Conditions: AIDS-Related Burkitt Lymphoma Atypical Burkitt/Burkitt-Like Lymphoma High Grade B-Cell Lymphoma With MYC and BCL2 or BCL6 Rearrangements High Grade B-Cell Lymphoma With MYC, BCL2, and BCL6 Rearrangements Recurrent Acute Lymphoblastic Leukemia Recurrent Burkitt Lymphoma Refractory Acute Lymphoblastic Leukemia Refractory Burkitt Lymphoma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 14
Healthy volunteers: no

Brief summary:
This phase II trial studies how well a dose adjusted regimen consisting of etoposide, prednisone, vincristine sulfate, cyclophosphamide, and doxorubicin hydrochloride (EPOCH) works in combination with ofatumumab or rituximab in treating patients with Burkitt lymphoma that is newly diagnosed, or has returned after a period of improvement (relapsed), or has not responded to previous treatment (refractory) or relapsed or refractory acute lymphoblastic leukemia. Drugs used in chemotherapy, such as etoposide, prednisone, vincristine sulfate, cyclophosphamide, and doxorubicin hydrochloride, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Monoclonal antibodies, such as ofatumumab and rituximab, may interfere with the ability of cancer cells to grow and spread. Giving more than one drug (combination chemotherapy) together with monoclonal antibody therapy may kill more cancer cells.

Detailed description:
PRIMARY OBJECTIVE:

I. To evaluate the clinical efficacy of the combination of dose adjusted (DA)-EPOCH + ofatumumab in patients with newly diagnosed or relapsed/refractory Burkitt leukemia or relapsed/refractory acute lymphoblastic leukemia (ALL) defined by complete response rate.

SECONDARY OBJECTIVE:

I. To evaluate the safety of this combination, the overall survival and event-free survival rates.

OUTLINE:

Patients receive DA-EPOCH regimen comprising doxorubicin hydrochloride intravenously (IV), vincristine sulfate IV, and etoposide IV continuously over 96 hours on days 1-4; cyclophosphamide IV over 1-2 hours on day 5; and prednisone orally (PO) twice daily (BID) on days 1-5. Patients also receive ofatumumab IV over 2 hours on days 1, 2, and 11 of cycle 1; on days 1 and 8 of cycles 2 and 4; and on days 1 and 11 of cycle 3 for a total of 9 injections. Patients may receive rituximab instead of ofatumumab if their insurance provider does not cover the cost of ofatumumab. Patients receive rituximab IV over 2 hours on days 1 and 11 of cycles 1 and 3 and on days 2 and 8 of cycles 2 and 4. Treatment repeats every 21-28 days for up to 8 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 2-4 months for 1 year and then every 4-8 months for 2 years.

Arms:
arm 1: Patients receive DA-EPOCH regimen comprising doxorubicin hydrochloride IV, vincristine sulfate IV, and etoposide IV continuously over 96 hours on days 1-4; cyclophosphamide IV over 1-2 hours on day 5; and prednisone PO BID on days 1-5. Patients also receive ofatumumab IV over 2 hours on days 1, 2, and 11 of cycle 1; on days 1 and 8 of cycles 2 and 4; and on days 1 and 11 of cycle 3 for a total of 9 injections. Patients may receive rituximab instead of ofatumumab if their insurance provider does not cover the cost of ofatumumab. Patients receive rituximab IV over 2 hours on days 1 and 11 of cycles 1 and 3 and on days 2 and 8 of cycles 2 and 4. Treatment repeats every 21-28 days for up to 8 cycles in the absence of disease progression or unacceptable toxicity.

Interventions: intervention 1: Cyclophosphamide intervention 2: Doxorubicin Hydrochloride intervention 3: Etoposide intervention 4: Ofatumumab intervention 5: Prednisone intervention 6: Rituximab intervention 7: Vincristine Sulfate
Intervention descriptions: intervention 1: Given IV intervention 2: Given IV intervention 3: Given IV intervention 4: Given IV intervention 5: Given PO intervention 6: Given IV intervention 7: Given IV

Protocol document:
Prot_SAP_000.pdf: 
2014-0123 
August 14, 2019 
 
Phase II Study of the Dose Adjusted EPOCH Regimen in 
Combination with Ofatumumab/Rituximab as Therapy for 
Patients with Newly Diagnosed or Relapsed/refractory Burkitt 
Leukemia or Relapsed/refractory Acute Lymphoblastic 
Leukemia 
 
1.0 
Objectives 
 
1.1 Primary Objective: To evaluate the clinical efficacy of the combination of DA-
EPOCH + ofatumumab in patients with newly diagnosed or relapsed/refractory Burkitt 
leukemia or relapsed/refractory ALL defined by complete response rate 
 
1.2 Secondary Objective: To evaluate the safety of this combination, the overall survival 
and event-free survival rates.  
 
2.0 Background 
 
2.1 Burkitt Leukemia 
 
Historically, adult patients with mature B-ALL had a very poor prognosis [1-5]. With 
conventional induction chemotherapy (vincristine and steroids), the complete response 
(CR) was about 60%. In addition, one-third of the patients presented with central 
nervous system (CNS) leukemia or most of them developed CNS leukemia during the 
course of the disease if they did not succumb earlier to their leukemia.  With the 
previous intensive regimens used for ALL (2-3 years of intensifications + maintenance) 
the long-term disease free survival was less than 10% to 20%.   
Patients with B-ALL may be divided into 1) Burkitt's L3 ALL or 2) non-Burkitt's B- ALL.  
The latter category is characterized by the presence of mature B cell markers (surface 
or cytoplasmic immunoglobulin [sIg or cIg] positivity) but without the French-American-
British (FAB) L3 morphology or typical Burkitt's karyotype [t(8;14) or the variants t(8;2) 
or t(8;22)]. While the prognosis of Burkitt's leukemia was extremely poor with 
conventional therapy, the patients with non-Burkitt's B-ALL appeared to have a slightly 
better prognosis, and did not seem to require long-term maintenance therapy [1-10].   
Subsequent studies emphasized the use of hyperfractionated cyclophosphamide, high-
dose cytarabine and high-dose methotrexate in the management of B-ALL and Burkitt's 
lymphoma (BL).  The treatments were intensive but only for 6-8 months.  This treatment 
regimen united the treatment of B-ALL and advanced-stage Burkitt’s NHL.  The 
rationale was that B-ALL (L3 sIg positive) in most cases represents an extreme form of 


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stage IV Burkitt’s NHL with marrow replacement, and that the clinical behavior of B-ALL 
and stage IV Burkitt’s NHL are virtually identical in their aggressiveness. 
Despite the advancements made in the treatment ALL most of them will relapse and 
essentially the outcome is very poor. In fact, in patients who relapse the median survival 
is only 5 months. The dose adjusted EPOCH regimen has shown significant activity in 
Burkitt Leukemia and therefore would like to extend the treatment to patients with adult 
ALL with relapse/refractory disease. We believe that this treatment will benefit this 
patient population where there are no minimal options available with a very poor 
outcome. 
2.2 Treatment with Hyper-CVAD and immunotherapy 
 
Murphy et al. designed an intensive, multi-agent chemotherapy program based on the 
concept of delivery of agents in rapid sequence in children with Burkitt's leukemias and 
lymphomas [4]. Because it was recognized that these lymphomas/leukemias have high 
growth fractions and doubling times as short as 25 hours, cyclosphosphamide was 
fractionated in the induction phase in an attempt to encompass the entire generation 
time of the tumor as well as to provide a smoother induction with fewer metabolic 
complications [5]. The Total B regimen consists of cycles of fractionated high-dose 
cyclophosphamide (300mg/m2 q 12 hours for six doses), vincristine, and doxorubicin 
alternating with high dose methotrexate (1g/m2) and escalating doses of ara-C. 
Kantarjian et al modified this program, and developed the regimen of hyper-CVAD 
(hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone 
alternating with high dose methotrexate and ara-C) [11-12]. This regimen has significant 
activity in the treatment of Burkitt's disease, mantle cell lymphoma, multiple myeloma, 
lymphoblastic lymphoma, and aggressive chronic lymphocytic leukemia with or without 
Richter's transformation. Of the 2004 patients with de novo ALL who were treated with 
hyper-CVAD protocol, 91% achieved a complete remission. The median time to achieve 
CR was 21 days with 81% of patients achieving CR after one course of chemotherapy. 
The estimated five-year survival was 39%, and the estimated median survival time was 
35 months. 
The addition of rituximab to the hyper-CVAD program in patients with CD20 expression 
(≥20%) improved outcome compared to historical experience, with 3-year CRD rates 
(68% vs 28%, p<0.001) and OS rates (65% vs 35%, p=0.01) approaching those of the 
CD20 negative counterparts [13]. 
We have recently reviewed the outcome of fifty-one patients with newly diagnosed non-
HIV Burkitt leukemia/lymphoma treated at our institution with R-HCVAD [14]. The 
overall CR rate in 41 evaluable non-HIV patients (10 in CR at start either due to one 
course of prior therapy or resected disease) was 95%; 2 patients achieved partial 


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response. All 11 patients aged 60 years or older achieved CR. One induction death was 
observed in the younger group. CR rate was 64% in the HIV-positive group (5 failures). 
After a median follow-up of 48 months (range, 2-114+ months) in the non-HIV group, 3 
relapses were observed. Nine patients died in CR related to infections (n=3), secondary 
malignancies (n=3), or other causes (n=3). For the non-HIV group, in comparison with 
48 historical patients treated with hyper-CVAD alone, the 4-year rates for OS (77% vs 
50%, p=.03), age <60 years (78% vs 70%, p=NS) and age 60 years or older (75% vs 
19%, p=.002) were superior for hyper-CVAD with rituximab. Over 90% of non-HIV 
patients were beyond 1 year of follow-up without disease recurrence. Toxicity profile 
was similar to hyper-CVAD alone. Three patients developed secondary dyscrasias 
(acute myelogenous leukemia [AML] at 7 years, myelodysplastic syndrome at 3-1/2 
years, AML with t(8;21) at 3 years).  
2.3 DA-EPOCH-R in BL 
 
Based on the hypothesis that DA-EPOCH-R may be effective in BL, given its 
established efficacy in DLBCL and its ability to overcome highly proliferative tumors, 
pilot studies had assessed whether DA-EPOCH-R could maintain the high cure rates of 
standard therapy in BL while minimizing treatment related toxicity in HIV negative 
patients. A total of 30 patients with BL have been treated at the NCI on two protocols 
using EPOCH and rituximab [15] [#93-C-0133 (DA-EPOCH-R in untreated DLBCL and 
BL), #01-C-0030 (DA-EPOCH-RR in untreated ARL)]. Characteristics of all 25 patients 
included median age 30 years (range, 18-66); male sex 20 (80%); median ECOG PS 1 
(range, 1-3); stage III/IV 54%; LDH > N 56%; extranodal sites 79% and ileocecal 
disease 54%. 8/25 (32%) had low-risk disease and 17/25 (68%) had high-risk disease. 
No patients had CNS involvement at diagnosis. All patients achieved a CR/CRu with 
one patient receiving consolidative radiation to a site of residual disease. OS and PFS 
are both 100% and EFS 96% at a median potential follow-up of 28 months. Significant 
toxicities included tumor lysis syndrome (TLS) in only one patient and fever/neutropenia 
in 16% of cycles. There were no treatment related deaths. These pilot results suggested 
that DA-EPOCH-R is effective regimen in newly diagnosed BL and is associated with 
low toxicity and low rates of TLS compared to “standard” high dose regimens used in 
BL. Hence, these results suggest that DA-EPOCH-R may significantly advance the 
therapeutic index in the treatment of BL [15]. 
 
 
2.3 Ofatumumab 
 


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Ofatumumab (HuMax-CD20) is a human monoclonal antibody that targets a unique 
small-loop epitope on CD20 and elicits potent in vitro complement-dependent 
cytotoxicity (CDC), even in malignant B cells with low CD20 expression levels. 
Ofatumumab was found to be more effective than rituximab in promoting lysis of 
opsonized B cells via classical pathway complement CDC. Classical pathway CDC is 
initiated by binding of C1q to aggregated IgG bound to cells. Taylor and colleagues 
have recently reported on the higher capacity of ofatumamab when compared to 
rituximab in promoting CDC [16]. In fact, their results indicated that binding of very small 
amounts of C1q to mAb-opsonized cells, far below the maximal C1q binding capacity of 
the cells, was sufficient to promote CDC. Greater CDC induced by ofatumumab 
compared with rituximab might be due in part to a higher level of binding of C1q to OFA-
opsonized B cells. Also, cell-bound C1q was found to be more closely associated with 
ofatumumab (based on the co-localization studies), likely functioning more effectively to 
activate the classical C pathway and promote CDC.  
 
Ofatumumab has been shown to be safe and active in chronic lymphocytic leukemia 
(CLL). In a phase I/II study, 12 of 26 relapsed patients who had received 4 weekly 
infusions of up to 2,000 mg of ofatumumab responded [17]. Time to progression and 
time to next therapy was 161 and 366 days, respectively. The interim results of a non-
randomized phase III registration trial in patients with CLL who progressed after 
fludarabine and alemtuzumab (DR) or who are refractory to fludarabine and have bulky 
adenopathy (BFR) have been recently reported. The objective response rate ORR was 
51% (34, 68%) for the DR group and 44% (30, 59%) for the BFR group. Median time to 
next CLL therapy was 9 months for the DR group and 8 months for the BFR group. The 
median OS was about 14 months for the DR group and 15 months for the BFR group 
[18]. A phase II study of ofatumumab combined with cyclophosphamide and fludarabine 
in previously untreated patients recently completed accrual. 
 
To date, we have treated 17 patients with de novo ALL and 2 patients in CR previously 
treated with HCVAD-ofatumumab [19]. Median age was 50 years (39–71). Median WBC 
at diagnosis was 5.5 x 109/L (1 -189 x 109/L). CD20 expression above 20% was found 
in 11 patients (58%), between 10 and 20% in 1 (5%) and below 10% in 7 (37%). 2 
patients (11%) had concomitant CNS disease at diagnosis. Among the 15 patients with 
evaluable baseline cytogenetic analysis, 10 (67%) were abnormal. All but one patient 
(94%) achieved a CR after cycle 1. All eighteen (100%) patients achieved minimal 
residual disease (MRD) negativity as assessed by FCI; of whom 12 (67%) achieved 
MRD negativity after induction. Grade ≥ 3 toxicity included increase of LFT’s in 7 
patients (37%), increase of bilirubin in 5(26%), thrombotic events in 1 (5%) and 
neuropathy in 1 (5%). With a median follow up of 8 months (1-23), 18 patients are alive 
in CR. The 1-year CRD and overall survival rates were 100% and 95% respectively.  


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3.0 Background Drug Information 
 
3.1 Drug information for the following agents is attached as an appendix to the back of 
this protocol (Appendix D). 
 Cyclophosphamide 
 Doxorubicin 
 Vincristine 
 MESNA 
 Methotrexate 
 Cytarabine (Ara-C) 
 Filgrastim Product (G-CSF) 
 Prednisone 
 Etoposide 
 
 
3.2 Ofatumumab [20] 
 
Ofatumumab is a clear colorless liquid concentrate intended for intravenous infusion 
after dilution in sterile, pyrogen free 0.9% sodium chloride. During its infusion, 
ofatumumab will be filtered using a 0.2 mm in-line filter. Ofatumumab is formulated at 20 
mg/mL adjusted to pH 6.5 and supplied in 5 mL and 50 mL glass vials. The 5 mL vial of 
ofatumumab (20 mg/mL) contains a total of 100 mg.  The 50 mL vial of ofatumumab (20 
mg/mL) contains a total of 1000 mg.   
 
 
3.2.1 Ofatumumab IMP composition: (ingredient Quantity per mL Function) 
 
Ofatumumab drug substance 20 mg Active ingredient 
Sodium acetate, trihydrate 6.8 mg  
Edetate disodium, dihydrate (EDTA) 0.019 mg 
L-arginine 10 mg 
Sodium chloride 2.98 mg 
Hydrochloric acid to give pH 5.5 
Water for injection q.s. to 1 mL  
 
 
3.2.2 Ofatumumab preparation: 
 
All doses of ofatumumab will be prepared in 1000 mL of 0.9% Sodium Chloride 
Injection, USP.   


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 300 mg dose:  withdraw and discard 15 mL from a 1000 mL polyolefin bag of 
0.9% Sodium Chloride Injection, USP.  Withdraw 5 mL from each of 3 vials of 
ofatumumab (each vial containing 100 mg) and add to the bag.  Mix diluted 
solution by gentle inversion. 
 2000 mg dose:  Withdraw and discard 100 mL from a 1000 mL polyolefin bag of 
0.9% Sodium Chloride Injection, USP.  Withdraw 50 mL from each of 2 vials 
(each vial containing 1000 mg) of ofatumumab and add to the bag.  Mix diluted 
solution by gentle inversion 
 
Table 1 
Dose of 
ofatumumab 
Infusion bag size 
Volume of Sodium 
chloride 0.9% to be 
removed from 
infusion bag 
Volume 
ofatumumab 
(number of 
ofatumab vials) 
300 mg 
1000 mL 
15 mL 
15 mL 
(3 vials, 5 mL/vial) 
2000 mg 
1000 mL 
100 mL 
100 mL 
(2 vials, 50 mL/vial) 
 
For intravenous administration, compatibility of the following components for 
ofatumumab in clinical studies has been established: 
 
Table 2 
Dosing component
Material of construction
Suggested vendor
1L sodium chloride 0.9% 
bags
Polyvinyl chloride (PVC) 
Baxter 
 
Polyolefin [polyethylene* 
(PE)/polypropylene (PP)] 
Baxter, B. Braun 
Administration set 
PVC 
Baxter 
PVC lined with polyethylene
B. Braun
Filter extension set 
Sterilizing-grade (0.22 m) 
hydrophilic filter
Durapore brand by Millipore 
 
Lines made of PVC, filter 
membrane material 
polyether sulfone
Baxter 
 
Lines made of PVC lined 
with polyethylene, filter 
membrane material 
polyether sulfone
Alaris/Cardinal Health 
*polyethylene (IUPAC name: polyethene. 
 
 
The following materials are needed when preparing and administering the infusion: 
 
 1000 mL sterile pyrogen free 0.9% saline (NaCl) infusion bag(s).  


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 Ofatumumab 100 mg and 1000 mg vials (commercial supply) 
 Needles and syringes (50 mL sterile syringe) 
 Intravenous (IV) cannula (not required if subject has central venous access) 
Infusion pump and infusion tubing set 
 In-line low protein binding, polyether sulfone filter 0.2 m  
 
Preparation of the 1000 mL infusion bags should be done on the day of planned 
infusion.  Store diluted solution between 2° C and 8° C.  Start infusion within 12 hours of 
preparation.  Discard prepared solution after 24 hours. 
 
3.2.3 Ofatumumab administration: 
 
Ofatumumab is to be administered using an infusion pump with a polyvinyl chloride 
(PVC) administration set and an in-line filter set provided with the product.  It is 
mandatory to use an in-line low protein binding 0.2 micron polyether sulfone filter for all 
IV dosing of ofatumumab drug product.  The line should be flushed with 0.9% Sodium 
Chloride Injection, USP before and after each dose. 
 
Pre-medication before each ofatumumab infusion must be given within 30 minutes to 2 
hours prior to the treatment: 
 
Table 3 - Pre-medication Requirements prior to Ofatumumab Infusions 
 
 
Infusions # 
Acetaminophen 
(po) or 
equivalent 
Antihistamine (iv or 
po) diphenhydramine 
or equivalent 
Glucocorticoid (iv) 
Prednisolone or 
equivalent 
1st 
1000 mg 
25 mg 
100 mg 
2nd 
1000 mg 
25 mg 
100 mg 
3rd –Nth 
1000 mg 
25 mg 
0-50 mg1 
 
If the second infusion has been completed without the subject experiencing any grade = 
3 adverse events (AEs), pre-medication with glucocorticoid may be reduced or omitted 
before the 3rd to Nth infusion at the discretion of the investigator. 
 
Ofatumumab dosing recommendation for combination therapy in ALL: the first 
cycle of ofatumumab in combination with chemotherapy should consist of an 
infusion of 300 mg on Day 1 and an infusion of 2000 mg of Days 2 and 11 for Cycle 1. 
For subsequent cycles, a dose of 2000 mg should be infused on Day 1 and 8 of Cycle 2 
and 4, and day 1 and 11 of Cycle 3.   


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First Infusion of 300 mg of ofatumumab 
 
The first dose administered of ofatumumab should be 300 mg to minimize infusion 
reactions. The initial rate of the first infusion of 300 mg (0.3 mg/mL) ofatumumab and 
the second infusion of 2000 mg ofatumumab (2 mg/mL) should be 12 mL/h. If no 
infusion reactions occur the infusion rate should be increased every +/- 30 minutes, to a 
maximum of 200 ml/h, according to the table below:  
 
Table 4 - Infusion rates of ofatumumab. 
 
Interval after start 
of infusion (min) 
Dose 1 
(mL/hr) 
Dose 2 
(mL/hr) 
Dose 3 and 
beyond (mL/hr) 
0-30 
12 
12 
25 
31-60 
25 
25 
50 
61-90 
50 
50 
100 
91-120 
100 
100 
200 
>120 
200 
200 
400 
  
 
Interrupt infusion for infusion reactions of any severity. For grade 4 infusion reactions, 
do not resume the infusion.  For grade 1, 2 or 3 infusion reactions, if the infusion 
reaction resolves or remains less than or equal to grade 2, resume infusion with the 
following modifications according to the initial rate of the infusion reactions. 
 
 Grade 1 or 2:  infuse at one-half the previous infusion rate 
 Grade 3:  infuse at a rate of 12 mL/hr 
 
If the infusion rate was 12 mL/hour before the pause, the infusion should be restarted at 
12 mL/hour. Hereafter, the infusion rate may be increased according to the table above 
and judgment of the investigator. 
 
 
Subsequent infusion of full dose of ofatumumab 
 
If the previous infusion has been completed without grade ≥ 3 infusion associated AEs, 
the subsequent infusion of the first full dose of ofatumumab can start at a rate of 25 
mL/hour and should be increased every 30 minutes up to a maximum of 400 mL/h, 
according to Table 4. If the previous infusion has been completed with grade ≥ 3 


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infusion associated AEs, the subsequent infusion should start at a rate of 12 mL/hour 
according to Table 4. 
 
During infusion the patient should be monitored closely and appropriate measurements 
should be performed whenever judged necessary. 
 
3.2.4 Dose Reduction: 
  
No dose reduction is planned for ofatumumab, its administration will be held for 
grade 3 or higher hepatic toxicity and can be omitted if clinically indicated. 
 
3.3. Rituximab 
 
Rituximab is a chimeric IgG1 kappa monoclonal antibody (with murine light- and heavy-
chain variable region sequences and human constant region sequences) that 
recognizes the CD20 antigen expressed on normal B cells and most malignant B-cell 
lymphomas [24,25].  It is composed of two heavy chains of 451 amino acids and two 
light chains of 213 amino acids (based on cDNA analysis) and has an approximate 
molecular weight of 145 kD.  
 
The CD20 antigen (human B-lymphocyte-restricted differentiation antigen, Bp35), 
important in cell cycle initiation and differentiation [26], is expressed strongly in over 
90% of B-cell lymphomas, including hairy cell leukemia.  It is a hydrophobic trans-
membrane protein which is not shed from the cell surface or internalized with antibody 
binding. CD20 is not found on hematopoietic stem cells, pro-B cells, or normal plasma 
cells.  Rituximab shows specificity for the CD20 antigen and binds with an apparent 
affinity of 5.2 x 10-9 M.   
 
3.3.1 Storage/Preparations 
 
3.3.1.1 
Clinical Formulation 
 
Rituximab (sterile, clear, colorless, preservative-free liquid concentrate) will be provided 
to the clinical sites packaged in single use 10 ml (100 mg) and 50 ml (500 mg) Type I 
glass vials at a concentration of 10 mg of protein per ml. The product is formulated for 
intravenous administration in 7.35 mg/ml sodium citrate dihydrate, 0.7 mg/ml 
polysorbate 80, 9.0 mg/ml sodium chloride and Sterile Water for Injection.  The pH is 
adjusted to 6.5. 
 
Rituximab may be produced by the mammalian (Chinese Hamster Ovary) cell 
suspension culture in a nutrient medium containing 100 mg/ml of the antibiotic 
gentamicin.  The antibiotic is not detectable in the final product.  The antibody is purified 


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by affinity and ion exchange chromatography.  The purification process includes specific 
viral inactivation and removal procedures. 
 
 
3.3.1.2 
Storage 
 
Rituximab for clinical use should be stored in a secure refrigerator at 2-8oC. 
 
  
3.3.1.3 
Reconstitution and Dilution of rituximab 
 
Using a sterile syringe and a 21 gauge or larger needle, transfer the necessary amount 
of Rituximab from the vial into a partially filled IV pack containing sterile, pyrogen-free 
0.9% Sodium Chloride, USP (saline solution).  The final concentration of Rituximab 
should be 1 mg/ml.  Mix by inverting bag gently. 
 
Caution should be taken during the preparation of the drug. Parenteral drug products 
should be inspected visually for particulate matter prior to administration.  Preparations 
of Rituximab containing visible particles should not be used.  As with all parenteral drug 
products, aseptic procedures should be used during the preparation and administration 
of Rituximab. 
 
 
4.0 Patient Eligibility 
 
4.1 Inclusion Criteria: 
 
1. Burkitt’s or Burkitt-like leukemia/lymphoma, either previously untreated, or 
relapsed/refractory, or HIV-related. Patient with double or triple hit high-grade 
leukemia/lymphoma are eligible also. Patients HIV positive will be described and 
reported separately; or relapsed/refractory acute lymphoblastic leukemia (ALL) 
2. All ages are eligible 
3. Zubrod performance status ≤ 3 (ECOG Scale, Appendix E) 
4. Adequate organ function with creatinine less than or equal to 2.0 mg/dL (unless 
considered tumor related), bilirubin less than or equal to 2.0 mg/dL (unless considered 
tumor related). 
5. Adequate cardiac function defined as no history of clinically significant arrhythmia, or 
history of MI within 3 months prior to study enrollment.  Cardiac function will be 
assessed by history and physical examination.  
 
4.2 Exclusion criteria: 
1. Pregnant or nursing women.  
2. Active and uncontrolled disease/infection as judged by the treating physician 
3. Unable or unwilling to sign the consent form 


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4. Subjects who have current active hepatic or biliary disease (with exception of 
patients with Gilbert's syndrome, asymptomatic gallstones, liver metastases or 
stable chronic liver disease per investigator assessment) 
 
 
 
5.0 Treatment Plan 
 
5.1 
All patients will be registered through CORe. 
5.2  
General considerations 
All patients will receive 8 cycles of EPOCH-O/R (2 doses of ofatumumab or rituximab 
per cycle for the first 4 cycles, except for Cycle 1, where it is necessary to administer 
one additional dose of ofatumumab to prevent infusion reactions). Rituximab will be 
administered instead of ofatumumab if insurance does not cover ofatumumab. In 
patients requiring emergent treatment, patients may be started on ofatumumab before 
insurance approval is received and switched to rituximab if it is determined that 
insurance will not cover ofatumumab. 
 
Pegfilgrastim / pegfilgrastim biosimilar 6 mg (flat dose) within 72 hours after 
completion of chemotherapy. Filgrastim product10 µg/kg/day (rounded) until neutrophil 
recovery 1 x 109/L or higher can be substituted or can be added to Pegfilgrastim if 
neutrophils have not recovered to 1 x 109/L by day 21. 
• 
The next course may be started when granulocytes are more than or equal to 1.0 
x 109/L and platelets are more than or equal to 50 x 109/L.  Therapy may start earlier or 
later depending on the clinical situation, with a minimum of 14 days between cycles. 
Courses may be started with dose reductions prior to full platelet recovery, if the 
treatment is delayed (e.g., greater than 28 days from last course). 
• 
Prophylactic antibiotics may be given with each course.  Prophylactic antibiotics 
will vary based on patient tolerance and allergy status.  Suggestions include: 
Levofloxacin 500 mg p.o. daily or other appropriate prophylactic antibacterial 
agents. 
Fluconazole 200 mg p.o. daily or other appropriate antifungal agent. 
Valacyclovir 500 mg p.o. daily or other appropriate antiviral agent. 
No maintenance phase chemotherapy will be planned. Patients who are unable 
to complete all 8 courses of planned chemotherapy will be monitored for disease-free 
and overall survival only, and will not be considered off-protocol. An end-of-treatment 
date will indicate completion of therapy.   


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Serial measurements of minimal residual disease will be obtained, and 
depending on the results, post remission or maintenance therapy programs for high risk 
patients may be developed. 
Patients with HIV disease will not be excluded, but should be evaluated for highly 
active antiretroviral therapy (HAART), in addition to antibiotic prophylaxis for 
Pneumocytis carini (PCP), cytomegalovirus, and Mycobacterium avium-intracellulare.   
An infectious disease consultation will be obtained for those patients not followed by an 
HIV specialist. 
No dose escalations beyond those specified in the protocol are allowed.  Other 
variations to the treatment plan as outlined are allowed if felt to be in the best clinical 
interest of the patient.  Examples of these clinical scenarios include: 
• 
Treatment delays (> 14 days from recovery) despite hematologic recovery for 
reasons of patient request or unavoidable social situations.  Treatment delays to allow 
recovery from infections or other toxicities of therapy will not be considered deviations, 
as these are expected complications of the therapy. 
• 
Dose reductions or alterations in the chemotherapy administration beyond those 
specified in the protocol for reasons of patient request or unavoidable social situations. 
Dose reductions performed for clinical reasons will not be considered deviations, as 
patients may have unique toxicities or tolerance not accounted for by standard dose 
reductions. 
• 
Other clinical scenarios after approval by the Principal Investigator. 
The induction chemotherapy and follow up will be at M. D. Anderson Cancer 
Center for the first 3-4 weeks. Other courses can be given at M. D. Anderson Cancer 
Center whenever possible. Subsequent courses of intensive chemotherapy can be 
given at M. D. Anderson or by the local oncologist after review of the outside laboratory 
data, discussion with the local physician, and preparation of the sample orders by the 
Principal Investigator and Research Nurse assigned to the protocol.  Supportive care, 
intrathecal chemotherapy, ofatumumab, and vincristine may be given by the local 
physician in all cases. 
Every effort will be made to adhere to the schedule of events and all protocol 
requirements. Variations in schedule of events and other protocol requirements that do 
not affect the rights and safety of the patient will not be considered as deviations.  Such 
variations may include laboratory assessments completed outside of schedule.  All dose 
adjustments will be made according to the protocol unless otherwise specified. 
5.3 EPOCH-O/R 


2014-0123 
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Ofatumumab 300 mg (FLAT DOSE) IV on day 1 (before infusions) and 2,000 mg (FLAT 
DOSE) on days 2 and 11 (plus or minus 3 days) during Cycle 1 only. Starting with Cycle 
2, patients will receive Ofatumumab 2,000 mg (FLAT DOSE) IV on days 1 and 8 (+/- 3) 
of Cycles 2 and 4, and day 1 and 11 (+/- 3) of Cycle 3 for a total of 9 injections of 
ofatumumab; see Section 3.2.6 for administration instructions 
Etoposide 50 mg/m2/day CIV infusion days 1- 4 (96 hour infusion) +/- 4 hours 
Doxorubicin 10 mg/m2/day CIV infusion days 1-4 (96 hour infusion) +/- 4 hours 
Vincristine 0.5 mg (FLAT DOSE) CIV infusion days 1-4 (96 hour infusion) +/- 4 hours 
Cyclophosphamide 750 mg/m2 IV day 5 over approximately 1 to 2 hours 
Prednisone 60 mg PO BID days 1-5 
Rituximab 375 mg/m2 IV days 1 and 11 (+/- 3) of Cycle 1 and 3 and days 2 and 8 (+/- 3) 
of Cycle 2 and 4 replaces ofatumumab if insurance does not approve ofatumumab.  
Variations in infusion times due to minor differences in IV bag overfill/underfill and 
institutional procedure on flushing chemotherapy lines will not result in protocol 
deviation.  All infusion times are considered approximate. 
 
5.3.1 Dose adjustments for inadequate myelosuppression between cycles  
Recent studies using the EPOCH regimen have enacted a dose adjustment strategy for 
the cytotoxic agents according to an individual’s level of myelosuppression experienced 
in the previous cycle. Myelosuppression is a surrogate marker of anti-
leukemia/lymphoma activity, so this strategy allows for the chemotherapy doses to be 
tailored to an individual patient’s “pharmacodynamic” response. We are suggesting a 
similar, yet simplified dose-adjustment policy for the present study. 
A patient’s starting dose level will depend on their age and performance status 
according to the table below as follows: 
< 60 years of age: dose level 1 
60 – 74 years of age and PS of 0 – 2: dose level -1 
> 74 years of age or > 60 years of age with PS 3: dose level -2 (In addition, vincristine 
dose will be reduced by 50%) 
-Patients will have a CBC with differential performed at least weekly between 
chemotherapy cycles 


2014-0123 
August 14, 2019 
 
-The definition of adequate myelosuppression is an ANC nadir of less than 
500/microliter 
-If the patient experiences an ANC nadir of less than 500/microliter, doses of 
chemotherapy will not be increased during the subsequent cycle 
-If a patient’s ANC nadir is above 500/microliter, doses of cyclophosphamide, etoposide, 
and doxorubicin should be increased by one dose level according to the table below 
-If a treating physician cannot determine the ANC nadir for a given cycle, there will be 
no dose increases in chemotherapy unless discussed with the PI 
-If the treating physician feels it is in the best interest of the patient to not have their 
chemotherapy doses increased despite a qualifying nadir ANC, this would be allowed 
-Further dose reductions of 20-25% are allowed as indicated below.   
Table 5 - Drug Dose Levels 
Drugs 
 
Drug Dosing per Dose Level 
-2 
-1 
1 
2 
Doxorubicin 
(mg/m2/day) 
6 
8 
10 
12 
Etoposide 
(mg/m2/day) 
30 
40 
50 
60 
Cyclophosphamide 
(mg/m2/day) 
500 
600 
750 
900 
 
5.4 Central Nervous System Management 
 
5.4.1 For previously untreated patients, treat with standard CNS 
prophylaxis with methotrexate and cytarabine for 2 intrathecal 
treatments (IT) with each course if no evidence of CNS 
disease. 
 
5.4.2 Total number of prophylactic intrathecal treatments for 
previously untreated patients will be 16 (2 with each course).  
Missed intrathecals (e.g., related to failed procedure attempts, 
scheduling issues, patient social situations) can be made up 
with later courses or upon completion of therapy to achieve 


2014-0123 
August 14, 2019 
 
the planned number of intrathecal treatments to prevent CNS 
relapse based on available data. IT prophylaxis consisted of 
cytarabine 100 mg alternating with methotrexate 12 mg.  
 
If CNS disease:  give methotrexate alternating with cytarabine twice 
weekly until CSF clear; then once weekly for 4 weeks, then back to 
prophylactic schedule.  Consider XRT to the base of the skull, with 
cranial nerve root involvement (cranial nerve palsies), except for 
instances where intrathecal therapy alone is expected to produce a 
response (e.g., mental neuropathy, isolated lateral rectus nerve 
palsy).   
 
 
5.5 
Suggested Dose Modifications 
 
5.5.1 Etoposide  
 For estimated creatinine clearance between 31 – 50 mL/min: reduce dose 
by 25% 
 For estimated creatinine clearance < 30 mL/min: reduce dose by 50% 
 Doses can be re-escalated if creatinine clearance improves at the discretion 
of the treating physician 
 For total bilirubin > 2: reduce dose by 50% 
 
5.5.2 Vincristine 0.25 mg (FLAT DOSE) via IV continuous infusion for 4 days on 
days 1 – 4  
• 
Bilirubin > 2.0 mg/dL and < 3.0 mg/dL. 
• 
Grade 2 persistent peripheral neuropathy. 
• 
Eliminate vincristine for grade 3-4 neurotoxicity, including ileus suspected 
to be related to vincristine, bilirubin > 3.0 mg/dL, peripheral neuropathy  
 
5.5.3 Doxorubicin: 
• 
Reduce by 50% for bilirubin 2 to 3 mg/dL, by 75% for bilirubin >3 to 5 mg/dL. 
Eliminate if bilirubin > 5 mg/dL 
 
 
 
5.6 
Administration of Rituximab 
 
CAUTION: DO NOT ADMINISTER AS AN INTRAVENOUS PUSH OR BOLUS 
 
 
5.6.1 Suggested premedication (two tablets [375 mg or 500 mg] of 
acetaminophen orally and 25 to 100 mg of diphenhydramine hydrochloride 
orally or intravenously) 30 to 60 minutes prior to starting each infusion of 
Rituximab. Other alternative prophylactic measures may be appropriate, 
such as hydrocortisone or Solu-Medrol. 
 


2014-0123 
August 14, 2019 
 
5.6.2 The drug may be administered via a peripheral or central intravenous line. 
The rate should be slowly escalated as tolerated. 
 
5.6.3 Rituximab is associated with hypersensitivity reactions (hypotension, 
bronchospasm, or angioedema) which may respond to adjustments in the 
infusion rate.  Transient fever and rigors may occur.  Rituximab should be 
interrupted for severe reactions and resumed at a reduced rate when 
symptoms have improved or resolved.  Supportive care such as IV saline, 
diphenhydramine, 
hydrocortisone, 
and 
acetaminophen 
should 
be 
considered as the clinical situation dictates.  
  
 
 6.0 
PRETREATMENT EVALUATION 
 
6.1 
History and physical examination. 
 
6.2 
CBC, platelet count, differential, creatinine, bilirubin, uric acid, LDH. 
 
6.3 
Bone marrow aspirate and cytogenetics within 2 weeks. 
 
6.4 
Echocardiogram or MUGA prior to doxorubicin for course 1 in patients with history 
of congestive heart failure or myocardial infarction. Cardiology consultation 
recommended in patients with reduced ejection fractions (< 40%). 
 
7.0  
EVALUATION DURING STUDY 
 
 
7.1 
At least once weekly CBC, platelet count, and differential (when granulocytes 
> 1.0 x 109/L) for course 1, then at least every 2 weeks during courses 2-8 of 
chemotherapy. Then every 2-4 months for the first year, then every 4-8 months for the 
next 2 years 
 
7.2 
Creatinine, bilirubin, uric acid, LDH at least every 2 weeks for course 1, then 
creatinine and bilirubin at least every 4 weeks during courses 2-8 of chemotherapy. Then 
every 2-4 months for the first year, then every 4-8 months for the next 2 years 
 
7.3  
 
Bone marrow aspiration on day 14  +/- 5 days of the first course of 
chemotherapy for patients with involvement of marrow prior to initiation of therapy, then in 
1-2 weeks +/- 5 days later to confirm response status (or at the time of hematologic 
recovery). Then every 2-4 months for the first year, then every 4-8 months for the next 2 
years. 
 
7.4  
 
Minimal residual disease assays (for patients with bone marrow involvement 
prior to initiation of therapy) at the time of CR, then every 2-4 months for the first year 
and every 4-8 months for the next 2 years.     
 
8.0 
Long-Term Follow-Up 
After last study visit, patients will be called by the study staff and asked about their 
health every 3-6 months for 1 year.  These calls should last about 5 minutes each. For 


2014-0123 
August 14, 2019 
 
patients registered on our long-term follow-up umbrella protocol DR09-0223, survival 
follow-up may be conducted under that protocol 
 
9.0 
CRITERIA FOR RESPONSE 
 
9.1 
Burkitt’s Leukemia or ALL 
 
9.1.1 Complete Remission:  Normalization of the peripheral blood and bone 
marrow with 5% or less blasts in a normocellular or hypercellular marrow 
with a granulocyte count of 1 x 109/L or above and platelet count of 100 x 
109/L or above.   Complete resolution of all sites of extramedullary disease 
is required for CR. 
 
8.1.2 Partial Response: as above except for the presence of 6-
25% marrow blasts. 
 
9.2 
Burkitt’s or Burkitt’s like Lymphoma 
 
9.2.1 Objective response of bi-dimensionally measurable and unidimensionally 
measurable parameters. 
 
Complete Response (CR).  Complete disappearance of all known 
disease. 
 
Partial Response (PR).  > 50% decrease in tumor size using the sum 
of the product (bi-perpendicular dimensions when available).  This 
includes a 50% volume decrease in lesions measurable in three 
dimensions. 
 
No Response (NR).  No significant change (includes stable disease).  
Lesions decreased in size but < 50% or lesions with slight enlargement 
but < 25% increase in size. 
 
Progressive Disease (PD).  Appearance of new lesions.   25% 
increase in size of existing lesions (increase > 50% if only one lesion is 
available and is  2 cm in size). 
 
9.2.2 Objective response for non-measurable parameters. 
 
CR, NR, and PD same as above but estimated. 
 
PR definite improvement estimated to be > 75% of lesion but not 
quantifiable by measurement. 
 
 
 
10.0 
EVALUATION OF TOXICITY 
 
9.1 
Toxicities will be graded according to the current NCI Expanded Common Toxicity 
Criteria. 
 
 
11.0 
CRITERIA FOR REMOVAL FROM THE STUDY 
 
11.1 
Progressive disease. 
 


2014-0123 
August 14, 2019 
 
11.2 
Non-compliance by the patient with protocol requirements or patient’s request to 
be removed from the study. 
 
 
 
 
12.0 
STATISTICAL CONSIDERATIONS 
 
General description 
 
This is a phase II study of dose adjusted EPOCH regimen in combination with 
ofatumumab/rituximab as therapy for patients with newly diagnosed or 
relapsed/refractory Burkitt leukemia or relapsed/refractory ALL. Up to 25-30 newly 
diagnosed patients and 10-15 relapsed/refractory patients will be enrolled in the study. 
The primary objective is to determine the efficacy of the study treatment, and the 
primary endpoint is defined as the complete response (CR) during the first two 
treatment cycles. The two treatment groups will be analyzed separately. 
 
New diagnosed patient cohort 
 
Up to 25-30 newly diagnosed patients will be enrolled in the study. The historical data 
indicated that the CR rate is 73% for newly diagnosed patients under standard 
treatment. It is expected that the proposed combination study can achieve a CR rate of 
87%, an increase of 14% in CR rate over the standard therapy. The study will monitor 
futility and toxicity using a Bayesian method to stop the study early if there is evidence 
to suggest that the experimental treatment is too toxic or the response rate is low.21 If 
the study is not stopped early and a maximum of 30 patients are enrolled, and 
assuming that we observe 22 (73%) patients have CR, then the 95% confidence interval 
for the CR rate will be (57.1%, 88.9%).   Assuming that we observe 26 (87%) patients 
have CR, the 95% confidence interval for the CR rate will be (75%, 99%). 
 
Futility and toxicity monitoring 
 
The accrual in the newly diagnosed cohort will be stopped early if the data suggested 
that:  
 
1) Pr(E < 0.14 + S |data)>0.95 or 
2) Pr(TE > 0.30 | data)  > 0.85 
 
Where E  represents the CR rate for experimental drug in this study and  S represents 
the CR rate for the standard practice, and  TE denotes the probability of toxicity, which is 
defined as treatment related grade 3 or higher non-hematological toxicity. The first rule 
is for futility monitoring. That is, if at any time during the study we determine that there is 
95% or more chance that the CR rate is less likely to improve by 14% than that under 
the standard treatment, we will terminate the study in this cohort. We assume that S 
has a distribution of beta (73, 27) to reflect the information on 100 patients for the 
historical data, which has a mean response rate of 0.73 and a variance of 0.002.  We 


2014-0123 
August 14, 2019 
 
also assume that E has a non-informative flat prior beta(1.46, 0.54) with mean of 0.73 
and variance of 0.0657. The second rule is for toxicity monitoring. Toxicity will be 
monitored closely and toxicity monitoring for stopping rules will apply to cycle 1 only. We 
will stop the trial if, at any time during the study, we determine that there is more than 
85% probability that the Toxicity rate is more than 30%.  We assume TE has a prior 
distribution of beta(0.6, 1.4). 
 
The stopping boundaries for futility monitoring based on the above rule and 
assumptions are listed in table 6. The monitoring will begin after the first 5 patients are 
treated and thereafter when every 5 patients are treated.  For example, accrual will 
cease if only two or fewer patients experience achieve a CR among the first 5 patients 
treated. 
 
Table 6. Stop accrual if the number with CR is less than 
or equal to indicated (i.e., # patients with CR) among the 
number of patients evaluated 
# patients 
evaluated 
5 
10 
15 
20 
25 
# patients with 
CR
0-2 
0-6 
0-10 
0-14 
0-17 
 
The stopping boundaries for the toxicity monitoring based on above toxicity monitoring 
rule are listed in table 7.  For example, accrual will cease if 3 or more patients 
experience toxicities among the first 5 patients treated or if 5 or more patients 
experience toxicities among the first 10 patients. 
 
 
Table 7. Stop accrual if the number of toxicities is greater 
than or equal to indicated (i.e., # patients with toxicities) 
among the number of patients evaluated 
# patients 
evaluated 
5 
10 
15 
20 
25 
# patients with 
toxicities
3-5 
5-10 
7-15 
9-20 
11-25 
 
The operating characteristics by simulations for futility and toxicity monitoring are 
presented in table 8.  There is 68% probability to stop the trial early when the CR rate is 
73% and the toxicity rate is 30%. There is only 7.9% chance to stop the trail early when 
CR rate is 87% and toxicity rate is 10%, however there will be 89% probability to stop 
the trial early when CR rate is 87% and toxicity rate is 50%. 
 
 
Table 8: Operating characteristics for futility and toxicity monitoring for the newly 
diagnosed patient cohort 
 


2014-0123 
August 14, 2019 
 
 
CR 
Rate
Toxicity rate
Probability of 
early stop 
Avg. Num. of patients 
treated
0.4
0.1
0.9995
6.875
0.4
0.3
0.9996
6.562
0.4
0.4
0.9998
6.246
0.4
0.5
0.9999
5.884
0.73
0.1
0.5577
20.186
0.73
0.3
0.6826
16.794
0.73
0.4
0.8291
13.109
0.73
0.5
0.947
9.543
0.87
0.1
0.079
28.519
0.87
0.3
0.339
23.012
0.87
0.4
0.644
16.957
0.87
0.5
0.89
11.266
0.97
0.1
0.0099
29.76
0.97
0.3
0.2894
23.94
0.97
0.4
0.6175
17.534
0.97
0.5
0.8814
11.527
 
Multc Lean Desktop (version 2.1.0) was used to generate the toxicity and futility 
stopping boundaries and the OC table (Table 8). 
 
Relapsed/refractory cohort 
 
10-15 relapsed/refractory patients will be enrolled over three years to receive the study 
treatment. Burkitt leukemia is a rare disease, a high proportion of patients treated 
achieved CR and the CR usually lasts a relatively long duration. However once disease 
relapses, patients will die quickly. No treatment has been established for this 
relapse/refractory disease. The objective is to see if there is any anti-disease activity 
among these 10 patients. Therefore, no interim futility monitoring is designed. We will 
stop the enrollment in this cohort if Pr(TE > 0.30 | data)  > 0.85. The corresponding 
stopping boundaries are: stop the enrollment if the Num. of patients with toxicity 
observed / number of patients evaluated ≥ 3/5, 4/6-7, 5/8-9.  
  
Table 9: OCs for toxicity monitoring  
Toxicity 
rate 
Probability of early stop
Avg. Num. of patients 
treated 
0.1 
0.0095 
9.955 
0.2 
0.069 
9.683 
0.3 
0.205 
9.087 
0.4 
0.406 
8.214 
0.5 
0.627 
7.212 


2014-0123 
August 14, 2019 
 
 
 
Analysis method 
 
Safety data will be summarized using frequency and percentage. Complete response 
rates will be estimated along with the 95% credible intervals. Overall survival time, 
event-free survival (EFS) and complete response duration (CRD) will be estimated 
using the Kaplan-Meier method.  
 
 
13.0 REPORTING REQUIREMENTS 
 
13.1 Adverse Events Requiring Expedited Reporting:    Serious unexpected 
adverse events (SAEs) considered associated with therapy should be 
reported as per institutional IRB policy. 
 
13.2 Expected Therapy Related Events 
 
Expected therapy-related events include those known toxicities or side 
effects related to the components of the chemotherapy.  These grade 4 or 
less events will not be reported as individual SAEs, but will be summarized 
in the annual report to the IRB. 
 
Examples include: 
 
Hyperglycemia 
Electrolyte abnormalities (e.g., hypokalemia, hypomagnesemia, 
hyponatremia, hypocalcemia).  
Renal failure related to tumor lysis syndrome, methotrexate or antibiotic 
therapy (e.g., AmBisome). 
Cytarabine related central nervous system toxicity. 
Catheter-related deep venous thrombosis. 
Coagulation abnormalities related to induction therapy (e.g., chemical DIC 
or hypofibrinogenemia). 
Ileus related to vincristine. 
Hepatotoxicity related to 6-MP or methotrexate. 
Post lumbar puncture headaches. 
Avascular necrosis related to corticosteroids. 
 
13.3 Events not considered to be serious events are hospitalizations for the 
routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 
 
13.3.1Treatment, which was elective or pre-planned, for a pre-existing 
condition that did not worsen. 
 


2014-0123 
August 14, 2019 
 
13.3.2 Treatment on an emergency outpatient basis for an event not fulfilling 
any of the definitions of serious given above and not resulting in hospital 
admission. 
 
 
 
 
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