 
study, if they continue to derive treatment benefit and benefit outweighs risk, in the opinion of 
the investigator. Patients who permanently discontinue both nivolumab and blinatumomab due 
to adverse events will be removed from the study. 
• Permanent discontinuation of ibrutinib for any reason will not be an indication to remove a 
patient from study, if, in the opinion of the investigator, the patient is deriving benefit from 
treatment and it is safe to continue the other agent(s). 
 


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13.0 CORRELATIVE STUDIES  
All correlative studies are optional and failure to collect these studies at any of the specified time-
points is not a protocol deviation. Patients will consent separately to having these studies taken. 
 
13.1 Immunologic analyses 
The purpose of these analyses is to determine pre-treatment immunologic parameters predictive of 
response to blinatumomab treatment and to evaluate treatment-induced immunologic changes within 
the blood and tumor tissue during treatment and their correlation with response: 
 
13.1.1 Studies on tumor tissue 
Patients will have surgical excisional biopsy or interventional radiology-guided core biopsies 
performed at baseline if required for diagnostic purposes. If patients consent to a separate IRB-
approved protocol (PA15-0965), excess tumor tissue will be cryopreserved and used for exploratory 
immunohistochemical characterization of tumor infiltrating lymphocyte (TIL) populations, including 
expression of immune checkpoint molecules (PD1 and PDL1). In addition, tissue will be 
cryopreserved for later genomic investigation (see section 13.2, below) 
 
13.1.2 Studies on peripheral blood T-cell population 
In addition, if patients consent, circulating T-cell numbers and function will be analyzed at the 
following time points: i) baseline; ii) 24-48 hours after initiation of cycle 1; iii) 1 week after initiation of 
cycle 1; iv) 4 weeks after initiation of cycle 1; v) prior to initiation of cycle 5; vi) at the completion of 
cycle 2. This comprehensive analysis will include both phenotypic and functional characterization of 
T-cells, as well as the expression levels of immune checkpoint molecules. We hypothesize that T-cell 
numbers and function will be predictive of response to blinatumomab and that up-regulation of PD1 
on T-cells will be a potential resistance mechanism. This testing will be performed on protocol PA16-
0360. 
 
13.2 Tumor banking. 
Patient tumor tissue, DNA, RNA and plasma will be stored pre-treatment and at relapse on a 
separate IRB-approved research protocols (PA15-0965). This will be optional and patients will sign 
separate consent forms for this. At a later date, this tissue may be used in genomic and proteomic 
studies to determine drivers of disease biology and resistance mechanisms to therapy. 


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13.3 Evaluation of plasma circulating tumor DNA (ctDNA) 
If patients consent, peripheral blood samples will be collected, processed and banked at baseline, 1st 
and 2nd response assessments, 12 and 24 months and at the time of relapse. We will bank saliva 
from patients at baseline; sequencing from saliva will serve as a normal control. In patients where 
there is a clinical need to perform a lymph node biopsy for diagnostic purposes (eg. suspicion of 
Richter Transformation), we will use leftover tissue for sequencing. Targeted next-generation 
sequencing will be performed on ctDNA and compared to bone marrow, peripheral blood 
mononuclear cells and lymph node tissue, where available. At disease progression, we will perform 
whole exome and low coverage whole genome sequencing, where appropriate, from the cellular 
component of peripheral blood, plasma and/or bone marrow at baseline and relapse and from nodal 
tissue where available, to identify mutations and copy number alterations which have emerged during 
therapy and may be responsible for resistance. This testing will be performed at Peter MacCallum 
Cancer Centre in Melbourne, Australia. If new, somatic mutations are identified at progression, 
targeted deep sequencing and/or digital PCR testing for these mutations will be performed from 
stored, serial plasma samples to identify and quantitate their presence in plasma over time. This 
testing will be performed on protocol PA16-0919 as an optional procedure. 
 
14.0. STATISTICAL CONSIDERATIONS 
The cohort of 9 patients already treated demonstrates the feasibility and safety of blinatumomab as a 
single agent for the treatment of RT. The overall toxicity profile of blinatumomab in RT was very 
favorable and this cohort of patients can be used as a “safety cohort,” prior to proceeding with a 
phase II study evaluating the combination with ibrutinib + nivolumab. As discussed above, the 
combination of ibrutinib and nivolumab was also very well tolerated. 
 
We have completed a phase II study of ibrutinib + nivolumab, and achieved an ORR of 43%. This will 
serve as our “base case” estimation of the response rate that we would see with the combination of 
ibrutinib + nivolumab. If blinatumomab (ORR 1/8 = 12.5%) provides additive benefit only, this will 
result in an ORR of 50-55% with the combination of ibrutinib + nivolumab and blinatumomab. 
However, we expect synergy between the two regimens. We have therefore designed our statistical 
analysis around achieving an ORR of approximately 60%, which would suggest some synergy 


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between the two regimens. Higher response rates would suggest a greater degree of synergy 
between blinatumomab and ibrutinib + nivolumab, which we hope to achieve. 
 
We propose to enroll an additional 21 patients, with the goal of evaluating the efficacy and safety of 
the proposed combination therapy. A sample size of 21 patients ensures that, if the trial is not 
terminated early, a posterior 90% credibility interval for overall response rate will have width of 0.33, 
under the assumption of a 60% of overall response rate (13/21 responses) and beta prior as 
described below. Under this scenario, the lower boundary of the 90% credibility interval matches the 
43% ORR that was seen with ibrutinib + nivolumab therapy. 
 
The primary outcome will be overall response (ORR), assessed after completion of 2 courses of 
blinatumomab. 
 
We will utilize a Bayesian trial design to enable simultaneous monitoring of efficacy and toxicity using 
the approach of Thall, Simon, and Estey (1995, 1996). After an initial 6 patient safety cohort, 
subsequent patients will be enrolled in cohorts of size 3. 
 
The existing trial of blinatumomab as a single agent assumes that a toxicity rate greater than 31% 
would be excessive. Since we propose combining blinatumomab with two additional agents, we aim 
to achieve a higher ORR, and allow for acceptable toxicity no higher than 40%. For the purposes of 
toxicity monitoring, toxicity will be defined as follows: grade 4-5 neurotoxicity or CRS; grade 3 
neurotoxicity or CRS that fails to resolve within 1 week or recurs at grade ≥3 severity on re-challenge; 
grade 3-5 therapy-related immune-related toxicity at least possibly related to nivolumab.  
 
For the Bayesian design, the following parameter settings will be used: 
• For the standard treatment response and toxicity rates, constant rates of 0.4 are assumed. 
• For the response and toxicity rates under the proposed treatment, a beta(0.8, 1.2) prior is 
assumed for each rate, which has the same mean as the rates under the standard treatment, and 
an effective sample size of 2. 
• The maximum number of patients if no early stopping is applied will be 21, and a minimum of 6 
patients will be treated before stopping. 
• The planned cohort size is 3. 


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• The trial will be stopped early based on response if the posterior probability that the response rate 
of the experimental treatment is less than the current standard rate is greater than 0.9. 
• The trial will be stopped early based on toxicity if the posterior probability that the toxicity rate of 
the experimental treatment is greater than the current standard rate is greater than 0.8. 
• Toxicity will be monitored continuously for the first year of treatment. 
 
Response Stopping Boundaries 
# Patients (in complete cohorts of 3) (inclusive) Stop the trial if there are this many responses total: 
# Responses (inclusive) 
3 
Never stop with this many patients 
6  
0  
9 
0-1 
12 
0-2 
15 
0-3 
18 
0-4 
21 
Always stop with this many patients 
 
 Stopping boundaries for toxicity 
# Patients (in complete cohorts of 3) (inclusive) 
Stop the trial if there are this many toxicities total: 
# Toxicities (inclusive) 
3 
Never stop with this many patients 
6 
4-6 
9 
5-9 
12 
7-12 
15 
8-15 
18 
10-18 
21 
Always stop with this many patients 
 


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Summary of operating characteristics 
The operating characteristics are summarized in the table below.  The probabilities of stopping the 
trial early are exact calculations from MultcLean Desktop under the assumption that response is 
independent of toxicity. 
 
True Toxicity 
Rate 
True OR Rate 
Prob(stop the trial early) 
Avg # patients enrolled 
(25th – 75th percentile) 
0.2 
0.6 
0.04 
20.5 (21 – 21) 
 
0.5 
0.07 
20.1 (21 – 21) 
 
0.4 
0.19 
19.0 (21 – 21) 
 
0.3 
0.45 
16.4 (12 – 21) 
0.3 
0.6 
0.14 
19.2 (21 – 21) 
 
0.5 
0.17 
18.8 (21 – 21) 
 
0.4 
0.28 
17.8 (15 – 21) 
 
0.3 
0.51 
15.5 (9 – 21) 
0.4 
0.6 
0.36 
16.4 (9 – 21) 
 
0.5 
0.39 
16.2 (9 – 21) 
 
0.4 
0.46 
15.4 (9 – 21) 
 
0.3 
0.63 
13.6 (6 – 21) 
0.5 
0.6 
0.64 
12.9 (6 – 21) 
 
0.5 
0.66 
12.7 (6 – 15) 
 
0.4 
0.70 
12.2 (6 – 21) 
 
0.3 
0.79 
11.1 (6 – 15) 
 
Analysis Plan 
Summary statistics will be provided for continuous variables.  Frequency tables will be used to 
summarize categorical variables.  Logistic regression will be utilized to assess the effect of patient 
prognostic factors on the response rate and the toxicity rate.  The distribution of time-to-event 
endpoints will be estimated using the method of Kaplan and Meier. Cox proportional hazard 
regression will be employed for multivariate analysis on time-to-event outcomes. 


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An Efficacy/Safety Summary will be submitted to the IND Office Medical Monitor, after the first 6 
evaluable patients complete 8 weeks of study treatment, and every 3 evaluable patients thereafter. 
Toxicity information of previously submitted patients will be updated during every submission. 
 
Trial Conduct 
Conducting a trial designed by this method does not require software since the stopping conditions 
have been tabulated before the trial begins. 
 
15.0 REFERENCES 
1. 
Bockorny B, Codreanu I, Dasanu CA. Hodgkin lymphoma as Richter transformation in chronic 
lymphocytic leukaemia: a retrospective analysis of world literature. Br J Haematol. 
2012;156(1):50-66. 
2. 
Parikh SA, Rabe KG, Call TG, et al. Diffuse large B-cell lymphoma (Richter syndrome) in 
patients with chronic lymphocytic leukaemia (CLL): a cohort study of newly diagnosed patients. 
Br J Haematol. 2013;162(6):774-782. 
3. 
Parikh SA, Kay NE, Shanafelt TD. How we treat Richter syndrome2014. 
4. 
Maddocks KJ, Ruppert AS, Lozanski G, et al. Etiology of Ibrutinib Therapy Discontinuation and 
Outcomes in Patients With Chronic Lymphocytic Leukemia. JAMA Oncol. 2015;1(1):80-87. 
5. 
Roberts AW, Davids MS, Pagel JM, et al. Targeting BCL2 with Venetoclax in Relapsed 
Chronic Lymphocytic Leukemia. N Engl J Med. 2016;374(4):311-322. 
6. 
Tsimberidou AM, O'Brien S, Khouri I, et al. Clinical outcomes and prognostic factors in patients 
with Richter's syndrome treated with chemotherapy or chemoimmunotherapy with or without 
stem-cell transplantation. J Clin Oncol. 2006;24(15):2343-2351. 
7. 
Rossi D, Spina V, Deambrogi C, et al. The genetics of Richter syndrome reveals disease 
heterogeneity and predicts survival after transformation. Blood. 2011;117(12):3391-3401. 
8. 
Tsimberidou AM, Kantarjian HM, Cortes J, et al. Fractionated cyclophosphamide, vincristine, 
liposomal daunorubicin, and dexamethasone plus rituximab and granulocyte-macrophage-
colony stimulating factor (GM-CSF) alternating with methotrexate and cytarabine plus 
rituximab and GM-CSF in patients with Richter syndrome or fludarabine-refractory chronic 
lymphocytic leukemia. Cancer. 2003;97(7):1711-1720. 
9. 
Tsimberidou AM, O'Brien SM, Cortes JE, et al. Phase II study of fludarabine, cytarabine (Ara-
C), cyclophosphamide, cisplatin and GM-CSF (FACPGM) in patients with Richter's syndrome 
or refractory lymphoproliferative disorders. Leukemia & lymphoma. 2002;43(4):767-772. 
10. 
Tsimberidou AM, Wierda WG, Plunkett W, et al. Phase I-II study of oxaliplatin, fludarabine, 
cytarabine, and rituximab combination therapy in patients with Richter's syndrome or 
fludarabine-refractory chronic lymphocytic leukemia. J Clin Oncol. 2008;26(2):196-203. 
11. 
Tsimberidou AM, Wierda WG, Wen S, et al. Phase I-II clinical trial of oxaliplatin, fludarabine, 
cytarabine, and rituximab therapy in aggressive relapsed/refractory chronic lymphocytic 
leukemia or Richter syndrome. Clinical lymphoma, myeloma & leukemia. 2013;13(5):568-574. 
12. 
Dabaja BS, O'Brien SM, Kantarjian HM, et al. Fractionated cyclophosphamide, vincristine, 
liposomal daunorubicin (daunoXome), and dexamethasone (hyperCVXD) regimen in Richter's 
syndrome. Leukemia & lymphoma. 2001;42(3):329-337. 


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13. 
Loffler A, Kufer P, Lutterbuse R, et al. A recombinant bispecific single-chain antibody, CD19 x 
CD3, induces rapid and high lymphoma-directed cytotoxicity by unstimulated T lymphocytes. 
Blood. 2000;95(6):2098-2103. 
14. 
Wolf E, Hofmeister R, Kufer P, Schlereth B, Baeuerle PA. BiTEs: bispecific antibody constructs 
with unique anti-tumor activity. Drug Discov Today. 2005;10(18):1237-1244. 
15. 
Dreier T, Lorenczewski G, Brandl C, et al. Extremely potent, rapid and costimulation-
independent cytotoxic T-cell response against lymphoma cells catalyzed by a single-chain 
bispecific antibody. Int J Cancer. 2002;100(6):690-697. 
16. 
Topp MS, Goekbuget N, Stein AS, et al. Confirmatory open-label, single-arm, multicenter 
phase 2 study of the BiTE antibody blinatumomab in patients (pts) with relapsed/refractory B-
precursor 
acute 
lymphoblastic 
leukemia 
(r/r 
ALL). 
ASCO 
Meeting 
Abstracts. 
2014;32(15_suppl):7005. 
17. 
Viardot A, Goebeler M-E, Hess G, et al. Phase 2 study of bispecific T-cell engager (BiTE®) 
antibody blinatumomab in relapsed/refractory diffuse large B cell lymphoma. Blood. 2016. 
18. 
Viardot A, Goebeler M, Hess G, et al. Treatment of Relapsed/Refractory Diffuse Large B-Cell 
Lymphoma with the Bispecific T-Cell Engager (BiTE®) Antibody Construct Blinatumomab: 
Primary Analysis Results from an Open-Label, Phase 2 Study. Blood. 2014;124(21):4460-
4460. 
19. 
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;32(27):3059-3068. 
20. 
Hallek M, Cheson BD, Catovsky D, et al. Guidelines for the diagnosis and treatment of chronic 
lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic 
Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood. 
2008;111(12):5446-5456. 
21. 
Institute NC. Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03. Vol 
2016: U.S. Department of Health and Human Services; 2010. 
22. 
Thall PF, Simon RM, Estey EH. Bayesian sequential monitoring designs for single-arm clinical 
trials with multiple outcomes. Stat Med. 1995;14(4):357-379. 
23. 
Thall PF, Simon RM, Estey EH. New statistical strategy for monitoring safety and efficacy in 
single-arm clinical trials. J Clin Oncol. 1996;14(1):296-303. 
24. 
Thall PF, Sung HG. Some extensions and applications of a Bayesian strategy for monitoring 
multiple outcomes in clinical trials. Stat Med. 1998;17(14):1563-1580. 
 


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 Appendix C. Grading of Cytokine Release Syndrome (CRS) 
CRS 
Parameter 
 
CRS grade 1 
CRS grade 2 
CRS grade 3 
CRS Grade 4 
Fever   
Temperature 
>/= 38oC 
Temperature 
>/= 38oC 
Temperature 
>/= 38oC 
Temperature 
>/= 38oC 
 
Hypotension 
None 
Not 
requiring 
vasopressors 
Requiring 
a 
vasopressor 
with or without 
vasopressin 
Requiring 
multiple 
vasopressors 
(excluding 
vasopressin 
 
 
 
 
 
and/or† 
 
Hypoxia 
None 
Requiring low-
flow 
nasal 
cannula‡ 
or 
blow-by 
 
Requiring 
high-flow 
nasal cannula, 
facemask, 
nonrebreather 
mask, 
or 
Venturi mask 
 Requiring 
positive 
pressure (eg. 
CPAP, BiPAP, 
intubation and 
mechanical 
ventilation) 
Fever is defined as temperature ≥38°C not attributable to any other cause. In patients who have 
CRS then receive antipyretic or anticytokine therapy such as tocilizumab or steroids, fever is no 
longer required to grade subsequent CRS severity. In this case, CRS grading is driven by 
hypotension and/or hypoxia. 
† CRS grade is determined by the more severe event: hypotension or hypoxia not attributable to any 
other cause. For example, a patient with temperature of 39.5°C, hypotension requiring 1 vasopressor, 
and hypoxia requiring low-flow nasal cannula is classified as grade 3 CRS. 
‡ Low-flow nasal cannula is defined as oxygen delivered at ≤6L/minute. Low flow also includes blow-
by oxygen delivery, sometimes used in pediatrics. High-flow nasal cannula is defined as oxygen 
delivered at >6L/minute 
 


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Appendix D: Definition of high-dose vasopressors 
Vasopressor 
Definition of high-dose vasopressor 
Norepinephrine monotherapy 
Greater than or equal to 20 mcg/minute 
Dopamine monotherapy 
Greater than or equal to 10 mcg/kg/minute 
Phenylephrine monotherapy 
Greater than or equal to 200 mcg/minute 
Epinephrine monotherapy 
Greater than or equal to 10 mcg/minute 
Vasopressin 
Vasopressin + norepinephrine equivalent of greater than or equal 
to 10mcg/minute 
Combination 
vasopressors 
(not including vasopressin) 
Norepinephrine equivalent of greater than or equal to 20 
mcg/minute 
5VASST Trial vasopressor equivalent equation: norepinephrine equivalent dose = [norepinephrine 
(mcg/minute)] + [dopamine (mcg/kg/minute)/2] + [epinephrine (mcg/minute)] + [phenylephrine 
(mcg/minute)/10]. 


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Appendix E: ASTCT INCANS Consensus Grading for Adults 
Neurotoxicity 
Domain 
Grade 1 
Grade 2  
Grade 3 
Grade 4 
ICE score
 
7-9 
3-6 
0-2 
0 (patient is unarousable 
and unable to perform 
ICE) 
Depressed level 
of 
consciousness† 
Awakens 
spontaneously 
Awakens 
to voice 
Awakens only to tactile 
stimulus 
Patient is unarousable or 
requires 
vigorous 
or 
repetitive tactile stimuli to 
arouse. Stupor or coma. 
Seizure 
N/A 
N/A 
Any 
clinical 
seizure, 
focal or generalized, that 
resolves rapidly or non-
convulsive seizures on 
EEG that resolve with 
intervention 
Life -threatening prolonged 
seizure 
(>5 
min); 
or 
repetitive 
clinical 
or 
electrical seizures without 
return 
to 
baseline 
in 
between 
Motor findings‡ 
N/A 
N/A 
N/A 
Deep 
focal 
motor 
weakness 
such 
as 
hemiparesis 
or 
paraparesis 
Elevated 
ICP/cerebral 
edema 
N/A 
N/A 
Focal/local edema on 
neuroimaging§ 
Diffuse cerebral edema 
on 
neuroimaging; 
decerebrate 
or 
decorticate posturing; or 
cranial nerve VI palsy; or 
papilledema; 
or 
Cushing’s triad 
ICANS grade is determined by the most severe event (ICE score, level of consciousness, seizure, 
motor findings, raised ICP/cerebral edema) not attributable to any other cause; for example, a patient 
with an ICE score of 3 who has a generalized seizure is classified as grade 3 ICANS. 
N/A indicates not applicable. 
A patient with an ICE score of 0 may be classified as grade 3 ICANS if awake with global aphasia, 
but a patient with an ICE score of 0 may be classified as grade 4 ICANS if unarousable. 
† Depressed level of consciousness should be attributable to no other cause (eg, no sedating 
medication). 


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‡ Tremors and myoclonus associated with immune effector cell therapies may be graded according to 
CTCAE v5.0, but they do not influence ICANS grading. 
§ Intracranial hemorrhage with or without associated edema is not considered a neurotoxicity feature 
and is excluded from ICANS grading. It may be graded according to CTCAE v5.0. 
 
 
Appendix F. CTCAE v5.0 grading of common adverse events 
Category 
Adverse event 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Cardiac 
Sinus 
tachycardia 
Asymptomatic, no 
intervention 
needed 
Symptomatic, non-
urgent intervention 
indicated 
Urgent intervention 
indicated 
 
 
Arrhythmia or 
heart block 
Asymptomatic, no 
intervention 
needed 
Symptomatic, non-
urgent intervention 
indicated 
Urgent intervention 
indicated 
Life threatening 
consequences 
 
Ejection 
fraction  
 
EF 40-50% or 10-
19% drop from 
baseline 
EF 20-39% or 
>/=20% drop from 
baseline 
EF <20% 
Respiratory 
Pleural 
effusion 
Asymptomatic, no 
intervention 
needed 
Symptomatic, 
intervention 
indicated (diuretics 
or thoracentesis) 
Symptomatic with 
respiratory distress; 
needs surgical 
intervention (chest 
tube or pleurodesis) 
Life-threatning 
respiratory or 
hemodynamic 
compromise; 
intubation or 
urgent 
intervention 
indicated 
 
Pulmonary 
edema 
Radiologic 
findings only; 
Minimal dyspnea 
on exertion 
Moderate dyspnea 
on exertion; 
medical 
intervention 
indicated; limits 
instrumental ADL 
Severe dyspnea or 
Dyspnea at rest; 
oxygen indicated; 
limits self-care ADL 
Life-threatening 
urgent intervention 
or intubation with 
ventilatory support 
indicated 
Gastro-
intestinal 
Nausea 
Loss of appetite 
without alteration 
in eating habits 
Oral intake 
decreased without 
significant 
dehydration, 
malnutrition or 
weight loss 
Inadequate oral 
caloric or fluid intake; 
receiving tube 
feeding,  TPN or 
hospitalization 
indicated 
 
 
Vomiting 
Intervention not 
indicated 
Outpatient IV 
hydration; 
medical 
intervention 
indicated 
tube feeding,TPN or 
hospitalization 
indicated 
Life-threatening 
 
Diarrhea 
Increase of 1-3 
stools/day over 
baseline; mild 
increase in 
ostomy output 
compared to 
baseline 
Increase of 4-6 
stools/day over 
baseline; 
moderate 
increase in 
ostomy output 
compared to 
baseline; limiting 
instrumental ADL 
Increase of  >6 
stools/day over 
baseline; 
hospitalization 
indicated; severe 
increase in ostomy 
output compared to 
baseline; limits self-
care ADL 
Life-threatening 
consequentes; 
urgent 
intervention 
indicated 
Hepatic 
AST or ALT 
>ULN to 3xULN if 
>3xULN to 5x ULN 
>5xULN to 20xULN if 
>20xULN if 


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increased 
baseline was 
normal; 1.5 – 
3.0 x baseline if 
baseline was 
abnormal 
if baseline was 
normal; >3.0-5.0 
x baseline if 
baseline was 
abnormal 
baseline was 
normal; >5.0-20.0 x 
baseline if baseline 
was abnormal 
baseline was 
normal; >20.0 x 
baseline if 
baseline was 
abnormal 
 
Total bilirubin 
increased 
>ULN to 1.5xULN 
if baseline was 
normal; >1.0-1.5 
x baseline if 
baseline was 
abnormal 
>1.5xULN to 
3xULN if baseline 
was normal; 
>1.5-3.0 x  
baseline if 
baseline was 
abnormal 
>3xULN to 10xULN if 
baseline was 
normal; >3.0 – 10.0 
x baseline if 
baseline was 
abnormal  
>10xULN if 
baseline was 
normal; >10.0 x 
baseline if 
baseline was 
abnormal 
Renal 
Urine output 
decreased 
 
 
Oliguria (<80mL/8 
hours) 
Anuria (<240mL/24 
hours) 
 
Acute kidney 
injury 
= 
 
Hospitalization 
indicated 
Life-threatening; 
dialysis indicated 
 
Creatinine 
increased  
>ULN – 1.5 x 
ULN 
>1.5 – 3.0 x 
baseline; >1.5 – 
3.0 x ULN 
>3.0 x baseline; 
>3.0-6.0 x ULN 
>6.0 x ULN 
Coagulopathy 
Disseminated 
intravascular 
coagulation 
(DIC) 
 
Laboratory findings 
with no bleeding 
Laboratory findings 
with bleeding 
Life-threatening; 
urgent intervention 
indicated 
 
 
 
 
 
 
 
Appendix G. Simplified 10-point neurologic examination 
• Orientation to year, month, city, hospital,: 4 points. 
• Ability to write a standard sentence (eg. The national bird is the bald eagle): 1 point. 
• Name 3 objects (eg. clock, pen, button): 3 points. 
• Count backwards from 100 by 10s: 1 point. 
• Can the patient follow commands? 1 point for yes. 


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Appendix H. Lugano Response Criteria for Malignant Lymphoma 
 
 


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Appendix I – response criteria in CLL. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix J – Grading of hematologic toxicity in CLL trials. 
 


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Appendix K – Management Algorithms. 
 
 
 
 
These general guidelines constitute guidance to the Investigator and may be supplemented by 
discussions with the Medical Monitor representing the Sponsor. The guidance applies to all immuno-
oncology agents and regimens.  
 
A general principle is that differential diagnoses should be diligently evaluated according to standard 
medical practice. Non-inflammatory etiologies should be considered and appropriately treated.  
 
Corticosteroids are a primary therapy for immuno-oncology drug-related adverse events. The oral 
equivalent of the recommended IV doses may be considered for ambulatory patients with low-grade 
toxicity. The lower bioavailability of oral corticosteroids should be taken into account when switching 
to the equivalent dose of oral corticosteroids.  
 
Consultation with a medical or surgical specialist, especially prior to an invasive diagnostic or 
therapeutic procedure, is recommended.  
 
The frequency and severity of the related adverse events covered by these algorithms will depend on 
the immuno-oncology agent or regimen being used. 
 
 


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Appendix L. Child-Pugh Grading System for Cirrhosis.